Editorial Views  |   November 2009
Lung Water: What You See (with Computed Tomography) and What You Get (with a Bedside Device)
Author Affiliations & Notes
  • Eduardo L. V. Costa, M.D., Ph.D.
  • Marcos F. Vidal Melo, M.D., Ph.D.
  • *Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Respiratory Intensive Care Unit, University of Sao Paulo School of Medicine, Sao Paulo, Brazil. †Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Article Information
Editorial Views / Radiological and Other Imaging / Respiratory System / Technology / Equipment / Monitoring
Editorial Views   |   November 2009
Lung Water: What You See (with Computed Tomography) and What You Get (with a Bedside Device)
Anesthesiology 11 2009, Vol.111, 933-935. doi:10.1097/ALN.0b013e3181bc99ed
Anesthesiology 11 2009, Vol.111, 933-935. doi:10.1097/ALN.0b013e3181bc99ed
NEWSPAPER headlines have greeted with circumspection the report from the Government Accountability Office on the US Food and Drug Administration (FDA) processes to regulate medical devices. They used headlines such as “Left to the FDA’s Own Devices”1 and “Is That Device Safe?”2 Such headlines bring attention to the fact that FDA requirements for approval and clearance of medical devices are markedly different from those for drugs.3,4 Most new devices are cleared, not approved, through the premarket notification (510(k)) pathway. This is an FDA process based on the assumption that the majority of new devices are essentially equivalent to those already approved. Physiologic monitors are usually among these and frequently enter the market because of their substantial equivalence to previous models, with limited scrutiny of efficacy.3,4 Therefore, as new monitors are introduced, it is crucial for good clinical practice to understand their principles, advantages, and limitations. In this issue of Anesthesiology, Easley et al.  5 apply functional lung imaging techniques to study measurements of extravascular lung water (EVLW) using the single-indicator (iced saline) transpulmonary thermodilution method. The device was recently cleared by the FDA (PiCCO®; Pulsion Medical Systems, Munich, Germany).
Measurement of EVLW has been of clinical and research interest for decades. The expectation is that it would be superior to blood oxygenation and chest radiography for assessment of pulmonary edema. Recently, availability of the transpulmonary thermodilution technology, which facilitated bedside measurements, revived the interest for that measurement.6 Many studies reinforced the concept that EVLW could be a useful clinical and research tool. EVLW was suggested as a predictor of mortality in patients with severe sepsis7 and acute lung injury (ALI),8,9 as a diagnostic tool in detecting early pulmonary edema,10 and in evaluating the effect of ventilatory modes during esophagectomy.11 The measurement has also been proposed to guide fluid therapy in acute respiratory distress syndrome12 and subarachnoid hemorrhage,13 and to assess the effect of steroids during cardiac surgery.14 EVLW was the primary outcome variable in clinical trials to study the efficacy of salbutamol to resolve pulmonary edema in patients with ALI/acute respiratory distress syndrome (the Beta-Agonist Lung Injury Trial)15 and lung resection.16 
Assessment of EVLW after an intravenous central injection of iced saline involves considerable and at times conflicting assumptions.17,18 The measurement premises include that the thermal indicator reaches and equilibrates equally in all lung regions and that the central circulation volumes between the injection and temperature measurement site can be described as a small number of individual well-mixed compartments, each showing a monoexponential decay of temperature with time. Certainly, these and other assumptions do not apply to all conditions and may significantly compromise the measurement.18 However, the relevant point is, are those premises acceptable in specific clinical conditions to allow for reliable measurements?
Pulmonary perfusion is heterogeneously distributed in the normal19 and diseased20 lung. Regional pulmonary perfusion is also altered by several factors, such as hypoxic pulmonary vasoconstriction,21 endogenous nitric oxide production,22 pulmonary embolism,23 inspired oxygen fraction,24 positive end-expiratory pressure,25 body position,19 and inhaled nitric oxide.26 Redistribution of lung aeration with perfusion clearly alter the arterial kinetics of centrally injected tracers.27 As a consequence, assumption of a homogeneous exposure of lung tissue to a thermoindicator and of a monoexponential behavior in the washout of that indicator may not be warranted.
Easley et al.  5 bring novel direct quantitative information on the topic in a dog model of ALI with saline lavage. The authors used high-resolution computed tomography (CT) techniques to assess total lung tissue and perfusion and show that, in the presence of transpulmonary thermodilution EVLW in the 20- to 30-ml/kg range, acute changes in regional perfusion due to intravenous endotoxin resulted in an average increase of 6 ml/kg in EVLW. Such increase occurred while CT-measured tissue volume was unchanged and pulmonary perfusion increased to regions of poor aeration. The findings indicate that redistribution of perfusion toward thermally silent regions can increase the measurement of EVLW without a real increase in lung water content.
This study highlights the importance of using a large animal in experiments to ensure results that are more relevant to patients. In fact, the used animal model produced a heterogeneous distribution of lung aeration and perfusion during ALI comparable to that observed in humans. Also, use of noninvasive imaging techniques allowed the authors to investigate in vivo  and in detail perfusion redistribution in a clinical-like condition, in contrast to previous invasive methods such as caval balloon occlusion.28 Whole lung CT quantification of lung tissue, a well-established method, is another strength of the study for accurate measurements in short intervals.
The results of Easley et al.  imply that in conditions where significant pulmonary edema develops, considerable differences in EVLW measurements could be caused by redistribution of lung perfusion. The observed differences were larger than those seen in the Beta-Agonist Lung Injury Trial between treatment and control groups.15 Accordingly, modifications in regional lung perfusion, similar to those that occur during sepsis or thromboembolism, could produce misleading EVLW measurements. This implies that the expected reliability of transpulmonary thermodilution EVLW to follow trends28 cannot be taken for granted. It requires interpretation in light of potential simultaneous changes in regional perfusion. Such results are consistent with the influence of the type of ALI on the accuracy of EVLW measurements.29–31 The results in this investigation are also similar to the results found in sepsis28 and ALI29 animal studies comparing gravimetric measurements of lung water, the gold standard of EVLW measurement but too invasive for human studies, to EVLW measurements using thermodilution or double-indicator methodology. Redistribution of pulmonary perfusion during human ALI may be smaller than that observed in animals,20 and this may reduce variability of EVLW measurements in humans. However, early and recent evidence of thromboembolic disease in acute respiratory distress syndrome32,33 suggest that significant changes in perfusion could occur. Unfortunately, there is limited information on the topographic distribution of lung perfusion in humans, particularly during ALI.
There are also limitations in the study. CT measurement of lung tissue represents radiologic density and does not differentiate between pulmonary edema, blood, and tissue. Assessment of regional lung perfusion with CT has not been comprehensively compared with more established methods in the setting of ALI and was performed using a single slice. Furthermore, endotoxin is known to produce a rapid recruitment of inflammatory cells to the lungs. These cells are composed mostly of water, constitute additional thermal volume in close contact with the indicator, and could be an additional factor modifying EVLW measurements. Given the nonsignificant changes in the CT estimates of lung tissue, the short time between measurements of lung tissue and perfusion before and after endotoxin, and the increasing experience with measurements of perfusion with CT, it is unlikely that such limitations alter the fundamental message of the study.
Topographic heterogeneity and mismatch of individual properties are essential characteristics of normal lung function, which become exaggerated in disease states. Therefore, any global measurement of EVLW will be inherently problematic in all conditions where lung perfusion is significantly altered, including sepsis, ALI, and thromboembolism. The approach of Easley et al.  in studying a global parameter with a clinically relevant model and using sophisticated noninvasive imaging methods is a welcome contribution. It provides us with quantitative data to ponder the balance between complex physiologic information and practicality. Bedside measurements of EVLW can be an important instrument for human research and, potentially, clinical decision making. Easley et al.  remind us that the application of transpulmonary thermodilution methodology is only helpful when lung physiology is understood, and the benefit of this technology in clinical practice needs further investigation.
Left to the FDA’s own devices. Boston Globe January 26, 2009
Is that device safe? The New York Times January 26, 2009
Feldman MD, Petersen AJ, Karliner LS, Tice JA: Who is responsible for evaluating the safety and effectiveness of medical devices? The role of independent technology assessment. J Gen Intern Med 2008; 23(suppl 1):57–63Feldman, MD Petersen, AJ Karliner, LS Tice, JA
Kessler L, Richter K: Technology assessment of medical devices at the Center for Devices and Radiological Health. Am J Manag Care 1998; 4 Spec. No.:SP129–35
Easley RB, Mulreany DG, Lancaster CT, Custer JW, Fernandez-Bustamante A, Colantuoni E, Simon BA: Redistribution of pulmonary blood flow impacts thermodilution-based extravascular lung water measurements in a model of acute lung injury. Anesthesiology 2009; 111:1064–73Easley, RB Mulreany, DG Lancaster, CT Custer, JW Fernandez-Bustamante, A Colantuoni, E Simon, BA
Sakka SG, Ruhl CC, Pfeiffer UJ, Beale R, McLuckie A, Reinhart K, Meier-Hellmann A: Assessment of cardiac preload and extravascular lung water by single transpulmonary thermodilution. Intensive Care Med 2000; 26:180–7Sakka, SG Ruhl, CC Pfeiffer, UJ Beale, R McLuckie, A Reinhart, K Meier-Hellmann, A
Martin GS, Eaton S, Mealer M, Moss M: Extravascular lung water in patients with severe sepsis: A prospective cohort study. Crit Care 2005; 9:R74–82Martin, GS Eaton, S Mealer, M Moss, M
Kuzkov VV, Kirov MY, Sovershaev MA, Kuklin VN, Suborov EV, Waerhaug K, Bjertnaes LJ: Extravascular lung water determined with single transpulmonary thermodilution correlates with the severity of sepsis-induced acute lung injury. Crit Care Med 2006; 34:1647–53Kuzkov, VV Kirov, MY Sovershaev, MA Kuklin, VN Suborov, EV Waerhaug, K Bjertnaes, LJ
Phillips CR, Chesnutt MS, Smith SM: Extravascular lung water in sepsis-associated acute respiratory distress syndrome: Indexing with predicted body weight improves correlation with severity of illness and survival. Crit Care Med 2008; 36:69–73Phillips, CR Chesnutt, MS Smith, SM
Fernandez-Mondejar E, Rivera-Fernandez R, Garcia-Delgado M, Touma A, Machado J, Chavero J: Small increases in extravascular lung water are accurately detected by transpulmonary thermodilution. J Trauma 2005; 59:1420–3Fernandez-Mondejar, E Rivera-Fernandez, R Garcia-Delgado, M Touma, A Machado, J Chavero, J
Michelet P, D’Journo XB, Roch A, Doddoli C, Marin V, Papazian L, Decamps I, Bregeon F, Thomas P, Auffray JP: Protective ventilation influences systemic inflammation after esophagectomy: A randomized controlled study. Anesthesiology 2006; 105:911–9Michelet, P D’Journo, XB Roch, A Doddoli, C Marin, V Papazian, L Decamps, I Bregeon, F Thomas, P Auffray, JP
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 1992; 145:990–8Mitchell, JP Schuller, D Calandrino, FS Schuster, DP
Mutoh T, Kazumata K, Ishikawa T, Terasaka S: Performance of bedside transpulmonary thermodilution monitoring for goal-directed hemodynamic management after subarachnoid hemorrhage. Stroke 2009; 40:2368–74Mutoh, T Kazumata, K Ishikawa, T Terasaka, S
von Spiegel T, Giannaris S, Wietasch GJ, Schroeder S, Buhre W, Schorn B, Hoeft A: Effects of dexamethasone on intravascular and extravascular fluid balance in patients undergoing coronary bypass surgery with cardiopulmonary bypass. Anesthesiology 2002; 96:827–34von Spiegel, T Giannaris, S Wietasch, GJ Schroeder, S Buhre, W Schorn, B Hoeft, A
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 2006; 173:281–7Perkins, GD McAuley, DF Thickett, DR Gao, F
Licker M, Tschopp JM, Robert J, Frey JG, Diaper J, Ellenberger C: Aerosolized salbutamol accelerates the resolution of pulmonary edema after lung resection. Chest 2008; 133:845–52Licker, M Tschopp, JM Robert, J Frey, JG Diaper, J Ellenberger, C
Isakow W, Schuster DP: Extravascular lung water measurements and hemodynamic monitoring in the critically ill: Bedside alternatives to the pulmonary artery catheter. Am J Physiol Lung Cell Mol Physiol 2006; 291:L1118–31Isakow, W Schuster, DP
Effros RM, Pornsuriyasak P, Porszasz J, Casaburi R: Indicator dilution measurements of extravascular lung water: Basic assumptions and observations. Am J Physiol Lung Cell Mol Physiol 2008; 294:L1023–31Effros, RM Pornsuriyasak, P Porszasz, J Casaburi, R
Musch G, Layfield JD, Harris RS, Melo MF, Winkler T, Callahan RJ, Fischman AJ, Venegas JG: Topographical distribution of pulmonary perfusion and ventilation, assessed by PET in supine and prone humans. J Appl Physiol 2002; 93:1841–51Musch, G Layfield, JD Harris, RS Melo, MF Winkler, T Callahan, RJ Fischman, AJ Venegas, JG
Schuster DP, Anderson C, Kozlowski J, Lange N: Regional pulmonary perfusion in patients with acute pulmonary edema. J Nucl Med 2002; 43:863–70Schuster, DP Anderson, C Kozlowski, J Lange, N
Harris RS, Winkler T, Tgavalekos N, Musch G, Melo MF, Schroeder T, Chang Y, Venegas JG: Regional pulmonary perfusion, inflation, and ventilation defects in bronchoconstricted patients with asthma. Am J Respir Crit Care Med 2006; 174:245–53Harris, RS Winkler, T Tgavalekos, N Musch, G Melo, MF Schroeder, T Chang, Y Venegas, JG
Rimeika D, Nyren S, Wiklund NP, Koskela LR, Torring A, Gustafsson LE, Larsson SA, Jacobsson H, Lindahl SG, Wiklund CU: Regulation of regional lung perfusion by nitric oxide. Am J Respir Crit Care Med 2004; 170:450–5Rimeika, D Nyren, S Wiklund, NP Koskela, LR Torring, A Gustafsson, LE Larsson, SA Jacobsson, H Lindahl, SG Wiklund, CU
Vidal Melo MF, Harris RS, Layfield D, Musch G, Venegas JG: Changes in regional ventilation after autologous blood clot pulmonary embolism. Anesthesiology 2002; 97:671–81Vidal Melo, MF Harris, RS Layfield, D Musch, G Venegas, JG
Ley S, Puderbach M, Risse F, Ley-Zaporozhan J, Eichinger M, Takenaka D, Kauczor HU, Bock M: Impact of oxygen inhalation on the pulmonary circulation: Assessment by magnetic resonance (MR)-perfusion and MR-flow measurements. Invest Radiol 2007; 42:283–90Ley, S Puderbach, M Risse, F Ley-Zaporozhan, J Eichinger, M Takenaka, D Kauczor, HU Bock, M
Musch G, Bellani G, Vidal Melo MF, Harris RS, Winkler T, Schroeder T, Venegas JG: Relation between shunt, aeration, and perfusion in experimental acute lung injury. Am J Respir Crit Care Med 2008; 177:292–300Musch, G Bellani, G Vidal Melo, MF Harris, RS Winkler, T Schroeder, T Venegas, JG
Speziale G, De Biase L, De Vincentis G, Ierardi M, Ruvolo G, La Francesca S, Scopinaro F, Marino B: Inhaled nitric oxide in patients with severe heart failure: Changes in lung perfusion and ventilation detected using scintigraphy. Thorac Cardiovasc Surg 1996; 44:35–9Speziale, G De Biase, L De Vincentis, G Ierardi, M Ruvolo, G La Francesca, S Scopinaro, F Marino, B
O’Neill K, Venegas JG, Richter T, Harris RS, Layfield JD, Musch G, Winkler T, Melo MF: Modeling kinetics of infused 13NN-saline in acute lung injury. J Appl Physiol 2003; 95:2471–84O’Neill, K Venegas, JG Richter, T Harris, RS Layfield, JD Musch, G Winkler, T Melo, MF
Rossi P, Wanecek M, Rudehill A, Konrad D, Weitzberg E, Oldner A: Comparison of a single indicator and gravimetric technique for estimation of extravascular lung water in endotoxemic pigs. Crit Care Med 2006; 34:1437–43Rossi, P Wanecek, M Rudehill, A Konrad, D Weitzberg, E Oldner, A
Roch A, Michelet P, Lambert D, Delliaux S, Saby C, Perrin G, Ghez O, Bregeon F, Thomas P, Carpentier JP, Papazian L, Auffray JP: Accuracy of the double indicator method for measurement of extravascular lung water depends on the type of acute lung injury. Crit Care Med 2004; 32:811–7Roch, A Michelet, P Lambert, D Delliaux, S Saby, C Perrin, G Ghez, O Bregeon, F Thomas, P Carpentier, JP Papazian, L Auffray, JP
Carlile PV, Gray BA: Type of lung injury influences the thermal-dye estimation of extravascular lung water. J Appl Physiol 1984; 57:680–5Carlile, PV Gray, BA
Kuntscher MV, Czermak C, Blome-Eberwein S, Dacho A, Germann G: Transcardiopulmonary thermal dye versus  single thermodilution methods for assessment of intrathoracic blood volume and extravascular lung water in major burn resuscitation. J Burn Care Rehabil 2003; 24:142–7Kuntscher, MV Czermak, C Blome-Eberwein, S Dacho, A Germann, G
Zapol WM, Kobayashi K, Snider MT, Greene R, Laver MB: Vascular obstruction causes pulmonary hypertension in severe acute respiratory failure. Chest 1977; 71:306–7Zapol, WM Kobayashi, K Snider, MT Greene, R Laver, MB
Idell S: Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Crit Care Med 2003; 31:S213–20Idell, S