Respiratory Physiology & Neurobiology 210 (2015) 51–52
Contents lists available at ScienceDirect
Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol
Letter to the Editor
Comments to Bodega et al. (2015) Daniela Negrini a,∗ , Andrea Moriondo a , Sylvain Mukenge b a b
Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy Department of Surgery, San Raffaele Hospital, Milan, Italy
a r t i c l e
i n f o
Article history: Accepted 9 January 2015 Available online 21 January 2015
We read with great interest the recent report of Bodega et al. (2015) in Respiratory Physiology & Neurobiology, in which the authors clearly state in the Introduction that this study was purposely carried on to disprove the conclusions presented in one of the previous papers from our group (Moriondo et al., 2005). Bodega et al. conclude, based on measurements of volume and protein concentration of collected pleural fluid and on the mesothelial kinetic coefficient friction that their data do indeed confute our data on pleural lymphatic function in spontaneous or mechanical ventilation. However, in our opinion, both the methods used and the conclusions drawn raise concerns, so we would like to propose to the reader few considerations on Bodega et al. report.
(1) In the Introduction, Bodega et al. state: “Though they considered that these pressure measurements might be affected by artifacts. . .”. Using the micropuncture technique, potential artifacts may come from excessive local distortion when introducing the micropipette into the tissue. However, being aware of this possible flaw, in the mentioned study, as well as in all measurements performed since our first micropuncture study (Miserocchi et al., 1988), we exclude such an artifact by performing the micropuncture measurements with an incident angle that minimizes tissue indentation and artifacts. In addition, the reproducibility of our interstitial and lymphatic pressure values and the fact that the pleural liquid pressure values that we measured with the micropuncture techniques are essentially equal to those we obtained with intrapleural fluid filled cannulas, indicate that our micropuncture data were not affected by artifact as Bodega et al. maintain.
∗ Corresponding author at: Department of Surgical and Morphological Sciences, University of Insubria, Via J.H. Dunant 5, 21100 Varese, Italy. Tel.: +39 0332 397104; fax: +39 0332 397119. E-mail address: [email protected] (D. Negrini). http://dx.doi.org/10.1016/j.resp.2015.01.008 1569-9048/© 2015 Elsevier B.V. All rights reserved.
(2) Always in the Introduction, Bodega et al. report the intercostal lymphatic pressure values from Moriondo et al. (2005), and then state that we based our conclusions on the effect of spontaneous or mechanical ventilation on lymphatic pleural drainage on these pressure values. This is unfortunately far from being correct. Indeed, since it is well known that fluid fluxes are sustained by hydraulic pressure gradients, in order to attempt a study of the mechanisms of lymphatic flow in spontaneous or mechanical ventilation, in Moriondo et al. (2005) we simultaneously measured lymphatic pressure and interstitial pressure in the adjacent tissue, so as to obtain the transmural fluid pressure acting between the interstitium and the lymphatic lumen. Note that to simultaneously insert two pressure recording micropipettes in spontaneous or mechanically ventilated thoracic tissues was a quite demanding effort from the experimental standpoint. Our data revealed that the intercostal interstitial-to-lymphatic hydraulic pressure gradient was in favor of lymphatic absorption in spontaneous ventilation, but it was nil in case of mechanical ventilation. (3) Our “. . .view that pleural fluid is drained by lymphatics even when its volume is nearly physiological. . .” is based on direct measurements of pleural fluid pressure and lymphatic pressure in closed chest and by several researches published in major scientific Journals both in the last few years and, previously, in the period of our long lasting collaboration with Prof. Miserocchi at the University of Milan. Please note that all our papers, as well as all other manuscripts published on Journals like Respiratory Physiology and Neurobiology, Journal of Physiology, the American Journal of Physiology, Acta Physiologica and so forth, passed through a very selective and serious peer review by the international scientific community. (4) The fact that mechanical ventilation triggers lung edema and pleural effusion is a well known complication, addressed by several Reviews in the most qualified Journals, that anesthesiologists everyday face in their clinics and intensive care units
52
D. Negrini et al. / Respiratory Physiology & Neurobiology 210 (2015) 51–52
and complicates indeed the choice of the strategy to adequately ventilate their patients by simultaneously minimizing the risks of ventilatory-induced acute lung injury (VALI). Hence, after finding that mechanical ventilation may nullify interstitial-tolymphatic hydraulic pressure gradient in intercostal tissues, we just briefly proposed that impaired lymphatic function might be one of the potential phenomena leading to pleural effusion and lung edema. However, this was a final consideration, not the target of the manuscript that was much more articulated and complex than that described by Bodega et al. (5) We expect that, particularly in absence of a frank inflammatory pleural or pulmonary event, pleural effusion and lung edema evolve slowly after lymphatic impairment so that 1 h may not be an adequate time to observe and quantify these phenomena, that anesthesiologists face in long term mechanical ventilation. However, even by analyzing Bodega et al. results at 1 h of mechanical ventilation (Table 1 of their report), we do not agree that their data disprove our previous finding. Indeed, from radioactive albumin clearance, it is possible to measure a pleural lymphatic flow of 0.019 ml/(kg h) under normal spontaneous breathing (Negrini et al., 1985). In Table 1 of Bodega et al. report, the total volume of pleural fluid collected from the right and left cavities after 1 h of mechanical ventilation was (0.24 + 0.27) ml = 0.51 ml which, expressed per unit body mass (3.01 kg) is 0.169 ml/kg. In spontaneous ventilation the total volume collected was (0.17 + 0.22) ml = 0.39 ml which, expressed per unit body mass (2.66 kg) is 0.146 ml/kg. Hence, after 1 h of mechanical ventilation the volume of collected pleural fluid was 0.023 ml/kg higher compared to spontaneous ventilation and ≈20% more than we would have expected from our measure of pleural lymphatic flux. Hence Bodega et al. results, rather than disproving our data, seem to confirm them. (6) It is to be expected that pleural fluid protein concentration does not change after 1 h of mechanical ventilation with room air. Indeed, due to plasma proteins molecular weight and dimension, the reflection coefficient of lymphatic stomata to proteins is zero and lymphatics drain simultaneously liquid and protein,
leaving pleural protein concentration unaffected compared to normal. These considerations come from the thermodynamic derivation and biophysical analysis of the original Staling equation for fluid fluxes, as described in details on several chapters of the Handbook of Physiology (Curry, 1984; Michel and Curry, 1999). The expectation that lymphatic impairment causes an immediate raise in interstitial or pleural fluid protein concentration comes instead from the never demonstrated assumption that lymphatics absorb anidrous proteins through a still undefined mechanism. (7) The fact that the coefficient of friction is normal is not surprising: indeed, it means that the permeability properties of the parietal and visceral mesothelium have not been affected by 1 h of mechanical ventilation. (8) Finally, among all our papers, the one that Bodega et al. criticize had the honor to be included with a figure (Fig. 8) and several citations in a recent Review published on the Physiological Reviews (Wiig and Swartz, 2011). References Bodega, F., Sironi, C., Porta, C., Zocchi, L., Agostoni, E., 2015. Pleural liquid and kinetic friction coefficient of mesothelium after mechanical ventilation. Respir. Physiol. Neurobiol. 206, 1–3. Curry, F.R., 1984. Mechanism and thermodynamics of transcapillary exchange. In: Renkin, E.M., Michel, C.C. (Eds.), Handbook of Physiology, The Cardiovascular System Microcirculation. IV, Section 2, Part I. The American Physiological Society, Bethesda, MD, pp. 309–374 (Chapter 8). Miserocchi, G., Kelly, S., Negrini, D., 1988. Pleural and extrapleural interstitial liquid pressure measured by cannulas and micropipettes. J. Appl. Physiol. 65 (2), 555–562. Michel, C., Curry, F., 1999. Microvascular permeability. Physiol. Rev. 79, 703–761. Moriondo, A., Mukenge, S., Negrini, D., 2005. Transmural pressure in rat initial subpleural lymphatics during spontaneous or mechanical ventilation. Am. J. Physiol. Heart Circ. Physiol. 289, 263L 269. Negrini, D., Pistolesi, M., Miniati, M., Bellina, C.R., Giuntini, C., Miserocchi, G., 1985. Regional protein absorption rates from the pleural cavity in dogs. J. Appl. Physiol. 58, 2062–2067. Wiig, H., Swartz, M.A., 2011. Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer. Physiol. Rev. 9, 1005–1060.
Contents lists available at ScienceDirect
Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol
Letter to the Editor
Comments to Bodega et al. (2015) Daniela Negrini a,∗ , Andrea Moriondo a , Sylvain Mukenge b a b
Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy Department of Surgery, San Raffaele Hospital, Milan, Italy
a r t i c l e
i n f o
Article history: Accepted 9 January 2015 Available online 21 January 2015
We read with great interest the recent report of Bodega et al. (2015) in Respiratory Physiology & Neurobiology, in which the authors clearly state in the Introduction that this study was purposely carried on to disprove the conclusions presented in one of the previous papers from our group (Moriondo et al., 2005). Bodega et al. conclude, based on measurements of volume and protein concentration of collected pleural fluid and on the mesothelial kinetic coefficient friction that their data do indeed confute our data on pleural lymphatic function in spontaneous or mechanical ventilation. However, in our opinion, both the methods used and the conclusions drawn raise concerns, so we would like to propose to the reader few considerations on Bodega et al. report.
(1) In the Introduction, Bodega et al. state: “Though they considered that these pressure measurements might be affected by artifacts. . .”. Using the micropuncture technique, potential artifacts may come from excessive local distortion when introducing the micropipette into the tissue. However, being aware of this possible flaw, in the mentioned study, as well as in all measurements performed since our first micropuncture study (Miserocchi et al., 1988), we exclude such an artifact by performing the micropuncture measurements with an incident angle that minimizes tissue indentation and artifacts. In addition, the reproducibility of our interstitial and lymphatic pressure values and the fact that the pleural liquid pressure values that we measured with the micropuncture techniques are essentially equal to those we obtained with intrapleural fluid filled cannulas, indicate that our micropuncture data were not affected by artifact as Bodega et al. maintain.
∗ Corresponding author at: Department of Surgical and Morphological Sciences, University of Insubria, Via J.H. Dunant 5, 21100 Varese, Italy. Tel.: +39 0332 397104; fax: +39 0332 397119. E-mail address: [email protected] (D. Negrini). http://dx.doi.org/10.1016/j.resp.2015.01.008 1569-9048/© 2015 Elsevier B.V. All rights reserved.
(2) Always in the Introduction, Bodega et al. report the intercostal lymphatic pressure values from Moriondo et al. (2005), and then state that we based our conclusions on the effect of spontaneous or mechanical ventilation on lymphatic pleural drainage on these pressure values. This is unfortunately far from being correct. Indeed, since it is well known that fluid fluxes are sustained by hydraulic pressure gradients, in order to attempt a study of the mechanisms of lymphatic flow in spontaneous or mechanical ventilation, in Moriondo et al. (2005) we simultaneously measured lymphatic pressure and interstitial pressure in the adjacent tissue, so as to obtain the transmural fluid pressure acting between the interstitium and the lymphatic lumen. Note that to simultaneously insert two pressure recording micropipettes in spontaneous or mechanically ventilated thoracic tissues was a quite demanding effort from the experimental standpoint. Our data revealed that the intercostal interstitial-to-lymphatic hydraulic pressure gradient was in favor of lymphatic absorption in spontaneous ventilation, but it was nil in case of mechanical ventilation. (3) Our “. . .view that pleural fluid is drained by lymphatics even when its volume is nearly physiological. . .” is based on direct measurements of pleural fluid pressure and lymphatic pressure in closed chest and by several researches published in major scientific Journals both in the last few years and, previously, in the period of our long lasting collaboration with Prof. Miserocchi at the University of Milan. Please note that all our papers, as well as all other manuscripts published on Journals like Respiratory Physiology and Neurobiology, Journal of Physiology, the American Journal of Physiology, Acta Physiologica and so forth, passed through a very selective and serious peer review by the international scientific community. (4) The fact that mechanical ventilation triggers lung edema and pleural effusion is a well known complication, addressed by several Reviews in the most qualified Journals, that anesthesiologists everyday face in their clinics and intensive care units
52
D. Negrini et al. / Respiratory Physiology & Neurobiology 210 (2015) 51–52
and complicates indeed the choice of the strategy to adequately ventilate their patients by simultaneously minimizing the risks of ventilatory-induced acute lung injury (VALI). Hence, after finding that mechanical ventilation may nullify interstitial-tolymphatic hydraulic pressure gradient in intercostal tissues, we just briefly proposed that impaired lymphatic function might be one of the potential phenomena leading to pleural effusion and lung edema. However, this was a final consideration, not the target of the manuscript that was much more articulated and complex than that described by Bodega et al. (5) We expect that, particularly in absence of a frank inflammatory pleural or pulmonary event, pleural effusion and lung edema evolve slowly after lymphatic impairment so that 1 h may not be an adequate time to observe and quantify these phenomena, that anesthesiologists face in long term mechanical ventilation. However, even by analyzing Bodega et al. results at 1 h of mechanical ventilation (Table 1 of their report), we do not agree that their data disprove our previous finding. Indeed, from radioactive albumin clearance, it is possible to measure a pleural lymphatic flow of 0.019 ml/(kg h) under normal spontaneous breathing (Negrini et al., 1985). In Table 1 of Bodega et al. report, the total volume of pleural fluid collected from the right and left cavities after 1 h of mechanical ventilation was (0.24 + 0.27) ml = 0.51 ml which, expressed per unit body mass (3.01 kg) is 0.169 ml/kg. In spontaneous ventilation the total volume collected was (0.17 + 0.22) ml = 0.39 ml which, expressed per unit body mass (2.66 kg) is 0.146 ml/kg. Hence, after 1 h of mechanical ventilation the volume of collected pleural fluid was 0.023 ml/kg higher compared to spontaneous ventilation and ≈20% more than we would have expected from our measure of pleural lymphatic flux. Hence Bodega et al. results, rather than disproving our data, seem to confirm them. (6) It is to be expected that pleural fluid protein concentration does not change after 1 h of mechanical ventilation with room air. Indeed, due to plasma proteins molecular weight and dimension, the reflection coefficient of lymphatic stomata to proteins is zero and lymphatics drain simultaneously liquid and protein,
leaving pleural protein concentration unaffected compared to normal. These considerations come from the thermodynamic derivation and biophysical analysis of the original Staling equation for fluid fluxes, as described in details on several chapters of the Handbook of Physiology (Curry, 1984; Michel and Curry, 1999). The expectation that lymphatic impairment causes an immediate raise in interstitial or pleural fluid protein concentration comes instead from the never demonstrated assumption that lymphatics absorb anidrous proteins through a still undefined mechanism. (7) The fact that the coefficient of friction is normal is not surprising: indeed, it means that the permeability properties of the parietal and visceral mesothelium have not been affected by 1 h of mechanical ventilation. (8) Finally, among all our papers, the one that Bodega et al. criticize had the honor to be included with a figure (Fig. 8) and several citations in a recent Review published on the Physiological Reviews (Wiig and Swartz, 2011). References Bodega, F., Sironi, C., Porta, C., Zocchi, L., Agostoni, E., 2015. Pleural liquid and kinetic friction coefficient of mesothelium after mechanical ventilation. Respir. Physiol. Neurobiol. 206, 1–3. Curry, F.R., 1984. Mechanism and thermodynamics of transcapillary exchange. In: Renkin, E.M., Michel, C.C. (Eds.), Handbook of Physiology, The Cardiovascular System Microcirculation. IV, Section 2, Part I. The American Physiological Society, Bethesda, MD, pp. 309–374 (Chapter 8). Miserocchi, G., Kelly, S., Negrini, D., 1988. Pleural and extrapleural interstitial liquid pressure measured by cannulas and micropipettes. J. Appl. Physiol. 65 (2), 555–562. Michel, C., Curry, F., 1999. Microvascular permeability. Physiol. Rev. 79, 703–761. Moriondo, A., Mukenge, S., Negrini, D., 2005. Transmural pressure in rat initial subpleural lymphatics during spontaneous or mechanical ventilation. Am. J. Physiol. Heart Circ. Physiol. 289, 263L 269. Negrini, D., Pistolesi, M., Miniati, M., Bellina, C.R., Giuntini, C., Miserocchi, G., 1985. Regional protein absorption rates from the pleural cavity in dogs. J. Appl. Physiol. 58, 2062–2067. Wiig, H., Swartz, M.A., 2011. Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer. Physiol. Rev. 9, 1005–1060.
