Lung injury during CPB: pathomechanisms and clinical relevance
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《血管的通路杂志》
Department of Cardiovascular Surgery, University of Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany
The authors Vedin et al. [1] present in this issue their results from a prospective clinical study investigating the effects of cardiopulmonary bypass (CPB) on lung function parameters. To that end, 50 low-risk patients suffering from coronary artery disease were randomised into two groups: the first group (n=25) underwent surgery with the use of CBP (on-pump), the other group (n=25) without CPB support (off-pump). Contrary to expectations, there was no difference in lung function parameters between the groups. However, gas exchange was impaired in both groups during the 20 h post-op observation period. The observation that lung function parameters deteriorate in the off-pump group is surprising, since the occurrence of organ dysfunction after heart operations has so far been assumed to be associated with use of CPB. Such organ dysfunction may affect the kidneys, myocardium and most particularly, the lungs [2–5]. The question remains, what is the cause, or which pathomechanism is responsible for their findings, when lung function impairment occurs equally in patients undergoing on- or off-pump surgery To answer this question it is necessary to thoroughly understand some important aspects of the clinical and pathophysiological basics involved during the use of CPB.
The use of cardiopulmonary bypass during heart operations is associated with an unspecific inflammatory reaction that correlates with the occurrence of organ dysfunction and sometimes even serious organ failure. Pulmonary dysfunction is a frequent complication during the postoperative course after cardiac surgery using CPB [6–10], clinically manifested as interstitial pulmonary oedema and the formation of excessive bronchial secretions [11,12]. In consequence, up to 20% of patients undergoing operations with the use of CPB need to be ventilated for more than 48 h postoperatively [13]. In particularly serious cases pulmonary dysfunction leads to an acute respiratory distress syndrome (ARDS), with an accompanying mortality rate of over 50% [14,15].
One major cause for organ dysfunction after cardiac surgery using CPB is believed to be an unspecific inflammatory reaction caused by the contact of blood cells with the foreign surface of the heart lung machine. Once an inflammatory reaction is initiated, it is maintained by a series of humoral and cellular factors (complement system, cytokines, endothelial interaction, the endogenous NO-system, prostaglandins and coagulation and/or fibrinolysis). The clinical phenomena (pulmonary oedema, secretions, impairment of gas exchange) associated with this inflammatory reaction are observed in the majority of patients after cardiac surgery using CPB [16]. The duration of CPB correlates directly with the severity of clinical symptoms [17]. Despite the apparent transparency of these findings, no correlation has been demonstrated between the concentration of inflammatory mediators and the severity of the resulting systemic inflammatory reaction. It is entirely conceivable that a rise in inflammatory factors in one patient leads to a minor inflammatory reaction, while in another patient, the same rise causes a pronounced inflammatory reaction. However, the complexity of these processes is enormous, and it is possible that these assumed correlations cannot yet be proved using the current measurement methods and techniques. It is therefore necessary to consider alternative explanations, such as those independent of potentially inflammatory processes.
There are indirect indications in the literature that pulmonary dysfunction might be related to ischemic injury of the lung during CPB [18,19]. Sievers' group [20] and others [7,21] showed in clinical trials that intermittent perfusion of the lung with cold blood during CPB improves the gas exchange during the immediate post-op period. However, the fundamental pathomechanism leading to functional improvement was not examined in those studies.
During total CPB blood flow to the lungs is limited to flow through the bronchial arteries. We were able to prove in an experimental study that bronchial artery blood circulation is substantially reduced during CPB [22,23]. The reduction in flow was associated with metabolic and ultrastructural changes of lung tissue suggesting the presence of ischemia of the lungs during CPB. All of these changes could be ameliorated by controlled perfusion of the pulmonary artery with cold blood during conventional CPB. Furthermore, we were able to demonstrate that indicators for an inflammatory response of the lungs obtained from bronchioalveolar lavage fluids could also be reversed by controlled perfusion of the lung. This was an unexpected observation since the accumulation of inflammatory mediators are thought to be caused by the cardiopulmonary bypass circuit. If this is the case, pulmonary perfusion while on bypass should not have been able to affect these parameters. This observation may suggest a different pathomechanism for CPB associated inflammatory changes, at least in lungs. Vedin et al.'s results allow us to come to the same conclusion, namely that other mechanisms play key roles in impairing lung function after cardiac surgery. However, the significance of this study is limited by the following factors:
1. This is a small study with few patients. We observe that the study's design lacks a power analysis. 2. The impairment of lung function was rather minimal. It is conceivable that, had this study been carried out on patients at high risk for lung dysfunction, one would observe less injury of the lung in the off-pump patients. In this case the authors' conclusion would not be valid. We therefore believe that the trial should be carried out on a larger cohort of patients with high risk for pulmonary complications.
In summary, the present study by Vedin et al. is another very important contribution in the search for perioperative strategies to reduce the pulmonary injury after cardiac operations.
References
Vedin J, Jensen U, Ericsson A, Samuelsson S, Vaage J. Pulmonary hemodynamics and gas exchange in off pump coronary artery bypass grafting. Interact CardioVasc Thorac Surg 2005;4:493–497.
Abel RM, Buckley MJ, Austen WG, Barnett GO, Beck CHJ, Fischer JE. Etiology, incidence, and prognosis of renal failure following cardiac operations. Results of a prospective analysis of 500 consecutive patients. J Thorac Cardiovasc Surg 1976;71:323–333.
Andersson LG, Ekroth R, Bratteby LE, Hallhagen S, Wesslen O. Acute renal failure after coronary surgery—a study of incidence and risk factors in 2009 consecutive patients. Thorac Cardiovasc Surg 1993;41:237–241.
Fischer UM, Weissenberger WK, Warters RD, Geissler HJ, Allen SJ, Mehlhorn U. Impact of cardiopulmonary bypass management on postcardiac surgery renal function. Perfusion 2002;17:401–406.
Treacher DF, Sabbato M, Brown KA, Gant V. The effects of leucodepletion in patients who develop the systemic inflammatory response syndrome following cardiopulmonary bypass. Perfusion 2001;16:67–73.
Bund M, Seitz W, Uthoff K, Krieg P, Struber M, Piepenbrock S. Monitoring of respiratory function before and after cardiopulmonary bypass using side-stream spirometry. Eur J Anaesthesiol 1998;15:44–49.
Chai PJ, Williamson JA, Lodge AJ, Daggett CW, Scarborough JE, Meliones JN, Cheifetz IM, Jaggers JJ, Ungerleider RM. Effects of ischemia on pulmonary dysfunction after cardiopulmonary bypass. Ann Thorac Surg 1999;67:731–735.
Friedman M, Sellke FW, Wang SY, Weintraub RM, Johnson RG. Parameters of pulmonary injury after total or partial cardiopulmonary bypass. Circulation 1994;90:II262–II268.
Serraf A, Sellak H, Herve P, Bonnet N, Robotin M, Detruit H, Baudet B, Mazmanian MG, Planche C. Vascular endothelium viability and function after total cardiopulmonary bypass in neonatal piglets. Am J Respir Crit Care Med 1999;159:544–551.
Weiss YG, Merin G, Koganov E, Ribo A, Oppenheim-Eden A, Medalion B, Peruanski M, Reider E, Bar-Ziv J, Hanson WC, Pizov R. Postcardiopulmonary bypass hypoxemia: a prospective study on incidence, risk factors, and clinical significance. J Cardiothorac Vasc Anesth 2000;14:506–513.
Sinclair DG, Haslam PL, Quinlan GJ, Pepper JR, Evans TW. The effect of cardiopulmonary bypass on intestinal and pulmonary endothelial permeability. Chest 1995;108:718–724.
Stiller B, Sonntag J, Dahnert I, Alexi-Meskishvili V, Hetzer R, Fischer T, Lange PE. Capillary leak syndrome in children who undergo cardiopulmonary bypass: clinical outcome in comparison with complement activation and C1 inhibitor. Intensive Care Med 2001;27:193–200.
Hammermeister KE, Burchfiel C, Johnson R, Grover FL. Identification of patients at greatest risk for developing major complications at cardiac surgery. Circulation 1990;82:IV380–IV389.
Fowler AA, Hamman RF, Good JT, Benson KN, Baird M, Eberle DJ, Petty TL, Hyers TM. Adult respiratory distress syndrome: risk with common predispositions. Ann Intern Med 1983;98:593–597.
Milot J, Perron J, Lacasse Y, Letourneau L, Cartier PC, Maltais F. Incidence and predictors of ARDS after cardiac surgery. Chest 2001;119:884–888.
Fitch JC, Rollins S, Matis L, Alford B, Aranki S, Collard CD, Dewar M, Elefteriades J, Hines R, Kopf G, Kraker P, Li L, O'Hara R, Rinder C, Rinder H, Shaw R, Smith B, Stahl G, Shernan SK. Pharmacology and biological efficacy of a recombinant, humanized, single-chain antibody C5 complement inhibitor in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. Circulation 1999;100:2499–2506.
Kirklin JK, Westaby S, Blackstone EH, Kirklin JW, Chenoweth DE, Pacifico AD. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;86:845–857.
Mendler N, Heimisch W, Schad H. Pulmonary function after biventricular bypass for autologous lung oxygenation. Eur J Cardiothorac Surg 2000;17:325–330.
Richter JA, Meisner H, Tassani P, Barankay A, Dietrich W, Braun SL. Drew-Anderson technique attenuates systemic inflammatory response syndrome and improves respiratory function after coronary artery bypass grafting. Ann Thorac Surg 2000;69:77–83.
Sievers HH, Freund-Kaas C, Eleftheriadis S, Fischer T, Kuppe H, Kraatz EG, Bechtel JF. Lung protection during total cardiopulmonary bypass by isolated lung perfusion: preliminary results of a novel perfusion strategy. Ann Thorac Surg 2002;74:1167–1172.
Suzuki T, Fukuda T, Ito T, Inoue Y, Cho Y, Kashima I. Continuous pulmonary perfusion during cardiopulmonary bypass prevents lung injury in infants. Ann Thorac Surg 2000;69:602–606.
Schlensak C, Doenst T, Preusser S, Wunderlich M, Kleinschmidt M, Beyersdorf F. Bronchial artery perfusion during cardiopulmonary bypass does not prevent ischemia of the lung in piglets: assessment of bronchial artery blood flow with fluorescent microspheres. Eur J Cardiothorac Surg 2001;19:326–331.
Schlensak C, Doenst T, Preusser S, Wunderlich M, Kleinschmidt M, Beyersdorf F. Cardiopulmonary bypass reduction of bronchial blood flow: a potential mechanism for lung injury in a neonatal pig model. J Thorac Cardiovasc Surg 2002;123:1199–1205.(Christian Schlensak and F)
The authors Vedin et al. [1] present in this issue their results from a prospective clinical study investigating the effects of cardiopulmonary bypass (CPB) on lung function parameters. To that end, 50 low-risk patients suffering from coronary artery disease were randomised into two groups: the first group (n=25) underwent surgery with the use of CBP (on-pump), the other group (n=25) without CPB support (off-pump). Contrary to expectations, there was no difference in lung function parameters between the groups. However, gas exchange was impaired in both groups during the 20 h post-op observation period. The observation that lung function parameters deteriorate in the off-pump group is surprising, since the occurrence of organ dysfunction after heart operations has so far been assumed to be associated with use of CPB. Such organ dysfunction may affect the kidneys, myocardium and most particularly, the lungs [2–5]. The question remains, what is the cause, or which pathomechanism is responsible for their findings, when lung function impairment occurs equally in patients undergoing on- or off-pump surgery To answer this question it is necessary to thoroughly understand some important aspects of the clinical and pathophysiological basics involved during the use of CPB.
The use of cardiopulmonary bypass during heart operations is associated with an unspecific inflammatory reaction that correlates with the occurrence of organ dysfunction and sometimes even serious organ failure. Pulmonary dysfunction is a frequent complication during the postoperative course after cardiac surgery using CPB [6–10], clinically manifested as interstitial pulmonary oedema and the formation of excessive bronchial secretions [11,12]. In consequence, up to 20% of patients undergoing operations with the use of CPB need to be ventilated for more than 48 h postoperatively [13]. In particularly serious cases pulmonary dysfunction leads to an acute respiratory distress syndrome (ARDS), with an accompanying mortality rate of over 50% [14,15].
One major cause for organ dysfunction after cardiac surgery using CPB is believed to be an unspecific inflammatory reaction caused by the contact of blood cells with the foreign surface of the heart lung machine. Once an inflammatory reaction is initiated, it is maintained by a series of humoral and cellular factors (complement system, cytokines, endothelial interaction, the endogenous NO-system, prostaglandins and coagulation and/or fibrinolysis). The clinical phenomena (pulmonary oedema, secretions, impairment of gas exchange) associated with this inflammatory reaction are observed in the majority of patients after cardiac surgery using CPB [16]. The duration of CPB correlates directly with the severity of clinical symptoms [17]. Despite the apparent transparency of these findings, no correlation has been demonstrated between the concentration of inflammatory mediators and the severity of the resulting systemic inflammatory reaction. It is entirely conceivable that a rise in inflammatory factors in one patient leads to a minor inflammatory reaction, while in another patient, the same rise causes a pronounced inflammatory reaction. However, the complexity of these processes is enormous, and it is possible that these assumed correlations cannot yet be proved using the current measurement methods and techniques. It is therefore necessary to consider alternative explanations, such as those independent of potentially inflammatory processes.
There are indirect indications in the literature that pulmonary dysfunction might be related to ischemic injury of the lung during CPB [18,19]. Sievers' group [20] and others [7,21] showed in clinical trials that intermittent perfusion of the lung with cold blood during CPB improves the gas exchange during the immediate post-op period. However, the fundamental pathomechanism leading to functional improvement was not examined in those studies.
During total CPB blood flow to the lungs is limited to flow through the bronchial arteries. We were able to prove in an experimental study that bronchial artery blood circulation is substantially reduced during CPB [22,23]. The reduction in flow was associated with metabolic and ultrastructural changes of lung tissue suggesting the presence of ischemia of the lungs during CPB. All of these changes could be ameliorated by controlled perfusion of the pulmonary artery with cold blood during conventional CPB. Furthermore, we were able to demonstrate that indicators for an inflammatory response of the lungs obtained from bronchioalveolar lavage fluids could also be reversed by controlled perfusion of the lung. This was an unexpected observation since the accumulation of inflammatory mediators are thought to be caused by the cardiopulmonary bypass circuit. If this is the case, pulmonary perfusion while on bypass should not have been able to affect these parameters. This observation may suggest a different pathomechanism for CPB associated inflammatory changes, at least in lungs. Vedin et al.'s results allow us to come to the same conclusion, namely that other mechanisms play key roles in impairing lung function after cardiac surgery. However, the significance of this study is limited by the following factors:
1. This is a small study with few patients. We observe that the study's design lacks a power analysis. 2. The impairment of lung function was rather minimal. It is conceivable that, had this study been carried out on patients at high risk for lung dysfunction, one would observe less injury of the lung in the off-pump patients. In this case the authors' conclusion would not be valid. We therefore believe that the trial should be carried out on a larger cohort of patients with high risk for pulmonary complications.
In summary, the present study by Vedin et al. is another very important contribution in the search for perioperative strategies to reduce the pulmonary injury after cardiac operations.
References
Vedin J, Jensen U, Ericsson A, Samuelsson S, Vaage J. Pulmonary hemodynamics and gas exchange in off pump coronary artery bypass grafting. Interact CardioVasc Thorac Surg 2005;4:493–497.
Abel RM, Buckley MJ, Austen WG, Barnett GO, Beck CHJ, Fischer JE. Etiology, incidence, and prognosis of renal failure following cardiac operations. Results of a prospective analysis of 500 consecutive patients. J Thorac Cardiovasc Surg 1976;71:323–333.
Andersson LG, Ekroth R, Bratteby LE, Hallhagen S, Wesslen O. Acute renal failure after coronary surgery—a study of incidence and risk factors in 2009 consecutive patients. Thorac Cardiovasc Surg 1993;41:237–241.
Fischer UM, Weissenberger WK, Warters RD, Geissler HJ, Allen SJ, Mehlhorn U. Impact of cardiopulmonary bypass management on postcardiac surgery renal function. Perfusion 2002;17:401–406.
Treacher DF, Sabbato M, Brown KA, Gant V. The effects of leucodepletion in patients who develop the systemic inflammatory response syndrome following cardiopulmonary bypass. Perfusion 2001;16:67–73.
Bund M, Seitz W, Uthoff K, Krieg P, Struber M, Piepenbrock S. Monitoring of respiratory function before and after cardiopulmonary bypass using side-stream spirometry. Eur J Anaesthesiol 1998;15:44–49.
Chai PJ, Williamson JA, Lodge AJ, Daggett CW, Scarborough JE, Meliones JN, Cheifetz IM, Jaggers JJ, Ungerleider RM. Effects of ischemia on pulmonary dysfunction after cardiopulmonary bypass. Ann Thorac Surg 1999;67:731–735.
Friedman M, Sellke FW, Wang SY, Weintraub RM, Johnson RG. Parameters of pulmonary injury after total or partial cardiopulmonary bypass. Circulation 1994;90:II262–II268.
Serraf A, Sellak H, Herve P, Bonnet N, Robotin M, Detruit H, Baudet B, Mazmanian MG, Planche C. Vascular endothelium viability and function after total cardiopulmonary bypass in neonatal piglets. Am J Respir Crit Care Med 1999;159:544–551.
Weiss YG, Merin G, Koganov E, Ribo A, Oppenheim-Eden A, Medalion B, Peruanski M, Reider E, Bar-Ziv J, Hanson WC, Pizov R. Postcardiopulmonary bypass hypoxemia: a prospective study on incidence, risk factors, and clinical significance. J Cardiothorac Vasc Anesth 2000;14:506–513.
Sinclair DG, Haslam PL, Quinlan GJ, Pepper JR, Evans TW. The effect of cardiopulmonary bypass on intestinal and pulmonary endothelial permeability. Chest 1995;108:718–724.
Stiller B, Sonntag J, Dahnert I, Alexi-Meskishvili V, Hetzer R, Fischer T, Lange PE. Capillary leak syndrome in children who undergo cardiopulmonary bypass: clinical outcome in comparison with complement activation and C1 inhibitor. Intensive Care Med 2001;27:193–200.
Hammermeister KE, Burchfiel C, Johnson R, Grover FL. Identification of patients at greatest risk for developing major complications at cardiac surgery. Circulation 1990;82:IV380–IV389.
Fowler AA, Hamman RF, Good JT, Benson KN, Baird M, Eberle DJ, Petty TL, Hyers TM. Adult respiratory distress syndrome: risk with common predispositions. Ann Intern Med 1983;98:593–597.
Milot J, Perron J, Lacasse Y, Letourneau L, Cartier PC, Maltais F. Incidence and predictors of ARDS after cardiac surgery. Chest 2001;119:884–888.
Fitch JC, Rollins S, Matis L, Alford B, Aranki S, Collard CD, Dewar M, Elefteriades J, Hines R, Kopf G, Kraker P, Li L, O'Hara R, Rinder C, Rinder H, Shaw R, Smith B, Stahl G, Shernan SK. Pharmacology and biological efficacy of a recombinant, humanized, single-chain antibody C5 complement inhibitor in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. Circulation 1999;100:2499–2506.
Kirklin JK, Westaby S, Blackstone EH, Kirklin JW, Chenoweth DE, Pacifico AD. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;86:845–857.
Mendler N, Heimisch W, Schad H. Pulmonary function after biventricular bypass for autologous lung oxygenation. Eur J Cardiothorac Surg 2000;17:325–330.
Richter JA, Meisner H, Tassani P, Barankay A, Dietrich W, Braun SL. Drew-Anderson technique attenuates systemic inflammatory response syndrome and improves respiratory function after coronary artery bypass grafting. Ann Thorac Surg 2000;69:77–83.
Sievers HH, Freund-Kaas C, Eleftheriadis S, Fischer T, Kuppe H, Kraatz EG, Bechtel JF. Lung protection during total cardiopulmonary bypass by isolated lung perfusion: preliminary results of a novel perfusion strategy. Ann Thorac Surg 2002;74:1167–1172.
Suzuki T, Fukuda T, Ito T, Inoue Y, Cho Y, Kashima I. Continuous pulmonary perfusion during cardiopulmonary bypass prevents lung injury in infants. Ann Thorac Surg 2000;69:602–606.
Schlensak C, Doenst T, Preusser S, Wunderlich M, Kleinschmidt M, Beyersdorf F. Bronchial artery perfusion during cardiopulmonary bypass does not prevent ischemia of the lung in piglets: assessment of bronchial artery blood flow with fluorescent microspheres. Eur J Cardiothorac Surg 2001;19:326–331.
Schlensak C, Doenst T, Preusser S, Wunderlich M, Kleinschmidt M, Beyersdorf F. Cardiopulmonary bypass reduction of bronchial blood flow: a potential mechanism for lung injury in a neonatal pig model. J Thorac Cardiovasc Surg 2002;123:1199–1205.(Christian Schlensak and F)