- Email: [email protected]
Cardiopulmonary Bypass During a Second-Lung Implantation Improves Postoperative Oxygenation After Sequential Double-Lung Transplantation
Cardiopulmonary Bypass During a Second-Lung Implantation Improves Postoperative Oxygenation After Sequential Double-Lung Transplantation Hadrien Roze´, MD,*†z Matthieu Thumerel, MD,#J Laurent Barandon, MD, PhD,†zz Claire Dromer, MD,#z Virginie Perrier, MD,* Jacques Jougon, MD,y Jean-Franc- ois Velly, MD,y and Alexandre Ouattara, MD, PhD*†z Objectives: During sequential double-lung transplantation (DLT), the newly implanted first lung receives the entire cardiac output during the implantation of the second one. This may be responsible for the increased hydrostatic pressure that causes severe interstitial and alveolar edema that can lead to allograft dysfunction. The authors tested the hypothesis that CPB started after first graft implantation and before second recipient lung removal should improve post-transplantation oxygenation and clinical outcomes. Design: Observational during 2 consecutive 1-year periods. Setting: University hospital. Participants: Nine consecutive patients undergoing sequential DLT with CPB started after first graft implantation and before second recipient lung removal were compared to controls, who were 10 consecutive patients who underwent sequential DLT but without CPB the year before. Measurements and Main Results: Oxygenation after transplantation was assessed. The use of CPB during the
implantation of the second lung was associated with an increased mean postoperative ratio of PaO2 to the fraction of inspired oxygen at 1 hour (363 ⫾ 51 v 240 ⫾ 113, p ¼ 0.01) and 6 hours (430 ⫾ 111 v 280 ⫾ 103, p ¼ 0.03). The mean duration of CPB was 111 ⫾ 19 min. The occurrence of primary graft dysfunction and the need for extracorporeal membrane oxygenation tended to be lower, but did not reach significance. Similarly, mortality rate was comparable between both groups, as was the rate of blood transfusions. Conclusions: The authors’ results suggest that the use of CPB started after first graft implantation and before second recipient lung removal appears to benefit oxygenation and reduces the occurrence of severe pulmonary edema in the first transplanted lung. & 2013 Elsevier Inc. All rights reserved.
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need for extracorporeal membrane oxygenation (ECMO),17 although these injuries do not occur in all patients. Moreover, preoperative variables are able to predict severe high-flow highpressure injuries. Pulmonary edema often appears late; it may be clinically symptomatic at the end of the second-lung implantation, and initially concerns the first implanted lung where total ischemic time was shorter. Based on all these considerations, CPB may be used systematically before implantation of the second lung to limit pulmonary perfusion flow and pressure by splitting the cardiac output between the CPB and the first implanted graft. The authors tested the hypothesis that sequential bipulmonary
OUBLE-LUNG TRANSPLANTATION (DLT) has become an established therapy for end-stage lung disease, and it was performed initially with airway anastomosis at the tracheal bifurcation under cardiopulmonary bypass (CPB). However, the complications related to ischemia of the bronchi and trachea around the carina prompted adoption of sequential single-lung implantations as the method of choice for DLT. The use of CPB has decreased dramatically over the last 2 decades, and primarily has been required in the presence of preoperative pulmonary hypertension, severe hypoxemia or hypercapnia or both, elevation of pulmonary-arterial hypertension, and reduction in cardiac index during one-lung ventilation.1-4 In the setting of lung transplantation, CPB may be responsible for acute lung injury and allograft dysfunction by inducing complement activation, endotoxin release, leukocyte activation, and expression of adhesion molecules.5-8 There has been significant progress in the technology of CPB, but potentially harmful effects of CPB during lung transplantation remain controversial. A retrospective study including patients with chronic obstructive pulmonary disease who required a lung transplantation reported deleterious effects on early graft function or adverse clinical outcomes when CPB was used.9 During routine bilateral lung transplantation, the first implanted lung receives the entire cardiac output during the implantation of the second lung. This results in increased blood flow and pulmonary arterial pressure.14 This may lead to high-flow high-pressure reperfusion injuries with severe interstitial and alveolar edema, as well as endothelial damage as a result of increased shear stress. Therefore, lowering reperfusion pressure can reduce injury after pulmonary ischemia and improve pulmonary function.13-15 The clinical consequence is primary graft dysfunction16 with severe post-transplantation hypoxemia and the
KEY WORDS: lung transplantation, cardiopulmonary bypass, postoperative oxygenation
From the *CHU de Bordeaux, Service d’Anesthe´sie-Re´animation II, Pessac, France, yUniv. Bordeaux, Adaptation cardiovasculaire a l’ische´mie, U1034, F-33600, Pessac, France, zINSERM, Adaptation cardiovasculaire a l’ische´mie, U1034, F-33600, Pessac, France, yCHU de Bordeaux, Service de Chirurgie Thoracique, Bordeaux, France, JINSERM, Centre de Recherche Cardio-thoracique de Bordeaux, U1034, F-33600, Bordeaux, France, zCHU de Bordeaux, Service de Chirurgie Cardiaque, Bordeaux, France; and #CHU de Bordeaux, Service de Pneumologie, Bordeaux, France. This study was presented in part at the 2011 Annual Meeting of the International Society of Heart and Lung Transplantation, San Diego, USA, April 17, 2011. Address reprint requests to Hadrien Roze´, MD, Service d’Anesthe´sieRe´animation 2, Hˆopital du Haut-Le´vˆeque, CHU de Bordeaux, Avenue Magellan, 33604 Pessac, France. E-mail: [email protected] & 2013 Elsevier Inc. All rights reserved. 1053-0770/2601-0001$36.00/0 http://dx.doi.org/10.1053/j.jvca.2012.11.005
Journal of Cardiothoracic and Vascular Anesthesia, Vol 27, No 3 (June), 2013: pp 467–473
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transplantation using CPB, initiated after first graft implantation and before removal of the second recipient lung, improves postoperative oxygenation and clinical outcomes. METHODS
This study was approved by the authors’ Lung Transplant Evaluation Committee and retrospectively included patients undergoing sequential DLT by comparing 2 consecutive 1-year periods between 2008 and 2010. Data were collected retrospectively and did not modify any care of patients, conformed to the standard procedures currently used in the authors’ institution, and informed consent was obtained from all patients. All patients in whom CPB was initiated before removal of the second recipient lung (from January 2009January 2010) were compared to a control group in whom CPB was not performed before removal of the second recipient lung (from January 2008-December 2008). To limit bias, the authors decided to compare the 2 groups during a short period, limited to 1 year for each group, with and without CPB. During the 2 years, patients who were placed on CPB before the first implantation were excluded from the analysis. General Conditions Anesthesia included propofol, administered by targetcontrolled intravenous anesthesia protocols, and sufentanil, and atracurium. A central venous catheter was inserted and the saturation of central venous oxygenation was monitored. Arterial pressure was monitored invasively through a radialartery catheter. Finally, transesophageal echocardiography was used systematically. A double-lumen tube was placed to allow isolated lung ventilation. Protective ventilation was used with a low tidal volume of 5 mL/kg of donor ideal body weight and low plateau pressure o 26 cm H20, 10 cm H2O of positive expiratory pressure was maintained (Fig 1), and nitric oxide was inhaled at 10 ppm. End-expiratory carbon dioxide (ETCO2) was monitored continuously. Intraoperative hemodynamic instability was corrected by fluids or infusion of norepinephrine or both. Ventilation of the transplanted lung was carried out progressively over 15 minutes with FIO2 o50% and pressurecontrolled ventilation with a plateau pressure o26 cmH20. A cell saver was used systematically. Immunosuppressive therapy, started after surgery, remained the same during the 2-year period and consisted of a triple regimen of glucocorticoids, cyclosporine, and mycophenolate mofetil. Surgical Procedure Lung harvesting Conditions of organ acceptance from the donor for transplantation remained the same during the study period and were based on commonly published criteria. Techniques for preservation during harvesting included intravenous heparin (300 IU/kg) and prostaglandin (20 mg) through the pulmonary artery, followed by an anterograde low-pressure (20 cmH2O) flush of perfadex (50 mL/kg), and a retrograde flush of perfadex (1 L) through the pulmonary veins. The lungs were conditioned in an inflated state in a cooled (41C) sterile bag for transport. Before implantation, a redo retrograde flush of perfadex (1 L for both lungs) was performed. During first-graft
Fig 1. Ventilatory settings during cardiopulmonary bypass (CPB) and ventilation of the first implanted lung. Protective ventilation with low VT of 230 mL, 10 cmH2O of PEP, and low respiratory frequency; the curve at the bottom represents ETCO2 with a value of 17.6 mmHg.
implantation, the second lung was stored in a sterile bag with perfadex and covered with ice slush. On-pump transplant procedure Perioperative heparin was given at 300 units/kg to maintain an activated coagulation time of 4450 seconds during the procedure. All patients had bilateral anterolateral thoracotomies without transverse sternotomy. CPB was established. The extracorporeal circuit of the CPB consisted of an open system with a nonheparin-coated tube system. A 1-stage cannula (3240 F) (Medtronic) was used to drain the venous blood from the right atrium, along with a 22-F aortic cannula (Stockert) for the distal ascending aorta. Vessel access always was performed through the right thoracotomy after a straight 10-cm pericardiotomy performed 2 cm above the right phrenic nerve. An umbilical tape encircled the ascending aorta if its right retraction was needed for arterial cannulation. The system was primed with 500 mL of Ringer’s lactate, 800 mL of hydroxy-ethyl-amidon, and 150 mL of 20% mannitol. Heparin (4,000 units) was added to the prime volume. A nonpulsatile HL-30 roller pump (Stockert) established blood flow to maintain partial perfusion of the first implanted graft and limit warm ischemia (Fig 1). CPB was established after slow reperfusion of the first implanted graft and before clamping of the contralateral pulmonary artery. To avoid contamination, pump suckers were turned off when the bronchus was opened. Blood was saved and collected in an open cardiotomy reservoir and transfused back to the patient. In this surgical group, an Apex (Stockert) oxygenator was used. During all the procedures, hematocrit was maintained between 25% and 28%, and the minimal rectal temperature was 361C. Off-pump transplant procedure Perioperative heparin was given at 100 units/kg, and all patients were given bilateral anterolateral thoracotomies without a transverse sternotomy (as above).
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CPB DURING SECOND-LUNG IMPLANTATION
Comparison between continuous varibles was performed using the Student’s t-test or Mann-Whitney U test as appropriate. Comparison between categoric variables was performed using the chi-squared test. All p-values were 2-tailed. A p value o0.05 was considered to eliminate the null hypothesis. Statistical analysis was performed using NCSS 2007 software (Statistical Solutions Ltd, Cork, Ireland). RESULTS
Fig 2. Postoperative ratio of the partial pressure of oxygen in arterial blood (PaO2) to the inspired oxygen fraction (FIO2), at 1 hour and 6 hours, in patients who had (white box) or did not have (gray box) cardiopulmonary bypass during a double-lung transplant. Lines within boxes represent median values. Upper and lower lines of boxes represent 25th and 75th percentiles, respectively. Upper and lower bars outside of boxes represent 95th and 5th percentiles, respectively. Black squares represent mean values.
Transplant procedure The lung with the lowest preoperative perfusion was explanted first. A thoracic surgeon explanted the lungs and performed bronchial anastomosis while a cardiac surgeon performed the vascular anastomosis. Standardized organ procurement and recipient-implantation techniques were utilized for the lung transplantation. The preservation solution was infused via the donor pulmonary artery at low pressure in an antegrade fashion immediately following intrapulmonary injection of prostaglandin. The DLT was performed using a sequential single-lung implantation procedure. Once the donor’s lung was present in the operating room, the recipient’s pneumonectomy was completed. Bronchial anastomosis was accomplished first and was followed by the left atrial cuff and pulmonary artery anastomoses using a continuous suture. Lung reperfusion was slow, with retrograde back blood flow from vein to pulmonary artery. Data Collection Assessment of early allograft function included a postoperative chest radiograph at the end of the procedure, with a bronchoscopy and arterial blood-gas analysis at 1 hour and 6 hours after surgery. Transfusion requirements, in terms of packed red blood cells, fresh frozen plasma, and platelets, were compared by reviewing blood bank records. The 1-year mortality rate was compared to examine intermediate-term clinical outcomes. Primary graft dysfunction (PGD) was defined according to the published International Society for Heart and Lung Transplantation classification.19 Statistical Analyses Data are expressed as means ⫾ standard deviations (SDs) for normally distributed continuous variables, as medians (interquartile range) for non-normally distributed continuous variables, and as numbers (percentage of patients) for categoric data. The normal distribution of continuous variables was assessed using skewness and kurtosis statistical tests.
During the first period (from January 2008-December 2008), 10 patients who underwent sequential DLT without CPB were studied (without CPB group). Additionally, 2 patients had CPB because of pulmonary arterial hypertension. During the second period (from January 2009-January 2010), 9 patients had sequential DLT, using CPB before extraction of the second recipient lung (with CPB group). During this period, 1 patient with pulmonary arterial hypertension and 3 with hemodynamic instability and hypoxemia had CPB after the beginning of surgery and, thus, were excluded from this study. The duration of the CPB in this group was 111 ⫾ 19 min. The CPB group of patients was compared with patients in whom the surgery was performed without CPB (Tables 1 and 2). Postoperative oxygenation was significantly higher in patients in whom surgery was performed under CPB (Fig 2). In patients without grade-3 PGD, the improvement in postoperative oxygenation at H þ 1 with CPB was almost significant (p ¼ 0.06). During transplantation, there were no significant differences in ischemic and surgery time between groups; CPB did not increase blood transfusion, vasopressor use, or postoperative lactate levels (Table 3), and there was no mismatch in size. DISCUSSION
The principal findings of the present study are that postoperative oxygenation, at 1 hour and 6 hours after lung transplantation, was improved significantly when CPB was used during the second-lung implantation. In the control group, without CPB, 3 patients (2 with cystic fibrosis, 1 with bronchiectasis) had early PGD with severe pulmonary edema, which occurred in the first implanted graft at the end of the second-graft implantation. These 3 patients had no preoperative pulmonary arterial hypertension, no mismatch in size; hemodynamic and oxygenation remained stable during the implantation of the first graft, and bleeding was controlled, except for 1 patient who had 12 units of packed red blood cells. This edema occurred between 40 and 60 min after pulmonary artery clamping, whereas hemodynamic levels were stable, and PaO2/FIO2 initially was Table 1. Diagnoses of Patients in the Study Diagnosis
Cystic fibrosis COPD Lymphangioleiomyomatosis Bronchiectasis Graft v host disease Bronchiolitis obliterans
Without CPB (n ¼ 10)
With CPB (n ¼ 9)
6 1 1 1 1 0
4 2 0 2 0 1
Abbreviations: COPD, chronic obstructive pulmonary disease; CPB, cardiopulmonary bypass.
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Table 2. Preoperative Patient Characteristics Variables
Age, y Sex (F) Body weight, kg Height, cm Emergency transplantation Retransplantation Donor PaO2/FIO2 Donor age, y
Without CPB (n ¼10)
With CPB (n ¼ 9)
p Value
39 ⫾ 13 5 (56%) 52 ⫾ 7 167 ⫾ 11 4 (44%) 2 (22%) 421 ⫾ 133 45 ⫾ 12
0.20 0.65 0.31 0.28 0.35 0.21 0.79 0.07
31 ⫾ 14 7 (70%) 48 ⫾ 8 162 ⫾ 8 2 (20%) 0 (0%) 407 ⫾ 88 33 ⫾ 15
NOTE. Data are expressed as mean ⫾ SD or n (% of patients). Abbreviation: CPB, cardiopulmonary bypass.
increased after clamping because of the reduction of the shunt-like effect. Immediate graft dysfunction after pulmonary transplantation is believed to be a manifestation of ischemia-reperfusion (IR) injury. It has become apparent that IR injury may contribute significantly to recipient morbidity, with increased utilization of critical care resources, as well as longer intensive care unit and hospital stays.10 Reperfusion injury is thought to be due to either inadequate preservation techniques or prolonged graft ischemia before implantation.11 Other reports have confirmed an increased incidence of clinically significant IR injuries in recipients with preoperative pulmonary artery hypertension.12 The improvement in oxygenation that the authors observed suggested that pulmonary vasculature was protected from high-flow highpressure injury from the first implanted graft by the use of CPB, which seemed to be more important than its potential deleterious effects in terms of inflammatory activation and acute
lung injury. The use of CPB could limit pulmonary vascular injury, as well as ventilation-induced lung injury in the first implanted graft. Indeed, CPB allowed the authors to ventilate patients with a very protective strategy that included low tidal volume, low plateau pressure, low respiratory frequency, low inspiratory oxygen fraction, and significant positive end-expiratory pressure. Both alveolar and vascular injuries are responsible for capillary–alveolar barrier fracture. Indeed, Laplace’s law predicts that elevations in transmural pressure gradients will increase vessel wall tension and that overdistended vessels that have a larger diameter will experience the highest levels of wall tension. High flow can distend small vessels and accentuate the wall tension generated by cyclic increases in downstream resistance caused by lung inflation. Thus, high vascular flow might increase both shear stress and capillary wall tension, potentially both triggering an injurious inflammatory response of the
Table 3. Perioperative Characteristics of Patients Variables
Surgery time, min Ischemic time, min Packed red blood cells, unit Redo Surgery Postoperative at H þ 1 VT, mL RR, cycle/min PEEP, cmH20 FIO2, % Norepinephrine (n) Norepinephrine, mg/kg/min Lactate level, mmol/L Postoperative H þ 48 pH PaO2, mmHg PaCO2, mmHg HCO3, mmol/L Intubated PGD Z 3 requiring ECMO One-year mortality
Without CPB (n ¼ 10)
With CPB (n ¼ 9)
p Value
488 ⫾ 85 432 ⫾ 74 6⫾3 3 (30%)
478 ⫾ 70 391 ⫾ 61 8⫾3 1 (11%)
0.78 0.21 0.27 0.31
372 ⫾ 77 19 ⫾ 3 6⫾2 67 ⫾ 23 6 0.53 [0.27-0.67] 3.9 [1.6-4.1]
396 ⫾ 44 18 ⫾ 4 7⫾2 48 ⫾ 10 4 0.14 [0.08-0.34] 2.0 [1.5-4.2]
0.47 0.85 0.65 0.06 0.07 0.38 0.81
7.38 ⫾ 0.04 90 ⫾ 34 42 ⫾ 5 24.9 ⫾ 2.8 4 (40%) 3 (30%) 2 (20%)
7.36 ⫾ 0.06 143⫾ 76 52 ⫾ 13* 29.5 ⫾ 3.8* 2 (20%) 0 (0%) 0
0.57 0.08 0.05 0.01 0.30 0.07 0.47
NOTE. Data are expressed as mean ⫾ SD or median (IQR) or n (% of patients); p value refers to between-groups comparisons. Surgery time is time spent between incision and skin closure. Abbreviations: CPB, cardiopulmonary bypass; Ischemic time, ischemic time of the last implanted graft; VT, tidal volume; RR, respiratory rhythm; PEEP, positive end-expiratory pressure; FIO2, oxygen inspiratory fraction; PaO2, arterial oxygen tension, PaCO2, carbon dioxide tension. HCO3, bicarbonate; PGD, primary graft dysfunction; ECMO, extracorporeal membrane oxygenation. *po0.05.
CPB DURING SECOND-LUNG IMPLANTATION
Fig 3. Transesophageal echocardiography representing a pulse Doppler of the right lower pulmonary vein in the first implanted lung during cardiopulmonary bypass (CPB). Difference between 2 different CPB cardiac indices (CI) regarding pulmonary venous return and ETCO2 during implantation of the second lung. Upper half of the figure, ETCO2 is low at 8 mmHg with a CI of 2 L/min/m2and almost no venous return; lower half of the figure, CI has been reduced slightly at 1.8 L/min/m2 to increase venous return and ETCO2 to 15 mmHg.
endothelium and inducing capillary–alveolar barrier fracture by direct mechanic stress. Moreover, this concept is experimentally produced in case of sequential double-lobe transplantation in which the vascular network volume of each graft is reduced. In acute lung injury models, increasing lung volume decreases the increased pressure experienced by alveolar vessels while they expand to that of exposed extra-alveolar vessels.18 As a result, extra-alveolar vessels tend to expand during tidal inflation, whereas alveolar vessels are compressed and decrease in diameter.19 Consequently, extra-alveolar vessels are exposed to increased wall tensions concurrent with alveolar vessels suffering exposure to augmented shear stresses (due to decreased cross-sectional area and increased flow). Increases in shear stress and wall tension can occur in both alveolar and extra-alveolar vessels.20 Moreover, during positive mechanical ventilation in transplantation surgery, the chest is opened and transmural pressure is increased because pleural pressure becomes equal to atmospheric pressure; this additional mechanism can worsen the deleterious effects of high vascular flow in the first implanted graft. In acute lung injury, even high cardiac outflow has been suggested to be deleterious because of the consequences of increased pulmonary blood flow for lung injury. Indeed, cardiac output has been reported to favor the accumulation of extravascular lung water in experimental models of acute lung injury.21 Once the transplanted graft is edematous, it tends to collapse under its own weight and to develop dependent atelectasis, which can lead to cyclic opening and collapse, intensified shear stress, and a tendency for ventilator-induced lung injury in dependent areas.22,23 Moreover, exudation of protein-rich fluid
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has the potential to inactivate surfactants, further altering membrane permeability, by increasing both surface tension and radial traction on pulmonary microvessels.23 Not all of the inflammatory proteins activated by CPB were measured in the present study, but postoperative oxygenation remained the most clinically relevant assessment of lung function between the 2 groups. Generally, the decision to use CPB is unpredictable.2,3 It can be based on the presence of preoperative pulmonary hypertension or when intraoperative factors make it necessary, such as hypoxemia, respiratory acidosis, or hemodynamic instability with pulmonary arterial pressure (PAP) elevation and right cardiac failure during onelung ventilation, or after pulmonary artery clamping. Therefore, CPB often is associated with more severe medical conditions. The use of CPB to limit high-pressure perfusion injuries has been proposed for many years24; however, the technology for CPB now has changed. Technologic developments, the use of improved biocompatible materials and equipment, advances in perfusion physiology, and education of personnel all have contributed to the increased safety of CPB. To date, the occurrence of CPB-induced acute lung injury is very low.25 In the present study, the short duration of CPB may have limited the potential deleterious effect of CPB compared to when CPB is carried out during the entire surgical procedure. The use of CPB was not associated with any increase in ischemia time and did not significantly delay reperfusion of the second lung. Theoretically, the use of CPB may be associated with harmful effects. As effective anticoagulation is required, bleeding may be profuse, particularly when significant pleural adhesions are encountered. In the present study, the number of blood transfusions was similar in both groups. Under CPB, reventilation of the newly implanted lung can be carried out progressively with pressure-controlled ventilation using incremental levels of inspiratory air, and positive expiratory pressures with low FIO2, to obtain alveolar recruitment and limit oxygen toxicity. Reperfusion of the second lung also can be carried out very slowly without hemodynamic instability. Indeed, the CPB reservoir is useful and limits inadequate blood volume, due to loss of blood from the extracted lung after removal of the pulmonary artery clamp from the newly implanted graft. Consequently, packed red blood cells and fresh frozen plasma often are transfused, not only because of hemodilution, low hematocrit, or bleeding, but also to achieve volume requirements by compensating for lost blood from the extracted lung, thereby maintaining hemodynamic stability. Concerning CPB flow, the use of ETCO2 and pulmonary venous return on transesophageal echocardiography allowed the authors to find the best value adapted for each patient. As shown in Fig 3, ETCO2 of the first implanted lung was very sensitive to any small variations in CPB flow; a CPB flow of 42.5 L/min/m2 led to ETCO2 levels close to 0, with almost no pulmonary venous return and the risk of warm ischemia. Veno-arterial ECMO has been proposed to replace CPB during DLT.25,26 ECMO has several potential advantages, such as less hemolysis and less heparin use. In a study in which no pump suckers were available, the intraoperative use of ECMO was associated with a significant increase in blood transfusions.26 It was thought that the negative effects of multiple blood
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transfusions in patients who underwent ECMO may have contributed to the extended ventilatory times, infectious complications, and mortality rates compared with the CPB-supported lung transplantation surgeries. The CPB reservoir and pump suckers are useful in cases of severe hemorrhage, whereas management of arterio-venous ECMO can be difficult. Moreover, the CPB reservoir with a roller pump is very efficient in aspirating pulmonary blood from the right atrium and can control precisely the right ventricle preload, which limits high-flow highpressure injuries. Indeed, in patients with normal cardiac function (eg, patients with cystic fibrosis), centrifugal pumps often are unable to sufficiently decrease right ventricular preload and, therefore, pulmonary blood flow, because central venous pressure remains 45 cmH2O during ECMO. Moreover, with a roller pump, it is possible to adapt CBP flow rate very precisely to ETCO2 to avoid warm ischemia. However, Aigner et al have implemented ECMO as the standard of intraoperative extracorporeal support in patients who have undergone lung transplantation with good results depending on various indications.27 Therefore, CPB probably remains the standard support technique if extracorporeal circulatory support is indicated to precisely limit first implanted lung high-flow perfusion, in patients with normal cardiac function. The following points should be considered when assessing the clinical relevance of the authors’ results. This study was purely observational, and the use of CPB was not randomized and compared to a control group without CPB; such a study is required. The number of patients was small in the 2 groups because the authors had deliberately chosen a short period of time (2 years) to remove additional noncontrollable confusing factors, which would be associated during long periods of
practice. During that short period of time, the management in the operating room and in intensive care was unchanged. The endpoint was limited to oxygenation at 1 hour and 6 hours because additional noncontrollable confusing factors can be associated during long periods of care in such small groups of patients. Moreover, postoperative oxygenation remained the most objective, clinically relevant assessment of lung function between the 2 groups at the bedside. Although the rationale for the present study was based principally on the limitation of pulmonary arterial pressure and flow, these variables were not measured. Lastly, even if mean PaO2-to-FIO2 ratio at 1 hour in the group without CPB was similar to a previous study,3 there was a relatively large number of grade-3 PGDs in the control group. This explains why the authors decided, in 2009, to change the protocol and to use CPB systematically. However, when the 3 patients with grade-3 PGDs (PaO2/FIO2 ratio o100) who required ECMO in the group without CPB were not included in the analysis, the improvement in postoperative oxygenation remained almost significant with CPB. Indeed, CPB improved oxygenation even in those patients without clinical evidence of pulmonary edema. In conclusion, the premise that CPB will protect the first implanted lung is not new, but the authors’ results suggest that a protocol with the systematic use of CPB, after first graft implantation and before removal of the second recipient lung, improves oxygenation and limits the risk for high-flow highpressure vascular injuries and unpredictable severe pulmonary edema, for DPGs Z3, and the need for postoperative ECMOs. In addition, CPB with central cannulation via right anterior thoracotomy is feasible and not associated with further complications such as bleeding and blood transfusions.
REFERENCES 1. Sheridan BC, Hodges TN, Zamora MR, et al: Acute and chronic effects of bilateral lung transplantation without cardiopulmonary bypass on the first transplanted lung. Ann Thorac Surg 66: 1755-1758, 1998 2. Marczin N, Royston D, Yacoub M: Pro: Lung transplantation should be routinely performed with cardiopulmonary bypass. J Cardiothorac Vasc Anesth 14:739-745, 2000 3. McRae K: Con: Lung transplantation should not be routinely performed with cardiopulmonary bypass. J Cardiothorac Vasc Anesth 14:746-750, 2000 4. Triantafillou AN, Pasque MK, Huddleston CB, et al: Predictors, frequency, and indications for cardiopulmonary bypass during lung transplantation in adults. Ann Thorac Surg 57:1248-1251, 1994 5. Bracken CA, Gurkowski MA, Naples JJ: Lung transplantation: Historical perspective, current concepts, and anesthetic considerations. J Cardiothorac Vasc Anesth 11:220-241, 1997 6. Wan S, LeClerc JL, Vincent JL: Inflammatory response to cardiopulmonary bypass: Mechanisms involved and possible therapeutic strategies. Chest 112:676-692, 1997 7. Levy JH, Tanaka KA: Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg 75:S715-S720, 2003 8. Gammie JS, Cheul Lee J, Pham SM, et al: Cardiopulmonary bypass is associated with early allograft dysfunction but not death after double-lung transplantation. J Thorac Cardiovasc Surg 115: 990-997, 1998 9. Aeba R, Griffith BP, Kormos RL, et al: Effect of cardiopulmonary bypass on early graft dysfunction in clinical lung transplantation. Ann Thorac Surg 57:715-722, 1994
10. Szeto WY, Kreisel D, Karakousis GC, et al: Cardiopulmonary bypass for bilateral sequential lung transplantation in patients with chronic obstructive pulmonary disease without adverse effect on lung function or clinical outcome. J Thorac Cardiovasc Surg 124:241-249, 2002 11. King RC, Binns OA, Rodriguez F, et al: Reperfusion injury significantly impacts clinical outcome after pulmonary transplantation. Ann Thorac Surg 69:1681-1685, 2000 12. Thabut G, Mal H, Cerrina J, et al: Graft ischemic time and outcome of lung transplantation: A multicenter analysis. Am J Respir Crit Care Med 171:786-791, 2005 13. Boujoukos AJ, Martich GD, Vega JD, et al: Reperfusion injury in single-lung transplant recipients with pulmonary hypertension and emphysema. J Heart Lung Transplant 16:439-448, 1997 14. Halldorsson AO, Kronon MT, Allen BS, et al: Lowering reperfusion pressure reduces the injury after pulmonary ischemia. Ann Thorac Surg 69:198-203, 2000 15. Hopkinson DN, Bhabra MS, Odom NJ, et al: Controlled pressure reperfusion of rat pulmonary grafts yields improved function after twenty-four-hours’ cold storage in University of Wisconsin solution. J Heart Lung Transplant 15:283-290, 1996 16. Christie JD, Carby M, Bag R, et al: ISHLT Working Group on Primary Lung Graft Dysfunction. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part II: Definition. A consensus statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 24:1454-1459, 2005 17. Oto T, Rosenfeldt F, Rowland M, et al: Extracorporeal membrane oxygenation after lung transplantation: Evolving technique improves outcomes. Ann Thorac Surg 78:1230-1235, 2004
CPB DURING SECOND-LUNG IMPLANTATION
18. West JB, Dollery CT, Naimark A: Distribution of blood flow in isolated lung; relation to vascular and alveolar pressures. J Appl Physiol 19:713-724, 1964 19. Hotchkiss JR Jr, Blanch L, Naveira A, et al: Relative roles of vascular and airspace pressures in ventilator-induced lung injury. Crit Care Med 29:1593-1598, 2001 20. Broccard AF, Vannay C, Feihl F, et al: Impact of low pulmonary vascular pressure on ventilator-induced lung injury. Crit Care Med 30: 2183-2190, 2002 21. Broccard AF, Hotchkiss JR, Kuwayama N, et al: Consequences of vascular flow on lung injury induced by mechanical ventilation. Am J Respir Crit Care Med 157:1935-1942, 1998 22. Mead J, Takishima T, Leith D: Stress distribution in lungs: A model of pulmonary elasticity. J Appl Physiol 28:596-608, 1970
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23. Ricard JD, Dreyfuss D, Saumon G: Ventilator-induced lung injury. Curr Opin Crit Care 8:12-20, 2002 24. Hasan A, Corris PA, Healy M, et al: Bilateral sequential lung transplantation for end stage septic lung disease. Thorax 50: 565-566, 1995 25. Asimakopoulos G, Taylor KM, Smith PL, et al: Prevalence of acute respiratory distress syndrome after cardiac surgery. J Thorac Cardiovasc Surg 117:620-621, 1999 26. Bittner HB, Binner C, Lehmann S, et al: Replacing cardiopulmonary bypass with extracorporeal membrane oxygenation in lung transplantation operations. Eur J Cardiothorac Surg 31:462-467, 2007 27. Aigner C, Wisser W, Taghavi S, et al: Institutional experience with extracorporeal membrane oxygenation in lung transplantation. Eur J Cardiothorac Surg 31:468-473, 2007
implantation of the second lung was associated with an increased mean postoperative ratio of PaO2 to the fraction of inspired oxygen at 1 hour (363 ⫾ 51 v 240 ⫾ 113, p ¼ 0.01) and 6 hours (430 ⫾ 111 v 280 ⫾ 103, p ¼ 0.03). The mean duration of CPB was 111 ⫾ 19 min. The occurrence of primary graft dysfunction and the need for extracorporeal membrane oxygenation tended to be lower, but did not reach significance. Similarly, mortality rate was comparable between both groups, as was the rate of blood transfusions. Conclusions: The authors’ results suggest that the use of CPB started after first graft implantation and before second recipient lung removal appears to benefit oxygenation and reduces the occurrence of severe pulmonary edema in the first transplanted lung. & 2013 Elsevier Inc. All rights reserved.
D
need for extracorporeal membrane oxygenation (ECMO),17 although these injuries do not occur in all patients. Moreover, preoperative variables are able to predict severe high-flow highpressure injuries. Pulmonary edema often appears late; it may be clinically symptomatic at the end of the second-lung implantation, and initially concerns the first implanted lung where total ischemic time was shorter. Based on all these considerations, CPB may be used systematically before implantation of the second lung to limit pulmonary perfusion flow and pressure by splitting the cardiac output between the CPB and the first implanted graft. The authors tested the hypothesis that sequential bipulmonary
OUBLE-LUNG TRANSPLANTATION (DLT) has become an established therapy for end-stage lung disease, and it was performed initially with airway anastomosis at the tracheal bifurcation under cardiopulmonary bypass (CPB). However, the complications related to ischemia of the bronchi and trachea around the carina prompted adoption of sequential single-lung implantations as the method of choice for DLT. The use of CPB has decreased dramatically over the last 2 decades, and primarily has been required in the presence of preoperative pulmonary hypertension, severe hypoxemia or hypercapnia or both, elevation of pulmonary-arterial hypertension, and reduction in cardiac index during one-lung ventilation.1-4 In the setting of lung transplantation, CPB may be responsible for acute lung injury and allograft dysfunction by inducing complement activation, endotoxin release, leukocyte activation, and expression of adhesion molecules.5-8 There has been significant progress in the technology of CPB, but potentially harmful effects of CPB during lung transplantation remain controversial. A retrospective study including patients with chronic obstructive pulmonary disease who required a lung transplantation reported deleterious effects on early graft function or adverse clinical outcomes when CPB was used.9 During routine bilateral lung transplantation, the first implanted lung receives the entire cardiac output during the implantation of the second lung. This results in increased blood flow and pulmonary arterial pressure.14 This may lead to high-flow high-pressure reperfusion injuries with severe interstitial and alveolar edema, as well as endothelial damage as a result of increased shear stress. Therefore, lowering reperfusion pressure can reduce injury after pulmonary ischemia and improve pulmonary function.13-15 The clinical consequence is primary graft dysfunction16 with severe post-transplantation hypoxemia and the
KEY WORDS: lung transplantation, cardiopulmonary bypass, postoperative oxygenation
From the *CHU de Bordeaux, Service d’Anesthe´sie-Re´animation II, Pessac, France, yUniv. Bordeaux, Adaptation cardiovasculaire a l’ische´mie, U1034, F-33600, Pessac, France, zINSERM, Adaptation cardiovasculaire a l’ische´mie, U1034, F-33600, Pessac, France, yCHU de Bordeaux, Service de Chirurgie Thoracique, Bordeaux, France, JINSERM, Centre de Recherche Cardio-thoracique de Bordeaux, U1034, F-33600, Bordeaux, France, zCHU de Bordeaux, Service de Chirurgie Cardiaque, Bordeaux, France; and #CHU de Bordeaux, Service de Pneumologie, Bordeaux, France. This study was presented in part at the 2011 Annual Meeting of the International Society of Heart and Lung Transplantation, San Diego, USA, April 17, 2011. Address reprint requests to Hadrien Roze´, MD, Service d’Anesthe´sieRe´animation 2, Hˆopital du Haut-Le´vˆeque, CHU de Bordeaux, Avenue Magellan, 33604 Pessac, France. E-mail: [email protected] & 2013 Elsevier Inc. All rights reserved. 1053-0770/2601-0001$36.00/0 http://dx.doi.org/10.1053/j.jvca.2012.11.005
Journal of Cardiothoracic and Vascular Anesthesia, Vol 27, No 3 (June), 2013: pp 467–473
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transplantation using CPB, initiated after first graft implantation and before removal of the second recipient lung, improves postoperative oxygenation and clinical outcomes. METHODS
This study was approved by the authors’ Lung Transplant Evaluation Committee and retrospectively included patients undergoing sequential DLT by comparing 2 consecutive 1-year periods between 2008 and 2010. Data were collected retrospectively and did not modify any care of patients, conformed to the standard procedures currently used in the authors’ institution, and informed consent was obtained from all patients. All patients in whom CPB was initiated before removal of the second recipient lung (from January 2009January 2010) were compared to a control group in whom CPB was not performed before removal of the second recipient lung (from January 2008-December 2008). To limit bias, the authors decided to compare the 2 groups during a short period, limited to 1 year for each group, with and without CPB. During the 2 years, patients who were placed on CPB before the first implantation were excluded from the analysis. General Conditions Anesthesia included propofol, administered by targetcontrolled intravenous anesthesia protocols, and sufentanil, and atracurium. A central venous catheter was inserted and the saturation of central venous oxygenation was monitored. Arterial pressure was monitored invasively through a radialartery catheter. Finally, transesophageal echocardiography was used systematically. A double-lumen tube was placed to allow isolated lung ventilation. Protective ventilation was used with a low tidal volume of 5 mL/kg of donor ideal body weight and low plateau pressure o 26 cm H20, 10 cm H2O of positive expiratory pressure was maintained (Fig 1), and nitric oxide was inhaled at 10 ppm. End-expiratory carbon dioxide (ETCO2) was monitored continuously. Intraoperative hemodynamic instability was corrected by fluids or infusion of norepinephrine or both. Ventilation of the transplanted lung was carried out progressively over 15 minutes with FIO2 o50% and pressurecontrolled ventilation with a plateau pressure o26 cmH20. A cell saver was used systematically. Immunosuppressive therapy, started after surgery, remained the same during the 2-year period and consisted of a triple regimen of glucocorticoids, cyclosporine, and mycophenolate mofetil. Surgical Procedure Lung harvesting Conditions of organ acceptance from the donor for transplantation remained the same during the study period and were based on commonly published criteria. Techniques for preservation during harvesting included intravenous heparin (300 IU/kg) and prostaglandin (20 mg) through the pulmonary artery, followed by an anterograde low-pressure (20 cmH2O) flush of perfadex (50 mL/kg), and a retrograde flush of perfadex (1 L) through the pulmonary veins. The lungs were conditioned in an inflated state in a cooled (41C) sterile bag for transport. Before implantation, a redo retrograde flush of perfadex (1 L for both lungs) was performed. During first-graft
Fig 1. Ventilatory settings during cardiopulmonary bypass (CPB) and ventilation of the first implanted lung. Protective ventilation with low VT of 230 mL, 10 cmH2O of PEP, and low respiratory frequency; the curve at the bottom represents ETCO2 with a value of 17.6 mmHg.
implantation, the second lung was stored in a sterile bag with perfadex and covered with ice slush. On-pump transplant procedure Perioperative heparin was given at 300 units/kg to maintain an activated coagulation time of 4450 seconds during the procedure. All patients had bilateral anterolateral thoracotomies without transverse sternotomy. CPB was established. The extracorporeal circuit of the CPB consisted of an open system with a nonheparin-coated tube system. A 1-stage cannula (3240 F) (Medtronic) was used to drain the venous blood from the right atrium, along with a 22-F aortic cannula (Stockert) for the distal ascending aorta. Vessel access always was performed through the right thoracotomy after a straight 10-cm pericardiotomy performed 2 cm above the right phrenic nerve. An umbilical tape encircled the ascending aorta if its right retraction was needed for arterial cannulation. The system was primed with 500 mL of Ringer’s lactate, 800 mL of hydroxy-ethyl-amidon, and 150 mL of 20% mannitol. Heparin (4,000 units) was added to the prime volume. A nonpulsatile HL-30 roller pump (Stockert) established blood flow to maintain partial perfusion of the first implanted graft and limit warm ischemia (Fig 1). CPB was established after slow reperfusion of the first implanted graft and before clamping of the contralateral pulmonary artery. To avoid contamination, pump suckers were turned off when the bronchus was opened. Blood was saved and collected in an open cardiotomy reservoir and transfused back to the patient. In this surgical group, an Apex (Stockert) oxygenator was used. During all the procedures, hematocrit was maintained between 25% and 28%, and the minimal rectal temperature was 361C. Off-pump transplant procedure Perioperative heparin was given at 100 units/kg, and all patients were given bilateral anterolateral thoracotomies without a transverse sternotomy (as above).
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CPB DURING SECOND-LUNG IMPLANTATION
Comparison between continuous varibles was performed using the Student’s t-test or Mann-Whitney U test as appropriate. Comparison between categoric variables was performed using the chi-squared test. All p-values were 2-tailed. A p value o0.05 was considered to eliminate the null hypothesis. Statistical analysis was performed using NCSS 2007 software (Statistical Solutions Ltd, Cork, Ireland). RESULTS
Fig 2. Postoperative ratio of the partial pressure of oxygen in arterial blood (PaO2) to the inspired oxygen fraction (FIO2), at 1 hour and 6 hours, in patients who had (white box) or did not have (gray box) cardiopulmonary bypass during a double-lung transplant. Lines within boxes represent median values. Upper and lower lines of boxes represent 25th and 75th percentiles, respectively. Upper and lower bars outside of boxes represent 95th and 5th percentiles, respectively. Black squares represent mean values.
Transplant procedure The lung with the lowest preoperative perfusion was explanted first. A thoracic surgeon explanted the lungs and performed bronchial anastomosis while a cardiac surgeon performed the vascular anastomosis. Standardized organ procurement and recipient-implantation techniques were utilized for the lung transplantation. The preservation solution was infused via the donor pulmonary artery at low pressure in an antegrade fashion immediately following intrapulmonary injection of prostaglandin. The DLT was performed using a sequential single-lung implantation procedure. Once the donor’s lung was present in the operating room, the recipient’s pneumonectomy was completed. Bronchial anastomosis was accomplished first and was followed by the left atrial cuff and pulmonary artery anastomoses using a continuous suture. Lung reperfusion was slow, with retrograde back blood flow from vein to pulmonary artery. Data Collection Assessment of early allograft function included a postoperative chest radiograph at the end of the procedure, with a bronchoscopy and arterial blood-gas analysis at 1 hour and 6 hours after surgery. Transfusion requirements, in terms of packed red blood cells, fresh frozen plasma, and platelets, were compared by reviewing blood bank records. The 1-year mortality rate was compared to examine intermediate-term clinical outcomes. Primary graft dysfunction (PGD) was defined according to the published International Society for Heart and Lung Transplantation classification.19 Statistical Analyses Data are expressed as means ⫾ standard deviations (SDs) for normally distributed continuous variables, as medians (interquartile range) for non-normally distributed continuous variables, and as numbers (percentage of patients) for categoric data. The normal distribution of continuous variables was assessed using skewness and kurtosis statistical tests.
During the first period (from January 2008-December 2008), 10 patients who underwent sequential DLT without CPB were studied (without CPB group). Additionally, 2 patients had CPB because of pulmonary arterial hypertension. During the second period (from January 2009-January 2010), 9 patients had sequential DLT, using CPB before extraction of the second recipient lung (with CPB group). During this period, 1 patient with pulmonary arterial hypertension and 3 with hemodynamic instability and hypoxemia had CPB after the beginning of surgery and, thus, were excluded from this study. The duration of the CPB in this group was 111 ⫾ 19 min. The CPB group of patients was compared with patients in whom the surgery was performed without CPB (Tables 1 and 2). Postoperative oxygenation was significantly higher in patients in whom surgery was performed under CPB (Fig 2). In patients without grade-3 PGD, the improvement in postoperative oxygenation at H þ 1 with CPB was almost significant (p ¼ 0.06). During transplantation, there were no significant differences in ischemic and surgery time between groups; CPB did not increase blood transfusion, vasopressor use, or postoperative lactate levels (Table 3), and there was no mismatch in size. DISCUSSION
The principal findings of the present study are that postoperative oxygenation, at 1 hour and 6 hours after lung transplantation, was improved significantly when CPB was used during the second-lung implantation. In the control group, without CPB, 3 patients (2 with cystic fibrosis, 1 with bronchiectasis) had early PGD with severe pulmonary edema, which occurred in the first implanted graft at the end of the second-graft implantation. These 3 patients had no preoperative pulmonary arterial hypertension, no mismatch in size; hemodynamic and oxygenation remained stable during the implantation of the first graft, and bleeding was controlled, except for 1 patient who had 12 units of packed red blood cells. This edema occurred between 40 and 60 min after pulmonary artery clamping, whereas hemodynamic levels were stable, and PaO2/FIO2 initially was Table 1. Diagnoses of Patients in the Study Diagnosis
Cystic fibrosis COPD Lymphangioleiomyomatosis Bronchiectasis Graft v host disease Bronchiolitis obliterans
Without CPB (n ¼ 10)
With CPB (n ¼ 9)
6 1 1 1 1 0
4 2 0 2 0 1
Abbreviations: COPD, chronic obstructive pulmonary disease; CPB, cardiopulmonary bypass.
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Table 2. Preoperative Patient Characteristics Variables
Age, y Sex (F) Body weight, kg Height, cm Emergency transplantation Retransplantation Donor PaO2/FIO2 Donor age, y
Without CPB (n ¼10)
With CPB (n ¼ 9)
p Value
39 ⫾ 13 5 (56%) 52 ⫾ 7 167 ⫾ 11 4 (44%) 2 (22%) 421 ⫾ 133 45 ⫾ 12
0.20 0.65 0.31 0.28 0.35 0.21 0.79 0.07
31 ⫾ 14 7 (70%) 48 ⫾ 8 162 ⫾ 8 2 (20%) 0 (0%) 407 ⫾ 88 33 ⫾ 15
NOTE. Data are expressed as mean ⫾ SD or n (% of patients). Abbreviation: CPB, cardiopulmonary bypass.
increased after clamping because of the reduction of the shunt-like effect. Immediate graft dysfunction after pulmonary transplantation is believed to be a manifestation of ischemia-reperfusion (IR) injury. It has become apparent that IR injury may contribute significantly to recipient morbidity, with increased utilization of critical care resources, as well as longer intensive care unit and hospital stays.10 Reperfusion injury is thought to be due to either inadequate preservation techniques or prolonged graft ischemia before implantation.11 Other reports have confirmed an increased incidence of clinically significant IR injuries in recipients with preoperative pulmonary artery hypertension.12 The improvement in oxygenation that the authors observed suggested that pulmonary vasculature was protected from high-flow highpressure injury from the first implanted graft by the use of CPB, which seemed to be more important than its potential deleterious effects in terms of inflammatory activation and acute
lung injury. The use of CPB could limit pulmonary vascular injury, as well as ventilation-induced lung injury in the first implanted graft. Indeed, CPB allowed the authors to ventilate patients with a very protective strategy that included low tidal volume, low plateau pressure, low respiratory frequency, low inspiratory oxygen fraction, and significant positive end-expiratory pressure. Both alveolar and vascular injuries are responsible for capillary–alveolar barrier fracture. Indeed, Laplace’s law predicts that elevations in transmural pressure gradients will increase vessel wall tension and that overdistended vessels that have a larger diameter will experience the highest levels of wall tension. High flow can distend small vessels and accentuate the wall tension generated by cyclic increases in downstream resistance caused by lung inflation. Thus, high vascular flow might increase both shear stress and capillary wall tension, potentially both triggering an injurious inflammatory response of the
Table 3. Perioperative Characteristics of Patients Variables
Surgery time, min Ischemic time, min Packed red blood cells, unit Redo Surgery Postoperative at H þ 1 VT, mL RR, cycle/min PEEP, cmH20 FIO2, % Norepinephrine (n) Norepinephrine, mg/kg/min Lactate level, mmol/L Postoperative H þ 48 pH PaO2, mmHg PaCO2, mmHg HCO3, mmol/L Intubated PGD Z 3 requiring ECMO One-year mortality
Without CPB (n ¼ 10)
With CPB (n ¼ 9)
p Value
488 ⫾ 85 432 ⫾ 74 6⫾3 3 (30%)
478 ⫾ 70 391 ⫾ 61 8⫾3 1 (11%)
0.78 0.21 0.27 0.31
372 ⫾ 77 19 ⫾ 3 6⫾2 67 ⫾ 23 6 0.53 [0.27-0.67] 3.9 [1.6-4.1]
396 ⫾ 44 18 ⫾ 4 7⫾2 48 ⫾ 10 4 0.14 [0.08-0.34] 2.0 [1.5-4.2]
0.47 0.85 0.65 0.06 0.07 0.38 0.81
7.38 ⫾ 0.04 90 ⫾ 34 42 ⫾ 5 24.9 ⫾ 2.8 4 (40%) 3 (30%) 2 (20%)
7.36 ⫾ 0.06 143⫾ 76 52 ⫾ 13* 29.5 ⫾ 3.8* 2 (20%) 0 (0%) 0
0.57 0.08 0.05 0.01 0.30 0.07 0.47
NOTE. Data are expressed as mean ⫾ SD or median (IQR) or n (% of patients); p value refers to between-groups comparisons. Surgery time is time spent between incision and skin closure. Abbreviations: CPB, cardiopulmonary bypass; Ischemic time, ischemic time of the last implanted graft; VT, tidal volume; RR, respiratory rhythm; PEEP, positive end-expiratory pressure; FIO2, oxygen inspiratory fraction; PaO2, arterial oxygen tension, PaCO2, carbon dioxide tension. HCO3, bicarbonate; PGD, primary graft dysfunction; ECMO, extracorporeal membrane oxygenation. *po0.05.
CPB DURING SECOND-LUNG IMPLANTATION
Fig 3. Transesophageal echocardiography representing a pulse Doppler of the right lower pulmonary vein in the first implanted lung during cardiopulmonary bypass (CPB). Difference between 2 different CPB cardiac indices (CI) regarding pulmonary venous return and ETCO2 during implantation of the second lung. Upper half of the figure, ETCO2 is low at 8 mmHg with a CI of 2 L/min/m2and almost no venous return; lower half of the figure, CI has been reduced slightly at 1.8 L/min/m2 to increase venous return and ETCO2 to 15 mmHg.
endothelium and inducing capillary–alveolar barrier fracture by direct mechanic stress. Moreover, this concept is experimentally produced in case of sequential double-lobe transplantation in which the vascular network volume of each graft is reduced. In acute lung injury models, increasing lung volume decreases the increased pressure experienced by alveolar vessels while they expand to that of exposed extra-alveolar vessels.18 As a result, extra-alveolar vessels tend to expand during tidal inflation, whereas alveolar vessels are compressed and decrease in diameter.19 Consequently, extra-alveolar vessels are exposed to increased wall tensions concurrent with alveolar vessels suffering exposure to augmented shear stresses (due to decreased cross-sectional area and increased flow). Increases in shear stress and wall tension can occur in both alveolar and extra-alveolar vessels.20 Moreover, during positive mechanical ventilation in transplantation surgery, the chest is opened and transmural pressure is increased because pleural pressure becomes equal to atmospheric pressure; this additional mechanism can worsen the deleterious effects of high vascular flow in the first implanted graft. In acute lung injury, even high cardiac outflow has been suggested to be deleterious because of the consequences of increased pulmonary blood flow for lung injury. Indeed, cardiac output has been reported to favor the accumulation of extravascular lung water in experimental models of acute lung injury.21 Once the transplanted graft is edematous, it tends to collapse under its own weight and to develop dependent atelectasis, which can lead to cyclic opening and collapse, intensified shear stress, and a tendency for ventilator-induced lung injury in dependent areas.22,23 Moreover, exudation of protein-rich fluid
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has the potential to inactivate surfactants, further altering membrane permeability, by increasing both surface tension and radial traction on pulmonary microvessels.23 Not all of the inflammatory proteins activated by CPB were measured in the present study, but postoperative oxygenation remained the most clinically relevant assessment of lung function between the 2 groups. Generally, the decision to use CPB is unpredictable.2,3 It can be based on the presence of preoperative pulmonary hypertension or when intraoperative factors make it necessary, such as hypoxemia, respiratory acidosis, or hemodynamic instability with pulmonary arterial pressure (PAP) elevation and right cardiac failure during onelung ventilation, or after pulmonary artery clamping. Therefore, CPB often is associated with more severe medical conditions. The use of CPB to limit high-pressure perfusion injuries has been proposed for many years24; however, the technology for CPB now has changed. Technologic developments, the use of improved biocompatible materials and equipment, advances in perfusion physiology, and education of personnel all have contributed to the increased safety of CPB. To date, the occurrence of CPB-induced acute lung injury is very low.25 In the present study, the short duration of CPB may have limited the potential deleterious effect of CPB compared to when CPB is carried out during the entire surgical procedure. The use of CPB was not associated with any increase in ischemia time and did not significantly delay reperfusion of the second lung. Theoretically, the use of CPB may be associated with harmful effects. As effective anticoagulation is required, bleeding may be profuse, particularly when significant pleural adhesions are encountered. In the present study, the number of blood transfusions was similar in both groups. Under CPB, reventilation of the newly implanted lung can be carried out progressively with pressure-controlled ventilation using incremental levels of inspiratory air, and positive expiratory pressures with low FIO2, to obtain alveolar recruitment and limit oxygen toxicity. Reperfusion of the second lung also can be carried out very slowly without hemodynamic instability. Indeed, the CPB reservoir is useful and limits inadequate blood volume, due to loss of blood from the extracted lung after removal of the pulmonary artery clamp from the newly implanted graft. Consequently, packed red blood cells and fresh frozen plasma often are transfused, not only because of hemodilution, low hematocrit, or bleeding, but also to achieve volume requirements by compensating for lost blood from the extracted lung, thereby maintaining hemodynamic stability. Concerning CPB flow, the use of ETCO2 and pulmonary venous return on transesophageal echocardiography allowed the authors to find the best value adapted for each patient. As shown in Fig 3, ETCO2 of the first implanted lung was very sensitive to any small variations in CPB flow; a CPB flow of 42.5 L/min/m2 led to ETCO2 levels close to 0, with almost no pulmonary venous return and the risk of warm ischemia. Veno-arterial ECMO has been proposed to replace CPB during DLT.25,26 ECMO has several potential advantages, such as less hemolysis and less heparin use. In a study in which no pump suckers were available, the intraoperative use of ECMO was associated with a significant increase in blood transfusions.26 It was thought that the negative effects of multiple blood
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transfusions in patients who underwent ECMO may have contributed to the extended ventilatory times, infectious complications, and mortality rates compared with the CPB-supported lung transplantation surgeries. The CPB reservoir and pump suckers are useful in cases of severe hemorrhage, whereas management of arterio-venous ECMO can be difficult. Moreover, the CPB reservoir with a roller pump is very efficient in aspirating pulmonary blood from the right atrium and can control precisely the right ventricle preload, which limits high-flow highpressure injuries. Indeed, in patients with normal cardiac function (eg, patients with cystic fibrosis), centrifugal pumps often are unable to sufficiently decrease right ventricular preload and, therefore, pulmonary blood flow, because central venous pressure remains 45 cmH2O during ECMO. Moreover, with a roller pump, it is possible to adapt CBP flow rate very precisely to ETCO2 to avoid warm ischemia. However, Aigner et al have implemented ECMO as the standard of intraoperative extracorporeal support in patients who have undergone lung transplantation with good results depending on various indications.27 Therefore, CPB probably remains the standard support technique if extracorporeal circulatory support is indicated to precisely limit first implanted lung high-flow perfusion, in patients with normal cardiac function. The following points should be considered when assessing the clinical relevance of the authors’ results. This study was purely observational, and the use of CPB was not randomized and compared to a control group without CPB; such a study is required. The number of patients was small in the 2 groups because the authors had deliberately chosen a short period of time (2 years) to remove additional noncontrollable confusing factors, which would be associated during long periods of
practice. During that short period of time, the management in the operating room and in intensive care was unchanged. The endpoint was limited to oxygenation at 1 hour and 6 hours because additional noncontrollable confusing factors can be associated during long periods of care in such small groups of patients. Moreover, postoperative oxygenation remained the most objective, clinically relevant assessment of lung function between the 2 groups at the bedside. Although the rationale for the present study was based principally on the limitation of pulmonary arterial pressure and flow, these variables were not measured. Lastly, even if mean PaO2-to-FIO2 ratio at 1 hour in the group without CPB was similar to a previous study,3 there was a relatively large number of grade-3 PGDs in the control group. This explains why the authors decided, in 2009, to change the protocol and to use CPB systematically. However, when the 3 patients with grade-3 PGDs (PaO2/FIO2 ratio o100) who required ECMO in the group without CPB were not included in the analysis, the improvement in postoperative oxygenation remained almost significant with CPB. Indeed, CPB improved oxygenation even in those patients without clinical evidence of pulmonary edema. In conclusion, the premise that CPB will protect the first implanted lung is not new, but the authors’ results suggest that a protocol with the systematic use of CPB, after first graft implantation and before removal of the second recipient lung, improves oxygenation and limits the risk for high-flow highpressure vascular injuries and unpredictable severe pulmonary edema, for DPGs Z3, and the need for postoperative ECMOs. In addition, CPB with central cannulation via right anterior thoracotomy is feasible and not associated with further complications such as bleeding and blood transfusions.
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18. West JB, Dollery CT, Naimark A: Distribution of blood flow in isolated lung; relation to vascular and alveolar pressures. J Appl Physiol 19:713-724, 1964 19. Hotchkiss JR Jr, Blanch L, Naveira A, et al: Relative roles of vascular and airspace pressures in ventilator-induced lung injury. Crit Care Med 29:1593-1598, 2001 20. Broccard AF, Vannay C, Feihl F, et al: Impact of low pulmonary vascular pressure on ventilator-induced lung injury. Crit Care Med 30: 2183-2190, 2002 21. Broccard AF, Hotchkiss JR, Kuwayama N, et al: Consequences of vascular flow on lung injury induced by mechanical ventilation. Am J Respir Crit Care Med 157:1935-1942, 1998 22. Mead J, Takishima T, Leith D: Stress distribution in lungs: A model of pulmonary elasticity. J Appl Physiol 28:596-608, 1970
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23. Ricard JD, Dreyfuss D, Saumon G: Ventilator-induced lung injury. Curr Opin Crit Care 8:12-20, 2002 24. Hasan A, Corris PA, Healy M, et al: Bilateral sequential lung transplantation for end stage septic lung disease. Thorax 50: 565-566, 1995 25. Asimakopoulos G, Taylor KM, Smith PL, et al: Prevalence of acute respiratory distress syndrome after cardiac surgery. J Thorac Cardiovasc Surg 117:620-621, 1999 26. Bittner HB, Binner C, Lehmann S, et al: Replacing cardiopulmonary bypass with extracorporeal membrane oxygenation in lung transplantation operations. Eur J Cardiothorac Surg 31:462-467, 2007 27. Aigner C, Wisser W, Taghavi S, et al: Institutional experience with extracorporeal membrane oxygenation in lung transplantation. Eur J Cardiothorac Surg 31:468-473, 2007