The clinical records of all consecutive patients undergoing LT at Transplant Centre of Policlinico Umberto I, University of Rome “Sapienza”, Rome, Italy, between November 2007 and March 2014, were retrieved with the approval of the Ethical Committee of Policlinico Umberto I (Protocol Number 756/13). Patients were categorized according to the clinical conditions into 3 groups: “high”, “low,” and “intermediate” intraoperative severity. Patients receiving preoperatively extracorporeal lung support (ECMO or ECCO2R) as a bridge to transplant, those undergoing re-transplant or those who developed intraoperative severe acute hypoxemia (PaO2/FiO2 ≤150) or hemodynamic instability (mean arterial pressure (MAP) ≤ 60 mmHg and Cardiac Index (CI) ≤ 2.5 L/min/m2, despite vasopressors infusion) were considered “high severity” and excluded from data analysis. Patients that intraoperatively maintained respiratory stability (i.e., pH ≥7.25, PaCO2 ≤60 mmHg, and PaO2/FiO2 >150) were considered “low risk” and excluded from this data analysis. Patients that developed intraoperative severe respiratory acidosis with maintained oxygenation function (i.e., pH <7.25, PaCO2 >60 mmHg, and PaO2/FiO2 >150), not associated with hemodynamic instability, were considered at “intermediate” intraoperative severity and their data were selectively analyzed. Data from patients presenting “intermediate” intraoperative severity treated between in the intervals 2007–2010 or 2011–2014 were analyzed as a historical comparison of case-matched cohort. Patients with “intermediate” intraoperative severity treated in the 2007–2010 interval received “standard intraoperative treatment” as compared with those treated in the 2011–2014 interval that received “standard intraoperative treatment + ECCO2R.”
For both groups, “standard intraoperative treatment” included protective mechanical ventilation, permissive hypercapnia ≤60 mmHg, and inhaled nitric oxide or a continuous infusion of prostaglandin. Pressure controlled mechanical ventilation (Zeus® Infinity® Dräger, Germany) was set in order to achieve a tidal volume (TV) of 6–8 ml/kg, a plateau pressure <30 cmH2O, pulmonary end-expiratory pressure (PEEP) 6–8 cmH2O, and FiO2 up to obtain peripheral oxygen saturation (SpO2) >90% [15–17].
Dobutamine and norepinephrine were titrated to maintain a CI ≥2.5 L/min/m2 and a MAP ≥60mmHg. To reduce pulmonary hypertension and to avoid lung ischemic-reperfusion damages, inhaled nitric oxide (iNO) 10–20 ppm was administered (Optikinox® Air Liquide, France) along with prostaglandin E2 continuous intravenous administration at 10–20 ng/kg/min rate . Anemia was treated with red blood cell pack transfusion, for hemoglobin values <9 g/dl. Patients who developed severe intraoperative hypoxemia (PaO2/FiO2 ≤150) or persistent severe respiratory acidosis (i.e., pH <7.25, PaCO2 >60 mmHg) received intraoperative ECMO. When ECMO was initiated during surgery, venous-arterial RotaFlow® (Maquet, Hirrlingen, Germany) was used after femoral artery and vein cannulation: the vein cannula was inserted using percutaneous Seldinger technique and the arterial with surgical preparation. Extracorporeal blood flow was started at 30% of CI. It was then modified according to hemodynamic parameters.
In patients undergoing LT during the 2011–2014 period and presenting “intermediate” clinical severity (i.e., pH <7.25, PaCO2 >60 mmHg, and PaO2/FiO2 >150), CO2 removal was achieved using ECCO2R (Prolung® device, Estor). The femoral or jugular vein was accessed via a double lumen catheter (14 F; Arrow International Inc. Reading PA) inserted and connected to the extracorporeal circuit. Blood flow was driven through the circuit by a non-occlusive low flow roller pump (80–350 ml/min) through a polimethylpentene oxygenator cartridge membrane connected to an 8 L/min sweep gas flow source delivering FiO2 1.0 oxygen.
The ECCO2R treatment was started at the intraoperative development of severe respiratory acidosis with maintained oxygenation function (i.e., pH <7.25, PaCO2 >60 mmHg, and PaO2/FiO2 >150) that always occurred after the beginning of the first OLV and before the clamping of the pulmonary artery.
Heparin continuous infusion administration of 10–15 IU/kg/h was used as an anticoagulant to maintain activated clotting time (ACT) between 120 and 150s in patients undergoing ECCO2R, while in patients undergoing ECO our anticoagulation target was an ACT between 180 and 200s with an activated partial thromboplastin Time (aPTT) ratio >2.
The following variables were recorded in all patients: MAP, heart rate (HR), mPAP, CI (Vigilance®, Edwards Lifescienses System), central venous pressure (CVP), mixed O2 venous saturation (SvO2), CO2 end-tidal (EtCO2), SpO2, body temperature, and diuresis. The primary endpoint was the emergency ECMO requirement in the 2 groups. Secondary endpoints were efficacy of ECCO2R measured as changes in blood gas analysis (BGA) and impact on systemic and pulmonary hemodynamic (i.e., MAP, HR, and mPAP) recorded every 20 min after the beginning of CO2 removal and throughout the intraoperative period. Length of intensive care unit (ICU) stay, duration of postoperative mechanical ventilation, and mortality at 30 postoperative days were also recorded. Complications related to ECCO2R use were also recorded, including mechanical complications due to circuit components or pump malfunction and patient-related complications: vascular damages, bleeding, hemodynamic instability, myocardial dysfunction, or cardiac arrhythmias and intravascular embolism.
Continuous variables were described by medians (interquartile ranges) or mean (standard deviation) as appropriate. SPSS Software (IBM) was used for statistical analysis. To evaluate differences between the 2 groups, Fisher’s exact test and χ2 test with 95% confidence intervals for categorical variables was used; Student’s t test was used to analyze continuous variables. Statistical significance was set at a p value lower than 0.05 for all variables. Assuming that 20% of the subjects in the reference population have the factor of interest, and after applying continuity correction, the study would require a sample size of 15 for each group (i.e., a total sample size of 30, assuming equal group sizes), to achieve a power of 80% for detecting a difference in proportions of 0.6 between the two groups (test - reference group) at a two-sided p value of 0.05.