Shahrokh Taghavi

Primary Lung Transplantation After Bridge With Extracorporeal Membrane Oxygenation: A Plea for a Shift in Our Paradigms for Indications

Background. The introduction of the lung allocation score has brought lung transplantation (LTX) of patients on extracorporeal membrane oxygenation (ECMO) bridge into the focus of interest. We reviewed our institutional experience with ECMO as a bridge to LTX. Methods. Between 1998 and 2011, 38 patients (median age 30.1 years, range 13–66 years) underwent ECMO support with intention to bridge to primary LTX. The underlying diagnosis was cystic fibrosis (n=17), pulmonary hypertension (n=4), idiopathic pulmonary fibrosis (n=9), adult respiratory distress syndrome (n=4), hemosiderosis (n=1), bronchiolitis obliterans (n=1), sarcoidosis (n=1), and bronchiectasis (n=1). The type of extracorporeal bridge was venovenous (n=18), venoarterial (n=15), interventional lung assist (n=1), or a stepwise combination of them (n=4). The median bridging time was 5.5 days (range 1–63) days. The type of transplantation was double LTX (n=7), size-reduced double LTX (n=8), lobar LTX (n=16), split LTX (n=2), and lobar LTX after ex vivo lung perfusion (n=1). Results. Four patients died before transplantation. Thirty-four patients underwent LTX, of them eight patients died in the hospital after a median stay of 24.5 days (range 1–180 days). Twenty-six patients left the hospital and returned to normal life (median hospital stay=47.5 days; range 21–90 days). The 1-, 3-, and 5-year survival for all transplanted patients was 60%, 60%, and 48%, respectively. The 1-, 3-, and 5-year survival conditional on 3-month survival for patients bridged with ECMO to LTX (78%, 78%, and 63%) was not worse than for other LTX patients within the same period of time (90%, 80%, and 72%, respectively, P=0.09, 0.505, and 0.344). Conclusion. Transplantation of patients bridged on ECMO to LTX is feasible and results in acceptable outcome.

Pulmonary Retransplantation: Is it Worth the Effort? A Long-term Analysis of 46 Cases

BACKGROUND Pulmonary retransplantation remains the only therapeutic option in some cases of severe primary graft dysfunction (PGD), advanced bronchiolitis obliterans syndrome (BOS), and in some cases of severe airway problems (AWP), mainly cicatriceal stenosis. However, its value has been questioned due to the overall scarcity of donor organs and reports indicating unsatisfactory outcome. We analyzed our institutional experience with pulmonary retransplantation to evaluate its value for different indications. METHODS We retrospectively analyzed all 46 patients undergoing pulmonary retransplantation from the 567 consecutive primary lung or heart-lung transplantations performed in our department from August 1995 to August 2006. We stratified patients according to indication for retransplantation and analyzed the outcome. RESULTS Forty-six patients (mean age 41 +/- 16 years, 18 men and 28 women) underwent pulmonary retransplantation (14 bilateral lung transplantations, 32 single-lung transplantations) for primary graft dysfunction (n = 23), bronchiolitis obliterans syndrome (n = 19) and airway problems (n = 4). Mean time to retransplantation was 26 +/- 27 days in the PGD group, 1,069 +/- 757 days in the BOS group and 220 +/- 321 days in the AWP group. Thirty-day, 1-year and 5-year survival rates after retransplantation were 52.2%, 34.8% and 29.0% in the PGD group and 89.2%, 72.5% and 61.3% in the BOS group, respectively. All 4 patients in the AWP group are presently alive (BOS vs PGD: p = 0.02; BOS vs AWP: p = 0.27; PGD vs AWP: p = 0.06). CONCLUSIONS Pulmonary retransplantation for bronchiolitis obliterans offers long-term survival rates in the range of primary lung transplantation for selected patients. Long-term survival rates for retransplantation due to PGD are significantly lower, warranting restrictive use in this setting. In our experience with a limited number of patients, retransplantation for airway problems has shown excellent results. Pulmonary retransplantation for chronic problems is a plausible approach, provided that patients are carefully selected. Retransplantation for PGD should be avoided.

VEGF-A and -C but not -B mediate increased vascular permeability in preserved lung grafts

Background. Vascular endothelial growth factor (VEGF) is a potent endothelial cell growth and permeability factor, expressed in the lung. Overexpression of VEGF is associated with increased vascular permeability in the early stage of acute lung injury in mice. The role of various forms of VEGF in transplantation-induced lung injury is not well understood. Methods. VEGF mRNA and protein expression was measured in biopsies of preserved donor lung grafts as well as in control lung biopsies, using real-time reverse transcriptase–polymerase chain reaction and Western blot analysis. VEGF tissue expression was also evaluated by immunocytochemistry. Serum VEGF was measured in recipients after transplantation and in controls using ELISA. Results. Although VEGF-A and VEGF-C protein expression was up-regulated, their mRNA levels were decreased in donor versus control lung biopsies (P <0.05). VEGF-B mRNA was decreased, but its protein level was unchanged in donors. Flt-1 was unchanged, KDR gene expression was down-regulated in donors (P <0.05), and both receptors’ protein expression was under the detection level in donor and control lungs. VEGF-A was detected in pulmonary vessels and bronchi, whereas VEGF-C was only detectable in vessels of both donor and control lungs. After transplantation, serum VEGF increased (P <0.05) and returned to control baseline levels 12 weeks after surgery. Wet-to-dry lung weight was increased in donor versus control lungs. Conclusions. These results indicate that unventilated hypoxia increases vascular permeability in lung grafts and that this process is mainly regulated at VEGF-A and VEGF-C translational but not transcriptional level. Selective VEGF antagonism during graft preservation might be of benefit to counteract edema formation.

Surgical specimens, haemodynamics and long-term outcomes after pulmonary endarterectomy

Background Chronic thromboembolic pulmonary hypertension is surgically curable by pulmonary endarterectomy (PEA). It is unclear whether PEA impacts primarily steady state right ventricular afterload (ie, pulmonary vascular resistance (PVR)) or pulsatile right ventricular afterload (ie, pulmonary arterial compliance (CPA)). Our objectives were to (1) quantify PEA specimens and measure the impact of PEA on PVR and CPA in a structure/function study and (2) analyse the effects of haemodynamic changes on long-term survival/freedom of lung transplantation in an outcome study. Methods Thrombi were laid out, weighed, photographed and measured. PVR, CPA and resistance times compliance (RC-time) were assessed at baseline, within 4 days after PEA (‘immediately postoperative’) and 1 year after PEA, in 110 consecutive patients who were followed for 34.5 (11.9; 78.3) months. Results Lengths and numbers of PEA specimen tails were inversely correlated with immediate postoperative PVR (p<0.0001, r=−0.566; p<0.0001, r=−0.580). PVR and CPA normalised immediately postoperatively while RC-time remained unchanged. Immediate postoperative PVR was the only predictor of long-term survival/freedom of lung transplantation (p<0.0001). Patients with immediate postoperative PVR<590 dynes.s.cm−5 had better long-term outcomes than patients with PVR≥590 dynes.s.cm−5 (p<0.0001, respectively). Conclusions PEA immediately decreased PVR and increased CPA under a constant RC-time. However, immediate postoperative PVR was the only predictor of long-term survival/freedom of lung transplantation. Our study confirms the importance of a complete, bilateral surgical endarterectomy. Low PVR measured immediately postoperative predicts excellent long-term outcome.

Prediction of lung-transplant rejection by hepatocyte growth factor

BACKGROUND Graft rejection is a major complication of lung transplantation. No serological marker of rejection is in common use. Hepatocyte growth factor (HGF) is highly expressed in the lung and produced after acute lung injury; serum concentrations increase in inflammatory lung diseases. We investigated whether HGF could be an accurate marker for prediction of lung-graft rejection. METHODS Serum concentrations of HGF were measured by ELISA in 109 patients who had undergone lung transplantation (65 for chronic obstructive pulmonary disease; 23 for cystic fibrosis; 21 for idiopathic lung fibrosis), comparing those who had no subsequent events and those with episodes of infection or rejection, as well as in 12 healthy controls. FINDINGS The mean baseline serum HGF concentration was 645 ng/L (SD 259) in controls and 1358 ng/L (603) in the patients before transplantation. After transplantation the mean concentration in patients with no events was 1147 ng/L (510) compared with 1559 ng/L (323) in patients with infection (p=0.001 vs controls; change from pretransplant value not significant). Patients with rejection had significantly higher concentrations than all other groups (3972 ng/L [1463], p<0.0001). Logistic regression identified HGF as a predictor for lung graft rejection (p=0.012). After steroid treatment, HGF concentrations returned almost to the preoperative values within 3 days. INTERPRETATION HGF might be a marker for graft rejection in lung transplantation. A potential link between viral infection, mainly cytomegalovirus, and HGF, however, remains to be investigated.

Endothelin-1 is a useful biomarker for early detection of bronchiolitis obliterans in lung transplant recipients

OBJECTIVES Bronchiolitis obliterans (BO) is a severe complication limiting long-term survival after lung transplantation. To date, no cure exists for BO, and the mechanisms leading to BO are not well understood. Endothelin-1 (ET-1) is a potent mitogenic and profibrotic peptide produced by pulmonary vascular endothelial cells that play a role in the pathophysiology of lung allograft dysfunction. Whether ET-1 could predict BO syndrome (BOS) development is unknown. METHODS Transbronchial biopsy specimens and serum and bronchoalveolar lavage were obtained from 30 lung transplantation patients with and 30 without BOS at 3 points. The serum and bronchoalveolar lavage ET-1 concentrations were measured by enzyme-linked immunosorbent assay, and the ET-1 mRNA expression in the transbronchial biopsy specimens was examined using real-time polymerase chain reaction. RESULTS The pretransplant ET-1 serum concentrations were greater in the patients with BOS (P = .02); and ET-1 mRNA was significantly upregulated in the lung grafts of those with versus those without BOS at 3 and 12 months after transplant (P = .01). At 3 and 12 months after transplantation, the ET-1 concentrations were significantly elevated in the serum (P < .01 and P < .0001, respectively) and bronchoalveolar lavage (P < .01 and P = .02, respectively) of patients with compared with those without BOS. On logistic regression analysis, the pretransplant and 3-month post-transplant serum ET-1 level predicted for BOS (odds ratio, 1.01; 95% confidence interval, 1.004-1.025; P < .007; odds ratio, 2.9; 95% confidence interval, 1.01-8.52; P < .001). The serum ET-1 level at 12 months was diagnostic for BOS (odds ratio, 3.9; 95% confidence interval, 1.42-10.80; P = .008). CONCLUSIONS Elevated serum ET-1 concentrations were predictive of BOS, and the assessment of circulating ET-1 might be beneficial in diagnosing and monitoring BO.

Extracorporeal Membrane Oxygenation Support for Resection of Locally Advanced Thoracic Tumors

BACKGROUND The international experience with resection of advanced thoracic malignancies performed with extracorporeal membrane oxygenation (ECMO) support is limited. We examined our results to assess the risks and benefits of this approach. METHODS We retrospectively analyzed all patients with thoracic malignancies who underwent tumor resection with ECMO support in our department between 2001 and 2010. RESULTS Nine patients (aged 21 to 71 years; mean, 54.8±7.5 years) underwent complex tracheobronchial resections (n=6) or resections of greater thoracic vessels (n=3) under venoarterial (VA) ECMO support. In 7 patients the underlying pathologic condition was non-small cell lung cancer, in 1 patient it was carcinoid tumor, and in 1 patient it was synovial sarcoma. The indication for extracorporeal support was complex tracheobronchial reconstruction (n=5), resection of the descending aorta (n=2), and resection of the inferior vena cava (n=1). ECMO cannulation was central (n=4), peripheral (n=4), or combined (n=1). Mean time on bypass was 110±19 minutes (range 40 to 135 minutes). A complete resection (R0) was achieved in 8 patients (89%). One patient died perioperatively as a result of hepatic necrosis. Eight patients were discharged from the hospital after 7 to 42 days (median, 10 days). Median time in the intensive care unit was 1 day (range, 0 to 36 days). The only complication related to the use of ECMO was a lymphatic fistula in the groin. Mean follow-up time was 38±42 months (range, 9 to 111 months). The actuarial 3-month survival was 88.9%, and the 1-year, 3-year, and 5-year survival was 76.7%. CONCLUSIONS Based on this experience, we consider VA ECMO support to be a safe alternative to cardiopulmonary bypass (CPB) for advanced general thoracic operations.

Concomitant endothelin-1 overexpression in lung transplant donors and recipients predicts primary graft dysfunction.

Primary graft dysfunction (PGD) causes significant morbidity following lung transplantation (LTX). Mortality is high in PGD and therapeutic strategies are limited. To investigate whether endothelin‐1 (ET‐1) that mediates increased vascular permeability and edema formation in lung grafts can predict PGD, ET‐1 mRNA expression was examined in lung tissue biopsies of 105 donors and recipients obtained shortly before LTX. Serum ET‐1 concentration was assessed by ELISA. PGD grade was diagnosed and scored by oxygenation and radiological characteristics according to ISHLT guidelines. PGD grade 3 developed in 11% of patients. ET‐1 mRNA expression was significantly increased in both donor (p < 0.0001) and recipient (p = 0.01) developing PGD as compared to no PGD group. Pretransplant ET‐1 serum concentrations were elevated in recipients with PGD as compared to no PGD group (p < 0.0001), although serum ET‐1 was not different between donors whose grafts developed PGD grades 0–3. In regression analysis, concomitant elevated donor tissue ET‐1 and recipient serum ET‐1 predicted PGD grade 3. This study indicates that pretransplant ET‐1 mRNA overexpression in donors associated with elevated pretransplant serum ET‐1 in recipients contribute to PGD development and that their assessment might be beneficial to predict PGD and to identify recipients who could benefit from a targeted ET‐1 blockade.

Extracorporeal CO2 removal as bridge to lung transplantation in life-threatening hypercapnia

In patients awaiting lung transplantation (LTX), adequate gas exchange may not be sufficiently achieved by mechanical ventilation alone if acute respiratory decompensation arises. We report on 20 patients with life‐threatening hypercapnia who received extracorporeal CO2 removal (ECCO2‐R) by means of the interventional lung assist (ILA®, Novalung) as bridge to LTX. The most common underlying diagnoses were bronchiolitis obliterans syndrome, cystic fibrosis, and idiopathic pulmonary fibrosis, respectively. The type of ILA was pumpless arteriovenous or pump‐driven venovenous (ILA activve®, Novalung) in 10 patients each. ILA bridging was initiated in 15 invasively ventilated and five noninvasively ventilated patients, of whom one had to be intubated prior to LTX. Hypercapnia and acidosis were effectively corrected in all patients within the first 12 h of ILA therapy: PaCO2 declined from 109 (70–146) to 57 (45–64) mmHg, P < 0.0001; pH increased from 7.20 (7.06–7.28) to 7.39 (7.35–7.49), P < 0.0001. Four patients were switched to extracorporeal membrane oxygenation due to progressive hypoxia or circulatory failure. Nineteen patients (95%) were successfully transplanted. Hospital and 1‐year survival was 75 and 72%, respectively. Bridging to LTX with ECCO2‐R delivered by arteriovenous pumpless or venovenous pump‐driven ILA is feasible and associated with high transplantation and survival rates.

Extracorporeal membrane oxygenation support for complex tracheo-bronchial procedures

OBJECTIVES The published experience with advanced broncho-plastic procedures performed with extracorporeal membrane oxygenation (ECMO) support is very limited. We examined our results to assess the risks and benefits of this approach. METHODS We retrospectively analysed all patients with thoracic malignancies who underwent complex tracheo-bronchial reconstruction under ECMO support in our department between 2001 and 2013. RESULTS Ten patients (age range 21-81 years, mean 54 ± 11 years) underwent complex tracheo-bronchial reconstructions under veno-arterial ECMO support. In 7 patients, the underlying pathology was non-small-cell lung cancer, in 2 cases carcinoid tumour and in 1 case adenoid cystic carcinoma. ECMO cannulation was central (n = 7) or peripheral (n = 3). Mean time on bypass was 113 ± 17 min (range 70-135 min). A complete resection (R0) was achieved in 8 patients (80%). There was no perioperative mortality. Patients were discharged from the hospital after 7-52 days (median 11 days). Median time on ICU was 1 day (range 1-36 days). There was no complication related to the use of ECMO in this series. Mean follow-up time was 1694 ± 1385 days (range 12-4338). The 1-, 3- and 5-year Kaplan-Meier survival was 100, 74 and 56%, respectively. CONCLUSIONS Based on this experience, we consider veno-arterial ECMO support as a safe and valuable approach for complex airway surgery.