Norihisa Shigemura

Efficacy of extracorporeal membrane oxygenation as a bridge to lung transplantation

BACKGROUND Preoperative extracorporeal membrane oxygenation (ECMO) is a risk factor for poor outcome and currently considered a contraindication to lung transplantation. The lung allocation score system was introduced in May 2005 and prioritizes lung allocation to those with the greatest respiratory impairment. The purpose of this study is to determine whether ECMO as a bridge to lung transplantation is an acceptable option to support those in respiratory failure until donor lungs become available in the lung allocation score era. METHOD A retrospective review of 715 consecutive lung transplants performed between May 2005 and September 2011 was conducted using a prospectively collected institutional registry database. Twenty-four lung transplants (3.4%) were performed in the 31 patients with attempted pretransplant ECMO; 7 patients who received ECMO patients did not survive or were deemed unfit for transplantation. These patients were compared with a control group of 691 patients who did not receive pretransplant ECMO. RESULTS The duration of pretransplant ECMO was 171 ± 242 hours (median, 91 hours). Venovenous ECMO was used for respiratory failure in 15 patients, whereas venoarterial ECMO was used for circulatory collapse due to pulmonary hypertension in 9 patients. Patients in the retransplant ECMO group were younger (46 ± 15 years vs 57 ± 14 years, P < .01) compared with the control group, with no difference in recipient gender (male/female: 10/14 vs 380/311), donor age (33 ± 14 years vs 36 ± 15 years), or donor gender (male/female: 10/14 vs 352/339). Emphysema was less common (1, 4% vs 260, 38%, P < .01), and cystic fibrosis (5, 21% vs 72, 10%, P = .09), redo lung transplant (3, 13% vs 28, 4%, P = .08), and bronchiectasis (2, 8% vs 6, 1%, P = .03) were more common in the pretransplant ECMO group. Patients in the pretransplant ECMO group had a significantly higher lung allocation score (87 ± 9 vs 44 ± 15, P < .01). All patients in the pretransplant ECMO group underwent double lung transplants on pump (cardiopulmonary bypass/ECMO), and single lung transplants were performed in 171 patients (25%) and pump was used in 243 patients (35%) in the control group. The cardiopulmonary bypass time was longer in the pretransplant ECMO group (277 ± 69 minutes vs 225 ± 89 minutes, P = .02), with no difference in ischemic time (343 ± 93 minutes vs 330 ± 98 minutes, P = .54). Cadaveric lobar lung transplants were performed because of the urgency to overcome size mismatch with an oversized donor more frequently in 25% (n = 6, no mortality with the longest follow-up at 6 years) of patients in the pretransplant ECMO group versus 0.3% (n = 2) of patients in the control group (P < .01). Post-transplant ECMO was used for primary graft dysfunction in 13 patients (54%) in the pretransplant ECMO group and 41 patients (6%) in the control group (P < .01). The median hospital stay was 46 days in the pretransplant ECMO group versus 27 days in the control group (P = .16). The actuarial survivals after lung transplants at 1, 3, 6, 12, and 24 months were 96%, 88%, 83%, 74%, and 74%, respectively, in the pretransplant ECMO group, and 97%, 94%, 90%, 83%, and 74%, respectively, in the control group (P = .787). CONCLUSIONS Although the incidence of primary graft dysfunction requiring post-transplant ECMO is higher and the hospital stay is longer in patients receiving pretransplant ECMO, the graft survival is good (2-year survival, 74%). ECMO is efficacious as a bridge to lung transplantation with good post-lung transplant outcomes.

Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplant: Midterm Outcomes

BACKGROUND Extracorporeal membrane oxygenation (ECMO) is used occasionally as a bridge to lung transplantation. The impact on mid-term survival is unknown. We analyzed outcomes after lung transplant over a 19-year period in patients who received ECMO support. METHODS From March 1991 to October 2010, 1,305 lung transplants were performed at our institution. Seventeen patients (1.3%) were supported with ECMO before lung transplant. Diagnoses included retransplantation (n = 6), pulmonary fibrosis (n = 6), cystic fibrosis (n = 4), and chronic obstructive pulmonary disease (n = 1). Fifteen patients underwent double lung transplant, one patient had single left lung transplant and one patient had a heart-lung transplant. Venovenous and venoarterial ECMO were implanted in eight and nine cases, respectively. Median duration of support was 3.2 days (range, 1 to 49 days). Mean patient follow-up was 2.3 years. RESULTS Thirty-day, 1-year, and 3-year survivals were 81%, 74%, and 65%, respectively, for the supported patients and 93%, 78%, and 62% in the control group (p = 0.56). Two-year survival was not affected by ECMO type, with survival of five out of nine patients supported by venoarterial ECMO vs seven out of eight patients supported by venovenous ECMO (p = 0.17). At 1- year follow-up, allograft function for the ECMO-supported patients did not differ from the control group (forced expiratory volume in one second, 2.35 L vs 2.09 L, p = 0.39) (forced vital capacity, 3.06 L vs 2.71 L, p = 0.34). CONCLUSIONS Extracorporeal membrane oxygenation as a bridge to lung transplantation is associated with higher perioperative mortality but acceptable mid-term survival in carefully selected patients. Late allograft function did not differ in patients who received ECMO support before lung transplant from those who did not receive ECMO.

Antireflux Surgery Preserves Lung Function in Patients With Gastroesophageal Reflux Disease and End-stage Lung Disease Before and After Lung Transplantation

BACKGROUND Gastroesophageal reflux disease (GERD) is common in patients with end-stage lung disease (ESLD). GERD may cause obliterative bronchiolitis after lung transplantation (LTx), represented by a decline in forced expiratory volume in 1 second (FEV(1)). OBJECTIVES To identify the patterns of reflux in patients with ESLD and to determine whether antireflux surgery (ARS) positively impacts lung function. DESIGN Retrospective review of prospectively collected data. SETTING Tertiary care university hospital. PATIENTS Forty-three patients with ESLD and documented GERD (pre-LTx, 19; post-LTx, 24). INTERVENTIONS Antireflux surgery. MAIN OUTCOME MEASURES Reflux patterns including laryngopharyngeal reflux as measured by esophageal impedance, and FEV(1), and episodes of pneumonia and acute rejection before and after ARS. RESULTS Before ARS, 19 of 43 patients (44%) were minimally symptomatic or asymptomatic. Laryngopharyngeal reflux events, which occurred primarily in the upright position, were common in post-LTx (56%) and pre-LTx (31%) patients. At 1 year after ARS, FEV(1) significantly improved in 91% of the post-LTx patients (P < .01) and 85% of the pre-LTx patients (P = .02). Of patients with pre-ARS declining FEV(1), 92% of post-LTx and 88% of pre-LTx patients had a reversal of this trend. Episodes of pneumonia and acute rejection were significantly reduced in post-LTx patients (P = .03) or stablilized in pre-LTx patients (P = .09). CONCLUSIONS There should be a low threshold for performing objective esophageal testing including esophageal impedance because GERD may be occult and ARS may improve or prolong allograft and native lung function.

Inhaled hydrogen gas therapy for prevention of lung transplant-induced ischemia/reperfusion injury in rats.

Background. Successful abrogation of ischemia/reperfusion (I/R) injury of lung grafts could significantly improve short- and long-term outcomes for lung transplant (LTx) recipients. Hydrogen gas has potent antioxidant and antiapoptotic properties and has been recently used in number of experimental and clinical studies. The purpose of this research was to investigate whether inhaled hydrogen gas could reduce graft I/R injury during lung transplantation. Methods. Orthotopic left LTxs were performed in syngenic Lewis rats. Grafts were perfused with and stored in low potassium dextran solution at 4°C for 6 hr. The recipients received 100% O2 or 98% O2 with 2% N2, 2% He, or 2% H2 during surgery and 1 hr after reperfusion. The effects of hydrogen were assessed by functional, pathologic, and molecular analysis. Results. Gas exchange was markedly impaired in animals exposed to 100% O2, 2% N2, or 2% He. Hydrogen inhalation attenuated graft injury as indicated by significantly improved gas exchange 2 hr after reperfusion. Graft lipid peroxidation was significantly reduced in the presence of hydrogen, demonstrating antioxidant effects of hydrogen in the transplanted lungs. Lung cold I/R injury causes the rapid production and release of several proinflammatory mediators and epithelial apoptosis. Exposure to 2% H2 significantly blocked the production of several proinflammatory mediators and reduced apoptosis with induction of the antiapoptotic molecules B-cell lymphoma-2 and B-cell lymphoma-extra large. Conclusion. Treatment of LTx recipients with inhaled hydrogen can prevent lung I/R injury and significantly improve the function of lung grafts after extended cold preservation, transplant, and reperfusion.

Autologous transplantation of adipose tissue-derived stromal cells ameliorates pulmonary emphysema.

Adipose tissue is a useful tool for management of most complex cardiothoracic problems, including the reinforcement of damaged lungs, and adipose tissue‐derived stromal cells (ASCs) have been suggested to secrete hepatocyte growth factor (HGF), a multipotent regenerative factor that contributes to the repair process after lung injury. The goal of this study was to demonstrate the therapeutic impact of autologous transplantation of ASCs through HGF supplementation for the enhancement of alveolar repair in a rat model of emphysema. ASCs were isolated from inguinal subcutaneous fat pads and characterized by flow cytometry. Cultured ASC were found to secrete significantly larger amounts of HGF (15 112 ± 1628 pg per 106 cells) than other angiogenic factors. Transplantation of ASCs into elastase‐treated emphysema models induced a significant increase in endogenous HGF expression in lung tissues with a small amount of increase in other organs, with the high levels lasting for up to 4 weeks after transplantation. Further, alveolar and vascular regeneration were significantly enhanced via inhibition of alveolar cell apoptosis, enhancement of epithelial cell proliferation and promotion of angiogenesis in pulmonary vasculature, leading to restoration of pulmonary function affected by emphysema. These data suggest that autologous ASC cell therapy may have a therapeutic potential for pulmonary emphysema, through inducing HGF expression selectively in injured lung tissues.

Amelioration of Pulmonary Emphysema by In Vivo Gene Transfection With Hepatocyte Growth Factor in Rats

Background—Hepatocyte growth factor (HGF) is an important mitogen and morphogen that contributes to the repair process after lung injury. The goal of the present study was to characterize its role in pulmonary emphysema, which may lead to the development of new treatment strategies with HGF. Methods and Results—HGF mRNA and protein levels in lung tissue and plasma from elastase-induced emphysema rats transiently increased, then declined significantly to below the basal level in a time-dependent manner (P<0.01). Furthermore, changes in HGF were correlated with histologically progressive emphysematous changes and deterioration in pulmonary physiology. Use of the HVJ (hemagglutinating virus of Japan) envelope method resulted in successful transfection of cDNA encoding human HGF, as demonstrated by an efficient expression of HGF in alveolar endothelial and epithelial cells. Transfection of HGF resulted in a more extensive pulmonary vasculature and inhibition of alveolar wall cell apoptosis, and those effects led to improved exercise tolerance and gas exchange (P<0.05), which persisted for more than 1 month. Conclusions—Decreased HGF expression due to a failure in sustained endogenous production after injury was associated with emphysema-related histopathologic and physiological changes in the present rat model. In addition, induction of HGF expression by a gene-transfection method resulted in improved pulmonary function via inhibition of alveolar cell apoptosis, enhancement of alveolar regeneration, and promotion of angiogenesis.

Complete versus assisted thoracoscopic approach: a prospective randomized trial comparing a variety of video-assisted thoracoscopic lobectomy techniques

BackgroundVideo-assisted thoracoscopic surgery (VATS) lobectomy does not represent a unified approach, but rather a spectrum of operative techniques ranging from a complete endoscopic thoracotomy to a minithoracotomy. A prospective randomized trial was conducted to compare the differences in these techniques and their results to determine the best of VATS lobectomy for lung cancer.MethodsThis study randomized 39 consecutive patients with clinical stage I lung cancer to undergo either a complete (C-VATS, n = 20) or an assisted (A-VATS, n = 19) VATS approach for pulmonary lobectomy.ResultsThe operating time was longer (p = 0.002) and blood loss was less (p = 0.004) with C-VATS than with A-VATS. Although there was no significant difference in analgesic use or duration of thoracic drainage between the groups, a shorter hospitalization was observed after C-VATS. Serum peak levels of postoperative inflammatory markers (white blood cell count, C-reactive protein, creatine phosphokinase) were lower with C-VATS and an earlier return to normalization than with A-VATS.ConclusionVarious differences exist among the VATS lobectomy techniques, and complete VATS lobectomy as a purely endoscopic surgery may be technically feasible and a satisfactory alternative to the conventional procedure for stage I lung cancer.

Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo

Hyperoxic lung injury is a major concern in critically ill patients who receive high concentrations of oxygen to treat lung diseases. Successful abrogation of hyperoxic lung injury would have a huge impact on respiratory and critical care medicine. Hydrogen can be administered as a therapeutic medical gas. We recently demonstrated that inhaled hydrogen reduced transplant-induced lung injury and induced heme oxygenase (HO)-1. To determine whether hydrogen could reduce hyperoxic lung injury and investigate the underlying mechanisms, we randomly assigned rats to four experimental groups and administered the following gas mixtures for 60 h: 98% oxygen (hyperoxia), 2% nitrogen; 98% oxygen (hyperoxia), 2% hydrogen; 98% balanced air (normoxia), 2% nitrogen; and 98% balanced air (normoxia), 2% hydrogen. We examined lung function by blood gas analysis, extent of lung injury, and expression of HO-1. We also investigated the role of NF-E2-related factor (Nrf) 2, which regulates HO-1 expression, by examining the expression of Nrf2-dependent genes and the ability of hydrogen to reduce hyperoxic lung injury in Nrf2-deficient mice. Hydrogen treatment during exposure to hyperoxia significantly improved blood oxygenation, reduced inflammatory events, and induced HO-1 expression. Hydrogen did not mitigate hyperoxic lung injury or induce HO-1 in Nrf2-deficient mice. These findings indicate that hydrogen gas can ameliorate hyperoxic lung injury through induction of Nrf2-dependent genes, such as HO-1. The findings suggest a potentially novel and applicable solution to hyperoxic lung injury and provide new insight into the molecular mechanisms and actions of hydrogen.

De novo donor-specific HLA antibodies are associated with early and high-grade bronchiolitis obliterans syndrome and death after lung transplantation

BACKGROUND The development of human leukocyte antigen (HLA) antibody responses has been associated with worse clinical outcomes, such as bronchiolitis obliterans syndrome (BOS) and death, in lung transplant recipients (LTRs). However, the role of donor-specific HLA antibody (DSA) responses as a risk factor for poor outcomes remains controversial. METHODS We prospectively screened 445 LTRs for DSA at our institution at the time of surveillance bronchoscopies for the first 2 years after transplantation between 2003 and 2008, and evaluated clinical outcomes. For this purpose, we used the combination of panel-reactive antibodies (PRA) by enzyme-linked immunosorbent assay (ELISA) and the Luminex single-antigen bead (SAB) assay (One Lambda, Canoga Park, CA). RESULTS We detected de novo DSA (dnDSA) in 58 of 445 (13%) LTRs in our cohort. Freedom from BOS was significantly reduced in LTRs with dnDSA versus those without dnDSA (p < 0.001). Using a Cox proportional hazards model, the development of dnDSA was associated with a significantly increased hazard ratio (HR = 6.59 [4.53 to 9.59]; p < 0.001) for BOS and high-grade BOS (Stage ≥ 2) (HR = 5.76 [3.48 to 9.52]; p < 0.001). Freedom from death was significantly reduced in LTRs with dnDSA (p < 0.001), including mortality attributable to BOS (HR = 9.86 [4.91 to 19.78]; p < 0.001). CONCLUSIONS Taken together, our findings provide evidence that dnDSA is associated with accelerated BOS kinetics and severity, as well as death due to BOS after lung transplantation. In addition, these data support regular monitoring for the development of dnDSA in LTRs and underscore the need for novel strategies to mitigate the increased risk of poor outcomes associated with dnDSA.

Hydrogen inhalation ameliorates ventilator-induced lung injury

IntroductionMechanical ventilation (MV) can provoke oxidative stress and an inflammatory response, and subsequently cause ventilator-induced lung injury (VILI), a major cause of mortality and morbidity of patients in the intensive care unit. Inhaled hydrogen can act as an antioxidant and may be useful as a novel therapeutic gas. We hypothesized that, owing to its antioxidant and anti-inflammatory properties, inhaled hydrogen therapy could ameliorate VILI.MethodsVILI was generated in male C57BL6 mice by performing a tracheostomy and placing the mice on a mechanical ventilator (tidal volume of 30 ml/kg without positive end-expiratory pressure, FiO2 0.21). The mice were randomly assigned to treatment groups and subjected to VILI with delivery of either 2% nitrogen or 2% hydrogen in air. Sham animals were given same gas treatments for two hours (n = 8 for each group). The effects of VILI induced by less invasive and longer exposure to MV (tidal volume of 10 ml/kg, 5 hours, FiO2 0.21) were also investigated (n = 6 for each group). Lung injury score, wet/dry ratio, arterial oxygen tension, oxidative injury, and expression of pro-inflammatory mediators and apoptotic genes were assessed at the endpoint of two hours using the high-tidal volume protocol. Gas exchange and apoptosis were assessed at the endpoint of five hours using the low-tidal volume protocol.ResultsVentilation (30 ml/kg) with 2% nitrogen in air for 2 hours resulted in deterioration of lung function, increased lung edema, and infiltration of inflammatory cells. In contrast, ventilation with 2% hydrogen in air significantly ameliorated these acute lung injuries. Hydrogen treatment significantly inhibited upregulation of the mRNAs for pro-inflammatory mediators and induced antiapoptotic genes. In the lungs treated with hydrogen, there was less malondialdehyde compared with lungs treated with nitrogen. Similarly, longer exposure to mechanical ventilation within lower tidal volume (10 mg/kg, five hours) caused lung injury including bronchial epithelial apoptosis. Hydrogen improved gas exchange and reduced VILI-induced apoptosis.ConclusionsInhaled hydrogen gas effectively reduced VILI-associated inflammatory responses, at both a local and systemic level, via its antioxidant, anti-inflammatory and antiapoptotic effects.