Daisuke Nakajima

Reconditioning of lungs donated after circulatory death with normothermic ex vivo lung perfusion

BACKGROUND The use of donation-after-circulatory-death (DCD) donors for lung transplantation has come into practice. In this study we investigated whether DCD lungs can be resuscitated after warm ischemia with normothermic ex vivo lung perfusion (EVLP). METHODS Four hours after cardiac arrest, beagle dogs were divided into two groups (n = 6 each): those with static cold storage (SCS group) and those with normothermic EVLP (EVLP group), for 3.5 hours. Physiologic lung functions were evaluated during EVLP. In both groups, the left lungs were then transplanted and reperfused for 4 hours to evaluate post-transplant lung functions. Lung tissue adenosine triphosphate (ATP) levels were measured at given time-points. RESULTS Lung oxygenation was significantly improved with EVLP (p < 0.01), and lung oxygenation at the end of EVLP significantly reflected post-transplant lung oxygenation (r = 0.99, p < 0.01). Post-transplant lung oxygenation was significantly better in the EVLP group than in the SCS group (p < 0.05). Both dynamic pulmonary compliance and wet-to-dry lung weight ratio 4 hours after transplantation were also significantly better in the EVLP group than in the SCS group (p < 0.05). Microthrombi in the donor lungs before transplantation were microscopically detected more often in the SCS group. The lung tissue ATP levels 4 hours after transplantation were significantly higher in the EVLP group compared with the SCS group (p = 0.03). CONCLUSIONS Normothermic ex vivo lung perfusion could resuscitate DCD lungs injured by warm ischemia, and may ameliorate ischemia-reperfusion injury.

Perioperative assessment of oversized lobar graft downsizing in living-donor lobar lung transplantation using three-dimensional computed tomographic volumetry

A 15‐year‐old boy with bronchiolitis obliterans after bone marrow transplantation successfully underwent bilateral living‐donor lobar lung transplantation (LDLLT) with segmentectomy of the superior segment of an oversized right lower lobe graft. As the recipient was small for his age, the predicted value of his functional vital capacity of the recipient was difficult to determine preoperatively. Three‐dimensional computed tomography (CT) volumetry revealed that the ratio of donor graft volume to recipient hemithorax volume was 159% on the right side and 82% on the left side. The patient is alive and well 7 months after transplantation, and three‐dimensional CT volumetry revealed that the right and left donor lungs were still compressed to 73% and 84% of the original size, respectively. In LDLLT, segmentectomy of the superior segment of the lower lobe is a useful option for downsizing an oversized graft and three‐dimensional CT volumetry can provide meaningful data for size matching.

Protective effect of plasmin in marginal donor lungs in an ex vivo lung perfusion model

BACKGROUND Donor lung thrombi are considered an important etiology for primary graft dysfunction in lung transplantation. We hypothesized that thrombolysis before lung transplantation could alleviate ischemia-reperfusion injury. This study was designed to evaluate the effect of the fibrinolytic agent plasmin on lungs damaged by thrombi in an ex vivo lung perfusion (EVLP) system. METHODS Rats were divided into control, non-plasmin, and plasmin groups (n = 7 each). In the control and plasmin groups, cardiac arrest was induced by withdrawal of mechanical ventilation without heparinization. Ventilation was restarted 150 minutes after cardiac arrest. The lungs were flushed, and the heart and lungs were excised en bloc. The lungs were perfused in the EVLP system for 60 minutes, and plasmin or placebo was administered upon EVLP initiation. RESULTS Fibrin/fibrinogen degradation products in the perfusate were significantly higher in the plasmin group than in the control and non-control groups (p < 0.001 for both). Plasmin administration significantly decreased pulmonary vascular resistance (plasmin vs non-plasmin, p = 0.011) and inhibited the exacerbation of dynamic compliance (plasmin vs non-plasmin, p = 0.003). Lung weight gain was less in the plasmin group than in the non-plasmin group (p = 0.04). CONCLUSIONS Our results confirmed that plasmin administration in an EVLP model dissolved thrombi in the lungs, resulting in reconditioning of the lungs as assessed by various physiologic parameters.

Search for the Θ+ via the K+p→π+X reaction with a 1.2 GeV/c K+ beam

The Θ + was searched for via the K + p 2→π + X reaction using the 1.2 GeV/c K+ beam at the K6 beam line of the KEK-PS 12 GeV Proton Synchrotron. In the missing mass spectrum of the K + p p→π + X reaction, no clear peak structure was observed. Therefore a 90% C.L. upper limit of 3.5 μb/sr was derived for the differential cross section averaged over 2° to 22° in the laboratory frame of the K + p → π + Θ + reaction. This upper limit is much smaller than the theoretical calculation for the t-channel process where a K 0 * is exchanged. From the present result, either the t-channel process is excluded or the coupling constant of gK*NΘ is quite small.

Low-dose computed tomography volumetry for subtyping chronic lung allograft dysfunction.

BACKGROUND The long-term success of lung transplantation is challenged by the development of chronic lung allograft dysfunction (CLAD) and its distinct subtypes of bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). However, the current diagnostic criteria for CLAD subtypes rely on total lung capacity (TLC), which is not always measured during routine post-transplant assessment. Our aim was to investigate the utility of low-dose 3-dimensional computed tomography (CT) lung volumetry for differentiating RAS from BOS. METHODS This study was a retrospective evaluation of 63 patients who had developed CLAD after bilateral lung or heart‒lung transplantation between 2006 and 2011, including 44 BOS and 19 RAS cases. Median post-transplant follow-up was 65 months in BOS and 27 months in RAS. The median interval between baseline and the disease-onset time-point for CT volumetry was 11 months in both BOS and RAS. Chronologic changes and diagnostic accuracy of CT lung volume (measured as percent of baseline) were investigated. RESULTS RAS showed a significant decrease in CT lung volume at disease onset compared with baseline (mean 3,916 ml vs 3,055 ml when excluding opacities, p < 0.0001), whereas BOS showed no significant post-transplant change (mean 4,318 ml vs 4,396 ml, p = 0.214). The area under the receiver operating characteristic curve of CT lung volume for differentiating RAS from BOS was 0.959 (95% confidence interval 0.912 to 1.01, p < 0.0001) and the calculated accuracy was 0.938 at a threshold of 85%. CONCLUSION In bilateral lung or heart‒lung transplant patients with CLAD, low-dose CT volumetry is a useful tool to differentiate patients who develop RAS from those who develop BOS.

Protective effect of pre-recovery surfactant inhalation on lungs donated after cardiac death in a canine lung transplantation model

BACKGROUND Warm ischemia-reperfusion injury related to donation after cardiac death is a crucial issue in transplantation. Because surfactant function deteriorates in lungs during warm ischemia, we hypothesized pre-recovery surfactant inhalation would mitigate warm ischemia-reperfusion injury. METHODS We rendered donor dogs cardiac dead and left them at room temperature. All animals received ventilation for 60 minutes starting at 240 minutes after cardiac arrest. The animals were divided into 2 groups: NS (normal saline, n = 7) group, which received aerosolized normal saline, and SF (surfactant; n = 5), which received aerosolized surfactant. The lungs were flushed and procured, and the left lung was transplanted into recipient dogs. At 45 minutes of reperfusion, the right pulmonary artery was ligated, and the left transplanted lung function was evaluated. RESULTS In the NS group, 2 of 7 dogs died at 75 minutes after reperfusion, whereas all 5 animals in the SF group survived for 240 minutes after reperfusion. The SF group showed significantly better dynamic compliance, oxygenation, and wet-to-dry weight ratio. Furthermore, the SF group had higher levels of high-energy phosphates in the lung tissues and lower levels of interleukin-8, tumor necrosis factor-α, and protein in the bronchoalveolar lavage fluid. Histologically, the lungs in the SF group showed fewer signs of interstitial edema and hemorrhage and significantly less neutrophilic sequestration than those of the NS group. CONCLUSIONS Our results indicated pre-recovery surfactant inhalation improved graft function, maintained adenine nucleotide levels, and prevented alveolar-capillary barrier leakage, resulting in the attenuation of warm ischemia-reperfusion injury.

Hypothermic machine perfusion ameliorates ischemia-reperfusion injury in rat lungs from non-heart-beating donors.

Background. The use of non-heart-beating donors (NHBD) has come into practice to resolve the shortage of donor lungs. This study investigated whether hypothermic machine perfusion (HMP) can improve the quality of NHBD lungs. Methods. An uncontrolled NHBD model was achieved in male Lewis rats. Ninety minutes after cardiac arrest, HMP was performed for 60 min at 6°C to 10°C. The first study investigated the physiological lung functions during HMP and the lung tissue energy levels before and after HMP. The second study divided the rats into three groups (n=6 each): no ischemia group; 90-min warm ischemia+60-min HMP+120-min static cold storage (SCS) (HMP group); and 90-min warm ischemia+180-min SCS group. All lungs were reperfused for 60 min at 37°C. Lung functions were evaluated at given timings throughout the experiments. Oxidative damage during reperfusion was evaluated immunohistochemically with a monoclonal antibody against 8-hydroxy-2′-deoxyguanosine. Results. The first study revealed that lung functions were stable during HMP. Lung tissue energy levels decreased during warm ischemia but were significantly increased by HMP (P<0.05). The second study confirmed that HMP significantly decreased pulmonary vascular resistance, increased pulmonary compliance, and improved pulmonary oxygenation. The ratio of 8-hydroxy-2′-deoxyguanosine positive cells to total cells significantly increased in the SCS group (P<0.01). Conclusions. Short-term HMP improved lung tissue energy levels that decreased during warm ischemia and ameliorated ischemia-reperfusion injury with decreased production of reactive oxygen species.

Living-donor lobar lung transplantation with sparing of bilateral native upper lobes: a novel strategy.

A 44-year-old man became wheelchair-bound due to sever bronchiolitis obliterans caused by peripheral blood stem cell transplantation for acute myelogenous leukemia. His lung donors, his sister and his wife, were 17 cm shorter than him. He successfully underwent living-donor lobar lung transplantation with sparing of the bilateral native upper lobes to address the size mismatch. Ten months after the transplantation, the patient has returned to a normal lifestyle without supplemental oxygen.

Effect of preprocurement ventilation on lungs donated after cardiac death in a canine lung transplantation model.

Background. One method of countering chronic lung donor shortages is the practice of donation after cardiac death (DCD). However, this technique inevitably leads to pulmonary dysfunction related to warm ischemia. One promising method of alleviating this problem is ventilation. However, it can rarely be initiated from the onset of cardiac arrest, particularly in uncontrolled DCD donors. We investigated the protective effect of the last 60 min of ventilation during a 240-min warm ischemic time. Methods. We rendered donor dogs cardiac dead and left them at room temperature. Six dogs received ventilation with 100% oxygen for 60 min starting at 180 min after cardiac arrest (ventilation group). Eight dogs received no ventilation. Lungs were harvested 240 min after cardiac arrest, then transplanted into recipient dogs. At 60 min after reperfusion, the right pulmonary artery was ligated, and the function of the left transplanted lung was evaluated. Results. In the ventilation group, all six animals survived for 240 min after reperfusion, whereas in the nonventilation group, only four of eight survived. The ventilation group demonstrated significantly better pulmonary oxygenation, shunt fraction, and wet-to-dry weight ratio. Furthermore, the ventilation group revealed significantly higher levels of high-energy phosphates in the lung tissues, fewer apoptotic cells, lower levels of tumor necrosis factor-&agr; and interleukin-8 messenger RNA in the lung tissues, and lower levels of interleukin-6 messenger RNA in the serum. Conclusion. Our results suggest that ventilation during the late phase of the preprocurement period may ameliorate ischemia-reperfusion injury in DCD donors.

Therapeutic effect of surfactant inhalation during warm ischemia in an isolated rat lung perfusion model

Warm ischemia‐reperfusion injury related to donation after cardiac death donors is a crucial and inevitable issue. As surfactant function is known to deteriorate during warm ischemia, we hypothesized that surfactant inhalation during warm ischemia would mitigate warm ischemia‐reperfusion injury. We used an isolated rat lung perfusion model. The rats were divided into three groups: sham, control, and surfactant. In the control and surfactant groups, cardiac arrest was induced by ventricular fibrillation. Ventilation was restarted 110 min later; subsequently, the lungs were flushed, and heart and lung block was recovered. In the surfactant group, a natural bovine surfactant Surfacten® was inhaled for 3 min at the end of warm ischemia. Then, the lungs were reperfused for 80 min. Surfactant inhalation significantly improved graft functions, effectively increased lung tissue ATP levels, and significantly decreased mRNA levels of IL‐6 and IL‐6/IL‐10 ratio at the end of reperfusion. Histologically, lungs in the surfactant group showed fewer signs of interstitial edema and hemorrhage, and significantly less neutrophilic infiltration than those in the control group. Our results indicated that surfactant inhalation in the last phase of warm ischemia maintained lung tissue energy levels and prevented cytokine production, resulting in the alleviation of warm ischemia‐reperfusion injury.