Background:Lung transplantation (LTx) is the only effective treatment for patients with end-stage idiopathic pulmonary fibrosis (IPF). However, little is known about the effect of extracorporeal membrane oxygenation (ECMO) on the prognosis of these patients. This study aimed to explore the association between ECMO duration and survival outcomes in IPF patients undergoing LTx. Methods:This was a single-center retrospective cohort study that included 276 IPF patients who underwent LTx at the Affiliated Wuxi People's Hospital of Nanjing Medical University China, between January 2015 and December 2020. The primary outcome was overall survival (OS). Several Cox proportional hazards regression models with a cubic spline function were established to analyze the association between ECMO duration and mortality. Results:Among the 276 recipients, the median duration of ECMO was 24 hours [interquartile range (IQR): 7.25-40.0 hours], with 80 (29.0%) receiving veno-arterial (VA) ECMO support, 149 (54.0%) receiving veno-venous (VV) ECMO support, and 47 (17.0%) not receiving any ECMO support. There was no statistically significant difference in cumulative survival among the ECMO support strategies (P=0.44). The main model showed a 13% increase in mortality risk for each additional day of ECMO use [hazard ratio (HR) =1.13, 95% confidence interval (CI): 1.07-1.20, P<0.001]. The continuous relationship between ECMO duration and mortality risk revealed a nonlinear association (P-overall ≤0.001; P-nonlinear =0.002), with 0.8 and 5.54 days identified as cutoff values. Conclusions:In IPF patients receiving LTx, ECMO duration demonstrates a strong nonlinear association with mortality. Longer duration of ECMO support serves as a robust indicator of underlying disease severity and postoperative complications predicting poor outcomes. The identified thresholds (0.8 and 5.54 days) provide clinically relevant markers for risk stratification and prognostication. Future prospective studies are needed to validate these inflection points and clarify interactions between ECMO duration, patient factors, and outcomes.

INTRODUCTION:The occurrence of lung ischemia-reperfusion injury (LIRI) after lung transplantation results in primary graft dysfunction (PGD) in more than 50% of cases, which seriously affects the prognosis of recipients. Currently, donor lung protection is the focus of research on improving graft survival in lung transplant recipients. Dexmedetomidine (Dex) is a widely used general anesthesia adjuvant in clinical practice to alleviate ischemia-reperfusion injury in the lungs, liver, heart, kidneys, and brain. However, intravenous infusion of Dex can cause negative effects on the cardiovascular system. Inhaling nebulized Dex can directly act on the alveolar tissue and alleviate its cardiovascular inhibitory effect by reducing drug intake. This study aimed to investigate the effect of donor nebulized Dex inhalation on LIRI after lung transplantation in rats. METHODS:We randomly divided the male Sprague-Dawley rats into donor rats and recipient rats, and allowed the donor rats to inhale nebulized Dex or physiological saline 15 min before surgery. The donor lung was refrigerated for 8 h before each single-lung transplant. After 2 h of reperfusion of the transplanted lung, serum and transplanted lung tissue were collected. The wet-to-dry weight ratio of the lung tissue was measured, arterial blood gas was detected, and histopathology changes, oxidative stress, inflammatory reactions, and apoptosis were evaluated. RESULTS:Pretransplant inhalation of Dex through the donor's lung reduced the injury of the transplanted lung, increased the levels of malondialdehyde and myeloperoxidase, and decreased the levels of superoxide dismutase and glutathione in the lung tissue. Moreover, nebulized Dex inhalation of the donor lung inhibited LIRI-induced tumor necrosis factor-α, interleukin-6, and inducible nitric oxide synthase expression and also suppressed nuclear factor kappa B phosphorylation. Nebulized Dex inhalation reduced the rate of cell apoptosis in the transplanted lung tissue by inhibiting the upregulation of Bax, downregulation of Bcl-2, and increase in caspase-3 lysis caused by LIRI. CONCLUSION:Inhalation of atomized Dex is a potential donor lung protection strategy, which can be used to reduce LIRI after lung transplantation and may be helpful to improve the occurrence of PGD and prognosis of lung transplant recipients.

Background: Lung ischemia-reperfusion injury (LIRI) is among the complications observed after lung transplantation and is associated with morbidity and mortality. Preconditioning of the donor lung before organ retrieval may improve organ quality after transplantation. We investigated whether preconditioning with metformin (Met) ameliorates LIRI after lung transplantation. Methods: Twenty Lewis rats were randomly divided into the sham, LIRI, and Met groups. The rats in the LIRI and Met groups received saline and Met, respectively, via oral gavage. Subsequently, a donor lung was harvested and kept in cold storage for 8 h. The LIRI and Met groups then underwent left lung transplantation. After 2 h of reperfusion, serum and transplanted lung tissues were examined. Results: The partial pressure of oxygen (PaO2) was greater in the Met group than in the LIRI group. In the Met group, wet-to-dry (W/D) weight ratios, inflammatory factor levels, oxidative stress levels and apoptosis levels were notably decreased. Conclusions: Met protects against ischemia-reperfusion injury after lung transplantation in rats, and its therapeutic effect is associated with its anti-inflammatory, antioxidative, and antiapoptotic properties.

目的 探讨供者年龄对特发性肺纤维化(IPF)患者肺移植术后短期生存结局的影响.方法 回顾性分析 235 例IPF肺移植供、受者的临床资料.使用单因素和多因素Cox比例风险回归模型分析供者年龄与IPF患者肺移植术后短期死亡风险的关系,采用Kaplan-Meier法绘制生存曲线.结果 单因素Cox回归分析结果显示,供者年龄与IPF患者肺移植术后 1 年病死率相关,供者年龄每增加 1 岁,受者术后 1 年死亡风险增加0.020倍(P=0.009).供者氧合指数,受者术前氧合指数、术前肺源分配评分、术前氨基末端脑钠肽前体、移植方式、术中体外膜氧合方式和术中输血量与肺移植术后1年病死率存在相关性(均为P<0.1).多因素Cox回归分析显示,供者年龄与IPF患者肺移植术后 30、90、180 d和 1 年的死亡风险无相关性(均为P>0.05).敏感性分析发现供者年龄<18 岁、18～33 岁、34～49 岁、≥50 岁的肺移植受者术后 30、90、180 d和 1 年死亡风险差异均无统计学意义(均为P>0.05).结论 本研究未观察到供者年龄对IPF患者肺移植术后短期生存存在影响,综合考虑供者机械通气时间、氧合指数、感染等因素后,可考虑扩大肺移植供者年龄范围.

OBJECTIVETo investigate the risk factors of early death after lung transplantation in patients with idiopathic pulmonary fibrosis (IPF) complicated with pulmonary arterial hypertension (PAH).METHODSA retrospective cohort study was conducted. The clinical data of 134 patients with IPF and PAH who underwent lung transplantation at Wuxi People's Hospital Affiliated to Nanjing Medical University from January 2017 to December 2020 were collected. The donor's gender, age, duration of mechanical ventilation, and cold ischemia time, the recipient's gender, age, body mass index (BMI), smoking, history of hypertension and diabetes, preoperative usage of hormones, mean pulmonary arterial pressure (mPAP), cardiac echocardiography and cardiac function, serum creatinine (SCr), N-terminal pro-brain natriuretic peptide (NT-proBNP) as well as surgical type, extracorporeal membrane oxygenation (ECMO) treatment, duration of operation, and plasma and red blood cell infusion ratio were collected. The cumulative survival rates of patients at 30, 60, and 180 days after lung transplantation were calculated by Kaplan-Meier method. The univariate and multivariate Cox proportional hazards regression models were used to analyze the effects of donor, recipient, and surgical factors on early survival in donors after lung transplantation.RESULTSThe majority of donors were male (80.6%). There was 63.4% of the donors older than 35 years old, 80.6% of the donors had mechanical ventilation duration less than 10 days, and the median cold ischemia time was 465.00 (369.25, 556.25) minutes. The recipients were mainly males (83.6%). Most of the patients were younger than 65 years old (70.9%). Most of them had no hypertension (75.4%) or diabetes (67.9%). The median mPAP of recipients was 36 (30, 43) mmHg (1 mmHg ≈ 0.133 kPa). There were 73 patients with single lung transplantation (54.5%), and 61 with double lung transplantation (45.5%). The survival rates of 134 IPF patients with PAH at 30, 60, 180 days after lung transplantation were 81.3%, 76.9%, and 67.4%, respectively. Univariate Cox proportional risk regression analysis showed that recipient preoperative use of hormone [hazard ratio (HR) = 2.079, 95% confidence interval (95%CI) was 1.048-4.128], mPAP ≥ 35 mmHg (HR = 2.136, 95%CI was 1.129-4.044), NT-proBNP ≥ 300 ng/L (HR = 2.411, 95%CI was 1.323-4.392), New York Heart Association (NYHA) cardiac function classification III-IV (HR = 3.021, 95%CI was 1.652-5.523) were the risk factors of early postoperative death in patients with IPF complicated with PAH (all P < 0.05). In the multivariable Cox proportional risk regression analysis, recipient preoperative hormone usage (model 1: HR = 2.072, 95%CI was 1.044-4.114, P = 0.037; model 2: HR = 2.098, 95%CI was 1.057-4.165, P = 0.034), NT-proBNP ≥ 300 ng/L (HR = 2.246, 95%CI was 1.225-4.116, P = 0.009) and NYHA cardiac function classification III-IV (HR = 2.771, 95%CI was 1.495-5.134, P = 0.001) were independent risk factors of early postoperative death in patients with IPF.CONCLUSIONSPreoperative hormone usage, NT-proBNP ≥ 300 ng/L, NYHA cardiac function classification III-IV are independent risk factors for early death in patients with IPF and PAH after lung transplantation. For these patients, attention should be paid to optimize their functional status before operation. Preoperative reduction of receptor hormone usage and improvement of cardiac function can improve the early survival rate of such patients after lung transplantation.

Objective:To explore the effect of acute kidney injury(AKI)on near-term survival after lung transplantation(LT)in patients with idiopathic pulmonary fibrosis(IPF).Methods:Through consulting electronic medical records, anesthetic modes and Chinese Lung Transplant Registration System, clinical data are retrospectively reviewed for 275 IPF patients undergoing LT at Affiliated Wuxi People's Hospital of Nanjing Medical University from January 2017 to April 2021.According to the diagnostic criteria of Kidney Disease: Improving Global Outcomes(KDIGO), they are divided into two groups of AKI(169 cases)and non-AKI(106 cases).Perioperative findings of two groups are recorded.Then univariate and multivariate Cox regression models are employed for determining whether or not inter-group differences existed in survival rates post-LT.Also AKI is staged according to the KDIGO.And the effect of stage 1/2/3 AKI on near-term postoperative prognosis is examined.Results:The differences are significantly different in recipient gender, creatinine, 6-minute walking test, forced vital capacity(FVC), lung allocation score, oxygenation index, N-terminal pro-brain natriuretic peptide(NT-Pro BNP), preoperative hormone use and volume of crystal infusion( P<0.05).After multivariate Cox regression correcting for covariates, no statistical significance exists in effect of AKI stage 1 on near-term postoperative survival rate( P<0.05).AKI stage 2/3 still has statistical significance in risk of mortality at Day 30/90/180/365 post-operation( P>0.05). Conclusions:As a common complication post-LT, AKI significantly affects near-term postoperative prognosis of transplant IPF patients.Stage 2/3 AKI impacts near-term postoperative survival while stage 1 AKI is not associated with higher mortality.

Objective:To explore the early prognosis on patient of idiopathic pulmonary fibrosis (IPF) combined with different degrees of pulmonary arterial hypertension (PAH) undertake lung transplantation (LTx).Methods:From January 2017 to December 2020, the clinical data of 134 patients with IPF who underwent LTx in Wuxi People's Hospital were analyzed retrospectively. According to the average pulmonary artery pressure detected by right cardiac catheter before operation, the patients were divided into mild PAH group (63 cases), moderate PAH group (47 cases) and severe PAH group (24 cases). The donor data and the recipient's preoperative, intraoperative and postoperative data were collected; the postoperative survival curve to analyze early survival among the three patient groups.Results:With the increase of pulmonary artery pressure, the rate of abnormal right ventricular function increased, the end diastolic diameter of left ventricle decreased before operation, and the rate of using veno-arterial extracorporeal membrane oxygenation (V-A ECMO) increased during the surgery ( P<0.05). Multivariate analysis found that combined severe PAH had significant effects on primary graft dysfunction (Primary graft dysfunction, PGD), retracheal intubation or tracheotomy, hypovolemic shock within 72 h, and 6-month survival after LTx. The survival surve showed that 30-day survival rates of patients with IPF complicated with mild, moderate and severe PAH were 85.7%, 80.8% and 66.7% respectively, and the 6-month survival rates were 80.9%, 74.0% and 62.2%, respectively. Conclusion:Patient of IPF combined with different degrees of PAH had a significant impact on cardiac function and intraoperative ECMO selection of LTx, and severe PAH could significantly reduce the early survival rate after LTx.

肺缺血再灌注损伤(LIRI)是发生在肺移植术后的一种急性肺损伤(ALI),是术后发生原发性移植物功能障碍(PGD)的主要危险因素.近年研究发现乌司他丁、伊马替尼、前列地尔等多种临床药物有减轻LIRI的作用.作者综述已有药物对LIRI的保护作用及其机制,为LIRI预防和治疗的进一步研究提供思路.

Background and Objective:Ischemia-reperfusion (IR) injury is the cause of morbidity and mortality in a variety of diseases and surgical procedures including organ transplantation surgeries, acute coronary syndrome, strokes, and limb injuries. IR injury causes dysfunction of tissues and organs, and oxidative stress plays an important role in driving this process. Curcumin (CUR), a polyphenolic compound derived from turmeric, protects against IR injury by alleviating oxidative stress, reactive oxygen species (ROS) inflammation, apoptosis, and fibrosis. We review the protective effects of CUR against IR.Methods:We searched PubMed, ScienceDirect, and Web of Science databases using the keywords: ischemic reperfusion, CUR and summarized the results.Key Content and Findings:The effects of CUR during IR have been reported for animal models in vitro and in vivo and the compound has been shown in various organs by suppression of oxidative stress, prevention of inflammation, inhibition of apoptosis and autophagy. CUR with nanocarriers showed many advantages than free CUR in the treatment of IR injury, such as improved bioavailability, sustained-release, better water solubility, better target organ accumulation, improved permeability across the blood-brain-barrier and more effective.Conclusions:Nanotechnology offers significant improvements and promising strategies to improve drug delivery to IR-injured tissues and achieve the desired protective effects. Thus, it is necessary to promote further clinical trials to promote the clinical application of CUR with nanocarriers.

缺血再灌注(ischemia reperfusion,I/R)引起的组织损伤是多种病理改变、疾病发生及死亡的主要原因.导致I/R损伤的潜在机制包括氧化应激/活性氧增加、炎症反应、线粒体功能障碍、细胞死亡和自噬异常等.二甲双胍(metformin,MET)是治疗2型糖尿病的一线药物,其在延缓衰老和抗肿瘤等方面具有保护作用.多项研究表明,MET对心肌、脑、肾、肝、肠和卵巢的I/R损伤也具有保护作用.本文作者通过综述MET对I/R损伤保护作用的机制及临床研究进展,为后续进一步研究MET在预防和治疗I/R损伤方面提供思路.

Objective:To compare the effect of extracorporeal membrane oxygenation(ECMO)on pulmonary transplantation(LTx)in patients with idiopathic pulmonary fibrosis(IPF)complicated with pulmonary hypertension(PH).Methods:From January 2017 to December 2020, clinical data were retrospectively reviewed for 112 IPF patients complicated with PH undergoing LTx assisted by venous ECMO(VV-ECMO group, n=68)or venous arterial ECMO(VA-ECMO group, n=44). Gender, age, mechanical ventilation time, oxygenation index, cold ischemic time, preoperative gender, age, smoking history, PO 2, PCO 2, PH degree, NYHA cardiac function grade, right cardiac function, ejection fraction(EF)and complications(hypertension & diabetes)of two groups were compared. Intraoperative approach, operative duration, ECMO transfer time, blood loss, blood transfusion, urine volume, postoperative blood transfusion, mechanical ventilation time, ICU stay time, re-thoracotomy, pulmonary infection, primary graft dysfunction(PGD)and renal insufficiency were recorded. And the effects of two different diversion modes on early postoperative complications and short-term outcomes of LTx were further analyzed by multiple factors. Cox proportional risk model was employed for comparing VV-ECMO and VA-ECMO flow patterns with factors related to recipient survival after transplantation. Results:The preoperative PO 2 of 58.3(51.3, 72.0)mmHg was significantly lower in VV-ECMO bypass group than that of 73.2(63.3, 96.8)mmHg in VA-ECMO group and the difference was statistically significant( P<0.006). Compared with VV-ECMO group, 24(54.5%), 15(34.1%)and 22(50.0%)had NYHA class Ⅲ, severe PH and preoperative right heart enlargement in VA-ECMO group respectively and the differences were statistically significant compared with 17(25.0%), 6(8.8%)and 16(23.5%)in VV-ECMO group( P<0.05 for all). No significant inter-group differences existed in postoperative PGD, postoperative mechanical ventilation time(≥3 d), pulmonary infection, postoperative thoracotomy ratio, postoperative renal insufficiency, ICU stay, hospital stay and other aspects( P>0.05). And 6-month postoperative survival rates of VV-ECMO and VA-ECMO groups were 80.9% and 61.4%, respectively and no significant inter-group difference existed in short-term survival rate(6 months)after adjustment by multivariate Cox regression model( P>0.05). Multivariate statistics indicated that the risk of delayed postoperative withdrawal was 14.452-fold higher in VV-ECMO group than in VA-ECMO group and the inter-group difference was statistically significant(95% CI: 2.448-85.323, P=0.03). Conclusions:No differences exist in postoperative complications or short-term survival rate between IPF recipients with mild PH on VV-ECMO mode and IPF recipients with severe PH on VA-ECMO mode. VV-ECMO flow reversal can delay the transplant back-off time.

肺移植是治疗终末期肺疾病的唯一有效方式,但肺移植受者的早期预后远不如其他实体器官移植受者,其中原发性移植物功能障碍(PGD)是影响其预后的主要原因之一.PGD是肺移植术后早期发生的一种急性肺损伤,是导致肺移植受者术后早期死亡的主要原因.肺移植受者术后PGD发生的危险因素包括供者、受者、手术等多方面.本文对肺移植术后发生PGD的危险因素进行综述,旨在为临床提供参考.