Ex Vivo Lung Perfusion of Cardiac-death Donor Lung in Pigs

Background : Lung transplantation (LTx) is a life-saving treatment for patients with end-stage lung disease; however, the shortage of donor lungs has been a major limiting factor to increasing the number of LTx. Growing experience following LTx using donor lungs after cardiac death (DCD) has been promising, although concerns remain. The purpose of this study was to develop a DCD lung harvest model using an ex vivo lung perfusion (EVLP) system and to assess the function of presumably damaged lungs harvested from the DCD donor in pigs. Methods : The 40 kg pigs were randomly divided into the control group with no ischemic lung injury (n=5) and the study group (n=5), which had 1 hour of warm ischemic lung injury after cardiac arrest. Harvested lungs were placed in the EVLP circuit and oxygen capacities (OC), pulmonary vascular resistance (PVR), and peak airway pressure (PAP) were evaluated every hour for 4 hours. At the end of EVLP, specimens were excised for pathologic review and wet/dry ratio. Results : No statistically significant difference in OC (P=0.353), PVR (P=0.951), and PAP (P=0.651) was observed in both groups. Lung injury severity score (control group vs. study group: 0.700±0.303 vs. 0.870±0.130; P=0.230) and wet/dry ratio (control group vs. study group: 5.89±0.97 vs. 6.20±0.57; P=0.560) also showed no statistically significant difference between the groups. Conclusions : The function of DCD lungs assessed using EVLP showed no difference from that of control lungs without ischemic injury; therefore, utilization of DCD lungs can be a new option to decrease the number of deaths on the waiting list.ope

Perioperative factors associated with 1-year mortality after lung transplantation: a single-center experience in Korea

Background: Most studies about the risk factors of 1-year mortality after lung transplantation were performed on non-Asians. This study aimed to evaluate the perioperative factors related to the 1-year mortality after lung transplantation in Korea. Methods: Sixty-eight consecutive patients who underwent lung transplantation without preoperative extracorporeal membrane oxygenation treatment at 1 tertiary hospital in South Korea between October 24, 2012, and October 16, 2015, were analyzed retrospectively. Results: Forty-four patients (64.7%) lived for >1 year after lung transplantation. The median age of all patients was 55 years (range, 16-75 years), and men accounted for 57.4%. The major cause of lung transplantation was idiopathic pulmonary fibrosis (48.5%); the other causes were interstitial lung disease related to connective tissue disease (17.6%) and bronchiolitis obliterans after stem cell transplantation (14.7%). In univariate analysis, higher median age (52 vs. 61.5 years, P5.5 higher than the preoperative DNI (22.7% vs. 70.8%, P<0.001) were significantly related to 1-year mortality. After adjustments, old age, postoperative increased DNI, and need for RRT after transplantation were the independent perioperative risk factors for 1-year mortality after lung transplantation. Conclusions: Recipients with advanced age should be carefully selected, and patients who need RRT or with increased DNI after transplantation should be managed accordingly.ope

Permissive fluid volume in adult patients undergoing extracorporeal membrane oxygenation treatment

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a cardiorespiratory support technique for patients with circulatory or pulmonary failure. Frequently, large-volume fluid resuscitation is needed to ensure sufficient extracorporeal blood flow in patients initiating ECMO. However, excessive overhydration is known to increase mortality in critically ill patients. Therefore, in order to define a tolerant volume range in patients undergoing ECMO treatment, the association between cumulative fluid balance (CFB) and outcome was evaluated in patients undergoing ECMO. METHODS: This retrospective multicenter cohort study was conducted with 723 patients who underwent ECMO in three tertiary care hospitals between 2005 and 2016. CFB was calculated as total fluid input minus total fluid output during the first 3 days from ECMO initiation. The patients were divided into groups that initiated ECMO owing to cardiovascular disease (CVD)-related or non-cardiovascular disease (non-CVD)-related causes. The primary endpoint was mortality within 90 days after ECMO commencement. RESULTS: Totals of 406 and 317 patients were included in the CVD and non-CVD groups, respectively. In the CVD group, the mean age was 58.4 ± 17.7 years, and 68.2% were male. The mean age was 55.7 ± 15.7 years, and 65.3% were male in the non-CVD group. The median CFB values were 64.7 and 53.5 ml/kg in the CVD and non-CVD groups, respectively. Multivariable analysis using Cox proportional hazards models revealed a significantly increased risk of 90-day mortality in patients with higher CFB values in both the CVD and non-CVD groups. However, the risks were elevated only in the two CFB quartile groups with the largest CFB amounts. Cubic spline models showed that mortality risk began to increase significantly when CFB was 82.3 ml/kg in the CVD group. In patients with respiratory diseases, the mortality risk increase was significant for those with CFB levels above 189.6 ml/kg. CONCLUSIONS: Mortality risk did not increase until a certain level of fluid overload was reached in patients undergoing ECMO. Adequate fluid resuscitation is critical to improving outcomes in these patients.ope

Implications of Plasma Renin Activity and Plasma Aldosterone Concentration in Critically Ill Patients with Septic Shock

Background : The renin-angiotensin-aldosterone system is closely associated with volume status and vascular tone in septic shock. The present study aimed to assess whether plasma renin activity (PRA) and plasma aldosterone concentration (PAC) measurements compared with conventional severity indicators are associated with mortality in patients with septic shock. Methods : We evaluated 105 patients who were admitted for septic shock. Plasma levels of the biomarkers PRA and PAC, the PAC/PRA ratio, C-reactive protein (CRP) level, and cortisol level on days 1, 3, and 7 were serially measured. During the intensive care unit stay, relevant clinical information and laboratory results were recorded. Results : Patients were divided into two groups according to 28-day mortality: survivors (n = 59) and non-survivors (n = 46). The survivor group showed lower PRA, PAC, Acute Physiologic and Chronic Health Evaluation (APACHE) II score, and Sequential Organ Failure Assessment (SOFA) score than did the non-survivor group (all P < 0.05). The SOFA score was positively correlated with PRA (r = 0.373, P < 0.001) and PAC (r = 0.316, P = 0.001). According to receiver operating characteristic analysis, the areas under the curve of PRA and PAC to predict 28-day mortality were 0.69 (95% confidence interval [CI], 0.58 to 0.79; P = 0.001) and 0.67 (95% CI, 0.56 to 0.77; P = 0.003), respectively, similar to the APACHE II scores and SOFA scores. In particular, the group with PRA value ≥3.5 ng ml-1 h-1 on day 1 showed significantly greater mortality than did the group with PRA value <3.5 ng ml-1 h-1 (log-rank test, P < 0.001). According to multivariate analysis, SOFA score (hazard ratio, 1.11; 95% CI, 1.01 to 1.22), PRA value ≥3.5 ng ml-1 h-1 (hazard ratio, 3.25; 95% CI, 1.60 to 6.60), previous history of cancer (hazard ratio, 3.44; 95% CI, 1.72 to 6.90), and coronary arterial occlusive disease (hazard ratio, 2.99; 95% CI, 1.26 to 7.08) were predictors of 28-day mortality. Conclusions : Elevated PRA is a useful biomarker to stratify the risk of critically ill patients with septic shock and is a prognostic predictor of 28-day mortality.ope

Clinical implications of the plasma EphA2 receptor level in critically ill patients with septic shock

The Eph/ephrin receptor ligand system is known to play a role in inflammation induced by infection, injury, and inflammatory diseases. The present study aimed to evaluate plasma EphA2 receptor levels in critically ill patients with sepsis. This study was a prospective cohort study evaluating samples and clinical data from the medical intensive care unit (MICU) of a 2000-bed university tertiary referral hospital in South Korea. Positive correlations of the plasma EphA2 receptor level with the acute physiology and chronic health evaluation (APACHE) II score and the sequential organ failure assessment (SOFA) score were observed. The area under the curve (AUC) for the plasma EphA2 receptor level on a receiver operating characteristic curve was 0.690 (95% confidence interval [CI], 0.608-0.764); the AUCs for the APACHE II score and SOFA scores were 0.659 (95% CI, 0.576-0.736) and 0.745 (95% CI, 0.666-0.814), respectively. A Cox proportional hazard model identified an association between an increased plasma EphA2 receptor level (>51.5 pg mL-1) and increased risk of 28-day mortality in the MICU (hazard ratio = 3.22, 95% CI, 1.709-6.049). An increased plasma EphA2 receptor level was associated with sepsis severity and 28-day mortality among sepsis patients.ope

Comparison of short-term outcomes for connective tissue disease-related interstitial lung disease and idiopathic pulmonary fibrosis after lung transplantation

Background: Pulmonary involvement is common in connective tissue disease (CTD), and respiratory failure is a major cause of morbidity and mortality in CTD-related interstitial lung disease (CTD-ILD). Lung transplantation is thus important for these patients. However, survival, outcomes, and management of these patients after transplantation have been debated. The aim of this study was to evaluate the outcomes for CTD-ILD compared to those for idiopathic pulmonary fibrosis (IPF) after lung transplantation. Methods: We performed a single-centre retrospective study of 62 patients with CTD-ILD or IPF who underwent lung transplantation at a tertiary hospital in South Korea between October 2012 and October 2016. Results: Patients with CTD-ILD (n=15) were younger (46 vs. 60 years, P=0.001) and were less likely to be male (33.3% vs. 76.6%, P=0.004) than were patients with IPF (n=47). The 1-year cumulative survival rate was 80.0% for CTD-ILD and 59.6% for IPF (log-rank P=0.394). There was no difference in the cumulative survival rate (log-rank P=0.613) of age- and sex-matched patients with CTD-ILD (n=15) and IPF (n=15). The incidence of primary graft dysfunction was similar (P=0.154), and 2 (18.2%) patients developed possible CTD flare. Conclusions: Patients with CTD-ILD and those with IPF who underwent lung transplantation had similar survival rates.ope

The influence of protein provision in the early phase of intensive care on clinical outcomes for critically ill patients on mechanical ventilation

Background and objectives: Mechanically ventilated patients often face progressive and rapid losses of body mass and muscle because of hypermetabolism and increased protein catabolism. To investigate the impact of adequate nutritional provision during the early phase of intensive care unit (ICU) admission on the clinical outcomes in patients with medical illnesses receiving mechanical ventilation support. Methods and study design: Two hundred and eleven mechanically ventilated patients admitted to a 30-bed medical ICU were included. Three groups, based on nutrition intake, were examined: adequate protein intake (aPI), n=34; insufficient protein intake/ adequate energy intake (iPI/aEI), n=25; insufficient protein and energy intake (iPI/iEI), n=152. Results: Patients' mean age was 65±14 years; body mass index, 22±4; Acute Physiology and Chronic Health Evaluation II score, 24±7. The aPI group had significantly lower rates of in-ICU (14.7%) and in-hospital (23.5%) mortality than patients with insufficient protein intake: in-ICU mortality, iPI/aEI, 36%; iPI/iEI, 44.1% (p=0.006); in-hospital mortality, iPI/aEI, 56.0%; iPI/iEI, 52.0% (p=0.008). In the multivariate analysis, the hazard ratios (95% confidence intervals) for 60-day survival were 2.59 (1.02-6.59; p=0.046) and 2.88 (1.33-6.26; p=0.008) for the iPI/aEI and iPI/iEI groups, respectively. Conclusions: Despite possible selection bias owing to the retrospective nature of the study, achievement of >90% of target protein intake was associated with improved ICU outcomes in mechanically ventilated critically ill patients, based on real-world clinical circumstances.ope

Feasibility of Immediate in-Intensive Care Unit Pulmonary Rehabilitation after Lung Transplantation: A Single Center Experience

Background Physical function may influence perioperative outcomes of lung transplantation. We investigated the feasibility of a pulmonary rehabilitation program initiated in the immediate postoperative period at an intensive care unit (ICU) for patients who underwent lung transplantation. Methods We retrospectively evaluated 22 patients who received pulmonary rehabilitation initiated in the ICU within 2 weeks after lung transplantation at our institution from March 2015 to February 2016. Levels of physical function were graded at the start of pulmonary rehabilitation and then weekly throughout rehabilitation according to criteria from our institutional pulmonary rehabilitation program: grade 1, bedside (G1); grade 2, dangling (G2); grade 3, standing (G3); and grade IV, gait (G4). Results The median age of patients was 53 years (range, 25 to 73 years). Fourteen patients (64%) were males. The initial level of physical function was G1 in nine patients, G2 in seven patients, G3 in four patients, and G4 in two patients. Patients started pulmonary rehabilitation at a median of 7.5 days (range, 1 to 29 days) after lung transplantation. We did not observe any rehabilitation-related complications during follow-up. The final level of physical function was G1 in six patients, G3 in two patients, and G4 in 14 patients. Fourteen of the 22 patients were able to walk with or without assistance, and 13 of them maintained G4 until discharge; the eight remaining patients never achieved G4. Conclusions Our results suggest the feasibility of early pulmonary rehabilitation initiated in the ICU within a few days after lung transplantation.ope

Prevalence of pre-transplant anti-HLA antibodies and their impact on outcomes in lung transplant recipients

BACKGROUND: Previous studies have suggested that antibodies against human leukocyte antigen (HLA) are associated with worse outcomes in lung transplantation. However, little is known about the factors associated with outcomes following lung transplantation in Asia. Accordingly, we investigated the prevalence of anti-HLA antibodies in recipients before transplantation and assessed their impact on outcomes in Korea. METHODS: A single-center retrospective study was conducted. The study included 76 patients who received a lung transplant at a tertiary hospital in South Korea between January 2010 and March 2015. RESULTS: Nine patients (11.8%) had class I and/or class II panel-reactive antibodies greater than 50%. Twelve patients (15.8%) had anti-HLA antibodies with a low mean fluorescence intensity (MFI, 1000-3000), 7 (9.2%) with a moderate MFI (3000-5000), and 12 (15.8%) with a high MFI (> 5000). Ten patients (13.2%) had suspected donor-specific antibodies (DSA), and 60% (6/10) of these patients had antibodies with a high MFI. In an analysis of outcomes, high-grade (>/=2) primary graft dysfunction (PGD) was more frequent in patients with anti-HLA antibodies with moderate-to-high MFI values than in patients with low MFI values (39.4% vs. 14.0%, p = 0.011). Of 20 patients who survived longer than 2 years and evaluated for pBOS after transplant, potential bronchiolitis obliterans syndrome (pBOS) or BOS was more frequent in patients with anti-HLA antibodies with moderate-to-high MFI than in patients with low MFI, although this difference was not statistically significant (50.0% vs. 14.3%, p = 0.131). CONCLUSIONS: The prevalence of anti-HLA antibodies with high MFI was not high in Korea. However, the MFI was relatively high in patients with DSA. Anti-HLA antibodies with moderate-to-high MFI values were related to high-grade PGD. Therefore, recipients with high MFI before lung transplantation should be considered for desensitization and close monitoring.ope

The Effects of Retinoic Acid and MAPK Inhibitors on Phosphorylation of Smad2/3 Induced by Transforming Growth Factor β1

BACKGROUND: Transforming growth factor β (TGF-β), retinoic acid (RA), p38 mitogen-activated protein kinase (MAPK), and MEK signaling play critical roles in cell differentiation, proliferation, and apoptosis. We investigated the effect of RA and the role of these signaling molecules on the phosphorylation of Smad2/3 (p-Smad2/3) induced by TGF-β1. METHODS: A549 epithelial cells and CCD-11Lu fibroblasts were incubated and stimulated with or without all-trans RA (ATRA) and TGF-β1 and with MAPK or MEK inhibitors. The levels of p-Smad2/3 were analyzed by western blotting. For animal models, we studied three experimental mouse groups: control, bleomycin, and bleomycin+ATRA group. Changes in histopathology, lung injury score, and levels of TGF-β1 and Smad3 were evaluated at 1 and 3 weeks. RESULTS: When A549 cells were pre-stimulated with TGF-β1 prior to RA treatment, RA completely inhibited the p-Smad2/3. However, when A549 cells were pre-treated with RA prior to TGF-β1 stimulation, RA did not completely suppress the p-Smad2/3. When A549 cells were pre-treated with MAPK inhibitor, TGF-β1 failed to phosphorylate Smad2/3. In fibroblasts, p38 MAPK inhibitor suppressed TGF-β1-induced p-Smad2. In a bleomycin-induced lung injury mouse model, RA decreased the expression of TGF-β1 and Smad3 at 1 and 3 weeks. CONCLUSION: RA had inhibitory effects on the phosphorylation of Smad induced by TGF-β1 in vitro, and RA also decreased the expression of TGF-β1 at 1 and 3 weeks in vivo. Furthermore, pre-treatment with a MAPK inhibitor showed a preventative effect on TGF-β1/Smad phosphorylation in epithelial cells. As a result, a combination of RA and MAPK inhibitors may suppress the TGF-β1-induced lung injury and fibrosis.ope