Toshiyuki Mizota

Living-donor lobar lung transplantation provides similar survival to cadaveric lung transplantation even for very ill patients †

OBJECTIVES Living-donor lobar lung transplantation (LDLLT) has been performed as a life-saving procedure for critically ill patients who are unlikely to survive the long wait for cadaveric lungs. The purpose of this study was to compare the preoperative condition and outcome of LDLLT patients with those of conventional cadaveric lung transplantation (CLT) patients. METHODS A new lung transplant programme was established in 2008 at Kyoto University. Between June 2008 and January 2014, we performed 79 lung transplants, including 42 LDLLTs (10 single, 32 bilateral) and 37 CLTs (22 single, 15 bilateral). Data collected included pre- and perioperative variables and mid-term survival. All data were analysed retrospectively as of January 2014. RESULTS The majority of patients were female (57.1%) in the LDLLT group and male (64.9%) in the CLT group. The average age was similar (36.6 ± 20.7 vs 39.7 ± 12.6 years, P = 0.42) between the two groups. Preoperatively, interstitial lung disease was more common in LDLLT patients than in CLT patients (47.6 vs 24.3%, P = 0.048); prior haematopoietic stem cell transplantation was performed more often in LDLLT patients than in CLT patients (33.3 vs 13.5%, P = 0.040) and there were more steroid-dependent LDLLT patients than CLT patients (64.3 vs 29.7%, P = 0.0022). Based on preoperative criteria of lower body mass index (17.2 ± 4.0 vs 19.3 ± 3.3 kg/m(2), P = 0.013), less ambulatory ability (42.9 vs 86.5%, P = 0.0001) and more ventilator dependence (11.9 vs 2.7%, P = 0.12), LDLLT patients were more debilitated than CLT patients. LDLLT patients required longer postoperative mechanical ventilation than CLT patients (15.6 ± 16.2 vs 8.5 ± 8.1 days, P = 0.025). However, 1- and 3-year survival rates were similar between the two groups (89.7 and 86.1% vs 88.3 and 83.1%, P = 0.55). All living donors returned to their previous lifestyles without restriction. CONCLUSIONS Although LDLLT patients were in a worse preoperative condition than CLT patients, LDLLT patients demonstrated survival rates similar to CLT patients. LDLLT is a viable option for patients too ill to survive a long waiting time for cadaveric donors.

Outcomes of various transplant procedures (single, sparing, inverted) in living-donor lobar lung transplantation

Objectives: In standard living‐donor lobar lung transplantation (LDLLT), the right and left lower lobes from 2 healthy donors are implanted. Because of the difficulty encountered in finding 2 donors with ideal size matching, various transplant procedures have been developed in our institution. The purpose of this retrospective study was to compare outcomes of nonstandard LDLLT with standard LDLLT. Methods: Between June 2008 and January 2016, we performed 65 LDLLTs for critically ill patients. Functional size matching was performed by estimating graft forced vital capacity based on the donors measured forced vital capacity and the number of pulmonary segments implanted. For anatomical size matching, 3‐dimensional computed tomography volumetry was performed. In cases of oversize mismatch, single‐lobe transplant or downsizing transplant was performed. In cases of undersize mismatch, native upper lobe sparing transplant or right‐left inverted transplant was performed. In right‐left inverted transplants, the donors right lower lobe was inverted and implanted into the recipients left chest cavity. Results: Twenty‐nine patients (44.6%) received nonstandard LDLLT, including 12 single‐lobe transplants, 7 native upper lobe sparing transplants, 6 right‐left inverted transplants, 2 sparing + inverted transplants, and 2 others. Thirty‐six patients (57.4%) received standard LDLLT. Three‐ and five‐year survival rates were similar between the 2 groups (89.1% and 76.6% after nonstandard LDLLT vs 78.0% and 71.1% after standard LDLLT, P = .712). Conclusions: Various transplant procedures such as single, sparing and inverted transplants are valuable options when 2 donors with ideal size matching are not available for LDLLT.

Morphine induces DNA damage and P53 activation in CD3+ T cells.

BACKGROUND Morphine has been shown to affect the function of immune system, but the precise mechanism remains to be elucidated. The present study was aimed to clarify the mechanism for the morphine-induced immune suppression by analyzing the direct effect of morphine on human CD3+ T cells. METHODS To identify genes up-regulated by action of morphine on the opioid receptor expressed in CD3+ T cells, PCR-select cDNA subtraction was performed by the use of total RNA from human CD3+ T cells treated with morphine in the presence and absence of naloxone. RESULTS We show that p53 and damage-specific DNA binding protein 2 (ddb2) genes are up-regulated by morphine in a naloxone-sensitive manner. Furthermore, the results indicate that DNA damage, quantified by apurinic-apyrimidinic site counting assay and phosphorylation of Ser-15 in P53 protein, is induced in CD3+ T cells by morphine in a naloxone-sensitive manner. GENERAL SIGNIFICANCE Because it was shown that only the kappa opioid receptor gene is expressed in CD3+ T cells in the opioid receptor family, the present study suggests that morphine induces DNA damage through the action on the kappa opioid receptor, which leads to immune suppression by activation of P53-mediated signal transduction.

Intraoperative oliguria predicts acute kidney injury after major abdominal surgery

Background The threshold of intraoperative urine output below which the risk of acute kidney injury (AKI) increases is unclear. The aim of this retrospective cohort study was to investigate the relationship between intraoperative urine output during major abdominal surgery and the development of postoperative AKI and to identify an optimal threshold for predicting the differential risk of AKI. Methods Perioperative data were collected retrospectively on 3560 patients undergoing major abdominal surgery (liver, colorectal, gastric, pancreatic, or oesophageal resection) at Kyoto University Hospital. We evaluated the relationship between intraoperative urine output and the development of postoperative AKI as defined by recent guidelines. Logistic regression analysis was performed to adjust for patient and operative variables, and the minimum P -value approach was used to determine the threshold of intraoperative urine output that independently altered the risk of AKI. Results The overall incidence of AKI in the study population was 6.3%. Using the minimum P -value approach, a threshold of 0.3 ml kg -1 h -1 was identified, below which there was an increased risk of AKI (adjusted odds ratio, 2.65; 95% confidence interval, 1.77-3.97; P <0.001). The addition of oliguria <0.3 ml kg -1 h -1 to a model with conventional risk factors significantly improved risk stratification for AKI (net reclassification improvement, 0.159; 95% confidence interval, 0.049-0.270; P =0.005). Conclusions Among patients undergoing major abdominal surgery, intraoperative oliguria <0.3 ml kg -1 h -1 was significantly associated with increased risk of postoperative AKI.

Relationship Between Intraoperative Hypotension and Acute Kidney Injury After Living Donor Liver Transplantation: A Retrospective Analysis

OBJECTIVE Acute kidney injury (AKI) is common after liver transplantation (LT) and has a significant impact on outcomes. Although several risk factors for post-LT AKI have been identified, the effect of intraoperative hemodynamic status on post-LT AKI remains unknown. Therefore, the authors aimed to investigate the relationship between hemodynamic parameters during LT and postoperative AKI. DESIGN A retrospective observational study. SETTING University hospital. PARTICIPANTS Patients who underwent living donor LT (n = 231). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Severe AKI (stages 2-3 according to recent guidelines) was the primary outcome. Multivariable logistic regression analysis was used to control for confounding variables to obtain the independent relationship between intraoperative hemodynamic parameters (mean arterial pressure [MAP] and cardiac index) and severe AKI. The prevalence of severe AKI was 30.7%. Nadir MAP during the surgery was independently predictive of severe AKI (adjusted odds ratio, 2.11 [95% confidence interval, 1.32-3.47] per 10-mmHg decrease; p = 0.002). Subgroup analyses based on various patient or operative variables and extensive sensitivity analyses showed substantially similar results. Severe hypotension (MAP<40 mmHg), even for fewer than 10 minutes, was related significantly to severe AKI (adjusted odds ratio, 3.80 [95% confidence interval, 1.17-12.30]; p = 0.026). In contrast, nadir cardiac index was not related significantly to severe AKI. CONCLUSIONS The authors found an independent relationship between degree of intraoperative hypotension and risk of severe AKI in living donor LT recipients. Severe hypotension, even for a short duration, was related significantly to severe AKI.

Dual modulation of the T-cell receptor-activated signal transduction pathway by morphine in human T lymphocytes

PurposeIn this study, we aimed to investigate the effect of morphine on the activation of extracellular signal-regulated kinase (ERK) and nuclear factor-κB (NF-κB), both of which play crucial roles in T-cell activation.MethodsHuman CD3+ T cells and Jurkat T cells were stimulated by anti-CD3 antibody or phorbol 12-myristate 13-acetate plus ionomycin with or without 24-h pretreatment with morphine. Activation of ERK was assessed by immunoblot analysis of phosphorylated ERK. Activation of the NF-κB signaling pathway was examined by analyzing nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) phosphorylation using immunoblotting, and interleukin-2 (IL-2) gene expression using quantitative real-time reverse-transcriptase polymerase chain reaction.ResultsMorphine pretreatment enhanced ERK phosphorylation, but inhibited IκBα phosphorylation and IL-2 gene expression in activated T cells. The effects of morphine on ERK phosphorylation and IL-2 gene expression were not antagonized by naloxone. We detected κ-opioid receptor transcript in T cells, but U50,488, a κ-receptor-selective agonist, did not enhance ERK phosphorylation.ConclusionMorphine enhances ERK signaling, whereas it inhibits NF-κB signaling in activated human T cells. These effects of morphine are unlikely to be mediated by known opioid receptors.

Graft dysfunction immediately after reperfusion predicts short-term outcomes in living-donor lobar lung transplantation but not in cadaveric lung transplantation

OBJECTIVES Primary graft dysfunction (PGD) is a major cause of early morbidity and mortality after cadaveric lung transplantation (CLT). This study examined the incidence, time course and predictive value of PGD after living-donor lobar lung transplantation (LDLLT). METHODS We retrospectively investigated 75 patients (42 with LDLLT and 33 with CLT) who underwent lung transplantation from January 2008 to December 2013. Patients were assigned PGD grades at six time points, as defined by the International Society for Heart and Lung Transplantation: immediately after final reperfusion, upon arrival at the intensive care unit (ICU), and 12, 24, 48 and 72 h after ICU admission. RESULTS The incidence of severe (Grade 3) PGD at 48 or 72 h after ICU admission was similar for LDLLT and CLT patients (16.7 vs 12.1%; P = 0.581). The majority of the LDLLT patients having severe PGD first developed PGD immediately after reperfusion, whereas more than half of the CLT patients first developed severe PGD upon ICU arrival or later. In LDLLT patients, severe PGD immediately after reperfusion was significantly associated with fewer ventilator-free days during the first 28 postoperative days [median (interquartile range) of 0 (0-10) vs 21 (13-25) days, P = 0.001], prolonged postoperative ICU stay [median (interquartile range) of 20 (16-27) vs 12 (8-14) days, P = 0.005] and increased hospital mortality (27.3 vs 3.2%, P = 0.02). Severe PGD immediately after reperfusion was not associated with ventilator-free days during the first 28 postoperative days, time to discharge from ICU or hospital, or hospital mortality in CLT patients. CONCLUSIONS Postoperative incidence of severe PGD was not significantly different between LDLLT and CLT patients. In LDLLT patients, the onset of severe PGD tended to be earlier than that in CLT patients. Severe PGD immediately after reperfusion was a significant predictor of postoperative morbidity and mortality in LDLLT patients but not in CLT patients.

Complete resection of a giant mediastinal leiomyosarcoma.

Primary mediastinal leiomyosarcoma is an extremely rare malignancy, and the only opportunity for a cure lies with an aggressive surgical approach. We report a 66-year-old woman who underwent complete resection of a giant mediastinal leiomyosarcoma located on the bilateral diaphragm. The tumor encased the inferior vena cava and compressed the adjacent structures. Using cardiopulmonary bypass with 20 minutes of hepatic ischemia, the tumor was completely resected with combined resection and reconstruction of the surrounding structures. Because of the tumor size and location in the boundary area between thoracic and abdominal surgeries, the procedure necessitated the cooperation of many expert surgeons.

Preoperative Hypercapnia as a Predictor of Hypotension During Anesthetic Induction in Lung Transplant Recipients.

OBJECTIVE To determine the incidence and predisposing factors of hypotension during anesthetic induction in lung transplant recipients. DESIGN Retrospective study. SETTING University hospital. PARTICIPANTS Patients who underwent lung transplantation between 2008 and 2013 (n = 68). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The authors analyzed the mean arterial pressure (MAP) from administration of anesthetic drugs to 10 minutes after endotracheal intubation (ie, the anesthetic induction) among participants who underwent lung transplantation. Patients were considered to have clinically significant hypotension (CSH) when the following criteria were fulfilled: An MAP decrease of>40% from baseline and MAP of<60 mmHg. Overall, 41.2% of patients experienced CSH during the induction of anesthesia. The preoperative partial pressure of carbon dioxide (PaCO2) was significantly higher in patients who experienced CSH during anesthetic induction than in those who did not (p = 0.005). Preoperative PaCO2 predicted the development of CSH during anesthetic induction (area under the curve = 0.702; p = 0.002), with an optimal cut-off point of 55 mmHg determined by maximizing the Youden index. The incidences of CSH during anesthetic induction for patients with (PaCO2 ≥ 55) and without (PaCO2<55) preoperative hypercapnia were 75.0% (95% confidence interval [CI] [53.8-89.2]) and 30.8% (95% CI 26.4-37.3), respectively. After adjustment for known predicting factors, the odds ratio for the relationship between preoperative hypercapnia and CSH during anesthetic induction was 12.54 (95% CI 3.10-66.66). CONCLUSIONS Hypotension during anesthetic induction is common in lung transplant recipients, and is independently predicted by preoperative hypercapnia.

Off-Pump Bilateral Cadaveric Lung Transplantation Is Associated With Profound Intraoperative Hypothermia

OBJECTIVES Changes in body temperature (BT) during lung transplantation never have been reported. The authors investigated the time-dependent changes in BT during lung transplantation and compared them between off-pump lung transplantation and lung transplantation using extracorporeal membrane oxygenation (ECMO). DESIGN A retrospective observational study. SETTING University hospital. PARTICIPANTS Patients who underwent cadaveric lung transplantation (15 bilateral lung transplantation [BLT] and 31 single-lung transplantation [SLT]). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS All patients received multimodal therapy to prevent intraoperative hypothermia, including increased environmental temperature, intravenous fluid warming, and the use of forced-air and circulating water warmers. Data of BT during the surgery were collected, and the time course and the extent of BT decrease during the surgery were analyzed. ECMO support during the surgery was necessary for 66.7% of BLT patients and 35.5% of SLT patients; patient characteristics were comparable between off-pump and ECMO-supported lung transplantation. In patients undergoing off-pump BLT, BT decreased continuously to 32.9°C when reperfusion was completed and gradually recovered thereafter. The decrease in BT was significantly larger during off-pump BLT compared with ECMO-supported BLT (3.5°C±0.5°C compared with 0.6°C±0.5°C, p = 0.002) and was≥3°C in all patients. Patients undergoing off-pump SLT had a similar time trend for their BTs (continuous decrease until reperfusion and subsequent recovery), but the extent of BT decrease was much smaller than that in off-pump BLT patients (1.0°C±0.5°C). CONCLUSIONS Patients undergoing off-pump BLT were at high risk of profound intraoperative hypothermia despite multimodal preventive therapy.