Perfluorocarbon-Based Oxygen Carriers and Subnormothermic Lung Machine Perfusion Decrease Production of Pro-Inflammatory Mediators.

The quality of marginal donor lungs is clinically assessed with normothermic machine perfusion. Although subnormothermic temperature and perfluorocarbon-based oxygen carriers (PFCOC) have proven favourable for other organ transplants, their beneficial use for ex vivo lung perfusion (EVLP) still requires further investigation. In a rat model, we evaluated on a 4 h EVLP time the effects of PFCOC with either 28 °C or 37 °C perfusion temperatures. During EVLP at 28 °C with PFCOC, we recorded significantly lower lung pulmonary vascular resistance (PVR), higher dynamic compliance (Cdyn), significantly lower potassium and lactate levels, higher lung tissue ATP content, and significantly lower myeloperoxidase tissue activity when compared to the 37 °C EVLP with PFCOC. In the subnormothermic EVLP with or without PFCOC, the pro-inflammatory mediator TNFα, the cytokines IL-6 and IL-7, the chemokines MIP-3α, MIP-1α, MCP-1, GRO/KC as well as GM-CSF, G-CSF and the anti-inflammatory cytokines IL-4 and IL-10 were significantly lower. The 28 °C EVLP improved both Cdyn and PVR and decreased pro-inflammatory cytokines and pCO2 levels compared to the 37 °C EVLP. In addition, the 28 °C EVLP with PFCOC produced a significantly lower level of myeloperoxidase activity in lung tissue. Subnormothermic EVLP with PFCOC significantly improves lung donor physiology and ameliorates lung tissue biochemical and inflammatory parameters.

Ex Vivo Lung Perfusion with K(ATP) Channel Modulators Antagonize Ischemia Reperfusion Injury.

Ex vivo lung perfusion (EVLP) has been implemented to increase the number of donor lungs available for transplantation. The use of K(ATP) channel modulators during EVLP experiments may protect against lung ischemia-reperfusion injury and may inhibit the formation of reactive oxygen species. In a rat model of donation after circulatory death with 2 h warm ischemic time, we evaluated rat lungs for a 4-hour time in EVLP containing either mitochondrial-specific or plasma membrane and/or sarcolemmal-specific forms of K(ATP) channel modulators. Lung physiological data were recorded, and metabolic parameters were assessed. When compared to the control group, in the EVLP performed with diazoxide or 5-hydroxydecanoic acid (5-HD) we recorded significantly lower pulmonary vascular resistance and only in the diazoxide group recorded significant lung weight loss. In the perfusate of the 5-HD group, interleukin-1ß and interleukin-1α were significantly lower when compared to the control group. Perfusate levels of calcium ions were significantly higher in both 5-HD and cromakalim groups, whereas the levels of calcium, potassium, chlorine and lactate were reduced in the diazoxide group, although not significantly when compared to the control. The use of a diazoxide mitochondrial-specific K(ATP) channel opener during EVLP improved lung physiological and metabolic parameters and reduced edema.

Subnormothermic ex vivo lung perfusion attenuates ischemia reperfusion injury from donation after circulatory death donors.

Use of normothermic ex vivo lung perfusion (EVLP) was adopted in clinical practice to assess the quality of marginal donor lungs. Subnormothermic perfusion temperatures are in use among other solid organs to improve biochemical, clinical and immunological parameters. In a rat EVLP model of donation after circulatory death (DCD) lung donors, we tested the effect of four subnormothermic EVLP temperatures that could further improve organ preservation. Warm ischemic time was of 2 hours. EVLP time was of 4 hours. Lung physiological data were recorded and metabolic parameters were assessed. Lung oxygenation at 21°C and 24°C were significantly improved whereas pulmonary vascular resistance and edema formation at 21°C EVLP were significantly worsened when compared to 37°C EVLP. The perfusate concentrations of potassium ions and lactate exiting the lungs with 28°C EVLP were significantly lower whereas sodium and chlorine ions with 32°C EVLP were significantly higher when compared to 37°C EVLP. Also compared to 37°C EVLP, the pro-inflammatory chemokines MIP2, MIP-1α, GRO-α, the cytokine IL-6 were significantly lower with 21°C, 24°C and 28°C EVLP, the IL-18 was significantly lower but only with 21°C EVLP and IL-1ß was significantly lower at 21°C and 24°C EVLP. Compared to the 37°C EVLP, the lung tissue ATP content after 21°C, 24°C and 28°C EVLP were significantly higher, the carbonylated protein content after 28°C EVLP was significantly lower and we measured significantly higher myeloperoxidase activities in lung tissues with 21°C, 24°C and 32°C. The 28°C EVLP demonstrated acceptable physiological variables, significantly higher lung tissue ATP content and decreased tissue carbonylated proteins with reduced release of pro-inflammatory cytokines. In conclusion, the 28°C EVLP is a non inferior setting in comparison to the clinically approved 37°C EVLP and significantly improve biochemical, clinical and immunological parameters and may reduce I/R injuries of DCD lung donors.

Subnormothermic Ex Vivo Lung Perfusion Temperature Improves Graft Preservation in Lung Transplantation.

Normothermic machine perfusion is clinically used to assess the quality of marginal donor lungs. Although subnormothermic temperatures have proven beneficial for other solid organ transplants, subnormothermia-related benefits of ex vivo lung perfusion (EVLP) still need to be investigated. Material and Methods: In a rat model, we evaluated the effects of 28 °C temperature on 4-h EVLPs with subsequent left lung transplantation. The recipients were observed for 2 h postoperatively. Lung physiology data were recorded and metabolic parameters were assessed. Results: During the 4-h subnormothermic EVLP, the lung oxygenation was significantly higher (p < 0.001), pulmonary vascular resistance (PVR) lower and dynamic compliance (Cdyn) higher when compared to the 37 °C EVLP. During an end-of-EVLP stress test, we recorded significantly higher flow (p < 0.05), lower PVR (p < 0.05) and higher Cdyn (p < 0.01) in the 28 °C group when compared to the 37 °C group. After the left lung transplantation, Cdyn and oxygenation improved in the 28 °C group, which were comparable to the 37 °C group. Chemokines RANTES, MIP-3α, MIP-1α MCP-1 GRO/KC and pro-inflammatory mediators GM-CSF, G-CSF and TNFα were significantly lower after the 28 °C EVLP and remained low in the plasma of the recipient rats after transplantation. The lungs of the 28 °C group showed significantly lowered myeloperoxidase activity and lowered levels of TNFα and IL-1ß. Conclusions: Compared to the normothermic perfusion, the 28 °C EVLP improved Cdyn and PVR and reduced both the release of pro-inflammatory cytokines and myeloperoxidase activity in lung tissue. These observations were also observed after the left lung transplantation in the subnormothermic group. The 28 °C EVLP significantly improved biochemical, physiological and inflammatory parameters in lung donors.

Perfusate adsorption during ex vivo lung perfusion improves early post-transplant lung function.

OBJECTIVE: Improvement in ex vivo lung perfusion protocols could increase the number of donors available for transplantation and protect the lungs from primary graft dysfunction. We hypothesize that perfusate adsorption during ex vivo lung perfusion reconditions the allograft to ischemia-reperfusion injury after lung transplantation. METHODS: Donor pig lungs were preserved for 24 hours at 4°C, followed by 6 hours of ex vivo lung perfusion according to the Toronto protocol. The perfusate was additionally adsorbed through a CytoSorb adsorber (CytoSorbents, Berlin, Germany) in the treatment group, whereas control lungs were perfused according to the standard protocol (n = 5, each). Ex vivo lung perfusion physiology and biochemistry were monitored. Upon completion of ex vivo lung perfusion, a left single lung transplantation was performed. Oxygenation function and lung mechanics were assessed during a 4-hour reperfusion period. The inflammatory response was determined during ex vivo lung perfusion and reperfusion. RESULTS: The cytokine concentrations in the perfusate were markedly lower with the adsorber, resulting in improved ex vivo lung perfusion physiology and biochemistry during the 6-hour perfusion period. Post-transplant dynamic lung compliance was markedly better during the 4-hour reperfusion period in the treatment group. Isolated allograft oxygenation function and dynamic compliance continued to be superior in the adsorber group at the end of reperfusion, accompanied by a markedly decreased local inflammatory response. CONCLUSIONS: Implementation of an additional cytokine adsorber has refined the standard ex vivo lung perfusion protocol. Furthermore, cytokine removal during ex vivo lung perfusion improved immediate post-transplant graft function together with a less intense inflammatory response to reperfusion in pigs. Further studies are warranted to understand the beneficial effects of perfusate adsorption during ex vivo lung perfusion in the clinical setting.

Negative impact of chemical pleurodesis on postoperative pulmonary function for managing prolonged air leakage after segmentectomy.

OBJECTIVE: Prolonged air leakage (PAL) is the most common postoperative complication after segmentectomy and chemical pleurodesis (CP) is one of the common procedures for managing PAL. However, the impact of CP on postoperative pulmonary function remains unclear. METHODS: We performed a propensity score matching analysis for postoperative pulmonary function in lung cancer patients who underwent segmentectomy. The percentage of postoperative functional change of forced vital capacity (δFVC) and forced expiratory volume in 1 s (δFEV1.0) at postoperative 6 and 12 months were compared between patients who were managed for PAL by CP (CP group, n = 21) and those who did not receive CP (non-CP, n = 21). The predicted δFVC and δFEV1.0 after segmentectomy and lobectomy were also assessed to evaluate the loss of preserved lung function. RESULTS: δFVC and δFEV1.0 in the CP group were confirmed by a significantly larger decline in postoperative pulmonary function than that seen in the non-CP group at postoperative 6 and 12 months (δFVC at 6 months, - 21.1% versus - 5.1%, - 20.8% versus - 6.8% at 12 months, δFEV1.0 at 6 months, - 19.1% versus - 7.2%, - 19.6% versus - 9.7%, at 12 months, p < 0.05 respectively). Both δFVC and δFEV1.0 in the CP group were significantly lower than those predicted after segmentectomy (p < 0.01). They were not statistically different from the values predicted if lobectomy was performed. CONCLUSIONS: CP after segmentectomy caused the same amount of loss in pulmonary function that was predicted if lobectomy was performed. The benefit of segmentectomy compared to lobectomy for preservation of pulmonary function is impaired by CP.

The Amide Local Anesthetic Ropivacaine Attenuates Acute Rejection After Allogeneic Mouse Lung Transplantation.

PURPOSE: Acute allograft rejection after lung transplantation remains an unsolved hurdle. The pathogenesis includes an inflammatory response during and after transplantation. Ropivacaine, an amide-linked local anesthetic, has been shown to attenuate lung injury due to its anti-inflammatory effects. We hypothesized that the drug would also be able to attenuate acute rejection (AR) after allogeneic lung transplantation. METHODS: Allogeneic, orthotopic, single left lung transplantation was performed between BALB/c (donors) and C57BL/6 (recipients) mice. Prior to explantation, lungs were flushed with normal saline with or without ropivacaine (final concentration 1 µM). Plasma levels of tumor necrosis factor-α and interleukins - 6 and - 10 were measured 3 h after transplantation by ELISA. Lung function was assessed on postoperative day five and transplanted lungs were analyzed using histology (AR), immunohistochemistry (infiltrating leukocytes) and Western blot (phosphorylation and expression of Src and caveolin-1). RESULTS: Ropivacaine pre-treatment significantly reduced AR scores (median 3 [minimum-maximum 2-4] for control vs. 2 [1-2] for ropivacaine, p < 0.001) and plasma levels of tumor necrosis factor-α (p = 0.01) compared to control, whereas plasma concentrations of interleukin - 6 (p = 0.008) and - 10 (p < 0.001) were increased by ropivacaine. The number of T-lymphocytes infiltrating the transplanted lung was attenuated (p = 0.02), while no differences in macrophage or B-lymphocyte numbers could be observed after ropivacaine pre-treatment. Caveolin-1 phosphorylation in ropivacaine-treated lungs was diminished (p = 0.004). CONCLUSIONS: Pre-treatment of donor lungs with the local anesthetic ropivacaine diminished histological signs of AR after orthotopic left lung transplantation in mice, most likely due to reduced infiltration of T-lymphocytes into the graft.

Utility of Objective Chest Tube Management After Pulmonary Resection Using a Digital Drainage System.

BACKGROUND: We sought to evaluate the clinical utility of chest tube management after pulmonary resection based on objective digital monitoring of pleural pressure and digital surveillance for air leaks. METHODS: We prospectively recorded the perioperative data of 308 patients who underwent pulmonary resection between December 2013 and January 2016. We used information from a digital monitoring thoracic drainage system to measure peak air leakage during the first 24 hours after the operation, patterns of air leakage over the first 72 hours, and patterns of pleural pressure changes until the chest tubes were removed. RESULTS: There were 240 patients with lung cancer and 68 patients with other diseases. The operations included 49 wedge resections, 58 segmentectomies, and 201 lobectomies. A postoperative air leak was observed in 61 patients (20%). A prolonged air leak exceeding 20 mL/min lasting 5 days or more was observed in 18 patients (5.8%). Multivariate analysis of various perioperative factors showed forced expiratory volume in 1 second below 70%, patterns of air leakage, defined as exacerbating and remitting or without a trend toward improvement, and peak air leakage of 100 mL/min or more were significant positive predictors of prolonged air leak. Fluctuations in pleural pressure occurred just after the air leakage rate decreased to less than 20 mL/min. CONCLUSIONS: Digital monitoring of peak air leakage and patterns of air leakage were useful for predicting prolonged air leak after pulmonary resection. Information on the disappearance of air leak could be derived from the change in the rate of air leakage and from the increase in fluctuation of pleural pressure.

Predictors of pathological non-invasive lung cancer with pure-solid appearance on computed tomography to identify possible candidates for sublobar resection.

PURPOSE: This study aimed to establish favorable predictors for patients with clinical stage IA radiological pure-solid lung cancer to identify possible candidates for sublobar resection. METHODS: We examined 275 patients with surgically resected clinical stage IA radiological pure-solid lung cancer. Pathological grade PL0, Ly0, V0, or N0 disease was defined as non-invasive pure-solid lung cancer (NIPS). RESULTS: Nodal involvement was observed in 63 (23 %) patients with clinical stage IA pure-solid lung cancer, while NIPS was identified in 77 (28 %). Multivariate analysis revealed that air bronchogram (p = 0.0328), clinical T1a (p = 0.0041), and SUVmax (p = 0.0002) were significant clinical predictors of NIPS. When these clinical predictors were combined and the relevant patients' disease was classified as favorable, the frequency of nodal involvement was only 4 %. Furthermore, the 3-year overall survival (OS) of the patients with "favorable" clinical stage IA pure-solid lung cancer was 100 % despite their operative modes. In contrast, the 3-year OS even for patients with clinical stage IA disease, if they had neither of these clinical predictors, was 74.1 %. CONCLUSIONS: Tumor size, the presence of air bronchogram, and the SUVmax level were significant favorable predictors of pathological non-invasive status, and patients with these clinical predictors could be candidates for sublobar resection for clinical stage IA pure-solid lung cancers.

The presence of air bronchogram is a novel predictor of negative nodal involvement in radiologically pure-solid lung cancer.

OBJECTIVES: Phase III trials regarding the feasibility of segmentectomy for lung cancer ≤ 2 cm in size are now underway in Japan and the USA. However, despite their small size, lung cancers that show a pure-solid appearance on thin-section computed tomography (CT) are considered to be invasive with a high frequency of nodal involvement. METHODS: Between 2008 and 2011, 556 clinical Stage IA lung cancer patients underwent pulmonary resection. For all patients, the findings obtained by preoperative thin-section CT were reviewed and the maximum standardized uptake value (SUVmax) on positron emission tomography was recorded. Several clinicopathological features were investigated to identify predictors of nodal metastasis using multivariate analyses. RESULTS: One hundred and eighty-four clinical Stage IA lung cancer patients showed a pure-solid appearance on thin-section CT. Among them, air bronchogram was found radiologically in 58 (32%) patients. Nodal involvement was observed in 10 (17%) patients with air bronchogram, compared with 43 (34%) without air bronchogram, in clinical Stage IA pure-solid lung cancer. A multivariate analysis revealed that air bronchogram, clinical T1a and SUVmax were significant predictors of postoperative nodal involvement (P < 0.01, <0.01, and 0.03, respectively). Furthermore, nodal metastasis was never seen in patients with clinical T1a pure-solid lung cancers who had both air bronchogram and low SUVmax. CONCLUSIONS: The presence of air bronchogram was a novel predictor of negative nodal involvement in clinical Stage IA pure-solid lung cancer. Segmentectomy with thorough lymph node dissection is a feasible option for these patients despite a pure-solid appearance.

The size of consolidation on thin-section computed tomography is a better predictor of survival than the maximum tumour dimension in resectable lung cancer.

OBJECTIVES: Ground-glass opacity (GGO) is a preoperative prognostic factor in resectable lung cancer. However, the impact of GGO on the T factor in the TNM staging system remains unclear and the maximum tumour dimension is also an uncertain measurement for assessing the prognosis of early lung cancer with a mixture of consolidation and GGO. Thus, we sought to determine which the better prognostic factor was, the size of the consolidation on computed tomography scan or the conventional maximum tumour dimension. METHODS: Between January 2004 and January 2011, 398 consecutive clinical stage IA lung cancer patients underwent surgical resection at our hospital. Univariate and multivariate analyses were performed by the logistic regression procedure to determine the relationship between pathological lymph node metastasis-positive status and clinical or radiological findings such as the maximum dimensions of consolidation and the tumour, the presence of air bronchogram, pleural indentation and the preoperative serum carcinoembryonic antigen (CEA) level. RESULTS: Of the 398 patients, 59 (14.8%) had pathological lymph node metastasis. Univariate analysis revealed four significant predictors of pathological nodal involvement: the presence of air bronchogram, the size of consolidation, the maximum tumour dimension and the preoperative CEA level (P < 0.01, respectively). In a multivariate analysis, the size of consolidation and the presence of air a bronchogram were significant predictors of nodal metastasis (P < 0.01, respectively). CONCLUSIONS: The maximum dimension of the consolidation was an independent unfavourable prognostic factor, regardless of the maximum tumour dimension. This could lead to the more accurate prediction of pathological lymph node metastasis with both GGO and consolidation.