The first case of ischemia-free organ transplantation in humans:A proof of concept

With great interest we have read the article by Xiaoshun He and colleagues regarding their first patient who underwent successful ischemia-free organ transplantation (IFOT).1 This group transplanted a liver donated after brain death to a 51-year-old patient with decompensated cirrhosis and hepatocellular carcinoma without any ischemic episode or interruption of the blood circulation. The graft was procured, ex-situ preserved and implanted under continuous normothermic machine perfusion using the Liver Assist device (Organ Assist, Groningen, The Netherlands). The donor liver had 85-95% macrovesicular steatosis, however there was no post-reperfusion syndrome observed after revascularization of the graft and the recipient had an uneventful recovery. This article is protected by copyright. All rights reserved

Measuring Mitochondrial Oxygen Tension during Red Blood Cell Transfusion in Chronic Anemia Patients:A Pilot Study

In light of the associated risks, the question has been raised whether the decision to give a blood transfusion should solely be based on the hemoglobin level. As mitochondria are the final destination of oxygen transport, mitochondrial parameters are suggested to be of added value. The aims of this pilot study were to investigate the effect of a red blood cell transfusion on mitochondrial oxygenation as measured by the COMET device in chronic anemia patients and to explore the clinical usability of the COMET monitor in blood transfusion treatments, especially the feasibility of performing measurements in an outpatient setting. To correct the effect of volume load on mitochondrial oxygenation, a red blood cell transfusion and a saline infusion were given in random order. In total, 21 patients were included, and this resulted in 31 observations. If patients participated twice, the order of infusion was reversed. In both the measurements wherein a blood transfusion was given first and wherein 500 mL of 0.9% saline was given first, the median mitochondrial oxygen tension decreased after red blood cell transfusion. The results of this study have strengthened the need for further research into the effect of blood transfusion tissue oxygenation and the potential role of mitochondrial parameters herein.</p

A monitor for Cellular Oxygen METabolism (COMET): monitoring tissue oxygenation at the mitochondrial level

After introduction of the protoporphyrin IX-triplet state lifetime technique as a new method to measure mitochondrial oxygen tension in vivo, the development of a clinical monitor was started. This monitor is the “COMET”, an acronym for Cellular Oxygen METabolism. The COMET is a non-invasive electrically powered optical device that allows measurements on the skin. The COMET is easy to transport, due to its lightweight and compact size. After 5-aminolevulinic acid application on the human skin, a biocompatible sensor enables detection of PpIX in the mitochondria. PpIX acts as a mitochondrially located oxygen-sensitive dye. Three measurement types are available in the touchscreen-integrated user interface, ‘Single’, ‘Interval’ and ‘Dynamic measurement’. COMET is currently used in several clinical studies in our institution. In this first description of the COMET device we show an incidental finding during neurosurgery. To treat persisting intraoperative hypertension a patient was administered clonidine, but due to rapid administration an initial phase of peripheral vasoconstriction occurred. Microvascular flow and velocity parameters measured with laser-doppler (O2C, LEA Medizintechnik) decreased by 44 and 16% respectively, but not the venous-capillary oxygen saturation. However, mitochondrial oxygen tension in the skin detected by COMET decreased from a steady state of 48 to 16 mmHg along with the decrease in flow and velocity. We conclude that COMET is ready for clinical application and we see the future for this bedside monitor on the intensive care, operating theater, and testing of mitochondrial effect of pharmaceuticals

Ex Situ Machine Perfusion of Human Donor Livers via the Surgically Reopened Umbilical Vein:A Proof of Concept

Background. Machine perfusion of donor livers is typically performed via the portal vein main stem. Instead, cannulation of a reopened umbilical vein could allow machine perfusion during organ procurement and subsequent implantation in the recipient without interruption of the portal venous circulation. We aimed to assess the feasibility of portal venous machine perfusion via the umbilical vein. Methods. During back table inspection of 5 human livers declined for transplantation, the umbilical vein was surgically reopened, dilated, and cannulated. Hypothermic and normothermic oxygenated machine perfusion (NMP) were performed using the umbilical vein for portal inflow. Three livers were perfused with hypothermic machine perfusion, 1 full liver graft underwent NMP for 4 hours, and 1 left lateral split procedure was performed under continuous NMP with portal perfusion via the umbilical vein. Results. In all livers, access to the portal venous system via the umbilical vein was successfully achieved with good portal flows and macroscopically homogeneous perfusion. The full liver graft that underwent NMP via the umbilical vein for 4 hours showed good lactate clearance, normalized pH, and achieved good bile production with pH >7.55. During the split procedure under continuous NMP via the umbilical vein, the left lateral segment and extended right lobe remained equally perfused, as demonstrated by Doppler ultrasound. Conclusions. Machine perfusion with portal perfusion via the umbilical vein is feasible. Portal venous flows were similar to those obtained after cannulation of the portal vein main stem. This technique enables continuous oxygenated perfusion of liver grafts during procurement, splitting, and implantation

Is logistically motivated ex vivo lung perfusion a good idea?

Ex vivo lung perfusion (EVLP) is a technique for reconditioning and evaluating lungs. However, the use of EVLP for logistical reasons is still under discussion. In this retrospective study, all EVLPs performed between July 2012 and October 2019 were analyzed for ventilation and perfusion data. After transplantation, primary graft dysfunction (PGD), lung function, chronic lung allograft dysfunction (CLAD)-free survival, and overall survival were analyzed. Fifty EVLPs were performed: seventeen logistic EVLPs led to 15 lung transplantations (LT) and two rejections (LR), and 33 medical EVLPs resulted in 26 lung transplantations (MT) and seven rejections (MR). Pre-EVLP PaO2 was lower for MT than LT (p &lt; 0.05). Dynamic lung compliance remained stable in MT and LT but decreased in MR and LR. Plateau airway pressure started at a higher level in MR (p &lt; 0.05 MT vs. MR at T60) and increased further in LR. After transplantation, there were no differences between MT and LT in PGD, lung function, CLAD-free survival, and overall survival. In addition, the LT group was compared with a cohort group receiving standard donor lungs without EVLP (LTx). There were no significant differences between LT and LTx for PGD, CLAD-free survival, and overall survival. FVC was significantly lower in LT than in LTx after 1 year (p = 0.005). We found that LT lungs appear to perform better than MT lungs on EVLP. In turn, the outcome in the LT group was comparable with the LTx group. Overall, lung transplantation after EVLP for logistic reasons is safe and makes transplantation timing controllable.<br/

Mitochondrial Oxygenation During Cardiopulmonary Bypass: A Pilot Study

ObjectiveAdequate oxygenation is essential for the preservation of organ function during cardiac surgery and cardiopulmonary bypass (CPB). Both hypoxia and hyperoxia result in undesired outcomes, and a narrow window for optimal oxygenation exists. Current perioperative monitoring techniques are not always sufficient to monitor adequate oxygenation. The non-invasive COMET® monitor could be a tool to monitor oxygenation by measuring the cutaneous mitochondrial oxygen tension (mitoPO2). This pilot study examines the feasibility of cutaneous mitoPO2 measurements during cardiothoracic procedures. Cutaneous mitoPO2 will be compared to tissue oxygenation (StO2) as measured by near-infrared spectroscopy.Design and MethodThis single-center observational study examined 41 cardiac surgery patients requiring CPB. Preoperatively, patients received a 5-aminolevulinic acid plaster on the upper arm to enable mitoPO2 measurements. After induction of anesthesia, both cutaneous mitoPO2 and StO2 were measured throughout the procedure. The patients were observed until discharge for the development of acute kidney insufficiency (AKI).ResultsCutaneous mitoPO2 was successfully measured in all patients and was 63.5 [40.0–74.8] mmHg at the surgery start and decreased significantly (p &lt; 0.01) to 36.4 [18.4–56.0] mmHg by the end of the CPB run. StO2 at the surgery start was 80.5 [76.8–84.3]% and did not change significantly. Cross-clamping of the aorta and the switch to non-pulsatile flow resulted in a median cutaneous mitoPO2 decrease of 7 mmHg (p &lt; 0.01). The cessation of the aortic cross-clamping period resulted in an increase of 4 mmHg (p &lt; 0.01). Totally, four patients developed AKI and had a lower preoperative eGFR of 52 vs. 81 ml/min in the non-AKI group. The AKI group spent 32% of the operation time with a cutaneous mitoPO2 value under 20 mmHg as compared to 8% in the non-AKI group.ConclusionThis pilot study illustrated the feasibility of measuring cutaneous mitoPO2 using the COMET® monitor during cardiothoracic procedures. Moreover, in contrast to StO2, mitoPO2 decreased significantly with the increasing CPB run time. Cutaneous mitoPO2 also significantly decreased during the aortic cross-clamping period and increased upon the release of the clamp, but StO2 did not. This emphasized the sensitivity of cutaneous mitoPO2 to detect circulatory and microvascular changes

Oxygen-dependent delayed fluorescence of protoporphyrin IX measured in the stomach and duodenum during upper gastrointestinal endoscopy

Protoporphyrin IX-triplet state lifetime technique (PpIX-TSLT) is a method used to measure oxygen (PO2) in human cells. The aim of this study was to assess the technical feasibility and safety of measuring oxygen-dependent delayed fluorescence of 5-aminolevulinic acid (ALA)-induced PpIX during upper gastrointestinal (GI) endoscopy. Endoscopic delayed fluorescence measurements were performed 4 hours after oral administration of ALA in healthy volunteers. The ALA dose administered was 0, 1, 5 or 20 mg/kg. Measurements were performed at three mucosal spots in the gastric antrum, duodenal bulb and descending duodenum with the catheter above the mucosa and while applying pressure to induce local ischemia and monitor mitochondrial respiration. During two endoscopies, measurements were performed both before and after intravenous administration of butylscopolamine. Delayed fluorescence measurements were successfully performed during all 10 upper GI endoscopies. ALA dose of 5 mg/kg showed adequate signal-to-noise ratio (SNR) values >20 without side effects. All pressure measurements showed significant prolongation of delayed fluorescence lifetime compared to measurements performed without pressure (P <.001). Measurements before and after administration of butylscopolamine did not differ significantly in the duodenal bulb and descending duodenum. Measurements of oxygen-dependent delayed fluorescence of ALA-induced PpIX in the GI tract during upper GI endoscopy are technically feasible and safe

Clinical Application of Mitochondrial Oxygen Tension Measurement

Mitochondrial use oxygen and are the powerhouses of the cell. A monitor has been developed to measure the mitochondrial oxygen tension. This thesis describes the application in photodynamic therapy, blood transfusion, validation of the calibration mitoPO2 in human skin, potential for chronic mesenteric ischemia detection. Lastly the first measurements during heart surgery with cardiopulmonary bypass