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Objectives: Describing mitochondrial oxygenation (mitoPO2) and its within- and between-subject variability over time after 5-aminolevulinic acid (ALA) plaster application in healthy volunteers. Design: Prospective cohort study. Setting: Measurements were performed in Leiden University Medical Center, the Netherlands. Participants: Healthy volunteers enrolled from July to September 2020. Interventions: Two ALA plasters were placed parasternal left and right, with a 3-hour time interval, to examine the influence of the calendar time on the value of mitoPO2. We measured mitoPO2 at 4, 5, 7, 10, 28, and 31 hours after ALA plaster 1 application, and at 4, 5, 7, 25, and 28 hours after ALA plaster 2 application. Primary and secondary outcome measures: At each time point, five mitoPO2 measurements were performed. Within-subject variability was defined as the standard deviation (SD) of the mean of five measurements per timepoint of a study participant. The between-subject variability was the SD of the mean mitoPO2 value of the study population per timepoint. Results: In 16 completed inclusions, median mitoPO2 values and within-subject variability were relatively similar over time at all time points for both plasters. An increase in overall between-subject variability was seen after 25 hours ALA plaster time (19.6 mm Hg vs 23.9 mm Hg after respectively 10 and 25 hours ALA plaster time). Conclusions: The mitoPO2 values and within-subject variability remained relatively stable over time in healthy volunteers. An increase in between-subject variability was seen after 25 hours ALA plaster time warranting replacement of the ALA plaster one day after its application. Trial registration: ClinicalTrials.gov with trial number NCT04626661. [ABSTRACT FROM AUTHOR]

Circulatory shock is the inadequacy to supply mitochondria with enough oxygen to sustain aerobic energy metabolism. A novel noninvasive bedside measurement was recently introduced to monitor the mitochondrial oxygen tension in the skin (mitoP o2). As the most downstream marker of oxygen balance in the skin, mitoPo2 may provide additional information to improve shock management. However, a physiological basis for the interpretation of mitoPo2 values has not been established yet. In this paper, we developed a mathematical model of skin mitoPo2 using a network of parallel microvessels, based on Krogh's cylinder model. The model contains skin blood flow velocity, heterogeneity of blood flow, hematocrit, arteriolar oxygen saturation, and mitochondrial oxygen consumption as major variables. The major results of the model show that normal physiological mitoPo2 is in the range of 40-60 mmHg. The relationship of mitoPo2 with skin blood flow velocity follows a logarithmic growth curve, reaching a plateau at high skin blood flow velocity, suggesting that oxygen balance remains stable while peripheral perfusion declines. The model shows that a critical range exists where mitoPo2 rapidly deteriorates if skin perfusion further decreases. The model intuitively shows how tissue hypoxia could occur in the setting of septic shock, due to the profound impact of microcirculatory disturbance on mitoPo2, even at sustained cardiac output. MitoPo2 is the result of a complex interaction between all factors of oxygen delivery and microcirculation. This mathematical framework can be used to interpret mitoPo2 values in shock, with the potential to enhance personalized clinical trial design. [ABSTRACT FROM AUTHOR]

Introduction: The newly introduced Cellular Oxygen METabolism (COMET®) monitor enables the measurement of mitochondrial oxygen tension (mitoPO2) using the protoporphyrin IX triplet state lifetime technique (PpIX-TSLT). This study aims to investigate the feasibility and applicability of the COMET® measurements in the operating theatre and study the behavior of the new parameter mitoPO2 during stable operating conditions. Methods: In this observational study mitochondrial oxygenation was measured in 20 patients during neurosurgical procedures using the COMET® device. Tissue oxygenation and local blood flow were measured by the Oxygen to See (O2C). Primary outcomes included mitoPO2, skin temperature, mean arterial blood pressure, local blood flow and tissue oxygenation. Results: All patients remained hemodynamically stable during surgery. Mean baseline mitoPO2 was 60 ± 19 mmHg (mean ± SD) and mean mitoPO2 remained between 40–60 mmHg during surgery, but tended to decrease over time in line with increasing skin temperature. Conclusion: This study presents the feasibility of mitochondrial oxygenation measurements as measured by the COMET® monitor in the operating theatre and shows the parameter mitoPO2 to behave in a stable and predictable way in the absence of notable hemodynamic alterations. The results provide a solid base for further research into the added value of mitochondrial oxygenation measurements in the perioperative trajectory. [ABSTRACT FROM AUTHOR]

Even though renal hypoxia is believed to play a pivotal role in the development of acute kidney injury, no study has specifically addressed the alterations in renal oxygenation in the early onset of renal ischemia-reperfusion (I/R). Renal oxygenation depends on a balance between oxygen supply and consumption, with the nitric oxide (NO) as a major regulator of microvascular oxygen supply and oxygen consumption. The aim of this study was to investigate whether I/R induces inducible NO synthase (iNOS)-dependent early changes in renal oxygenation and the potential benefit of iNOS inhibitors on such alterations. Anesthetized Sprague-Dawley rats underwent a 30-min suprarenal aortic clamping with or without either the nonselective NO synthase inhibitor [N.sup.[omega]]-nitro-L-arginine methyl ester (L-NAME) or the selective iNOS inhibitor L-[N.sup.6]-(1-iminoethyl)lysine hydrochloride (L-NIL). Cortical (C[micro][Po.sub.2]) and outer medullary (M[micro][Po.sub.2]) microvascular oxygen pressure ([micro][Po.sub.2]), renal oxygen delivery ([Do.sub.2ren]), renal oxygen consumption ([Vo.sub.2ren]), and renal oxygen extraction ([O.sub.2]ER) were measured by oxygen-dependent quenching phosphorescence techniques throughout 2 h of reperfusion. During reperfusion renal arterial resistance and oxygen shunting increased, whereas renal blood flow, C[micro][Po.sub.2], and M[micro][Po.sub.2] (-70, -42, and -42%, respectively, P < 0.05), [Vo.sub.2ren], and [Do.sub.2ren] (-70%, P < 0.0001, and -28%, P < 0.05) dropped. Whereas L-NAME further decreased [Do.sub.2ren], [Vo.sub.2ren], C[micro][Po.sub.2], and M[micro][Po.sub.2] and deteriorated renal function, L-NIL partially prevented the drop of [Do.sub.2ren] and [micro][Po.sub.2], increased [O.sub.2]ER, restored [Vo.sub.2ren] and metabolic efficiency, and prevented deterioration of renal function. Our results demonstrate that renal I/R induces early iNOS-dependent microvascular hypoxia in disrupting the balance between microvascular oxygen supply and [Vo.sub.2ren], whereas endothelial NO synthase activity is compulsory for the maintenance of this balance. L-NIL can prevent ischemic-induced renal microvascular hypoxia. acute kidney injury; nitric oxide; microcirculation

Renal oxygen consumption (V[O.sub.2,ren]) is an important parameter that has been shown to be influenced by various pathophysiological circumstances. V[O.sub.2,ren] has to be repeatedly measured during an experiment to gain insight in the dynamics of (dys)regulation of oxygen metabolism. In small animals, the classical approach of blood gas analysis of arterial and venous blood samples is only limitedly applicable due to fragile vessels and a low circulating blood volume. We present a phosphorescence lifetime technique that allows near-continuous measurement of renal venous P[O.sub.2] (vP[O.sub.2]) and V[O.sub.2,ren] in rats. The technique does not rely on penetration of the blood vessel. but uses a small reflection probe. This probe is placed in close proximity to the renal vein for detection of the oxygen-dependent phosphorescence of the injected water-soluble near-infrared phosphor Oxyphor G2. The technique was calibrated in vitro and the calibration constants were validated in vivo in anesthetized and mechanically ventilated male Wistar rats. The hemoglobin saturation curve and its pH dependency were determined for calculation of renal venous oxygen content. The phosphorescence technique was in good agreement with blood gas analysis of renal venous blood samples, for both P[O.sub.2] and hemoglobin saturation. To demonstrate its feasibility in practice, the technique was used in four rats during endotoxin infusion (10 mg x [kg.sup.-1] x [h.sup.-1] during 1 h). Renal vP[O.sub.2] reduced by 40% upon reduction in oxygen delivery to 30% of baseline, but V[O.sub.2] remained unchanged. This study documents the feasibility of near-continuous. nondestructive measurement of renal vP[O.sub.2] and V[O.sub.2] by oxygen-dependent quenching of phosphorescence. oxygen-dependent quenching; Oxyphor G2; time-resolved spectroscopy; Pd-porphyrin

Large differences in the tolerance of organ systems to conditions of decreased [O.sub.2] delivery such as hemodilution exist. The kidney receives ~25% of the cardiac output and [O.sub.2] delivery is in excess of the oxygen demand under normal circumstances. In a rat model of acute normovolemic hemodilution (ANH), we studied the effect of reduced hematocrit on renal regional and microvascular oxygenation. Experiments were performed in 12 anesthetized male Wistar rats. Six animals underwent four steps of ANH (hematocrit 25, 15, 10, and phosphorescence quenching; tissue oxygenation; renal microvascular oxygenation; kidney; oxygen consumption

Introduction The recently developed protoporphyrin IX-triple state lifetime technique measures mitochondrial oxygenation tension (mitoPO2 ) in vivo at the bedside. MitoPO2 might be an early indicator of oxygen disbalance in cells of critically ill patients and therefore may support clinical decisions regarding red blood cell (RBC) transfusion. We aim to investigate the effect of RBC transfusion and the associated changes in haemoglobin concentration on mitoPO2 and other physiological measures of tissue oxygenation and oxygen balance in critically ill patients with anaemia. We present the protocol and pilot results for this study. Methods and analysis We perform a prospective multicentre observational study in three mixed intensive care units in the Netherlands with critically ill patients with anaemia in whom an RBC transfusion is planned. The skin of the anterior chest wall of the patients is primed with a 5-aminolevulinic acid patch for 4 hours for induction of mitochondrial protoporphyrin-IX to enable measurements of mitoPO2, which is done with the COMET monitoring device. At multiple predefined moments, before and after RBC transfusion, we assess mitoPO2 and other physiological parameters of oxygen balance and tissue oxygenation. Descriptive statistics will be used to describe the data. A linear mixed-effect model will be used to study the association between RBC transfusion and mitoPO2 and other traditional parameters of oxygenation, oxygen delivery and oxygen balance. Missing data will be imputed using multiple imputation methods. Ethics and dissemination The institutional ethics committee of each participating centre approved the study (reference P16.303), which will be conducted according to the 1964 Helsinki declaration and its later amendments. The results will be submitted for publication in peerreviewed journals and presented at scientific conferences. [ABSTRACT FROM AUTHOR]