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INTRODUCTION: Closed-loop spinal cord stimulation (CL-SCS) is a recently introduced system that records evoked compound action potentials (ECAPs) from the spinal cord elicited by each stimulation pulse and uses this information to automatically adjust the stimulation strength in real time, known as ECAP-controlled SCS. This innovative system compensates for fluctuations in the distance between the epidural leads and the spinal cord by maintaining the neural response (ECAP) at a predetermined target level. This data collection study was designed to assess the performance of the first CL-SCS system in a real-world setting under normal conditions of use in multiple European centers. The study analyzes and presents clinical outcomes and electrophysiological and device data and compares these findings with those reported in earlier pre-market studies of the same system. METHODS: This prospective, multicenter, observational study was conducted in 13 European centers and aimed to gather electrophysiological and device data. The study focused on the real-world application of this system in treating chronic pain affecting the trunk and/or limbs, adhering to standard conditions of use. In addition to collecting and analyzing basic demographic information, the study presents data from the inaugural patient cohort permanently implanted at multiple European centers. RESULTS: A significant decrease in pain intensity was observed for overall back or leg pain scores (verbal numerical rating score [VNRS]) between baseline (mean ± standard error of the mean [SEM]; n = 135; 8.2 ± 0.1), 3 months (n = 93; 2.3 ± 0.2), 6 months (n = 82; 2.5 ± 0.3), and 12 months (n = 76; 2.5 ± 0.3). Comparison of overall pain relief (%) to the AVALON and EVOKE studies showed no significant differences at 3 and 12 months between the real-world data release (RWE; 71.3%; 69.6%) and the AVALON (71.2%; 73.6%) and EVOKE (78.1%; 76.7%) studies. Further investigation was undertaken to objectively characterize the physiological parameters of SCS therapy in this cohort using the metrics of percent time above ECAP threshold (%), dose ratio, and dose accuracy (µV), according to previously described methods. Results showed that a median of 90% (40.7-99.2) of stimuli were above the ECAP threshold, with a dose ratio of 1.3 (1.1-1.4) and dose accuracy of 4.4 µV (0.0-7.1), based on data from 236, 230, and 254 patients, respectively. Thus, across all three metrics, the majority of patients had objective therapy metrics corresponding to the highest levels of pain relief in previously reported studies (usage over threshold > 80%, dose ratio > 1.2, and error < 10 µV). CONCLUSIONS: In conclusion, this study provides valuable insights into the real-world application of the ECAP-controlled CL-SCS system, highlighting its potential for maintaining effective pain relief and objective neurophysiological therapy metrics at levels seen in randomized control trials, and potential for quantifying patient burden associated with SCS system use via patient-device interaction metrics. CLINICAL TRIAL REGISTRATION: In the Netherlands, the study is duly registered on the International Clinical Trials Registry Platform (Trial NL7889). In Germany, the study is duly registered as NCT05272137 and in the United Kingdom as ISCRTN27710516 and has been reviewed by the ethics committee in both countries.

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BACKGROUND AND OBJECTIVES: Acute kidney injury (AKI) is a clinical condition associated with a degree of morbidity and mortality despite supportive care, and ischemia/reperfusion injury (I/R) is one of the main causes of AKI. The pathophysiology of I/R injury is a complex cascade of events including the release of free oxygen radicals followed by damage to proteins, lipids, mitochondria, and deranged tissue oxygenation. In this study, we investigated whether the antioxidant ascorbic acid would be able to largely prevent oxidative stress and consequently, reduce I/R-related injury to the kidneys in terms of oxygenation, inflammation, and renal failure. MATERIALS AND METHODS: Rats were divided into three groups (n = 6/group): (1) a time control group; (2) a group subjected to renal ischemia for 60 min by high aortic occlusion followed by 2 h of reperfusion (I/R); and (3) a group subjected to I/R and treated with an i.v. 100 mg/kg bolus ascorbic acid 15 min before ischemia and continuous infusion of 50 mg/kg/hour for 2 h during reperfusion (I/R + AA). We measured renal tissue oxidative stress, microvascular oxygenation, renal oxygen delivery and consumption, and renal expression of inflammatory and injury markers. RESULTS: We demonstrated that aortic clamping and release resulted in increased oxidative stress and inflammation that was associated with a significant fall in systemic and renal hemodynamics and oxygenation parameters. The treatment of ascorbic acid completely abrogated oxidative stress and inflammatory parameters. However, it only partly improved microcirculatory oxygenation and was without any effect on anuria. CONCLUSION: The ascorbic acid treatment partly improves microcirculatory oxygenation and prevents oxidative stress without restoring urine output in a severe I/R model of AKI.

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BACKGROUND: In this study we investigated whether storage of red blood cells (RBCs) leads to alterations in nitrite reductase activity, hence in altered hypoxia-induced nitric oxide (NO) bioavailability and methemoglobin formation. STUDY DESIGN AND METHODS: Hypoxia-induced NO bioavailability and methemoglobin formation were measured in vitro after nitrite administration to fresh (<1 week of storage) and aged (5-6 weeks of storage) human RBC units and in blood samples of hemodiluted rats subjected to hypoxic ventilation after transfusion with fresh or aged human RBCs. RESULTS: In vitro, NO and methemoglobin levels 10 minutes after nitrite administration were lower in the fresh RBC samples compared to the aged RBC samples (p = 0.026 and p = 0.022, respectively). In vivo, NO bioavailability was also significantly lower in the rats receiving fresh RBCs compared to the group receiving aged RBCs (p = 0.003). In line with NO bioavailability, methemoglobin levels were higher, albeit not significantly, in the group receiving aged RBCs compared to in the group receiving fresh RBCs (p = 0.154). The difference in methemoglobin formation after nitrite administration between fresh and aged RBCs was only present under deoxygenated conditions and not under oxygenated conditions. There were no differences in methemoglobin reductase activity between fresh and aged RBCs. CONCLUSIONS: Storage of RBCs leads to an increased rate of hypoxia-induced nitrite reduction to NO and this is associated with increased methemoglobin formation. The increased methemoglobin formation and consequent decrease in oxygen delivery capacity might contribute to the storage-related impairment of aged RBCs to oxygenate the microcirculation.

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BACKGROUND: The aim of the present study was to test the potential protective effects of the organic vanadium salt bis (maltolato) oxovanadium (BMOV; 15 mg/kg) in the context of renal ischemia/reperfusion (30 min of ischemia) and its effects on renal oxygenation and renal function in the acute phase of reperfusion (up to 90 min post-ischemia). METHODS: Ischemia was established in anesthetized and mechanically ventilated male Wistar rats by renal artery clamping. Renal microvascular and venous oxygenation were measured using phosphorimetry. Creatinine clearance rate, sodium reabsorption, and renal oxygen handling efficiency were considered markers for renal function. RESULTS: The main findings were that BMOV did not affect the systemic and renal hemodynamic and oxygenation variables and partially protected renal sodium reabsorption. CONCLUSIONS: Pretreatment with the organic vanadium compound BMOV did not protect the kidney from I/R injury.

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INTRODUCTION: We aimed to test whether continuous recombinant human activated protein C (APC) administration would be able to protect renal oxygenation and function during endotoxemia in order to provide more insight into the role of coagulation and inflammation in the development of septic acute kidney injury. METHODS: In anesthetized, mechanically ventilated Wistar rats, endotoxemia was induced by lipopolysaccharide administration (10 mg/kg i.v. over 30 min). One hour later, the rats received fluid resuscitation with 0 (LPS + FR group; n = 8), 10 (APC10 group; n = 8), or 100 (APC100 group; n = 8) µg/kg/h APC for 2 h. Renal microvascular oxygenation in the cortex and medulla were measured using phosphorimetry, and renal creatinine clearance rate and sodium reabsorption were measured as indicators of renal function. Statistical significance of differences between groups was tested using two-way ANOVA with Bonferroni post hoc tests. RESULTS: APC did not have notable effects on systemic and renal hemodynamic and oxygenation variables or creatinine clearance. The changes in renal microvascular oxygenation in both the cortex (r = 0.66; p < 0.001) and medulla (r = 0.80; p < 0.001) were correlated to renal sodium reabsorption. CONCLUSION: Renal sodium reabsorption is closely correlated to renal microvascular oxygenation during endotoxemia. In this study, fluid resuscitation and APC supplementation were not significantly effective in protecting renal microvascular oxygenation and renal function. The specific mechanisms responsible for these effects of APC warrant further study.

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INTRODUCTION: Fluid resuscitation therapy is the initial step of treatment for hemorrhagic shock. In the present study we aimed to investigate the acute effects of acetate-balanced colloid and crystalloid resuscitation on renal oxygenation in a rat model of hemorrhagic shock. We hypothesized that acetate-balanced solutions would be superior in correcting impaired renal perfusion and oxygenation after severe hemorrhage compared to unbalanced solutions. METHODS: In anesthetized, mechanically ventilated rats, hemorrhagic shock was induced by withdrawing blood from the femoral artery until mean arterial pressure (MAP) was reduced to 30 mmHg. One hour later, animals were resuscitated with either hydroxyethyl starch (HES, 130/0.42 kDa) dissolved in saline (HES-NaCl; n=6) or a acetate-balanced Ringer's solution (HES-RA; n=6), as well as with acetated Ringer's solution (RA; n=6) or 0.9% NaCl alone (NaCl; n=6) until a target MAP of 80 mmHg was reached. Oxygen tension in the renal cortex (CµPO2), outer medulla (MµPO2), and renal vein were measured using phosphorimetry. RESULTS: Hemorrhagic shock (MAP=30 mmHg) significantly decreased renal oxygenation and oxygen consumption. Restoring the MAP to 80 mmHg required 24.8±1.7 ml of NaCl, 21.7±1.4 ml of RA, 5.9±0.5 ml of HES-NaCl (p<0.05 vs. NaCl and RA), and 6.0±0.4 ml of HES-RA (p<0.05 vs. NaCl and RA). NaCl, RA, and HES-NaCl resuscitation led to hyperchloremic acidosis, while HES-RA resuscitation did not. Only HES-RA resuscitation could restore renal blood flow back to ∼85% of baseline level (from 1.9±0.1 ml/min during shock to 5.1 ml±0.2 ml/min 60 min after HES-RA resuscitation) which was associated with an improved renal oxygenation (CµPO2 increased from 24±2 mmHg during shock to 50±2 mmHg 60 min after HES-RA resuscitation) albeit not to baseline level. At the end of the protocol, creatinine clearance was decreased in all groups with no differences between the different resuscitation groups. CONCLUSION: While resuscitation with the NaCl and RA (crystalloid solutions) and the HES-NaCl (unbalanced colloid solution) led to hyperchloremic acidosis, resuscitation with the HES-RA (acetate-balanced colloid solution) did not. The HES-RA was furthermore the only fluid restoring renal blood flow back to ∼85% of baseline level and most prominently improved renal microvascular oxygenation.

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BACKGROUND: Perioperative red blood cell transfusions are commonly used in patients undergoing cardiac surgery to correct anemia caused by blood loss and hemodilution associated with cardiopulmonary bypass circulation. The aim of this investigation was to test the hypothesis that blood transfusion has beneficial effects on sublingual microcirculatory density, perfusion, and oxygenation. To this end, sidestream dark field (SDF) imaging and spectrophotometry were applied sublingually before and after blood transfusion during cardiac surgery. STUDY DESIGN AND METHODS: Twenty-four adult patients undergoing on-pump cardiac surgery, including coronary artery bypass grafting, cardiac-valve surgery, or a combination of these two procedures, were included consecutively in this prospective, observational study. Sublingual microcirculatory density and perfusion were assessed using SDF imaging in 12 patients (Group A). Sublingual reflectance spectrophotometry was applied in 12 patients (Group B) to monitor microcirculatory oxygenation and hemoglobin (Hb) concentration. RESULTS: Blood transfusion caused an increase in systemic Hb concentration (p < 0.01) and hematocrit (p < 0.01). At the microcirculatory level, blood transfusion resulted in increased microcirculatory density (from 10.5 ± 1.2 to 12.9 ± 1.2 mm capillary/mm(2) tissue, p < 0.01) as shown using SDF imaging. In concert with the SDF measurements, spectrophotometry showed that microcirculatory Hb content increased from 61.4 ± 5.9 to 70.0 ± 4.7 AU (p < 0.01) and that microcirculatory Hb oxygen saturation increased from 65.6 ± 8.3% to 68.6 ± 8.4% (p = 0.06). CONCLUSION: In this study we have shown that blood transfusion: 1) improves the systemic circulation and oxygen-carrying capacity, 2) improves sublingual microcirculatory density but not perfusion velocity, and 3) improves microcirculatory oxygen saturation.

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Although it is generally accepted that oxygen-quenched phosphorescence decay traces can be analyzed using the exponential series method (ESM), its application until now has been limited to a few (patho)physiological studies, probably because the reliability of the recovered oxygen tension (pO(2)) histograms has never been extensively evaluated and lacks documentation. The aim of this study was, therefore, to evaluate the use of the ESM to adequately determine pO(2) histograms from phosphorescence decay traces. For this purpose we simulated decay traces corresponding to uni- and bimodal pO(2) distributions and recovered the pO(2) histograms at different signal-to-noise ratios (SNRs). Ultimately, we recovered microvascular pO(2) histograms measured in the rat kidney in a model of endotoxemic shock and fluid resuscitation and showed that the mean microvascular oxygen tension, [Symbol: see text]pO(2)[Symbol: see text], decreased after induction of endotoxemia and that after 2 h of fluid resuscitation, [Symbol: see text]pO(2)[Symbol: see text] remained low, but the hypoxic peak that had arisen during endotoxemia was reduced. This finding illustrates the importance of recovering pO(2) histograms under (patho)physiological conditions. In conclusion, this study has characterized how noise affects the recovery of pO(2) histograms using the ESM and documented the reliability of the ESM for recovering both low- and high-pO(2) distributions for SNRs typically found in experiments. This study might therefore serve as a frame of reference for investigations focused on oxygen (re)distribution during health and disease and encourage researchers to (re-)analyze data obtained in (earlier) studies possibly revealing new insights into complex disease states and treatment strategies.

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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(omega)-nitro-L-arginine methyl ester (L-NAME) or the selective iNOS inhibitor L-N(6)-(1-iminoethyl)lysine hydrochloride (L-NIL). Cortical (CmicroPo(2)) and outer medullary (MmicroPo(2)) microvascular oxygen pressure (microPo(2)), renal oxygen delivery (Do(2ren)), renal oxygen consumption (Vo(2)(ren)), and renal oxygen extraction (O(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, CmicroPo(2), and MmicroPo(2) (-70, -42, and -42%, respectively, P < 0.05), Vo(2)(ren), and Do(2ren) (-70%, P < 0.0001, and -28%, P < 0.05) dropped. Whereas L-NAME further decreased Do(2ren), Vo(2)(ren), CmicroPo(2), and MmicroPo(2) and deteriorated renal function, L-NIL partially prevented the drop of Do(2ren) and microPo(2), increased O(2)ER, restored Vo(2)(ren) 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(2)(ren), whereas endothelial NO synthase activity is compulsory for the maintenance of this balance. L-NIL can prevent ischemic-induced renal microvascular hypoxia.

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Despite the common use of red-blood-cell transfusions in clinical practice, actual beneficial effects of red blood cells have never been demonstrated. On the contrary, several studies suggest that red-blood-cell transfusions are associated with higher risks of morbidity and mortality. The effects of the duration of storage on the efficacy of red blood cells have therefore been questioned in a number of studies. Recent insights into the physiology of red blood cells such as the role of the hypoxia-induced vasodilator-releasing function of red blood cells--is discussed in relation to the controversy surrounding the use of blood transfusions in clinical practice.

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