Tissue Oxygen Pressure Research Articles

Impact of intracranial hypertension and cerebral perfusion pressure on spreading depolarization.

Spreading depolarization (SD) develops after stroke and traumatic brain injury and may contribute to secondary brain damage. These diseases are often accompanied by intracranial hypertension, but little is known about the effects of intracranial pressure (ICP) on SD. Here, we study the effect of increased ICP on hemodynamic and metabolic response to SD in rats. SDs were triggered at different ICPs and cerebral perfusion pressures (CPP). The regional cerebral blood flow (rCBF), partial pressure of brain tissue oxygen (PbtO2), cerebral extracellular glucose and lactate concentrations were recorded. Fluoro-Jade staining was used to quantify neuronal injury in cortex. At high ICP (50 mmHg) with low CPP (30 mmHg), rCBF and PbtO2 were monophasically decreased in contrast to a monophasically increased pattern under normal conditions. Neuronal death increased in both hemispheres but much more on the side where SDs were triggered. At high ICP (50 mmHg) with normal CPP (70 mmHg), CBF and metabolism during SD did not differ from baseline, and neuronal death did not increase even on the side of SD induction. These data suggest that maintaining CPP at 70 mmHg, even when the ICP is as high as 50 mmHg, preserves normal blood flow and metabolism during SD events and prevents neuronal degeneration.

Brain tissue oxygen pressure combined with intracranial pressure monitoring may improve clinical outcomes for patients with severe traumatic brain injury: a systemic review and meta-analysis.

Although the optimization of brain oxygenation is thought to improve the prognosis, the effect of brain tissue oxygen pressure (PbtO2) for patients with severe traumatic brain injury (STBI) remains controversial. Therefore, the present study aimed to determine whether adding PbtO2 to intracranial pressure (ICP) monitoring improves clinical outcomes for patients with STBI. PubMed, Embase, Scopus and Cochrane Library were searched for eligible trials from their respective inception through April 10th, 2024. We included clinical trials contrasting the combined monitoring of PbtO2 and ICP versus isolated ICP monitoring among patients with STBI. The primary outcome was favorable neurological outcome at 6 months, and secondary outcomes including the in-hospital mortality, long-term mortality, length of stay in intensive care unit (ICU) and hospital. A total of 16 studies (four randomized studies and 12 cohort studies) were included in the meta-analysis. Compared with isolated ICP monitoring, the combined monitoring was associated with a higher favorable neurological outcome rate at 6 months (RR 1.33, 95% CI [1.17-1.51], P<0.0001, I2 = 0%), reduced long-term mortality (RR 0.72, 95% CI [0.59-0.87], P=0.0008, I2 = 2%). No significant difference was identified in the in-hospital mortality (RR 0.81, 95% CI 0.66 to 1.01, P=0.06, I2 = 32%), length of stay in ICU (MD 2.10, 95% CI [-0.37-4.56], P=0.10, I2 = 78%) and hospital (MD 1.07, 95% CI [-2.54-4.67], P=0.56, I2 = 49%) between two groups. However, the pooled results of randomized studies did not show beneficial effect of combined monitoring in favorable neurological outcome and long-term mortality. Currently, there is limited evidence to prove that the combined PbtO2 and ICP monitoring may contribute to improved neurological outcome and long-term mortality for patients with STBI. However, the benefit of combined monitoring should be further validated in more randomized studies.

Main findings from the use of ozone therapy alone or combined with conventional treatments in root canal treatment: a systematic review

Introduction: The positive effects of ozone on biological properties include antimicrobial, immunostimulating, and biosynthetic impacts used in the treatment and maintenance of good oral hygiene. Ozone results in alteration in the metabolism of cells by raising the partial pressure of oxygen in tissues which improves the transporting capacity of oxygen in the blood. Ozone causes more blood supply to the ischemic zones due to surgical interventions like tooth extractions and implant placement. In this context of decontamination of root and periapical canals, ozone has emerged as an important sanitizer. Objective: It was to develop a systematic review of the literature to list the main findings of the use of ozone therapy alone or combined with conventional treatments in the treatment of root canals. Methods: The PRISMA Platform systematic review rules were followed. The search was carried out from March to June 2024 in the Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: A total of 122 articles were found, 35 articles were evaluated in full and 11 were included and developed in the present systematic review study. Considering the Cochrane tool for risk of bias, the overall assessment resulted in 25 studies with a high risk of bias and 22 studies that did not meet GRADE and AMSTAR-2. Most studies did not show homogeneity in their results, with X2=88.5%&lt;50%. Results and Conclusion: It is concluded that ultrasonic and sonic ozone activation resulted in less pain in patients undergoing single-session endodontics compared to no ozone treatment. Ozonated olive oil with zinc oxide and olive oil paste with zinc oxide demonstrated good clinical and radiographic success for pulpectomy of primary teeth. Furthermore, low-intensity laser and ozone therapy are useful methods for postoperative pain in vital symptomatic teeth, but they are not superior to each other.

Oxygen-Based Autoregulation Indices Associated with Clinical Outcomes and Spreading Depolarization in Aneurysmal Subarachnoid Hemorrhage.

Impairment in cerebral autoregulation has been proposed as a potentially targetable factor in patients with aneurysmal subarachnoid hemorrhage (aSAH); however, there are different continuous measures that can be used to calculate the state of autoregulation. In addition, it has previously been proposed that there may be an association of impaired autoregulation with the occurrence of spreading depolarization (SD) events. Study participants with invasive multimodal monitoring and aSAH were enrolled in an observational study. Autoregulation indices were prospectively calculated from this database as a 10s moving correlation coefficient between various cerebral blood flow (CBF) surrogates and mean arterial pressure (MAP). In study participants with subdural electrocorticography (ECoG) monitoring, SD was also scored. Associations between clinical outcomes using the modified Rankin scale and occurrence of either isolated or clustered SD were assessed. A total of 320 study participants were included, 47 of whom also had ECoG SD monitoring. As expected, baseline severity factors, such as modified Fisher scale score and World Federation of Neurosurgical Societies scale grade, were strongly associated with the clinical outcome. SD probability was related to blood pressure in a triphasic pattern, with a linear increase in probability below MAP of ~ 100 mm Hg. Multiple autoregulation indices were available for review based on moving correlations between mean arterial pressure (MAP) and various surrogates of cerebral blood flow (CBF). We calculated the pressure reactivity (PRx) using two different sources for intracranial pressure (ICP). We calculated the oxygen reactivity (ORx) using the partial pressure of brain tissue oxygen (PbtO2) from the Licox probe. We calculated the cerebral blood flow reactivity (CBFRx) using perfusion measurements from the Bowman perfusion probe. Finally, we calculated the cerebral oxygen saturation reactivity (OSRx) using regional cerebral oxygen saturation measured by near-infrared spectroscopy from the INVOS sensors. Only worse ORx and OSRx were associated with worse clinical outcomes. Both ORx and OSRx also were found to increase in the hour prior to SD for both sporadic and clustered SD. Impairment in autoregulation in aSAH is associated with worse clinical outcomes and occurrence of SD when using ORx and OSRx. Impaired autoregulation precedes SD occurrence. Targeting the optimal MAP or cerebral perfusion pressure in patients with aSAH should use ORx and/or OSRx as the input function rather than intracranial pressure.

Hyperglycemia induces microglial pyroptosis by increasing oxygen extraction rate: Implication in neurological impairment during ischemic stroke.

Elevated levels of blood glucose in patients with ischemic stroke are associated with a worse prognosis. The present study aimed to explore whether hyperglycemia promotes microglial pyroptosis by increasing the oxygen extraction rate in an acute ischemic stroke model. C57BL/6 mice that underwent middle cerebral artery occlusion were used for assessment of blood glucose level and neurological function. The cerebral oxygen extraction ratio (CERO2), oxygen consumption rate (OCR) and partial pressure of brain tissue oxygen (PbtO2) were measured. To investigate the significance of the NOD‑like receptor protein 3 (NLRP3) inflammasome, NLRP3‑/‑ mice were used, and the expression levels of NLRP3, caspase‑1, full‑length gasdermin D (GSDMD‑FL), GSDMD‑N domain (GSDMD‑N), IL‑1β and IL‑18 were evaluated. In addition, Z‑YVAD‑FMK, a caspase‑1 inhibitor, was used to treat microglia to determine whether activation of the NLRP3 inflammasome was required for the enhancing effect of hyperglycemia on pyroptosis. It was revealed that hyperglycemia accelerated cerebral injury in the acute ischemic stroke model, as evidenced by decreased latency to fall and the percentage of foot fault. Hyperglycemia aggravated hypoxia by increasing the oxygen extraction rate, as evidenced by increased CERO2 and OCR, and decreased PbtO2 in response to high glucose treatment. Furthermore, hyperglycemia‑induced microglial pyroptosis was confirmed by detection of increased levels of caspase‑1, GSDMD‑N, IL‑1β and IL‑18 and a decreased level of GSDMD‑FL. However, the knockout of NLRP3 attenuated these effects. Pharmacological inhibition of caspase‑1 also reduced the expression levels of GSDMD‑N, IL‑1β and IL‑18 in microglial cells. These results suggested that hyperglycemia stimulated NLRP3 inflammasome activation by increasing the oxygen extraction rate, thus leading to the aggravation of pyroptosis following ischemic stroke.

Brain tissue oxygen plus intracranial pressure monitoring versus isolated intracranial pressure monitoring in patients with traumatic brain injury: an updated meta-analysis of randomized controlled trials.

Intracranial pressure (ICP) monitoring plays a key role in patients with traumatic brain injury (TBI), however, cerebral hypoxia can occur without intracranial hypertension. Aiming to improve neuroprotection in these patients, a possible alternative is the association of Brain Tissue Oxygen Pressure (PbtO2) monitoring, used to detect PbtO2 tension. We systematically searched PubMed, Embase and Cochrane Central for RCTs comparing combined PbtO2 + ICP monitoring with ICP monitoring alone in patients with severe or moderate TBI. The outcomes analyzed were mortality at 6months, favorable outcome (GOS ≥ 4 or GOSE ≥ 5) at 6months, pulmonary events, cardiovascularevents and sepsis rate. We included 4 RCTs in the analysis, totaling 505 patients. Combined PbtO2 + ICP monitoring was used in 241 (47.72%) patients. There was no significant difference between the groups in relation to favorable outcome at 6months (RR 1.17; 95% CI 0.95-1.43; p = 0.134; I2 = 0%), mortality at 6months (RR 0.82; 95% CI 0.57-1.18; p = 0.281; I2 = 34%), cardiovascular events (RR 1.75; 95% CI 0.86-3.52; p = 0.120; I2 = 0%) or sepsis (RR 0.75; 95% CI 0.25-2.22; p = 0.604; I2 = 0%). The risk of pulmonary eventswas significantly higher in the group with combined PbtO2 + ICP monitoring (RR 1.44; 95% CI 1.11-1.87; p = 0.006; I2 = 0%). Our findings suggest that combined PbtO2 + ICP monitoring does not change outcomes such as mortality, functional recovery, cardiovascularevents or sepsis. Furthermore, we found a higher risk of pulmonaryevents in patients undergoing combined monitoring.

Hyperbaric oxygen therapy for the treatment of hypoxic/ischemic injury upon perinatal asphyxia-are we there yet?

Birth asphyxia and its main sequel, hypoxic-ischemic encephalopathy, are one of the leading causes of children's deaths worldwide and can potentially worsen the quality of life in subsequent years. Despite extensive research efforts, efficient therapy against the consequences of hypoxia-ischemia occurring in the perinatal period of life is still lacking. The use of hyperbaric oxygen, improving such vital consequences of birth asphyxia as lowered partial oxygen pressure in tissue, apoptosis of neuronal cells, and impaired angiogenesis, is a promising approach. This review focused on the selected aspects of mainly experimental hyperbaric oxygen therapy. The therapeutic window for the treatment of perinatal asphyxia is very narrow, but administering hyperbaric oxygen within those days improves outcomes. Several miRNAs (e.g., mir-107) mediate the therapeutic effect of hyperbaric oxygen by modulating the Wnt pathway, inhibiting apoptosis, increasing angiogenesis, or inducing neural stem cells. Combining hyperbaric oxygen therapy with drugs, such as memantine or ephedrine, produced promising results. A separate aspect is the use of preconditioning with hyperbaric oxygen. Overall, preliminary clinical trials with hyperbaric oxygen therapy used in perinatal asphyxia give auspicious results.

Intraparenchymal near-infrared spectroscopy for detection of delayed cerebral ischemia in poor-grade aneurysmal subarachnoid hemorrhage

ObjectiveDetection of delayed cerebral ischemia (DCI) is challenging in comatose patients with poor-grade aneurysmal subarachnoid hemorrhage (aSAH). Brain tissue oxygen pressure (PbtO2) monitoring may allow early detection of its occurrence. Recently, a probe for combined measurement of intracranial pressure (ICP) and intraparenchymal near-infrared spectroscopy (NIRS) has become available. In this pilot study, the parameters PbtO2, Hboxy, Hbdeoxy, Hbtotal and rSO2 were measured in parallel and evaluated for their potential to detect perfusion deficits or cerebral infarction. MethodsIn patients undergoing multimodal neuromonitoring due to poor neurological condition after aSAH, Clark oxygen probes, microdialysis and NIRS-ICP probes were applied. DCI was suspected when the measured parameters in neuromonitoring deteriorated. Thus, perfusion CT scan was performed as follow up, and DCI was confirmed as perfusion deficit. Median values for PbtO2, Hboxy, Hbdeoxy, Hbtotal and rSO2 in patients with perfusion deficit (Tmax > 6 s in at least 1 vascular territory) and/or already demarked infarcts were compared in 24- and 48-hour time frames before imaging. ResultsData from 19 patients (14 University Hospital Zurich, 5 Charité Universitätsmedizin Berlin) were prospectively collected and analyzed. In patients with perfusion deficits, the median values for Hbtotal and Hboxy in both time frames were significantly lower. With perfusion deficits, the median values for Hboxy and Hbtotal in the 24 h time frame were 46,3 [39.6, 51.8] µmol/l (no perfusion deficits 53 [45.9, 55.4] µmol/l, p = 0.019) and 69,3 [61.9, 73.6] µmol/l (no perfusion deficits 74,6 [70.1, 79.6] µmol/l, p = 0.010), in the 48 h time frame 45,9 [39.4, 51.5] µmol/l (no perfusion deficits 52,9 [48.1, 55.1] µmol/l, p = 0.011) and 69,5 [62.4, 74.3] µmol/l (no perfusion deficits 75 [70,80] µmol/l, p = 0.008), respectively. In patients with perfusion deficits, PbtO2 showed no differences in both time frames. PbtO2 was significantly lower in patients with infarctions in both time frames. The median PbtO2 was 17,3 [8,25] mmHg (with no infarctions 29 [22.5, 36] mmHg, p = 0.006) in the 24 h time frame and 21,6 [11.1, 26.4] mmHg (with no infarctions 31 [22,35] mmHg, p = 0.042) in the 48 h time frame. In patients with infarctions, the median values of parameters measured by NIRS showed no significant differences. ConclusionsThe combined NIRS-ICP probe may be useful for early detection of cerebral perfusion deficits and impending DCI. Validation in larger patient collectives is needed.

Transcutaneous oximetry of angiosomes of maxillary and facial arteries

Aim. To qualitatively predict and control the quality of periodontal diseases treatment, to determine changes in the transcutaneous pressure of oxygen and carbon dioxide in angiosomes of maxillary and facial arteries in healthy adults. Materials and methods. 17 healthy people participated in this study. There were 10 (58 %) men aged 24 (22–27), weight 66 (62–80) kg and height 175 (169–182) cm and 7 (42 %) women, whose average age was 23 (20–26) years old, weight 58 (47–72) kg, height 165 (160–178) cm. Results. The highest values of tissue perfusion with oxygen were observed in the angiosomes of the upper jaw compared to the angiosomes of the lower jaw, where this indicator ranged from 105 to 153 mm Hg. On the lower jaw, the maximum value of the regional perfusion index (RPI) of 1.70 ± 0.04 was observed at the point of measurement where a. mentalis exits through the homonymous chin orifice, anastomosing with the branches of a. facialis. The highest values of tissue perfusion with carbon dioxide were observed in angiosomes of the lower jaw (28–36 mm Hg). In general, non-invasive measurements of oxygen and carbon dioxide pressure in tissues allow more accurate and direct visualization and control of microcirculation in the tissues of the corresponding angiosomes. Conclusions. The index of regional perfusion on the upper jaw is normally in the range of 2.2 to 2.6 (р &lt; 0.0001). In the angiosome of the lower jaw, the RPI value is within 1.3–1.7, respectively (p &lt; 0.0001). The tension of carbon dioxide in the tissues of the upper and lower jaw averages 31–34 mm Hg (р &lt; 0.05), reaches its maximum in the zones of the lowest oxygen perfusion.

Predictive value of intracranial pressure-related parameters and coagulation on the prognosis in patients with traumatic brain injury.

This study investigated the factors affecting the prognosis of patients with traumatic brain injury (TBI) and assessed the predictive value of intracranial pressure-related parameters and coagulation on prognosis. Seventy TBI patients admitted between January 2020 and January 2021 were catego-rized into good prognosis (n=42) and poor prognosis (n=28) groups according to the Glasgow Outcome Scale (GOS) score upon discharge. Factors affecting prognosis were analyzed, and differences in intracranial pressure and coagula-tion between the two groups were compared. The receiver operating charac-teristic curve (ROC) was used to calculate the predictive value of intracranial pressure-related parameters and coagulation function on prognosis. Within 24 h postoperatively, the good prognosis group had lower levels of intracra-nial pressure (ICP) and partial pressure of oxygen in brain tissue (PbtO2) and higher cerebral perfusion pressure (CPP) and cerebral hemodynamic param-eters than the poor prognosis group (p&lt;0.05). The good prognosis group had significantly lower prothrombin time (PT), activated partial thromboplastin time (aPTT),and prothrombin time (TT) levels and higher platelets (PLT) and fibrinogen (Fib) levels than the poor prognosis group (p&lt;0.05). Regression analysis revealed that CPP, systolic blood flow velocity (Vs), end-diastolic blood flow velocity (Vd), mean blood flow velocity (Vm), PLT, Fib were independent protective factors for the prognosis, and ICP, PbtO2, PT, APTT, and TT were risk factors for prognosis. The ROC revealed that ICP, CPP, PbtO2, Vs, Vd, Vm, APTT, PLT, Fib exhibited high diagnostic value for poor prognosis (AUC=0.732, 0.940, 0.796, 0.706, 0.914, 0.729, 0.876, 0.709, 0.866), with ICP showing the highest diagnostic sensitivity and Vd showing the highest diagnostic specificity. Intracranial pressure-related parameters and coagulation indicators are prog-nosis-related indexes in patients with TBI, and the prognosis and survival can be improved by controlling intracranial pressure and improving coagulation.

Exploration of the relationship between partial pressure of brain tissue oxygen and intracranial pressure

IntroductionPartial pressure of brain tissue oxygen (PbtO2) has been shown to be a safe an effective monitoring modality to compliment intracranial pressure (ICP) monitoring. It is related to metabolic activity, disease severity and mortality. Research questionUnderstanding the complex relationship between PbtO2 and ICP for patients with traumatic brain injury will enable better clinical decision making beyond simple threshold treatment strategies. Material and methodsPatients with PbtO2 monitoring were identified from the BrainIT database, a multi-centre dataset, containing minute by minute PbtO2 and ICP readings. Missing data was imputed and a multi-level log-normal regression model with a compound symmetry correlation structure was built. This accounted for any increased correlation due to the repeated measurements. The model was adjusted for mean arterial pressure and the partial pressure of carbon dioxide. Non-linearity was assessed using analysis of deviance and trends using expected marginal means. Results11 subjects with over 82,000 readings were included. They had a median age of 38 (IQR: 37–47), 73% were male, a median length of stay of 11.8 (IQR: 6.6–19.7) days and a median extended Glasgow outcome scale of 7.00 (IQR: 5–8).There is a statistically significant (p < 0.001) non-linear effect of ICP on PbtO2. With an overall increase in PbtO2 of 5.2% (95% CI 4%–6.4%, p < 0.001) for a 10 mmHg increase in ICP below 22 mmHg and a decrease of 5.5% (95% CI 2.7%–8.3%, p=<0.001) in PbtO2 for a 10 mmHg increase in ICP above 22 mmHg. As well as a decrease of 40.9% (95% CI 2.3%–64.3%, p = 0.040) in PbtO2 per day in the intensive care unit. Discussion and conclusionThis model demonstrates that there is a significant non-linear relationship between ICP and PbtO2, however, this is a small heterogeneous cohort and further validation will be required.

Impact of Therapeutic Interventions on Cerebral Autoregulatory Function Following Severe Traumatic Brain Injury: A Secondary Analysis of the BOOST-II Study.

The Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II randomized controlled trial used a tier-based management protocol based on brain tissue oxygen (PbtO2) and intracranial pressure (ICP) monitoring to reduce brain tissue hypoxia after severe traumatic brain injury. We performed a secondary analysis to explore the relationship between brain tissue hypoxia, blood pressure (BP), and interventions to improve cerebral perfusion pressure (CPP). We hypothesized that BP management below the lower limit of autoregulation would lead to cerebral hypoperfusion and brain tissue hypoxia that could be improved with hemodynamic augmentation. Of the 119 patients enrolled in the Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II trial, 55 patients had simultaneous recordings of arterial BP, ICP, and PbtO2. Autoregulatory function was measured by interrogating changes in ICP and PbtO2 in response to fluctuations in CPP using time-correlation analysis. The resulting autoregulatory indices (pressure reactivity index and oxygen reactivity index) were used to identify the "optimal" CPP and limits of autoregulation for each patient. Autoregulatory function and percent time with CPP outside personalized limits of autoregulation were calculated before, during, and after all interventions directed to optimize CPP. Individualized limits of autoregulation were computed in 55 patients (mean age 38years, mean monitoring time 92h). We identified 35 episodes of brain tissue hypoxia (PbtO2 < 20mm Hg) treated with CPP augmentation. Following each intervention, mean CPP increased from 73 ± 14mm Hg to 79 ± 17mm Hg (p = 0.15), and mean PbtO2 improved from 18.4 ± 5.6mm Hg to 21.9 ± 5.6mm Hg (p = 0.01), whereas autoregulatory function trended toward improvement (oxygen reactivity index 0.42 vs. 0.37, p = 0.14; pressure reactivity index 0.25 vs. 0.21, p = 0.2). Although optimal CPP and limits remained relatively unchanged, there was a significant decrease in the percent time with CPP below the lower limit of autoregulation in the 60min after compared with before an intervention (11% vs. 23%, p = 0.05). Our analysis suggests that brain tissue hypoxia is associated with cerebral hypoperfusion characterized by increased time with CPP below the lower limit of autoregulation. Interventions to increase CPP appear to improve autoregulation. Further studies are needed to validate the importance of autoregulation as a modifiable variable with the potential to improve outcomes.

Isoflurane lowers the cerebral metabolic rate of oxygen and prevents hypoxia during cortical spreading depolarization in vitro: An integrative experimental and modeling study

Cortical spreading depolarization (SD) imposes a massive increase in energy demand and therefore evolves as a target for treatment following acute brain injuries. Anesthetics are empirically used to reduce energy metabolism in critical brain conditions, yet their effect on metabolism during SD remains largely unknown. We investigated oxidative metabolism during SD in brain slices from Wistar rats. Extracellular potassium ([K+]o), local field potential and partial tissue oxygen pressure (ptiO2) were measured simultaneously. The cerebral metabolic rate of oxygen (CMRO2) was calculated using a reaction-diffusion model. By that, we tested the effect of clinically relevant concentrations of isoflurane on CMRO2 during SD and modeled tissue oxygenation for different capillary pO2 values. During SD, CMRO2 increased 2.7-fold, resulting in transient hypoxia in the slice core. Isoflurane decreased CMRO2, reduced peak [K+]o, and prolonged [K+]o clearance, which indicates reduced synaptic transmission and sodium-potassium ATPase inhibition. Modeling tissue oxygenation during SD illustrates the need for increased capillary pO2 levels to prevent hypoxia. In the absence thereof, isoflurane could improve tissue oxygenation by lowering CMRO2. Therefore, isoflurane is a promising candidate for pre-clinical studies on neuronal survival in conditions involving SD.

Intracranial pressure monitoring with and without brain tissue oxygen pressure monitoring for severe traumatic brain injury in France (OXY-TC): an open-label, randomised controlled superiority trial

Optimisation of brain oxygenation might improve neurological outcome after traumatic brain injury. The OXY-TC trial explored the superiority of a strategy combining intracranial pressure and brain tissue oxygen pressure (PbtO2) monitoring over a strategy of intracranial pressure monitoring only to reduce the proportion of patients with poor neurological outcome at 6 months. We did an open-label, randomised controlled superiority trial at 25 French tertiary referral centres. Within 16 h of brain injury, patients with severe traumatic brain injury (aged 18-75 years) were randomly assigned via a website to be managed during the first 5 days of admission to the intensive care unit either by intracranial pressure monitoring only or by both intracranial pressure and PbtO2 monitoring. Randomisation was stratified by age and centre. The study was open label due to the visibility of the intervention, but the statisticians and outcome assessors were masked to group allocation. The therapeutic objectives were to maintain intracranial pressure of 20 mm Hg or lower, and to keep PbtO2 (for those in the dual-monitoring group) above 20 mm Hg, at all times. The primary outcome was the proportion of patients with an extended Glasgow Outcome Scale (GOSE) score of 1-4 (death to upper severe disability) at 6 months after injury. The primary analysis was reported in the modified intention-to-treat population, which comprised all randomly assigned patients except those who withdrew consent or had protocol violations. This trial is registered with ClinicalTrials.gov, NCT02754063, and is completed. Between June 15, 2016, and April 17, 2021, 318 patients were randomly assigned to receive either intracranial pressure monitoring only (n=160) or both intracranial pressure and PbtO2 monitoring (n=158). 27 individuals with protocol violations were not included in the modified intention-to-treat analysis. Thus, the primary outcome was analysed for 144 patients in the intracranial pressure only group and 147 patients in the intracranial pressure and PbtO2 group. Compared with intracranial pressure monitoring only, intracranial pressure and PbtO2 monitoring did not reduce the proportion of patients with GOSE score 1-4 (51% [95% CI 43-60] in the intracranial pressure monitoring only group vs 52% [43-60] in the intracranial pressure and PbtO2 monitoring group; odds ratio 1·0 [95% CI 0·6-1·7]; p=0·95). Two (1%) of 144 participants in the intracranial pressure only group and 12 (8%) of 147 participants in the intracranial pressure and PbtO2 group had catheter dysfunction (p=0.011). Six patients (4%) in the intracranial pressure and PbtO2 group had an intracrebral haematoma related to the catheter, compared with none in the intracranial pressure only group (p=0.030). No significant difference in deaths was found between the two groups at 12 months after injury. At 12 months, 33 deaths had occurred in the intracranial pressure group: 25 (76%) were attributable to the brain trauma, six (18%) were end-of-life decisions, and two (6%) due to sepsis. 34 deaths had occured in the intracranial pressure and PbtO2 group at 12 months: 25 (74%) were attributable to the brain trauma, six (18%) were end-of-life decisions, one (3%) due to pulmonary embolism, one (3%) due to haemorrhagic shock, and one (3%) due to cardiac arrest. After severe non-penetrating traumatic brain injury, intracranial pressure and PbtO2 monitoring did not reduce the proportion of patients with poor neurological outcome at 6 months. Technical failures related to intracerebral catheter and intracerebral haematoma were more frequent in the intracranial pressure and PbtO2 group. Further research is needed to assess whether a targeted approach to multimodal brain monitoring could be useful in subgroups of patients with severe traumatic brain injury-eg, those with high intracranial pressure on admission. The French National Program for Clinical Research, La Fondation des Gueules Cassées, and Integra Lifesciences.

The effect of increased positive end expiratory pressure on brain tissue oxygenation and intracranial pressure in acute brain injury patients

Cerebral hypoxia is an important cause of secondary brain injury. Improving systemic oxygenation may increase brain tissue oxygenation (PbtO2). The effects of increased positive end-expiratory pressure (PEEP) on PbtO2 and intracranial pressure (ICP) needs to be further elucidated. This is a single center retrospective cohort study (2016–2021) conducted in a 34-bed Department of Intensive Care unit. All patients with acute brain injury under mechanical ventilation who were monitored with intracranial pressure and brain tissue oxygenation (PbtO2) catheters and underwent at least one PEEP increment were included in the study. Primary outcome was the rate of PbtO2 responders (increase in PbtO2 > 20% of baseline) after PEEP increase. ΔPEEP was defined as the difference between PEEP at 1 h and PEEP at baseline; similarly ΔPbtO2 was defined as the difference between PbtO2 at 1 h after PEEP incrementation and PbtO2 at baseline. We included 112 patients who underwent 295 episodes of PEEP increase. Overall, the median PEEP increased form 6 (IQR 5–8) to 10 (IQR 8–12) cmH2O (p = 0.001), the median PbtO2 increased from 21 (IQR 16–29) mmHg to 23 (IQR 18–30) mmHg (p = 0.001), while ICP remained unchanged [from 12 (7–18) mmHg to 12 (7–17) mmHg; p = 0.42]. Of 163 episode of PEEP increments with concomitant PbtO2 monitoring, 34 (21%) were PbtO2 responders. A lower baseline PbtO2 (OR 0.83 [0.73–0.96)]) was associated with the probability of being responder. ICP increased in 142/295 episodes of PEEP increments (58%); no baseline variable was able to identify this response. In PbtO2 responders there was a moderate positive correlation between ΔPbtO2 and ΔPEEP (r = 0.459 [95% CI 0.133–0.696]. The response in PbtO2 and ICP to PEEP elevations in brain injury patients is highly variable. Lower PbtO2 values at baseline could predict a significant increase in brain oxygenation after PEEP increase.

105.4: Development of a novel method for measuring tissue oxygen pressure to improve the hypoxic condition in subcutaneous islet transplantation

105.4: Development of a novel method for measuring tissue oxygen pressure to improve the hypoxic condition in subcutaneous islet transplantation

The anaemia treatment journey of CKD patients: from epoetins to hypoxia-inducible factor-prolyl hydroxylase inhibitors.

The discovery and development of erythropoiesis-stimulating agents was a journey lasting more than a century, leading to the cloning and approval of recombinant human erythropoietin (rHuEpo). This was an impressive clinical advance, providing the possibility of correcting the symptoms associated with anaemia in chronic kidney disease. Associated iron use was needed to produce new haemoglobin-containing blood red cells. Partial anaemia correction became the standard of care since trials aiming for near-normal haemoglobin levels showed a higher risk of adverse cardiovascular events. Hoping to reduce the cardiovascular risks, a new category of drugs was developed and tested. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are small molecules than can be formulated into orally active pills. They simulate reduced tissue oxygen pressure, thus stimulating the production of endogenous erythropoietin (Epo) by the kidneys and liver. Clinical trials with these compounds demonstrated that HIF-PHIs are at least as effective as rHuEpo in treating or correcting anaemia in non-dialysis and dialysis patients. Trials with HIF-PHIs did not demonstrate superiority in safety outcomes and in some trials, outcomes were worse. There was also a focus on oral delivery, a possible beneficial iron-sparing effect and the ability to overcome Epo resistance in inflamed patients. A negative effect is possible iron depletion, which may explain adverse outcomes.

Insights into Neonatal Cerebral Autoregulation by Blood Pressure Monitoring and Cerebral Tissue Oxygenation: A Qualitative Systematic Review.

The aim of this qualitative systematic review was to identify publications on blood pressure monitoring in combination with cerebral tissue oxygenation monitoring during the first week after birth focusing on cerebral autoregulation. A systematic search was performed on PubMed. The following search terms were used: infants/newborn/neonates, blood pressure/systolic/diastolic/mean/MAP/SAP/DAP, near-infrared spectroscopy, oxygenation/saturation/oxygen, and brain/cerebral. Additional studies were identified by a manual search of references in the retrieved studies and reviews. Only human studies were included. Thirty-one studies focused on preterm neonates, while five included preterm and term neonates. In stable term neonates, intact cerebral autoregulation was shown by combining cerebral tissue oxygenation and blood pressure during immediate transition, while impaired autoregulation was observed in preterm neonates with respiratory support. Within the first 24 h, stable preterm neonates had reduced cerebral tissue oxygenation with intact cerebral autoregulation, while sick neonates showed a higher prevalence of impaired autoregulation. Further cardio-circulatory treatment had a limited effect on cerebral autoregulation. Impaired autoregulation, with dependency on blood pressure and cerebral tissue oxygenation, increased the risk of intraventricular hemorrhage and abnormal neurodevelopmental outcomes. Integrating blood pressure monitoring with cerebral tissue oxygenation measurements has the potential to improve treatment decisions and optimizes neurodevelopmental outcomes in high-risk neonates.

Cervical spinal hemisection effects on spinal tissue oxygenation and long-term facilitation of phrenic, renal and splanchnic sympathetic nerve activity

HypothesesModerate acute intermittent hypoxia (mAIH) elicits plasticity in both respiratory (phrenic long-term facilitation; pLTF) and sympathetic nerve activity (sympLTF) in rats. Although mAIH produces pLTF in normal rats, inconsistent results are reported after cervical spinal cord injury (cSCI), possibly due to greater spinal tissue hypoxia below the injury site. There are no reports concerning cSCI effects on sympLTF. Since mAIH is being explored as a therapeutic modality to restore respiratory and non-respiratory movements in humans with chronic SCI, both effects are important. To understand cSCI effects on mAIH-induced pLTF and sympLTF, partial or complete C2 spinal hemisections (C2Hx) were performed and, 2 weeks later, we assessed: 1) ipsilateral cervical spinal tissue oxygen tension; 2) ipsilateral & contralateral pLTF; and 3) ipsilateral sympLTF in splanchnic and renal sympathetic nerves. MethodsMale Sprague-Dawley rats were studied intact, or after partial (single slice) or complete C2Hx (slice with ∼1 mm aspiration). Two weeks post-C2Hx, rats were anesthetized and prepared for recordings of bilateral phrenic nerve activity and spinal tissue oxygen pressure (PtO2). Splanchnic and renal sympathetic nerve activity was recorded in intact and complete C2Hx rats. ResultsSpinal PtO2 near phrenic motor neurons was decreased after C2Hx, an effect most prominent with complete vs. partial injuries; baseline PtO2 was positively correlated with mean arterial pressure. Complete C2Hx impaired ipsilateral but not contralateral pLTF; with partial C2Hx, ipsilateral pLTF was unaffected. In intact rats, mAIH elicited splanchnic and renal sympLTF. Complete C2Hx had minimal impact on baseline ipsilateral splanchnic or renal sympathetic nerve activity and renal, but not splanchnic, sympLTF remained intact. ConclusionGreater tissue hypoxia likely impairs pLTF and splanchnic sympLTF post-C2Hx, although renal sympLTF remains intact. Increased sympathetic nerve activity post-mAIH may have therapeutic benefits in individuals living with chronic SCI since anticipated elevations in systemic blood pressure may mitigate hypotension characteristic of people living with SCI.

Pattern of Acute Intermittent Hypoxia Protocol Impacts Phrenic Long-term Facilitation

An important model of respiratory motor plasticity is phrenic long-term facilitation (pLTF), a prolonged increase in phrenic nerve activity following intermittent exposure to low oxygen (acute intermittent hypoxia, AIH). pLTF arises from distinct intracellular signaling cascades initiated by serotonin 2 and adenosine 2A (A 2A ) receptor activation, respectively, that interact via powerful crosstalk inhibition. Studies of AIH-induced motor plasticity typically use moderate AIH protocols consisting of 3, 5 min hypoxic episodes in rodent models, but 15, 1 min hypoxic episodes in humans. Since certain factors ( e.g. severity or duration of hypoxia) influence pLTF expression, it is essential to understand the influence of AIH protocol details on motor plasticity. Here we tested the hypothesis that serotonin-dominant plasticity is enhanced when the duration of hypoxic episodes in the AIH protocol is shorter due to less hypoxia-evoked adenosine release, eliminating adenosine constraint and revealing enhanced plasticity. Anesthetized, vagotomized, paralyzed and ventilated male Sprague-Dawley rats were exposed to different AIH protocols with the same cumulative duration (15 min) and severity (arterial Po2 = 40-55mmHg) of hypoxic episodes: 1) 3, 5 min episodes with 5 min intervals (3x5); and 2) 15, 1 min hypoxic episodes with 1 min intervals (15x1). Consistent with prior reports, 3x5 AIH elicits ~60% pLTF (56±5%; n=7). In contrast, 15x1 AIH elicits significantly greater pLTF (139±14%; n=7; p&lt;0.001). To determine if this effect is due to differences in hypoxia evoked-adenosine release in the ventral C 4 spinal cord, tissue oxygen pressure and spinal adenosine concentration were measured with an oxygen optode, and adenosine probe, respectively. Although tissue oxygen pressure between protocols was not different, hypoxia-evoked adenosine release was substantially greater with the 3x5 vs. 15x1 AIH protocols (p&lt;0.001; both n=3). To verify pLTF magnitude results from differential spinal A 2A receptor activation, rats were pretreated with a selective A 2A receptor antagonist, MSX-3 (10uM; 12 uL) delivered intrathecally at C 4 ; with the 3x5 AIH protocol, pLTF was enhanced as expected (141±15%; p&lt;0.001; n=7). However, MSX-3 had no effect on pLTF elicited by the 15x1 AIH protocol (122±11%; n=7; p=0.931). Thus, the mechanism driving pLTF is serotonin-dominant and adenosine-constrained with 3x5 AIH, but adenosine- unconstrained with the 15x1 AIH protocol. We conclude that, by shortening hypoxic episodes from 5 to 1 min (with the same cumulative hypoxic duration), reduced hypoxia-evoked adenosine release reveals the full extent of serotonin-driven plasticity. AIH is emerging as a promising therapeutic modality to restore respiratory and non-respiratory movements in people with spinal injury and ALS. Thus, knowledge that the AIH protocol can be optimized by reducing the length of individual hypoxic episodes has important experimental, biological and translational implications. Supported by: NIH R01HL148030, R01HL149800 &amp; T32HL134621 (ABM), and UF Brain Spinal Cord Research Trust Fund (BSCIRTF) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.