Marker Of Tissue Hypoxia Research Articles

Estimation of blood lactate and bicarbonate levels after stored blood transfusion to predict ICU admission in patients undergoing major head and neck surgeries: A prospective observational study

Abstract Background and Aims: Major head neck surgeries are often associated with major blood loss requiring blood transfusion. However, in spite of transfusion, patients usually suffer adverse postoperative outcomes. Biomarkers can help in identifying such events early. This observational study was conducted to compare blood lactate and bicarbonate levels as predictors of adverse postoperative outcomes. Materials and Methods: Forty-eight adult American Society of Anesthesiologists Physical Status I–III patients met the inclusion criteria. Intraoperative blood loss was managed with stored blood transfusion as per transfusion trigger. Blood lactate and bicarbonate levels were measured preoperatively (Tbas), at the immediate postoperative period (T0), and at 8 h (T8), 16 h (T16), and 24 h (T24) postoperatively. Outcomes such as need for intensive care unit (ICU) admission, length of ICU stay, intraoperative blood transfusion, re-exploration rate, and mortality were recorded. Results: Blood transfusions and ICU admissions were required in 19 (39.6%) and 24 (50%) patients, respectively. Lactate levels of patients requiring blood transfusion and admission to ICU rose significantly from their baseline (1.30 ± 0.41 mmol/l) to 2.80 ± 1.14 mmol/l at the immediate postoperative period, which fell to 2.06 ± 0.78 mmol/l at 24 h postoperatively, compared to other patients who did not require transfusion and ICU admission (P < 0.001). The bicarbonate value did not show any significant change from its baseline (22.68 ± 1.83 mEq/l) at all time points (P = 0.8). In addition, no significant difference was noted regarding ICU admissions (P = 0.659) or blood transfusions (P = 0.788). Conclusions: Following major head and neck surgeries, blood lactate level is a good predictor, but bicarbonate is a poor predictor of the need for blood transfusions and ICU admission. Intraoperative blood transfusion failed to prevent rise in blood lactate level, which is taken as a surrogate marker of tissue hypoxia.

Foxe1 mutant zebrafish show indications of a hypothyroid phenotype and increased sensitivity to ethanol for craniofacial malformations.

FOXE1 mutations in humans are associated with cleft palate and hypothyroidism. We previously developed a foxe1 mutant zebrafish demonstrating mineralization defects in larvae. In the present study, we investigate the thyroid status and skeletal phenotype of adult foxe1 mutants. Mutant fish have increased expression of tshβ in the pituitary, and of hepatic dio1 and dio2. In plasma, we found higher Mg levels. Together these findings are indicative of hypothyroidism. We further observed mineralization defects in scales due to enhanced osteoclast activity as measured by increased expression levels of tracp, ctsk, and rankl. Gene-environment interactions in the etiology of FOXE1-related craniofacial abnormalities remain elusive, which prompts the need for models to investigate genotype-phenotype associations. We here investigated whether ethanol exposure increases the risk of developing craniofacial malformations in foxe1 mutant larvae that we compared to wild types. We found in ethanol-exposed mutants an increased incidence of developmental malformations and marked changes in gene expression patterns of cartilage markers (sox9a), apoptotic markers (casp3b), retinoic acid metabolism (cyp26c1), and tissue hypoxia markers (hifaa, hifab). Taken together, this study shows that the foxe1 mutant zebrafish recapitulates phenotypes associated with FOXE1 mutations in human patients and a clear foxe1-ethanol interaction.

Placental ACE2 Expression: A Possible Pathogenetic Mechanism for Infantile Hemangiomas.

ACE2 is a mono-carboxypeptidase with remarkable vasculo-protective properties, and its expression in the human placenta plays a central role in blood pressure homeostasis and fetal perfusion. Therefore, an alteration in the placental expression of ACE2 could be responsible for reduced placental perfusion and infantile hemangioma (IH) development. Study placentae were collected from patients affected by IHs who were referred to our Dermatology Clinic from 2016 to 2022, while control placentae were randomly collected while matching cases for gestational age. Immunohistochemical investigations were performed with a recombinant anti-ACE2 rabbit monoclonal antibody. A total of 47 placentae were examined, including 20 study placentae and 27 control ones. The mean placental weight was significantly lower in the study group (380.6 g vs. 502.3 g; p = 0.005), while subclinical chorioamnionitis occurred more frequently in the study group (20% vs. 0%, p = 0.03). The mean ACE2 expression was dramatically lower in the study group (χ2 = 42.1 p < 0.001), and the mean placental weight was significantly lower when ACE2 was not expressed compared to the 25-75% and >75% classes of expression (p < 0.05). This study demonstrated that ACE2, as a marker for tissue hypoxia, is dramatically hypo-expressed in placentae belonging to mothers who delivered one or more babies with IH compared to the controls.

Can plethysmographic capillary refill time predict lactate during sepsis? An observational study from Morocco

IntroductionBlood lactate is a marker of tissue hypoxia while capillary refill time (CRT) is a surrogate of tissue perfusion. Measuring these parameters is recommended for assessing circulatory status and guiding resuscitation. However, blood lactate is not widely available in African emergency departments. Additionally, CRT assessment faces challenges related to its precision and reproducibility. This study aims to evaluate the accuracy of visual CRT(V-CRT) compared to plethysmographic CRT (P-CRT) in predicting lactate levels among septic patients. MethodsThis prospective observational study enrolled consecutive patients with sepsis or septic shock over a 6-month period from a tertiary hospital in Marrakech, Morroco. V-CRT and P-CRT were evaluated upon admission, and simultaneous measurements of arterial lactate levels were obtained. The precision of V-CRT and P-CRT in predicting arterial lactate was assessed using ROC curve analysis. ResultsForty-three patients aged of 64±15 years, of whom 70 % were male, were included in the study. Of these, 23 patients (53 %) had sepsis, and 20 patients (47 %) experienced septic shock. Both V-CRT and P-CRT demonstrated statistically significant correlations with arterial lactate, with correlation coefficients of 0.529 (p < 0.0001) and 0.517 (p = 0.001), respectively. ROC curve analysis revealed that V-CRT exhibited satisfactory accuracy in predicting arterial lactate levels >2 mmol/l, with an area under the curve (AUC) of 0.8 (95 % CI=0.65 – 0.93; p < 0.0001). The prediction ability of P-CRT was lower than V-CRT with an AUC of 0.73 (95 % CI: 0.57–0.89; p = 0.043). The optimal thresholds were determined as 3.4 s for V-CRT (sensitivity = 90 %, specificity = 58 %) and 4.1 s for P-CRT (sensitivity = 85 %, specificity = 62 %). ConclusionThese findings suggest that the plethysmographic evaluation did not improve the accuracy of CRT for predicting lactate level. However, V-CRT may still serve as a viable surrogate for lactate in septic patients in low-income settings.

Hyperkalaemia in bleeding trauma patients: A potential marker of disease severity – A retrospective cohort study

BackgroundHyperkalaemia is a common electrolyte abnormality seen in critically ill patients. In haemorrhagic shock, it may contribute to cardiac arrest and has been identified as a potential marker for tissue hypoxia. However, the significance of its role in haemorrhagic shock and its contribution to mortality remains unclear. This study aimed to examine the potential underlying pathophysiology and evaluate the incidence and characteristics of patients with hyperkalaemia on hospital arrival in bleeding trauma patients before transfusions and its mortality. MethodsA retrospective cohort study was conducted on adult patients with traumatic bleeding admitted to a European Major Trauma Centre between January 2016 and December 2021. Patients were classified according to their serum potassium levels on arrival, and relevant clinical parameters between non-hyperkalaemic and hyperkalaemic patients were compared. ResultsAmong the 83 patients in this study, 8 (9.6 %) presented with hyperkalaemia on arrival. The median shock index showed a higher tendency in the hyperkalaemic group. Hyperkalaemia was found to be more common among younger patients who sustained penetrating trauma. Mortality rates were higher in the hyperkalaemic group, but the difference was not statistically significant. ConclusionOur results suggest that hyperkalaemia occurs frequently in bleeding trauma patients on hospital arrival pre-transfusions, indicating a more severe illness. Our findings provide insights into the pathophysiology and characteristics of hyperkalaemia in bleeding trauma patients. Further studies are required to investigate the mechanisms by which hyperkalaemia contributes to mortality in haemorrhagic shock patients.

Prognostic significance of respiratory quotient in patients undergoing extracorporeal cardiopulmonary resuscitation in Korea.

Respiratory quotient (RQ) may be used as a tissue hypoxia marker in various clinical settings but its prognostic significance in patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR) is not known. Medical records of adult patients admitted to the intensive care units after ECPR in whom RQ could be calculated from May 2004 to April 2020 were retrospectively reviewed. Patients were divided into good neurologic outcome and poor neurologic outcome groups. Prognostic significance of RQ was compared to other clinical characteristics and markers of tissue hypoxia. During the study period, 155 patients were eligible for analysis. Of them, 90 (58.1%) had a poor neurologic outcome. The group with poor neurologic outcome had a higher incidence of out-of-hospital cardiac arrest (25.6% vs. 9.2%, P=0.010) and longer cardiopulmonary resuscitation to pump-on time (33.0 vs. 25.2 minutes, P=0.001) than the group with good neurologic outcome. For tissue hypoxia markers, the group with poor neurologic outcome had higher RQ (2.2 vs. 1.7, P=0.021) and lactate levels (8.2 vs. 5.4 mmol/L, P=0.004) than the group with good neurologic outcome. On multivariable analysis, age, cardiopulmonary resuscitation to pump-on time, and lactate levels above 7.1 mmol/L were significant predictors for a poor neurologic outcome but not RQ. In patients who received ECPR, RQ was not independently associated with poor neurologic outcome.

Serum Lactate, an Independent Prognostic Marker in Normotensive Patients With Acute Pulmonary Thromboembolism

Abstract Objective Serum lactate, a marker of tissue hypoxia, is an important prognostic factor in sepsis, trauma, and cardiogenic shock. Data on the direct correlation of serum lactate and in-hospital mortality in normotensive acute pulmonary thromboembolism (APE) patients, however, remains scarce. Material and methods We analyzed normotensive APE patients admitted to our clinic from January 1, 2014, to December 31, 2021. Serum lactate was collected from arterial blood at admission. Results The study sample included 161 patients with an average age of 68.61 ± 11.54 years. 54.94% were female. In-hospital mortality was 19.88%. In ROC analysis, serum lactate was a predictor of in-hospital mortality with an AUC of 0.662 (95%CI 0.584 – 0.735, p = 0.005). The cut-off level identified by the Youden index-associated criterion was &gt; 38 mg/dL (34.38% sensitivity, 94.57% specificity). In multivariable analysis for in-hospital mortality alongside the biomarkers proposed by the 2019 ESC guidelines for severity assessment, lactate &gt; 38 mg/dL was an independent predictor of mortality (OR 10.92, 95%CI 3.04 – 39.29, p &lt; 0.001). The prediction model including PESI score, right ventricular dysfunction, troponin I, and lactate &gt; 38 mg/dL had the best predictive performance for in-hospital mortality (AUC 0.807, p &lt; 0.001). Conclusions Elevated serum lactate is an independent predictor of all-cause in-hospital mortality of normotensive APE patients, with the optimal cut-off &gt; 38 mg/dL. Adding the lactate level for mortality prediction outperformed the 2019 ESC guidelines algorithm for severity assessment of normotensive APE patients.

Venous-arterial oxygen saturation and serum lactate in the postoperative period of cardiac surgery.

Oxygen saturation and lactate are markers of tissue hypoxia; they are obtained from central venous and mixed venous sample of the pulmonary artery. The simultaneous behavior of these parameters in the postoperative period of cardiac surgery is unknown. To characterize the lactate and oxygen saturation of the venous-arterial circuit of the postoperative patient from cardiac surgery. Design: Analytical cross-sectional. In consecutive patients after cardiac surgery, serum lactate and oxygen saturation of the venous-arterial circuit were obtained. The variables were reported with median (25.75 percentiles). They were analyzed with Kruskal-Wallis ANOVA and respective adjustment, Spearman correlation, the descriptive Bland-Altman statistic and intraclass correlation coefficient (95% confidence interval). A p < 0.05 was considered significant. 244 blood samples from 61 patients were studied. Women 30 (49%). (Oxygen saturation) [lactate] were: arterial 98 (95.3, 99.4%) and 1.7 (1.1, 2.1); peripheral venous 85 (75.4, 94%) and [1.9 (1.35, 2.3)]; central venous 68.8 (58.74, 70.2%) and 1.8 (1.3, 2.3); mixed central venous 66.8 (61.2, 73.1%) and 1.8 (1.3, 2.2), p < 0.05. The best intraclass correlation coefficient for oxygen saturation were from central vein to mixed central vein 0.856 (0.760,0.914); and lactate: 0.954 (0.923, 0.972). The oxygen saturation differs in the venous-arterial circuit unlike lactate where they are similar. The best values of the intraclass correlation coefficient for lactate and oxygen saturation were those obtained in central vein and mixed central vein.

Tactics for treating young children with pyelonephritis and vesicoureteral reflux associated with impaired fibrillogenesis.

The purpose of this study is to substantiate the choice and evaluate the effectiveness of therapeutic tactics aimed at suppressing collagen formation and improving metabolic processes in the kidney parenchyma in young children with pyelonephritis against the background of vesicoureteral reflux associated with undifferentiated tissue dysfunction. 67 children from 2weeks to 3years old with pyelonephritis and vesicoureteral reflux were examined. All children during the period of remission of the inflammatory process were examined for the content of oxyproline in the urine. Urine crystallinity and urinary excretion were determined, and markers of the morphofunctional state of the cytomembranes of the renal epithelium were determined: calcification test-the presence of polar lipids in the urine and test for the presence of lipid peroxidation products in the urine. Children with high urinary hydroxyproline excretion prior to protocol treatment of pyelonephritis during the remission of the inflammatory process at the stage of maintenance therapy were recommended to receive metabolic preparations that can inhibit collagen formation and improve parenchyma metabolic processes during the month-vitamin E 10% and L-carnitine in age-related doses. After 6months, a study was made on the functional state of the renal parenchyma in the dynamics of treatment. After metabolic antihypoxic and membrane-protective therapy, there was a significant positive dynamic of all markers of tissue hypoxia and membrane destruction in the kidney parenchyma, which confirms the inhibition of collagen formation processes and a decrease in tissue hypoxia with vitamin E and L-carnitine in age-related doses.

Should lactate be added to Tokyo criteria for the evaluation of patients with acute cholangitis?

Tokyo guidelines (TG13/18) are used for the severity assessment of acute cholangitis (AC). Lactate is a clinical marker of tissue hypoxia and disease severity, independent from blood pressure. The aim of this study is to investigate the relationship between blood lactate level and TG13/18 criteria in patients diagnosed with AC. One hundred fifteen patients with AC were included in this retrospective study. Demographic characteristics of the patients and laboratory data were scanned from their hospital medical records. According to TG13/18 guidelines, the patients were divided into 3 groups as mild (grade 1), moderate (grade 2), and severe (grade 3) AC. Sixty three (54.7%) of the patients were grade 1, 37 (32.1%) were grade 2, and 15 (13.0%) were grade 3. It was found that blood lactate level increased significantly from grade 1 to grade 3 (p < 0.001). In logistic regression analysis, white blood cell (WBC) count, total bilirubin and blood lactate levels independently determined the patients to be grade 2 or 3 AC. When the blood lactate cut-off value was taken as 16.5mg/dL, we diagnosed grade 2 or 3 AC with a sensitivity of 78.8% and a specificity of 75.7%. From among lactate, WBC, and C reactive protein, lactate showed the highest value regarding the area under the curve, which is an index for predicting grade III upon ROC analysis. The blood lactate level is associated with the severity of AC. In addition to TG13/18 guidelines, blood lactate level can be a useful biomarker in the severity grading of AC.

Renal Parenchymal Hypoxia in Young Children in the Period of Complete Remission of Acute Uncomplicated Pyelonephritis without Renal Impairment

Introduction. After establishing the diagnosis of pyelonephritis, there is a need to determine, whether renal parenchymal hypoxia remains in the period of remission. The least studied methods up to now are functional ones, which allow to verify the presence and degree of tissue hypoxia in secondary pyelonephritis and to evaluate the results of the medical measures to restore kidney function. Objective: to clarify the presence of renal parenchymal hypoxia and membrane destruction of the renal epithelium in young children with pyelonephritis without anatomic congenital malformations of the urinary system during its remission.Materials and methods of the study. The study involved 65 children with acute uncomplicated pyelonephritis, who after nephro-urological examination did not reveal anatomical malformations of the urinary system. General clinical examination was carried out, markers of tissue hypoxia and morphofunctional state of cell membranes of renal epithelium were determined.Discussion of the study results. The ability of urine to prevent crystal formation was significantly reduced to oxalates and phosphates in 40.0 and 47.7 % of the surveyed children. In one-third of children with pyelonephritis, oxalate excretion was significantly higher than in healthy children, hypophosphaturia was detected in 52.3 % of cases and the tendency to reduce the excretion of urates in 10.8 % of pediatric patients with pyelonephritis. The content of lipid peroxidation products in urine was increased in 41.5 % of the surveyed children with pyelonephritis, and appearance of polar lipids was observed in 46.2 % of patients.Conclusions. To predict the formation and for the purpose of early diagnosis of renal parenchymal hypoxia and the processes of nephrothelial membrane destruction in young children with pyelonephritis, it is recommended to use such markers, as indicators of urine ability to prevent crystal formation, daily excretion of salts, excretion of lipid peroxidation products and polar lipids in the urine. It is recommended to apply the methods to correct these changes.

Роль метаболической терапии в лечении гипоксии паренхимы почек у детей с пиелонефритом, ассоциированным с недифференцированной дисплазией соединительной ткани

Цель: обосновать выбор и оценить эффективность применения метаболического лечебного комплекса (витамин Е и L-карнитин), направленного на уменьшение тканевой гипоксии и улучшение метаболических процессов в паренхиме почек в терапии острого пиелонефрита на фоне пузырно-мочеточникового рефлюкса как висцерального проявления недифференцированной дисплазии соединительной ткани у детей раннего возраста. Материалы и методы. Обследованы 67 детей с пиелонефритом и пузырно-мочеточниковым рефлюксом (ПМР), ассоциированным с недифференцированной дисплазией соединительной ткани (НДСТ), в возрасте от 3 месяцев до 3 лет. В контрольную группу вошли 65 детей раннего возраста с острым пиелонефритом, у которых после обследования не было выявлено ПМР и признаков НДСТ. Вторую группу контроля составили 40 соматически здоровых детей этого же возраста. С целью диагностики наличия недифференцированной дисплазии соединительной ткани всем детям в периоде ремиссии воспалительного процесса проводился тест на содержание оксипролина в моче. Определялись маркеры недифференцированной тканевой гипоксии паренхимы почек: тест на антикристаллобразующую функцию мочи и суточную экскрецию солей в моче по методике Ю.Е.Вельтищева и Э.А.Юрьевой. Исследовались маркеры морфофункционального состояния цитомембран почечного эпителия: проба на кальцификацию — наличие полярных липидов в моче и тест на наличие продуктов перекисного окисления липидов в моче. Детям раннего возраста с пиелонефритом, ПМР и НДСТ, в моче которых была установлена высокая экскреция оксипролина, в дополнение к протокольному лечению в периоде ремиссии воспалительного процесса был рекомендован прием в течение месяца комплекса витамина Е и L-карнитина в возрастных дозах, способного улучшать метаболические процессы в паренхиме почек. Результаты. После метаболической терапии с антигипоксантным и мембранопротекторным действием у обследованных детей наблюдалась значительная положительная динамика изучаемых маркеров тканевой гипоксии и мембранодеструкции паренхимы почек. Выводы. Выявлено положительное влияние метаболического комплекса (витамин Е и L-карнитин) в периоде ремиссии воспалительного процесса почек, который выразился в уменьшении степени тканевой гипоксии и мембранодеструкции, что подтверждает возможность уменьшения тканевой гипоксии у детей с пиелонефритом и пузырно-мочеточниковым рефлюксом, ассоциированным с недифференцированной дисплазией соединительной ткани, при применении витамина Е и L-карнитина в возрастных дозах в течение месяца и позволяет рекомендовать этим детям проведение метаболической терапии.

Tissue Expression of Carbonic Anhydrase IX Correlates to More Aggressive Phenotype of Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most common cancer in the white-skinned population accounting for about 15% of all neoplasms. Its incidence is increasing worldwide, at a rate of about 10% per year. BCC, although infrequently metastasizing, very often causes extensive tissue losses, due to the high propensity toward stromal infiltration, particularly in its dedifferentiated forms, with disfiguring and debilitating results. To date, there still is limited availability of therapeutic treatments alternative to surgery. We evaluated the immunohistochemical expression of the carbonic anhydrase IX (CAIX), one of the main markers of tissue hypoxia, in a set of 85 archived FFPE BCC tissues, including the main subtypes, with different clinical outcomes, to demonstrate a possible relationship between hypoxic phenotype and biological aggressiveness of these neoplasms. Our results showed that the expression level of the CAIX protein contributes to the stratification of BCC in the different risk classes for recurrence. We hypothesize for CAIX a potential therapeutic role as a target therapy in the treatment of more aggressive BCCs, thus providing an alternative to surgical and pharmacological therapy with Hedgehog inhibitors, a promising example of target therapy in BCCs.

Tissue hypoxia in Crohn’s disease in children: markers and coping methods

Objective: to identify markers of tissue hypoxia in Crohn’s disease in children: markers and methods for overcoming it.Materials and methods: 27 children with Crohn’s disease (CD) aged from 1 year to 18 years were examined. Histological, histomorphometric and immunohistochemical analysis of biopsy samples of the colon mucosa.Results: morphological markers of tissue hypoxia in CD were identified: the presence of predominantly immature fibroblasts, infiltration of the muscle plate by neutrophilic granulocytes, necrotizing vasculitis, the phenomenon of the grouping of inactive macrophages with each other with the formation of multinucleated cells, which are the precursors of multinucleated granules according to the Pigorov-Lanhans typeConclusion: in identifying markers of tissue hypoxia, leading to a worsening prognosis of the course of CD and the development of complications, it is necessary to determine the tactics of accelerated “step-up” therapy using anticytokine drugs and use the method of hyperbaric oxygenation.

Mediators of cerebral hypoperfusion and blood-brain barrier leakiness in Alzheimer's disease, vascular dementia and mixed dementia.

In vascular dementia (VaD) and Alzheimer’s disease (AD), cerebral hypoperfusion and blood‐brain barrier (BBB) leakiness contribute to brain damage. In this study, we have measured biochemical markers and mediators of cerebral hypoperfusion and BBB in the frontal (BA6) and parietal (BA7) cortex and underlying white matter, to investigate the pathophysiology of vascular dysfunction in AD, VaD and mixed dementia. The ratio of myelin‐associated glycoprotein to proteolipid protein‐1 (MAG:PLP1), a post‐mortem biochemical indicator of the adequacy of ante‐mortem cerebral perfusion; the concentration of fibrinogen adjusted for haemoglobin level, a marker of blood‐brain barrier (BBB) leakiness; the level of vascular endothelial growth factor‐A (VEGF), a marker of tissue hypoxia; and endothelin‐1 (EDN1), a potent vasoconstrictor, were measured by ELISA in the frontal and parietal cortex and underlying white matter in 94 AD, 20 VaD, 33 mixed dementia cases and 58 age‐matched controls. All cases were assessed neuropathologically for small vessel disease (SVD), cerebral amyloid angiopathy (CAA) severity, Aβ and phospho‐tau parenchymal load, and Braak tangle stage. Aβ40 and Aβ42 were measured by ELISA in guanidine‐HCl tissue extracts. We found biochemical evidence of cerebral hypoperfusion in AD, VaD and mixed dementia to be associated with SVD, Aβ level, plaque load, EDN1 level and Braak tangle stage, and to be most widespread in mixed dementia. There was evidence of BBB leakiness in AD—limited to the cerebral cortex and related to EDN1 level. In conclusion, abnormalities of cerebral perfusion and BBB function in common types of dementia can largely be explained by a combination of arteriolosclerosis, and Aβ‐, tau‐ and endothelin‐related vascular dysfunction. The relative contributions of these processes vary considerably both between and within the diseases.

Brain interstitial glycerol correlates with evolving brain injury in paediatric traumatic brain injury

A better understanding of the complex pathophysiology of traumatic brain injury (TBI) is needed to improve our current therapies. Cerebral microdialysis (CMD) is an advanced method to monitor the brain, but little is known about its parameters in children. Brain glycerol, one of the CMD variables, is an essential component of the phospholipid bilayer cell membrane and is considered a useful marker of tissue hypoxia in adults. This study examined the time course of glycerol and its associations in paediatric TBI. In this retrospective cohort study, we collected data on children (< 13years) with severe TBI who underwent CMD monitoring. The relationship of glycerol was examined with respect to physiological, radiological variables, and clinical outcome. Twenty-eight children underwent CMD monitoring and had evaluable data. Lesion progression on head computed tomography (CT) demonstrated a strong relationship with glycerol (median glycerol, maximum and initial-to-maximum) when lesion size increased by > 30% (p=0.01, p=0.04 and p=0.004). Absolute glycerol values had a weak but statistically significant association with intracranial pressure and brain oxygenation. We did not find an association with clinical outcome. This is the first study to provide data on brain interstitial glycerol in children. CMD glycerol, particularly an increase from baseline, is associated with other markers of injury and with a significant increase in lesion size on repeat head CT. As such, it may represent a useful monitorable marker for evolving injury in paediatric TBI.

Hemodynamic support in septic shock.

The current article reviews recent findings on the monitoring and hemodynamic support of septic shock patients. The ultimate goal of hemodynamic resuscitation is to restore tissue oxygenation. A multimodal approach combining global and regional markers of tissue hypoxia seems appropriate to guide resuscitation. Several multicenter clinical trials have provided evidence against an aggressive fluid resuscitation strategy. Fluid administration should be personalized and based on the evidence of fluid responsiveness. Dynamic indices have proven to be highly predictive of responsiveness. Recent data suggest that balanced crystalloids may be associated with less renal failure. When fluid therapy is insufficient, a multimode approach with different types of vasopressors has been suggested as an initial approach. Dobutamine remains the firs inotropic option in patients with persistent hypotension and decrease ventricular systolic function. Calcium sensitizer and phosphodiesterase inhibitors may be considered, but evidence is still limited. Veno-arterial extracorporeal membrane oxygenation may be considered in selected unresponsive patients, particularly with myocardial depression, and in a highly experienced center. Resuscitation should be personalized and based on global and regional markers of tissue hypoxia as well as the fluid responsiveness indices. The beneficial effect of multimode approach with different types of vasopressors, remains to be determined.

Impact of Inhaled Oxygen on Reactive Oxygen Species Production and Oxidative Damage during Spontaneous Ventilation in a Murine Model of Acute Renal Ischemia and Reperfusion.

Acute kidney injury (AKI) affects 10% of patients following major surgery and is independently associated with extra-renal organ injury, development of chronic kidney disease, and death. Perioperative renal ischemia and reperfusion (IR) contributes to AKI by, in part, increasing production of reactive oxygen species (ROS) and leading to oxidative damage. Variations in inhaled oxygen may mediate some aspects of IR injury by affecting tissue oxygenation, ROS production, and oxidative damage. We tested the hypothesis that provision of air (normoxia) compared to 100% oxygen (hyperoxia) during murine renal IR affects renal ROS production and oxidative damage. We administered 100% oxygen or 21% oxygen (air) to 8-9 week-old FVB/N mice and performed dorsal unilateral nephrectomy with contralateral renal ischemia/reperfusion surgery while mice spontaneously ventilated. We subjected mice to 30 minutes of ischemia and 30 minutes of reperfusion prior to sacrifice. We obtained an arterial blood gas (ABG) by performing sternotomy and left cardiac puncture. We stained the kidney with pimonidazole, a marker of tissue hypoxia; 4-HNE, a marker of ROS-production; and we measured F2-isoprostanes in homogenized tissue to quantify oxidative damage. Hyperoxia during IR increased arterial oxygen content compared to normoxia, but both groups of mice were hypoventilating at the time of ABG sampling. Renal tissue hypoxia following reperfusion was similar in both treatment groups. ROS production was similar in the cortex of mice (3.8% area in hyperoxia vs. 3.1% in normoxia, P=0.19) but increased in the medulla of hyperoxia-treated animals (6.3% area in hyperoxia vs. 4.5% in nomoxia, P=0.02). Renal F2-isoprostanes were similar in treatment groups (2.2 pg/mg kidney in hyperoxia vs. 2.1 pg/mg in normoxia, P=0.40). Hyperoxia during spontaneous ventilation in murine renal IR did not appear to affect renal hypoxia following reperfusion, but hyperoxia increased medullary ROS production compared to normoxia.

Role of central venous-arterial PCO2 difference in prediction of clinical outcome in ICU septic patients

ABSTRACT Background: Identification of tissue hypoxia and hypoperfusion plays an important role in the management of critically ill patients. Although the venous-arterial PCO2 difference (ΔPCO2) cannot serve as a marker of tissue hypoxia, it is considered a marker of the adequacy of venous blood flow (Cardiac output). The present study aimed to evaluate the role of venous-arterial PCO2 gradient in prediction of outcome in septic patients admitted to ICU. Patients and methods: 100 adult patients fulfilled the criteria of severe sepsis or septic shock admitted to Emergency Intensive Care Unit, were divided in two groups according to ΔPCO2. The high ΔpCO2 group (ΔpCO2 > 6 mmHg) included 58 patients and the normal ΔpCO2 (ΔpCO2 ≤ 6 mmHg) included 42 patients. Clinical scoring systems were recorded. Clinical outcome including organ dysfunction and mortality was recorded. Results: The high ΔPCO2 group showed significant lower blood glucose level (p = 0.038) than the normal ΔPCO2 group. Serum lactate, heart rate, and APACHE score were significantly higher in high ΔPCO2 group than normal ΔPCO2 group (p, 0.012, 0.013, and 0.020, respectively). As regard to the clinical outcome, patient mortality was significantly higher (p = 0.042) in high ΔPCO2 group than normal ΔPCO2 group and the number of organ dysfunction was higher in high ΔPCO2 group than normal ΔPCO2 group but not reached a significant level (p = 0.625). Conclusions: ΔPCO2 is a reliable index for early prediction of clinical outcome including organ dysfunction and mortality in patients with sepsis and septic shock.

Correlative Analyses Between Immune Markers, Tumor Hypoxia And Outcomes Of Head-And-Neck Cancer Patients Undergoing Chemoradiation: Results From A Prospective Trial

Tumor-infiltrating lymphocytes (TILs) influence the response of patients with head-and-neck squamous cell carcinomas (HNSCCs) to chemoradiation and are modulated by the tumor microenvironment and tumor-associated hypoxia. This analysis aimed to assess the prognostic value of TILs and their association with the dynamic tumor hypoxia during chemoradiation in a prospective trial of HNSCC patients. 49 patients with locally advanced HNSCCs were enrolled in this prospective trial prior to undergoing definitive chemoradiation. Patients received tumor biopsies and [18F]-FDG-PET imaging at baseline and [18F]-FMISO hypoxia PET at baseline and in weeks 2 and 5 into treatment. Total lymphocytes, CD3-, CD4-, CD8-positive lymphocytes and expression of PD-1 and PD-L1 were quantified by immunohistochemistry in tumoral and stromal areas of the biopsies and correlated with the tissue hypoxia markers HIF1α, CAIX, CD34 and the longitudinal hypoxia PET/CT data. Potential correlations of immune markers with locoregional control and patient survival were assessed. Patients with high TIL numbers demonstrated increased locoregional control (p = 0.007) and progression-free survival (p = 0.003) compared to patients with lower levels in the biopsies. High numbers of CD3-positive T lymphocytes correlated with improved progression-free (p = 0.018) and overall survival (p = 0.037). In contrast, there was a trend towards impaired progression-free survival for high numbers of CD4-positive regulatory T lymphocytes (p = 0.091), while neither CD8-positive cytotoxic T lymphocytes nor PD-1 or PD-L1 expression correlated with patient outcomes. High levels of TILs were linked to an increased density of CD34-positive microvessels, but not increased levels of hypoxia markers HIF1α or CAIX. No significant correlations could be observed between TILs and dynamic hypoxia PET imaging parameters. In contrast, high expression of intratumoral and stromal PD-1 was associated with low initial tumor hypoxia levels (p = 0.023 for intratumoral PD-1, p = 0.004 for stromal PD-1) as well as a further decrease in the PET hypoxia signal between treatment initiation and week 5 (p = 0.033 for intratumoral PD-1, p = 0.001 for stromal PD-1). In this trial, infiltration of CD3-positive, but not CD4-positive or CD8-positive lymphocytes correlated with an improved locoregional control and increased survival of HNSCC patients after chemoradiation. While no clear associations were found between lymphocyte counts and tumor hypoxia, tumoral PD-1 expression was linked to low initial hypoxia levels and further reductions during treatment. The interplay between tumor hypoxia and tumor-associated immune patterns warrants further investigations to predict treatment response of HNSCC patients.