Presence Of Tissue Hypoxia Research Articles

Case of lactacidosis in acute kidney damage and metformin therapy

Тhe article provides a clinical observation of the development of a rare pathological condition of lactic acidosis in a patient with acute kidney injury while taking metformin and confirms the need for timely determination of blood lactate.
 Тhe clinical case confirms that the development of lactic acidosis in a patient with diabetes mellitus may have a mixed etiology and be associated not only with the use of metformin, but also with the presence of tissue hypoxia, exposure to an infectious process, and impaired renal function.
 The development of lactic acidosis is associated with an increase in secretion and / or a decrease in the rate of excretion of lactate, which is expressed in a state of metabolic acidosis and severe cardiovascular insufficiency. The development of lactic acidosis is most often associated with the presence of renal and / or hepatic insufficiency, diabetes mellitus, lung pathology, macromicrocirculation disorders, and hemoglobin function defects, the treatment with biguanide drugs (metformin). Diagnosis of lactic acidosis is based on the data from a biochemical blood test and electrolyte parameters the concentration of blood plasma lactate, the study of acid-base state of the blood and anion gap.

Diagnostic value of markers of oxidative stress and metabolic disorders in preterm infants in the early neonatal period

The aim of the study was to evaluate the markers of oxidative stress and metabolic disorders in preterm infants and to examine their association with short-term outcomes in the early neonatal period to identify the predictors of unfavourable outcome. The study included 46 preterm infants, gestational age ≤32 weeks, in the early neonatal period, i.e. group 1 of 12 infants with lethal outcome and group 2 of 34 preterm infants with favourable outcome. Markers of metabolic disorders, oxidative stress and antioxidant system were analysed in cord blood and urine on the first/second day of life. Evaluation of oxidative (8-isoprostane) and antioxidant system (catalase and superoxide dismutase (SOD) activity) and metabolic (lactate, pyruvate, lactate to pyruvate ratio (LPR), NAD+/NADH) stress parameters confirmed energy imbalance and presence of tissue hypoxia in preterm newborns with adverse outcomes. The following risk factors of unfavourable prognosis in preterm infants in the early neonatal period were identified: asphyxia (p=0.038), early-onset sepsis (p=0.003), intraventricular haemorrhage (p=0.029), hyperlactatemia (p=0.013), increased pyruvate level (p=0.002), increased LPR (p=0.008), decreased catalase (p=0.003) and SOD (p=0.001) activity. Logistic regression indicated that mortality rate was positively related to asphyxia, early-onset sepsis and lactate level, and negatively related to SOD activity. In conclusion, intensive oxidative and metabolic stress in preterm infants is associated with adverse outcomes in the early neonatal period. A combination of asphyxia and early-onset sepsis together with high lactate level and decreased SOD activity is a predictor of unfavourable out- come in the early neonatal period.

Severe type-B lactic acidosis in a patient with bilateral renal Burkitt's lymphoma.

Introduction: Lactic acidosis (LA) can be categorized as type A, which occurs in the presence of tissue hypoxia, or type B, occurring in the absence of tissue hypoxia. Hematologic malignancies are an uncommon cause of type B LA. Case presentation: A 63-year-old man, HIV-negative, with a history of diabetes mellitus, hypothyroidism, and non‐alcoholic fatty liver disease (NAFLD), presented to the ED complaining of acute-on-chronic lumbar pain, and was found to have high serum anion gap (AG) LA. The rest of chemistry and infectious workup was within normal limits. Despite bicarbonate therapy and fluid resuscitation, the patient remained with persistent AG metabolic acidosis and increasing lactic acid up to 14.5 mmol/L. An abdominal computerized tomography (CT) revealed multiple bilateral enhancing lesions in the kidneys, as well as gastric wall thickening. Upper gastrointestinal endoscopy with biopsy showed a high-grade Burkitt’s lymphoma. Further staging showed bone marrow involvement and extensive abdominal adenopathy. After two cycles of inpatient chemotherapy with dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab), the patient developed multifocal pneumonia complicated by respiratory failure. Following a prolonged ICU stay, after discussion with the family members, a decision of withdrawal of life-sustaining therapy was reached. Conclusion: Persistent LA, without identifiable causes of tissue hypoxia, should prompt clinicians to suspect non-hypoxic etiologies, including occult high-grade malignancies. Hematological malignancies constitute an extremely rare cause of type-B LA, carrying a poor prognosis.

Pathogenetic and substitution correction of anemia in patients with malignant neoplasms

Anemia in patients with malignant neoplasms affects the quality of life of the patient and sometimes limits the timely implementation of antitumor treatment. In the pathogenesis of anemia of the malignant neoplasms the largest role play infiltration of the bone marrow by tumor cells, suppression of hematopoiesis by inflammation cytokines, development of functional iron deficiency, reduction of sensitivity of receptors to erythropoietin or its synthesis. The doctor can prescribe effective pathogenetic therapy after evaluating the mechanisms of anemia development in this category of patients. In the article are described in detail the methods of pathogenetic correction of anemic syndrome using parenteral iron preparations, recombinant erythropoietin, indications for their appointment, effectiveness in patients with cancer, as well as possible side effects and complications of therapy. The mechanisms of action, pharmacokinetics, and features of the use of different erythropoietin adents are described. It is shown the effectiveness of erythropoietin preparations in patients with lymphoproliferative disorders based on the results of our own study. A positive response was observed in 77.3 % of patients with non-Hodgkin’s lymphomas, in 61.8 % – with multiple myeloma and 60.9 % with chronic lymphocytic leukemia. It is presented the prognostic factors for the response to erythropoietin therapy and showed own datum in patients with myelodysplastic syndrome (in case of the serum erythropoietin <500 mMU / ml a positive response was found in 35.6 %, with higher level – no response) and with lymphoproliferative disorders (in case of erythropoietin was <130 mMU / ml, the positive response was 80 %, at 130–499 mMU / ml – 63.6 %, and at ≥500 mMU / ml – 25 %). In the article are described the principles of anemia correction using red blood cells transfusions and features of their use in patients with cancer. Special attention is paid to the study of blood saturation as one of the indicators that allow us to assess the adequacy of the gas transport function of blood during red blood cells transfusions. The algorithm for correcting anemia in malignant neoplasms using red blood cells transfusions and erythropoietin agents are presented. It is shown low blood saturation (<60 %) in 32 % hematological malignancie’s patients with a hemoglobin 8.0 g / dL. This datum suggests presence of tissue hypoxia and gives approval to expand the threshold for red blood cells transfusions

Diagnostic value of markers of oxidative stress and metabolic disorders in preterm infants in the early neonatal period

The aim of the study was to evaluate the markers of oxidative stress and metabolic disorders in preterm infants and to examine their association with short-term outcomes in the early neonatal period to identify the predictors of unfavourable outcome. The study included 46 preterm infants, gestational age ≤32 weeks, in the early neonatal period, i.e. group 1 of 12 infants with lethal outcome and group 2 of 34 preterm infants with favourable outcome. Markers of metabolic disorders, oxidative stress and antioxidant system were analysed in cord blood and urine on the first/second day of life. Evaluation of oxidative (8-isoprostane) and antioxidant system (catalase and superoxide dismutase (SOD) activity) and metabolic (lactate, pyruvate, lactate to pyruvate ratio (LPR), NAD+/NADH) stress parameters confirmed energy imbalance and presence of tissue hypoxia in preterm newborns with adverse outcomes. The following risk factors of unfavourable prognosis in preterm infants in the early neonatal period were identified: asphyxia (p=0.038), early-onset sepsis (p=0.003), intraventricular haemorrhage (p=0.029), hyperlactatemia (p=0.013), increased pyruvate level (p=0.002), increased LPR (p=0.008), decreased catalase (p=0.003) and SOD (p=0.001) activity. Logistic regression indicated that mortality rate was positively related to asphyxia, early-onset sepsis and lactate level, and negatively related to SOD activity. In conclusion, intensive oxidative and metabolic stress in preterm infants is associated with adverse outcomes in the early neonatal period. A combination of asphyxia and early-onset sepsis together with high lactate level and decreased SOD activity is a predictor of unfavourable out- come in the early neonatal period.

PB2289 HEALTH‐RELATED QUALITY OF LIFE AND OXYGEN TRANSPORT IN PATIENTS WITH NEPHROGENIC ANEMIA

Background:End‐stage renal disease (EsRD) is often associated with an anemia. Most patients retrieve erythropoiesis stimulating agents, and so they presents with mild anemia. The tolerance of anemia of each patient is individual. Determination of venous blood gas (VBG) in conjunction with study of health‐related quality of life (HRQoL) can help in the individualization of treatment.Aims:To investigate the relationship between health‐related quality of life and venous blood gas in patients with nephrogenic anemia.Methods:30 patients with EsRD undergoing hemodialysis and receiving erythropoes stimulating therapy were involved in the study. 20 men, median age 52 years. Polycystic kidney disease was caused by the development of EsRD in 7 (23%) patients, diabetic nephropathy in 6 (20%) patients, glomerulonephritis also in 6 (20%) patients, nephrosclerosis in 5 (17%), and other causes in the remaining 6 patients (20%). HRQoL was studied using the FACT (Functional Assessment of Cancer Therapy Scale) questionnaire. Indicators of complete blood count, VBG were evaluated.Results:The hemoglobin median in the studied patients showed 105 g/l (81‐112 g/l), 26 patients experienced mild anemia (87%), 3 patients (10%) ‐ moderate anemia. in 1 patient there was no anemic syndrome. SvO2 median is 62.3%, while in only 18 (60%) patients the level of SvO2 is ≥60%. In general, the results of HRQoL analysis showed its deterioration in patients on all scales of the FACT questionnaire; the highest score was obtained in the scales “Physical well‐being” (Me 11 points) and “Anemia” (Me 30 points). When conducting a correlation analysis of hemoglobin and HRQoL, a statistically significant relationship was found on the scales “Physical well‐being” (r = ‐0.45; p < 0.05), “Emotional well‐being” (r = ‐0.39 p < 0, 05) and Anemia (r = ‐0.51; p < 0.05). A statistically significant correlation was obtained between the level of hemoglobin and the level of oxygen in venous blood. At the same time, no significant correlation was established between HRQoL and the saturation of venous blood (p > 0.2).Summary/Conclusion:According to the results of the HRQoL analysis, it was established that in patients with nephrogenic anemia, HRQoL decreases depending on the concentration of hemoglobin. The generally accepted target level of hemoglobin (100‐110 g/l) allows to avoid severe complications, but not in all cases it can adequately meet the need for O2 in patients. According to the data obtained, only 60% of patients achieved SvO2 ≥ 60%, which indicates the presence of tissue hypoxia.

Role of hypoxia-activated prodrugs in combination with radiation therapy: An in silico approach.

Tumour hypoxia has been associated with increased resistance to various cancer treatments, particularly radiation therapy. Conversely, tumour hypoxia is a validated and ideal target for guided cancer drug delivery. For this reason, hypoxia-activated prodrugs (HAPs) have been developed, which remain inactive in the body until in the presence of tissue hypoxia, allowing for an activation tendency in hypoxic regions. We present here an experimentally motivated mathematical model predicting the effectiveness of HAPs in a variety of clinical settings. We first examined HAP effectiveness as a function of the amount of tumour hypoxia and showed that the drugs have a larger impact on tumours with high levels of hypoxia. We then combined HAP treatment with radiation to examine the effects of combination therapies. Our results showed radiation-HAP combination therapies to be more effective against highly hypoxic tumours. The analysis of combination therapies was extended to consider schedule sequencing of the combination treatments. These results suggested that administering HAPs before radiation was most effective in reducing total cell number. Finally, a sensitivity analysis of the drug-related parameters was done to examine the effect of drug diffusivity and enzyme abundance on the overall effectiveness of the drug. Altogether, the results highlight the importance of the knowledge of tumour hypoxia levels before administration of HAPs in order to ensure positive results.

Understanding the venous-arterial CO2 to arterial-venous O2 content difference ratio.

Introduction Early identification of tissue hypoperfusion is a cornerstone of shock management [1]. Normal macrohemodynamic and oxygen-derived parameters do not, however, rule out the presence of tissue hypoxia [2]. In this setting, carbon dioxide (CO2)-derived variables may provide information on macroand microvascular blood flow [3] and also on the presence of anaerobic metabolism [4, 5]. Importantly, variations in CO2 occur more rapidly than changes in lactate kinetics, making the former an attractive biomarker for monitoring, especially during the early stages of resuscitation [6, 7].

Venous oximetry

Tissue hypoxia is the central pathophysiological process in shock and an important co-factor in the development of organ dysfunction. Hemodynamic parameters, usually used to assess the perfusion of organs and tissues, like arterial blood pressure, heart rate, urine output and blood gases can be normal in the presence of tissue hypoxia and cannot rule out  imbalances between global oxygen supply and demand. Mixed venous oxygen saturation (SvO2) is a sensitive indicator of the adequacy of whole-body tissue oxygenation. However, it requires the placement of a pulmonary artery catheter, which is an invasive procedure with the possibility of numerous complications and is increasingly questioned due to the lack of evidence that it improves outcome. Central venous oxygen saturation (ScvO2) requires the insertion of a central venous catheter, which is routinely used in most critically ill patients, but it reflects the adequacy of oxygenation in the brain and upper part of the body and differs from SvO2. Still, it can be used as a surrogate for mixed venous oxygen saturation because the changes and trends of both variables parallel each other. Both variables are used extensively in the treatment of patients with severe sepsis, shock and trauma. In combination with other hemodynamic and biochemical parameters, they have diagnostic and prognostic value and allow for rational treatment of critically ill patients.

Update on chronic-venous-insufficiency-induced inflammatory processes.

The causes of venous ulceration remain unclear. Twentieth-century hypotheses concentrated on the possibility that this problem was caused by failure of oxygen delivery to the skin. However, it has been difficult to substantiate these predictions in practice. Although the presence of tissue hypoxia has been suggested by studies in which transcutaneous oxygen tension has been assessed with transducers heated to unphysiological temperatures, when oxygen measurements are made at room temperature there is little evidence of tissue hypoxia. This has led to the assessment of alternative mechanisms of ulcer development. There has been considerable interest in recent years in the inflammatory processes that surround venous ulceration. A complex sequence of events appears to surround the development of leg ulceration. Increased leukocyte activation has been shown in patients with venous disease as well as increased expression of soluble endothelial adhesion molecules. Histologic studies of the skin in patients with chronic venous disease show a perivascular infiltration of the capillaries of the papillary plexus (the most superficial part of the dermis) with monocytes, macrophages, and connective tissue proteins including fibrin. Fibrosis of the skin and subcutaneous tissues may be initiated by increased gene expression and production of transforming growth factor-beta1. Vascular endothelial growth factor may be involved in the capillary proliferation that has been reported in the skin by a number of authors. Increased expression of several tissue metalloproteinases has been reported both in liposclerotic skin and periulcer skin. The tissue inhibitors of metalloproteinases are also increased and the net result is unclear. Treatment of venous disease using micronized purified flavonoid fraction moderates some of the inflammatory markers, including leukocyte ligand expression and endothelial adhesion molecule shedding. These compounds have also been shown to reduce leukocyte-endothelial adhesion in animal models of ischemia-reperfusion injury. Many inflammatory processes have now been shown to be involved in the development of the skin changes in patients with chronic venous disease. However, the precise sequence of events that leads to leg ulceration is still unclear. Pharmacologic treatments aimed at moderating some of these inflammatory processes are now under investigation as potential ways of treating patients with the more advanced stages of venous disease.

Critical Oxygen Delivery in Patients With Sepsis-Reply

In Reply. —Drs Bredle and Reinhart contend that our data do not refute the approach of increasing Do 2 to supranormal levels in critically ill patients to increase Vo 2 and hopefully improve outcome. They are right. Our study was not designed to test this hypothesis. However, our study and others have more clearly delineated the relationship between Do 2 and Vo 2 in humans and demonstrated that the rationale for increasing Do 2 to supranormal levels is based on an incorrect understanding of this relationship. The technique of increasing Do 2 to supranormal levels in critically ill patients has been based on the rationale that tissue hypoxia is present despite aggressive early resuscitation and return of adequate tissue perfusion according to traditional clinical and laboratory measurement. The presence of tissue hypoxia in these patients has been inferred from finding a correlation between Do 2 and Vo 2 when Do

Management of retinal vein occlusion.

Recent research into the relationship between retinal venous occlusion and general vascular disorders has shown that retinal venous occlusion seems to be related only to systemic hypertension. The role of systemic hemorrheologic parameters in the pathophysiology of venous occlusion is a controversial one. Of the various treatment modalities, isovolemic hemodilution has been found to improve retinal perfusion, but the treatment must be repeated about once a week for at least 2 months. The presence of tissue hypoxia in areas of ischemic venous occlusion has been confirmed by measurements of preretinal oxygen pressure in experimental venous occlusion. Reduced preretinal oxygen pressure in these experimental cases normalized after retinal scatter photocoagulation. The inhibiting role of posterior vitreous detachment on posterior segment neovascularization and the fact that panretinal photocoagulation has a better effect on anterior than on posterior segment neovascularization have been evaluated in clinical studies.

Cerebral regional capillary perfusion and blood flow after carbon monoxide exposure

Alterations in regional cerebral blood flow (rCBF) and percent perfused capillaries (indicative of functional intercapillary distance) were determined in conscious male Long-Evans rats after reducing their blood O2-carrying capacity by exposing them to 1% CO for 12 min. rCBF was determined by the iodoantipyrine method. rCBF increased from a mean of 106 +/- 8 (SE) ml.min-1.100 g-1 before CO exposure to 173 +/- 14 ml.min-1.100 g-1 after CO exposure. There was a greater flow increase (126%) in the cerebral cortex than in the lower brain stem [pons (45%), medulla (39%)]. Presence of fluorescein isothiocyanate-labeled dextran identified the perfused capillaries before and after CO exposure. The volume fraction (Vv) and number/mm2 (Na) of all capillaries (perfused and nonperfused) in a given area of brain were determined after staining for alkaline phosphatase. The percent Vv and percent Na of perfused capillaries increased uniformly (from approximately 50% to approximately 80%) in all parts of the brain after CO exposure. In the presence of tissue hypoxia with undiminished plasma PO2, the brain vasculature allowed greater flow of blood while the microvasculature adjusted to reduce the diffusion distance for O2.

A Biochemical and Pharmacological Approach to the Genesis of Ulcer Disease II

Biochemical and molecular pharmacological studies were carried out in the gastric fundic mucosa during the development of stress ulcer in rats. The aims of this study were: (1) to evaluate the changes in membrane-bound ATP-dependent energy systems during the development of stress ulcer; (2) to prove (or to exclude) the presence of tissue hypoxia in the rat gastric mucosa during the development of stress ulcer; (3) to obtain further evidence of the existence of a feedback mechanism between ATP-ADP, ATP-cAMP, and cAMP-AMP transformations during the development of stress ulcer; (4) to analyze the different biochemical changes in the gastric mucosa before and after the macroscopic appearance of stress-induced gastric mucosal lesions (ulcers). The observations were carried out on both sexes of CFY-strain rats of 180 to 210 g body weight. The animals were deprived of food for 24 hours before the experiments. The animals were forced to swim in water (at 24 degrees C) for five hours. They were sacrificed at 0, 1, 2, 3, 4, and 5 hours after the introduction of stress. The tissue levels of ATP, ADP, AMP/ADP, and lactate were enzymatically measured; the cAMP was measured by radioimmunoassay. The adenylate pool (ATP + ADP + AMP), ratio of ATP/ADP, and "energy charge" [(ATP + 0.5 ADP)/(ATP + ADP + AMP)] were calculated. The membrane (Mg2(+)-Na(+)-K(+)-dependent) ATPase was prepared from the rat gastric fundic mucosa. Dose-response curves for epinephrine, cAMP, and AMP were determined on Na(+)-K(+)-dependent ATPase; also, the affinity, intrinsic activity curves, pD2, pA2 and alpha were calculated for all components. It was found that: (1) gastric mucosal lesions appeared and increased gradually from three hours after introduction of stress; (2) the extent of ATP-cAMP and cAMP-AMP transformations was increased considerably during the development of stress ulcer; (3) the extent of ATP-ADP transformation was completely inhibited; (4) the activity of Na(+)-K(+)-dependent ATPase from rat gastric fundic mucosa could be inhibited by epinephrine, cAMP, and AMP; (5) the ratio of ATP/ADP was unchanged in the first time period (from 0 to 3 hours), after which its value increased; (6) the value of "energy charge" (e.g., the extent of phosphorylation and/or dephosphorylation) of cells was decreased at two and three hours, after which its value returned to a normal level; (7) there was no increase in the tissue level of lactate; (8) several biochemical changes (decrease of ATP, ADP, "energy charge," increase of cAMP, AMP) preceded the macroscopic appearance of stress ulcer.(ABSTRACT TRUNCATED AT 400 WORDS)

Blood component therapy. New guidelines for avoiding complications.

Transfusion medicine is an expanding subspecialty that continues to be reshaped and redefined. The current indications for red blood cell (RBC) transfusion are the presence of tissue hypoxia or a hemoglobin level of less than 7 g/dL. Platelet concentrates should be given prophylactically for severe thrombocytopenia secondary to production defects. In the patient who is in need of an invasive procedure or is bleeding, therapeutic platelet transfusion may be needed if the platelet count is less than 50,000/microL or the bleeding time is twice the upper limit of normal or more. Both RBC and platelet transfusion should be avoided if specific therapy is available for the underlying condition. Transfusion of fresh frozen plasma is indicated for reversal of inherited isolated coagulation factor deficiencies, emergent reversal of the effects of warfarin sodium (Coumadin, Panwarfin, Sofarin), antithrombin III deficiency, and thrombotic thrombocytopenic purpura. No blood transfusion is without risk to the recipient. Two of the major transfusion-related complications are alloimmunization and graft-versus-host disease. Techniques for preventing these conditions are available.

The effects of hypercapnia and hypocapnia upon the cerebrospinal fluid lactate and pyruvate concentrations and upon the lactate, pyruvate, ATP, ADP, phosphocreatine and creatine concentrations of cat brain tissue.

AbstractThe lactate and pyruvate concentrations in cisternal cerebrospinal fluid (CSF), and the lactate, pyruvate, ATP, ADP, phosphocreatine, and creatine concentrations in brain tissue were measured in cats during hyper‐ and hypocapnia. (PaCO2 10–100 mm Hg). Both the CSF and the tissue concentrations of lactate and pyruvate varied inversely with the arterial CO2 tension. In hypercapnia the tissue lactate/pyruvate ratio increased in accordance with a theoretical curve, calculated for a pH dependent equilibrium between the lactate/pyruvate and the NADH/NAD+ systems. In hypocapnia, however, there was no corresponding decrease in the CSF and tissue lactate/pyruvate ratios but a progressive increase at arterial CO2 tensions below 25–20 mm Hg. The inter‐pretation of these results, which indicate the presence of tissue hypoxia at such low CO2 tensions, were complicated by the presence of unchanged tissue levels of ATP and phosphocreatine. The results also showed that in hypocapnia, pyruvate, but not lactate, was distributed between the extra‐ and intracellular spaces according to the pH gradient, while in hypercapnia, lactate, but not pyruvate, had this distribution. The similarity of the changes in CSF and tissue lactate and pyruvate concentrations lend further support to the assumption that the CSF lactate/pyruvate system reflects cellular redox states.