Impact of reduced cerebral perfusion pressure on outcome after severe traumatic brain injury is dependent on brain tissue oxygen pressure

INTRODUCTION. Reduced cerebral perfusion pressure (CPP) may worsen secondary damage and outcome after severe traumatic brain injury (TBI), however the optimal management of CPP is still debated. STUDY HYPOTHESIS: We hypothesized that the impact of CPP on outcome is related to brain tissue oxygen tension (PbtO2) level and that reduced CPP may worsen TBI prognosis when it is associated with brain hypoxia. DESIGN. Retrospective analysis of prospective database. METHODS. We analyzed 103 patients with severe TBI who underwent continuous PbtO2 and CPP monitoring for an average of 5 days. For each patient, duration of reduced CPP (\60 mm Hg) and brain hypoxia (PbtO2\15 mm Hg for[30 min [1]) was calculated with linear interpolation method and the relationship between CPP and PbtO2 was analyzed with Pearson's linear correlation coefficient. Outcome at 30 days was assessed with the Glasgow Outcome Score (GOS), dichotomized as good (GOS 4-5) versus poor (GOS 1-3). Multivariable associations with outcome were analyzed with stepwise forward logistic regression. RESULTS. Reduced CPP (n=790 episodes; mean duration 10.2 ± 12.3 h) was observed in 75 (74%) patients and was frequently associated with brain hypoxia (46/75; 61%). Episodes where reduced CPP were associated with normal brain oxygen did not differ significantly between patients with poor versus those with good outcome (8.2 ± 8.3 vs. 6.5 ± 9.7 h; P=0.35). In contrast, time where reduced CPP occurred simultaneously with brain hypoxia was longer in patients with poor than in those with good outcome (3.3±7.4 vs. 0.8±2.3 h; P=0.02). Outcome was significantly worse in patients who had both reduced CPP and brain hypoxia (61% had GOS 1-3 vs. 17% in those with reduced CPP but no brain hypoxia; P\0.01). Patients in whom a positive CPP-PbtO2 correlation (r[0.3) was found also were more likely to have poor outcome (69 vs. 31% in patients with no CPP-PbtO2 correlation; P\0.01). Brain hypoxia was an independent risk factor of poor prognosis (odds ratio for favorable outcome of 0.89 [95% CI 0.79-1.00] per hour spent with a PbtO2\15 mm Hg; P=0.05, adjusted for CPP, age, GCS, Marshall CT and APACHE II). CONCLUSIONS. Low CPP may significantly worsen outcome after severe TBI when it is associated with brain tissue hypoxia. PbtO2-targeted management of CPP may optimize TBI therapy and improve outcome of head-injured patients.

Cardiopulmonary support and extracorporeal membrane oxygenation for cardiac assist.

BACKGROUND: Use of cardiopulmonary bypass for emergency resuscitation is not new. In fact, John Gibbon proposed this concept for the treatment of severe pulmonary embolism in 1937. Significant progress has been made since, and two main concepts for cardiac assist based on cardiopulmonary bypass have emerged: cardiopulmonary support (CPS) and extracorporeal membrane oxygenation (ECMO). The objective of this review is to summarize the state of the art in these two technologies. METHODS: Configuration of CPS is now fairly standard. A mobile cart with relatively large wheels allowing for easy transportation carries a centrifugal pump, a back-up battery with a charger, an oxygen cylinder, and a small heating system. Percutaneous cannulation, pump-driven venous return, rapid availability, and transportability are the main characteristics of a CPS system. Cardiocirculatory arrest is a major predictor of mortality despite the use of CPS. In contrast, CPS appears to be a powerful tool for patients in cardiogenic shock before cardiocirculatory arrest, requiring some type of therapeutic procedures, especially repair of anatomically correctable problems or bridging to other mechanical circulatory support systems such as ventricular assist devices. CPS is in general not suitable for long-term applications because of the small-bore cannulas, resulting in significant pressure gradients and eventually hemolysis. RESULTS: In contrast, ECMO can be designed for longer-term circulatory support. This requires large-bore cannulas and specifically designed oxygenators. The latter are either plasma leakage resistent (true membranes) or relatively thrombo-resistant (heparin coated). Both technologies require oxygenator changeovers although the main reason for this is different (clotting for the former, plasma leakage for the latter). Likewise, the tubing within a roller pump has to be displaced and centrifugal pump heads have to be replaced over time. ECMO is certainly the first choice for a circulatory support system in the neonatal and pediatric age groups, where the other assist systems are too bulky. ECMO is also indicated for patients improving on CPS. Septic conditions are, in general, considered as contraindications for ECMO. CONCLUSIONS: Ease of availability and moderate cost of cardiopulmonary bypass-based cardiac support technologies have to be balanced against the significant immobilization of human resources, which is required to make them successful.

Nonenzymatic oxidation of trienoic fatty acids contributes to reactive oxygen species management in Arabidopsis.

In higher plants such as Arabidopsis thaliana, omega-3 trienoic fatty acids (TFAs), represented mainly by alpha-linolenic acid, serve as precursors of jasmonic acid (JA), a potent lipid signal molecule essential for defense. The JA-independent roles of TFAs were investigated by comparing the TFA- and JA-deficient fatty acid desaturase triple mutant (fad3-2 fad7-2 fad8 (fad3 fad7 fad8)) with the aos (allene oxide synthase) mutant that contains TFAs but is JA-deficient. When challenged with the fungus Botrytis, resistance of the fad3 fad7 fad8 mutant was reduced when compared with the aos mutant, suggesting that TFAs play a role in cell survival independently of being the precursors of JA. An independent genetic approach using the lesion mimic mutant accelerated cell death2 (acd2-2) confirmed the importance of TFAs in containing lesion spread, which was increased in the lines in which the fad3 fad7 fad8 and acd2-2 mutations were combined when compared with the aos acd2-2 lines. Malondialdehyde, found to result from oxidative TFA fragmentation during lesion formation, was measured by gas chromatography-mass spectrometry. Its levels correlated with the survival of the tissue. Furthermore, plants lacking TFAs overproduced salicylic acid (SA), hydrogen peroxide, and transcripts encoding several SA-regulated and SA biosynthetic proteins. The data suggest a physiological role for TFAs as sinks for reactive oxygen species.

Mitochondrial reactive oxygen species generation triggers inflammatory response and tissue injury associated with hepatic ischemia-reperfusion: Therapeutic potential of mitochondrially targeted antioxidants.

Mitochondrial reactive oxygen species generation has been implicated in the pathophysiology of ischemia-reperfusion (I/R) injury; however, its exact role and its spatial-temporal relationship with inflammation are elusive. Herein we explore the spatial-temporal relationship of oxidative/nitrative stress and inflammatory response during the course of hepatic I/R and the possible therapeutic potential of mitochondrial-targeted antioxidants, using a mouse model of segmental hepatic ischemia-reperfusion injury. Hepatic I/R was characterized by early (at 2h of reperfusion) mitochondrial injury, decreased complex I activity, increased oxidant generation in the liver or liver mitochondria, and profound hepatocellular injury/dysfunction with acute proinflammatory response (TNF-α, MIP-1α/CCL3, MIP-2/CXCL2) without inflammatory cell infiltration, followed by marked neutrophil infiltration and a more pronounced secondary wave of oxidative/nitrative stress in the liver (starting from 6h of reperfusion and peaking at 24h). Mitochondrially targeted antioxidants, MitoQ or Mito-CP, dose-dependently attenuated I/R-induced liver dysfunction, the early and delayed oxidative and nitrative stress response (HNE/carbonyl adducts, malondialdehyde, 8-OHdG, and 3-nitrotyrosine formation), and mitochondrial and histopathological injury/dysfunction, as well as delayed inflammatory cell infiltration and cell death. Mitochondrially generated oxidants play a central role in triggering the deleterious cascade of events associated with hepatic I/R, which may be targeted by novel antioxidants for therapeutic advantage.

Effect of sodium loading/depletion on renal oxygenation in young normotensive and hypertensive men

Rapport de synthèse:Le but de cette étude était d'investiguer pour la première fois chez l'homme l'effet du sodium alimentaire et de l'hypertension artérielle sur l'oxygénation tissulaire par une technique spéciale d'imagerie à résonance magnétique nommée 'BOLD-IRM' (Blood Oxygen Level Dependent-IRM). Le BOLD-IRM est une technique nouvelle qui permet de mesurer la bio disponibilité tissulaire d'oxygène de façon non-invasive chez l'homme, en utilisant le déoxyhémoglobine comme produit de contraste endogène.Le rational de cette étude était double. Premièrement, des changements dans l'apport sodique alimentaire devraient théoriquement influencer l'oxygénation tissulaire rénale, étant donné que la réabsorption tubulaire du sodium est un transport actif nécessitant de l'énergie et de l'oxygène. Deuxièmement, des études chez l'animal suggèrent une rôle possible de l'hypoxie tissulaire dans le développement de la néphropathie hypertensive.Nous avons déterminé l'oxygénation rénale avec le BOLD-IRM chez dix hommes normo tendus (âgés de 26.5±7.4 ans) et huit hommes hypertendus non-traités (âgés de 28.8±5.7 ans) une semaine après un régime riche en sel (>200 mmol/jour), et de nouveau une semaine après un régime pauvre en sel (<100 mmol/jour). En parallèle, nous avons mesuré la clearance de l'inuline, du p- aminohippurate (PAH) et du lithium endogène, afin de déterminer respectivement la filtration glomérulaire, le flux sanguin rénal et le 'renal sodium handling', tous des paramètres ayant la capacité d'influencer la consommation et/ou la disponibilité d'oxygène tissulaire. Nous nous attendions d'une côté à une oxygénation rénale diminuée chez les sujets hypertendus par rapport aux sujets normo tendus, et d'une autre côté à une augmentation de l'oxygénation tissulaire rénale après une semaine de régime pauvre en sel par rapport à la phase d'un régime riche en sel.Nous retenons comme résultat principal une augmentation de l'oxygénation rénale médullaire suite à une restriction sodique par rapport à un régime riche en sel chez tous les participants (normo-et hypertendus). Chez les participants normotendus ces changements correlaient avec des changements dans le transport actif du sodium, et ceci indépendamment du flux sanguin rénal. Contrairement à ce qu'on attendait, l'oxygénation rénale médullaire était plus élevé chez les sujets hypertendus par rapport aux sujets normotendus.En résumé, ces observations offrent possiblement une explication pour les bénéfices rénaux liés à un régime pauvre en sel. En plus, la combinaison d'études de clearance et le BOLD- IRM comme utilisé dans cette étude se sont révélés un outil performant et prometteur qui peut stimuler la recherche dans ce domaine.

Hyperthermia and maximal oxygen uptake in men and women.

To compare the effect of hyperthermia on maximal oxygen uptake (VO2max) in men and women, VO2max was measured in 11 male and 11 female runners under seven conditions involving various ambient temperatures (Ta at 50% RH) and preheating designed to manipulate the esophageal (Tes) and mean skin (Tsk) temperatures at VO2max. The conditions were: 25 degrees C, no preheating (control); 25, 35, 40, and 45 degrees C, with exercise-induced preheating by a 20-min walk at approximately 33% of control VO2max; 45 degrees C, no preheating; and 45 degrees C, with passive preheating during which Tes and Tsk were increased to the same degree as at the end of the 20-min walk at 45 degrees C. Compared to VO2max (l x min(-1)) in the control condition (4.52+/-0.46 in men, 3.01+/-0.45 in women), VO2max in men and women was reduced with exercise-induced or passive preheating and increased Ta, approximately 4% at 35 degrees C, approximately 9% at 40 degrees C and approximately 18% at 45 degrees C. Percentage reductions (7-36%) in physical performance (treadmill test time to exhaustion) were strongly related to reductions in VO2max (r=0.82-0.84). The effects of hyperthermia on VO2max and physical performance in men and women were almost identical. We conclude that men and women do not differ in their thermal responses to maximal exercise, or in the relationship of hyperthermia to reductions in VO2max and physical performance at high temperature. Data are reported as mean (SD) unless otherwise stated.

Dynamic responses of oxygen uptake at the onset and end of moderate and heavy exercise in trained subjects.

Inconsistencies about dynamic asymmetry between the on- and off-transient responses in VO2 are found in the literature. Therefore the purpose of this study was to examine VO2 on- and off-transients during moderate- and heavy-intensity cycling exercise in trained subjects. Ten men underwent an initial incremental test for the estimation of ventilatory threshold (VT) and, on different days, two bouts of square-wave exercise at moderate (<VT) and heavy (>VT) intensities. VO2 kinetics in exercise and recovery were better described by a single exponential model (<VT), or by a double exponential with two time delays (>VT). For moderate exercise, we found a symmetry of VO2 kinetics between the on- and off-transients (i.e., fundamental component), consistent with a system manifesting linear control dynamics. For heavy exercise, a slow component superimposed on the fundamental phase was expressed in both the exercise and recovery, with similar parameter estimates. But the on-transient values of the time constant were appreciably faster than the associated off-transient, and independent of the work rate imposed (<VT and >VT). Our results do not support a dynamically linear system model of VO2 during cycling exercise in the heavy-intensity domain.

Reliability of stable carbon and oxygen isotope compositions of pedogenic needle fibre calcite as environmental indicators: examples from Western Europe.

Stable carbon and oxygen isotope analyses were conducted on pedogenic needle fibre calcite (NFC) from seven sites in areas with roughly similar temperate climates in Western Europe, including the Swiss Jura Mountains, eastern and southern France, northern Wales, and north-eastern Spain. The δ(13)C values (-12.5 to-6.8 0/00 Vienna Pee Dee Belemnite (VPDB)) record the predominant C(3) vegetation cover at the sites. A good correlation was found between mean monthly climatic parameters (air temperature, number of frost days, humidity, and precipitation) and δ(18)O values (-7.8 to-3.40/00 VPDB) of all the NFC. Similar seasonal variations of δ(18)O values for monthly NFC samples from the Swiss sites and those of mean monthly δ(18)O values of local precipitation and meteorological data point out precipitation and preferential growth/or recrystallisation of the pedogenic needle calcite during dry seasons. These covariations indicate the potential of stable isotope compositions of preserved NFC in fossil soil horizons as a promising tool for palaeoenvironmental reconstructions.

Right-left digit ratio (2D:4D) and maximal oxygen uptake.

A low digit ratio (2D:4D) and low 2D:4D in the right compared with the left hand (right-left 2D:4D) are thought to be determined by high in utero concentrations of testosterone, and are related to "masculine" traits such as aggression and performance in sports like running and rugby. Low right-left 2D:4D is also related to sensitivity to testosterone as measured by the number of cytosine-adenine-guanine triplet repeats in exon 1 of the androgen receptor gene. Here we show that low right-left 2D:4D is associated with high maximal oxygen uptake (VO2(max)), high velocity at VO2(max), and high maximum lactate concentration in a sample of teenage boys. We suggest that low right-left 2D:4D is linked to performance in some sports because it is a proxy of high sensitivity to prenatal and maybe also circulating testosterone and high VO2(max).

Acute oxygen sensing in heme oxygenase-2 null mice.

Hemeoxygenase-2 (HO-2) is an antioxidant enzyme that can modulate recombinant maxi-K(+) channels and has been proposed to be the acute O(2) sensor in the carotid body (CB). We have tested the physiological contribution of this enzyme to O(2) sensing using HO-2 null mice. HO-2 deficiency leads to a CB phenotype characterized by organ growth and alteration in the expression of stress-dependent genes, including the maxi-K(+) channel alpha-subunit. However, sensitivity to hypoxia of CB is remarkably similar in HO-2 null animals and their control littermates. Moreover, the response to hypoxia in mouse and rat CB cells was maintained after blockade of maxi-K(+) channels with iberiotoxin. Hypoxia responsiveness of the adrenal medulla (AM) (another acutely responding O(2)-sensitive organ) was also unaltered by HO-2 deficiency. Our data suggest that redox disregulation resulting from HO-2 deficiency affects maxi-K(+) channel gene expression but it does not alter the intrinsic O(2) sensitivity of CB or AM cells. Therefore, HO-2 is not a universally used acute O(2) sensor.

Validation d'une nouvelle grille de codage de la régulation émotionnelle avec le Laboratory Temperament Assessment Battery (Lab-TAB)

L'objectif de cette étude est de valider une nouvelle grille de codage pour le Lab-TAB (Goldsmith et Rothbart, 1999). Cette grille mesure l'intensité émotionnelle et les comportements de régulation chez l'enfant âgé de six mois. L'accord interjuge se révèle satisfaisant. Les analyses factorielles ont mis en évidence trois facteurs - attention, niveau d'activité et détournement actif - retrouvés dans la littérature comme stratégies de régulation émotionnelle. Les analyses de consistance interne démontrent une bonne homogénéité de ces facteurs. La validité externe se révèle satisfaisante aux niveaux concourant et prédictif. Enfin, cet outil de codage permet de distinguer les prématurés et les nés à terme. L'ensemble de ces résultats indiquent que l'outil élaboré présente de bonnes qualités psychométriques.

Effects of dopamine on total oxygen consumption and oxygen delivery in healthy men.

The effect of acute intravenous dopamine (DA) administration at three sequential (but randomized) infusion rates was studied in eight young male volunteers. DA was infused at 2.5, 5, and 10 micrograms.kg-1.min-1. O2 consumption (VO2) and CO2 production (VCO2) were measured continuously by means of a computerized indirect calorimeter (blood system). In response to the 5- and 10-micrograms.kg-1.min-1 DA infusion rates, a significant increase (P less than 0.01) in VO2 corresponding to a 6% (range, 3-10) and 15% (range, 12-23) increase, respectively, of preinfusion values was observed. In contrast, at the low dose (2.5 micrograms.kg-1.min-1), DA induced no significant change in VO2. Cardiac output (Qc) increased significantly after the three DA administration rates [19% (range, 0-42), 34% (range, 17-71), and 25% (range, -3 to +47)] for the doses 2.5, 5, and 10 micrograms.-kg-1.min-1, respectively. The increase in O2 delivery (QO2) outweighed VO2 at all administration rates despite the relative drop in QO2 at the maximal DA administration rate. These results indicate that in humans DA improves net O2 supply to tissues proportionally more than it increases VO2 at all doses used in the present study.