Effect of Supplemental Oxygen versus Dobutamine Administration on Liver Oxygen Tension in dPP-Guided Normovolemic Pigs

Background: Difference in pulse pressure (dPP) confirms adequate intravascular filling as a prerequisite for tissue perfusion. We hypothesized that both oxygen and dobutamine increase liver tissue oxygen tension (ptO(2)). Methods: Eight anesthetized pigs received dPP-guided fluid management. Hepatic pO(2) was measured with Clark-type electrodes placed subcapsularly, and on the liver surface. Pigs received: (1) supplemental oxygen (F(i)O(2) 1.0); (2) dobutamine 2.5 mug/kg/min, and (3) dobutamine 5 mug/kg/min. Data were analyzed using repeated-measures ANOVA followed by a Tukey post-test for multiple comparisons. ptO(2 )measured subcapsularly and at the liver surface were compared using the Bland-Altman plot. Results: Variation in F(i)O(2) changed local hepatic tissue ptO(2) [subcapsular measurement: 39 +/- 12 (F(i)O(2) 0.3), 89 +/- 35 mm Hg (F(i)O(2) 1.0, p = 0.01 vs. F(i)O(2) 0.3), 44 +/- 10 mm Hg (F(i)O(2) 0.3, p = 0.05 vs. F(i)O(2) 1.0); surface measurement: 52 +/- 35 (F(i)O(2) 0.3), 112 +/- 24 mm Hg (F(i)O(2) 1.0, p = 0.001 vs. F(i)O(2) 0.3), 54 +/- 24 mm Hg (F(i)O(2) 0.3, p = 0.001 vs. F(i)O(2) 1.0)]. Surface measurements were widely scattered compared to subcapsular measurements (bias: -15 mm Hg, precision: 76.3 mm Hg). Dobutamine did not affect hepatic oxygenation. Conclusion: Supplemental oxygen increased hepatic tissue pO(2) while dobutamine did not. Although less invasive, the use of surface measurements is discouraged.

Hemodynamic parameters change earlier than tissue oxygen tension in hemorrhage

BACKGROUND: Untreated hypovolemia results in impaired outcome. This study tests our hypothesis whether general hemodynamic parameters detect acute blood loss earlier than monitoring parameters of regional tissue beds. MATERIALS AND METHODS: Eight pigs (23-25 kg) were anesthetized and mechanically ventilated. A pulmonary artery catheter and an arterial catheter were inserted. Tissue oxygen tension was measured with Clark-type electrodes in the jejunal and colonic wall, in the liver, and subcutaneously. Jejunal microcirculation was assessed by laser Doppler flowmetry (LDF). Intravascular volume was optimized using difference in pulse pressure (dPP) to keep dPP below 13%. Sixty minutes after preparation, baseline measurements were taken. At first, 5% of total blood volume was withdrawn, followed by another 5% increment, and then in 10% increments until death. RESULTS: After withdrawal of 5% of estimated blood volume, dPP increased from 6.1% +/- 3.0% to 20.8% +/- 2.7% (P < 0.01). Mean arterial pressure (MAP), mean pulmonary artery pressure (PAP) and pulmonary artery occlusion pressure (PAOP) decreased with a blood loss of 10% (P < 0.01). Cardiac output (CO) changed after a blood loss of 20% (P < 0.05). Tissue oxygen tension in central organs, and blood flow in the jejunal muscularis decreased (P < 0.05) after a blood loss of 20%. Tissue oxygen tension in the skin, and jejunal mucosa blood flow decreased (P < 0.05) after a blood loss of 40% and 50%, respectively. CONCLUSIONS: In this hemorrhagic pig model systemic hemodynamic parameters were more sensitive to detect acute hypovolemia than tissue oxygen tension measurements or jejunal LDF measurements. Acute blood loss was detected first by dPP.

A hypoxia complement differentiates the muscle response to endurance exercise

Metabolic stress is believed to constitute an important signal for training-induced adjustments of gene expression and oxidative capacity in skeletal muscle. We hypothesized that the effects of endurance training on expression of muscle-relevant transcripts and ultrastructure would be specifically modified by a hypoxia complement during exercise due to enhanced glycolytic strain. Endurance training of untrained male subjects in conditions of hypoxia increased subsarcolemmal mitochondrial density in the recruited vastus lateralis muscle and power output in hypoxia more than training in normoxia, i.e. 169 versus 91% and 10 versus 6%, respectively, and tended to differentially elevate sarcoplasmic volume density (42 versus 20%, P = 0.07). The hypoxia-specific ultrastructural adjustments with training corresponded to differential regulation of the muscle transcriptome by single and repeated exercise between both oxygenation conditions. Fine-tuning by exercise in hypoxia comprised gene ontologies connected to energy provision by glycolysis and fat metabolism in mitochondria, remodelling of capillaries and the extracellular matrix, and cell cycle regulation, but not fibre structure. In the untrained state, the transcriptome response during the first 24 h of recovery from a single exercise bout correlated positively with changes in arterial oxygen saturation during exercise and negatively with blood lactate. This correspondence was inverted in the trained state. The observations highlight that the expression response of myocellular energy pathways to endurance work is graded with regard to metabolic stress and the training state. The exposed mechanistic relationship implies that the altitude specificity of improvements in aerobic performance with a 'living low-training high' regime has a myocellular basis.

Different molecular and structural adaptations with eccentric and conventional strength training in elderly men and women

Reprogramming of gene expression contributes to structural and functional adaptation of muscle tissue in response to altered use. The aim of this study was to investigate mechanisms for observed improvements in leg extension strength, gain in relative thigh muscle mass and loss of body and thigh fat content in response to eccentric and conventional strength training in elderly men (n = 14) and women (n = 14; average age of the men and women: 80.1 ± 3.7 years) by means of structural and molecular analyses. Biopsies were collected from m. vastus lateralis in the resting state before and after 12 weeks of training with two weekly resistance exercise sessions (RET) or eccentric ergometer sessions (EET). Gene expression was analyzed using custom-designed low-density PCR arrays. Muscle ultrastructure was evaluated using EM morphometry. Gain in thigh muscle mass was paralleled by an increase in muscle fiber cross-sectional area (hypertrophy) with RET but not with EET, where muscle growth is likely occurring by the addition of sarcomeres in series or by hyperplasia. The expression of transcripts encoding factors involved in muscle growth, repair and remodeling (e.g., IGF-1, HGF, MYOG, MYH3) was increased to a larger extent after EET than RET. MicroRNA 1 expression was decreased independent of the training modality, and was paralleled by an increased expression of IGF-1 representing a potential target. IGF-1 is a potent promoter of muscle growth, and its regulation by microRNA 1 may have contributed to the gain of muscle mass observed in our subjects. EET depressed genes encoding mitochondrial and metabolic transcripts. The changes of several metabolic and mitochondrial transcripts correlated significantly with changes in mitochondrial volume density. Intramyocellular lipid content was decreased after EET concomitantly with total body fat. Changes in intramyocellular lipid content correlated with changes in body fat content with both RET and EET. In the elderly, RET and EET lead to distinct molecular and structural adaptations which might contribute to the observed small quantitative differences in functional tests and body composition parameters. EET seems to be particularly convenient for the elderly with regard to improvements in body composition and strength but at the expense of reducing muscular oxidative capacity.

Diagnostic value of animal-side antibody assays for rapid detection of Mycobacterium bovis or Mycobacterium microti infection in South American camelids

Tuberculosis (TB) in South American camelids (SAC) is caused by Mycobacterium bovis or Mycobacterium microti. Two serological methods, rapid testing (RT) and the dual-path platform (DPP) assay, were evaluated using naturally infected SAC. The study population included 156 alpacas and 175 llamas in Great Britain, Switzerland, and the United States. TB due to M. bovis (n = 44) or M. microti (n = 8) in 35 alpacas and 17 llamas was diagnosed by gross pathology examination and culture. Control animals were from herds with no TB history. The RT and the DPP assay showed sensitivities of 71% and 74%, respectively, for alpacas, while the sensitivity for llamas was 77% for both assays. The specificity of the DPP assay (98%) was higher than that of RT (94%) for llamas; the specificities of the two assays were identical (98%) for alpacas. When the two antibody tests were combined, the parallel-testing interpretation (applied when either assay produced a positive result) enhanced the sensitivities of antibody detection to 89% for alpacas and 88% for llamas but at the cost of lower specificities (97% and 93%, respectively), whereas the serial-testing interpretation (applied when both assays produced a positive result) maximized the specificity to 100% for both SAC species, although the sensitivities were 57% for alpacas and 65% for llamas. Over 95% of the animals with evidence of TB failed to produce skin test reactions, thus confirming concerns about the validity of this method for testing SAC. The findings suggest that serological assays may offer a more accurate and practical alternative for antemortem detection of camelid TB.

Hypoxia-induced gene activity in disused oxidative muscle

Hypoxia is an important modulator of the skeletal muscle's oxidative phenotype. However, little is known regarding the molecular circuitry underlying the muscular hypoxia response and the interaction of hypoxia with other stimuli of muscle oxidative capacity. We hypothesized that exposure of mice to severe hypoxia would promote the expression of genes involved in capillary morphogenesis and glucose over fatty acid metabolism in active or disused soleus muscle of mice. Specifically, we tested whether the hypoxic response depends on oxygen sensing via the alpha-subunit of hypoxia-inducible factor-1 (HIF-1 alpha). Spontaneously active wildtype and HIF-1 alpha heterozygous deficient adult female C57B1/6 mice were subjected to hypoxia (PiO2 70 mmHg). In addition, animals were subjected to hypoxia after 7 days of muscle disuse provoked by hindlimb suspension. Soleus muscles were rapidly isolated and analyzed for transcript level alterations with custom-designed AtlasTM cDNA expression arrays (BD Biosciences) and cluster analysis of differentially expressed mRNAs. Multiple mRNA elevations of factors involved in dissolution and stabilization of blood vessels, glycolysis, and mitochondrial respiration were evident after 24 hours of hypoxia in soleus muscle. In parallel transcripts of fat metabolism were reduced. A comparable hypoxia-induced expression pattern involving complex alterations of the IGF-I axis was observed in reloaded muscle after disuse. This hypoxia response in spontaneously active animals was blunted in the HIF-1 alpha heterozygous deficient mice demonstrating 35% lower HIF-1 alpha mRNA levels. Our molecular observations support the concept that severe hypoxia provides HIF-1-dependent signals for remodeling of existing blood vessels, a shift towards glycolytic metabolism and altered myogenic regulation in oxidative mouse muscle and which is amplified by enhanced muscle use. These findings further imply differential mitochondrial turnover and a negative role of HIF-1 alpha for control of fatty acid oxidation in skeletal muscle exposed to one day of severe hypoxia.

Effect of acute hypoxia on maximal oxygen uptake and maximal performance during leg and upper-body exercise in Nordic combined skiers

We examined the effect of normobaric hypoxia (3200 m) on maximal oxygen uptake (VO2max) and maximal power output (Pmax) during leg and upper-body exercise to identify functional and structural correlates of the variability in the decrement of VO2max (DeltaVO2max) and of maximal power output (DeltaPmax). Seven well trained male Nordic combined skiers performed incremental exercise tests to exhaustion on a cycle ergometer (leg exercise) and on a custom built doublepoling ergometer for cross-country skiing (upper-body exercise). Tests were carried out in normoxia (560 m) and normobaric hypoxia (3200 m); biopsies were taken from m. deltoideus. DeltaVO2max was not significantly different between leg (-9.1+/-4.9%) and upper-body exercise (-7.9+/-5.8%). By contrast, Pmax was significantly more reduced during leg exercise (-17.3+/-3.3%) than during upper-body exercise (-9.6+/-6.4%, p<0.05). Correlation analysis did not reveal any significant relationship between leg and upper-body exercise neither for DeltaVO2max nor for DeltaPmax. Furthermore, no relationship was observed between individual DeltaVO2max and DeltaPmax. Analysis of structural data of m. deltoideus revealed a significant correlation between capillary density and DeltaPmax (R=-0.80, p=0.03), as well as between volume density of mitochondria and DeltaPmax (R=-0.75, p=0.05). In conclusion, it seems that VO2max and Pmax are differently affected by hypoxia. The ability to tolerate hypoxia is a characteristic of the individual depending in part on the exercise mode. We present evidence that athletes with a high capillarity and a high muscular oxidative capacity are more sensitive to hypoxia.

Endurance training modulates the muscular transcriptome response to acute exercise

We hypothesized that in untrained individuals (n=6) a single bout of ergometer endurance exercise provokes a concerted response of muscle transcripts towards a slow-oxidative muscle phenotype over a 24-h period. We further hypothesized this response during recovery to be attenuated after six weeks of endurance training. We monitored the expression profile of 220 selected transcripts in muscle biopsies before as well as 1, 8, and 24 h after a 30-min near-maximal bout of exercise. The generalized gene response of untrained vastus lateralis muscle peaked after 8 h of recovery (P=0.001). It involved multiple transcripts of oxidative metabolism and glycolysis. Angiogenic and cell regulatory transcripts were transiently reduced after 1 h independent of the training state. In the trained state, the induction of most transcripts 8 h after exercise was less pronounced despite a moderately higher relative exercise intensity, partially because of increased steady-state mRNA concentration, and the level of metabolic and extracellular RNAs was reduced during recovery from exercise. Our data suggest that the general response of the transcriptome for regulatory and metabolic processes is different in the trained state. Thus, the response is specifically modified with repeated bouts of endurance exercise during which muscle adjustments are established.

Assessing intravascular volume by difference in pulse pressure in pigs submitted to graded hemorrhage

We assessed changes in intravascular volume monitored by difference in pulse pressure (dPP%) after stepwise hemorrhage in an experimental pig model. Six pigs (23-25 kg) were anesthetized (isoflurane 1.5 vol%) and mechanically ventilated to keep end-tidal CO2 (etCO2) at 35 mmHg. A PA-catheter and an arterial catheter were placed via femoral access. During and after surgery, animals received lactated Ringer's solution as long as they were considered volume responders (dPP>13%). Then animals were allowed to stabilize from the induction of anesthesia and insertion of catheters for 30 min. After stabilization, baseline measurements were taken. Five percent of blood volume was withdrawn, followed by another 5%, and then in 10%-increments until death from exsanguination occurred. After withdrawal of 5% of blood volume, all pigs were considered volume responders (dPP>13%); dPP rose significantly from 6.1+/-3.3% to 19.4+/-4.2%. The regression analysis of stepwise hemorrhage revealed a linear relation between blood loss (hemorrhage in %) and dPP (y=0.99*x+14; R2=0.7764; P<.0001). In addition, dPP was the only parameter that changed significantly between baseline and a blood loss of 5% (P<0.01), whereas cardiac output, stroke volume, heart rate, MAP, central venous pressure, pulmonary artery occlusion pressure, and systemic vascular resistance, respectively, remained unchanged. We conclude that in an experimental hypovolemic pig model, dPP correlates well with blood loss.

Biologically relevant sex differences for fitness-related parameters in active octogenarians

The number of elderly people is growing in western populations, but only few maximal performance data exist for people >75 years, in particular for European octogenarians. This study was performed to characterize maximal performance of 55 independently living subjects (32 women, 81.1 +/- 3.4 years; 23 men, 81.7 +/- 2.9 years) with a focus on sex differences. Maximal performance was determined in a ramp test to exhaustion on a bicycle ergometer with ergospirometry, electrocardiogram and blood lactate measurements. Maximal isometric extension strength of the legs (MEL) was measured on a force platform in a seated position. Body composition was quantified by X-ray absorptiometry. In >25% of the subjects, serious cardiac abnormalities were detected during the ramp test with men more frequently being affected than women. Maximal oxygen consumption and power output were 18.2 +/- 3.2 versus 25.9 +/- 5.9 ml min(-1) kg(-1) and 66 +/- 12 versus 138 +/- 40 W for women versus men, with a significant sex difference for both parameters. Men outperformed women for MEL with 19.0 +/- 3.8 versus 13.6 +/- 3.3 N kg(-1). Concomitantly, we found a higher proportion of whole body fat in women (32.1 +/- 6.2%) compared to men (20.5 +/- 4.4%). Our study extends previously available maximal performance data for endurance and strength to independently living European octogenarians. As all sex-related differences were still apparent after normalization to lean body mass, it is concluded that it is essential to differentiate between female and male subjects when considering maximal performance parameters in the oldest segment of our population.

Muscle transcriptome adaptations with mild eccentric ergometer exercise

The muscle has a wide range of possibilities to adapt its phenotype. Repetitive submaximal concentric exercise (i.e., shortening contractions) mainly leads to adaptations of muscle oxidative metabolism and endurance while eccentric exercise (i.e., lengthening contractions) results in muscle growth and gain of muscle strength. Modified gene expression is believed to mediate these exercise-specific muscle adjustments. In the present study, early alterations of the gene expression signature were monitored by a muscle-specific microarray. Transcript profiling was performed on muscle biopsies of vastus lateralis obtained from six male subjects before and in a 24-h time course after a single bout of mild eccentric ergometer exercise. The eccentric exercise consisted of 15 min of eccentric cycling at 50% of the individual maximal concentric power output leading to muscle soreness (5.9 on a 0-10 visual analogue scale) and limited muscle damage (1.7-fold elevated creatine kinase activity). Muscle impairment was highlighted by a transient reduction in jumping height after the eccentric exercise. On the gene expression level, we observed a general early downregulation of detected transcripts, followed by a slow recovery close to the control values within the first 24 h post exercise. Only very few regulatory factors were increased. This expression signature is different from the signature of a previously published metabolic response after an intensive endurance-type concentric exercise as well as after maximal eccentric exercise. This is the first description of the time course of changes in gene expression as a consequence of a mild eccentric stimulus.

[Arterial pressure curve and fluid status.]

Fluid optimization is a major contributor to improved outcome in patients. Unfortunately, anesthesiologists are often in doubt whether an additional fluid bolus will improve the hemodynamics of the patient or not as excess fluid may even jeopardize the condition. This article discusses physiological concepts of liberal versus restrictive fluid management followed by a discussion on the respective capabilities of various monitors to predict fluid responsiveness. The parameter difference in pulse pressure (dPP), derived from heart-lung interaction in mechanically ventilated patients is discussed in detail. The dPP cutoff value of 13% to predict fluid responsiveness is presented together with several assessment techniques of dPP. Finally, confounding variables on dPP measurements, such as ventilation parameters, pneumoperitoneum and use of norepinephrine are also mentioned.

Impact of working memory training on memory performance in old-old adults

Memory impairments constitute an increasing objective and subjective problem with advancing age. The aim of the present study was to investigate the impact of working memory training on memory performance. The authors trained a sample of 80-year-old adults twice weekly over a time period of 3 months. Participants were tested on 4 different memory measures before, immediately after, and 1 year after training completion. The authors found overall increased memory performance in the experimental group compared to an active control group immediately after training completion. This increase was especially pronounced in visual working memory performance and, to a smaller degree, also in visual episodic memory. No group differences were found 1 year after training completion. The results indicate that even in old?old adults, brain plasticity is strong enough to result in transfer effects, that is, performance increases in tasks that were not trained during the intervention.

Different response to eccentric and concentric training in older men and women

Sarcopenia is the age-related loss of muscle mass and strength and has been associated with an increased risk of falling and the development of metabolic diseases. Various training protocols, nutritional and hormonal interventions have been proposed to prevent sarcopenia. This study explores the potential of continuous eccentric exercise to retard age-related loss of muscle mass and function. Elderly men and women (80.6 +/- 3.5 years) were randomized to one of three training interventions demanding a training effort of two sessions weekly for 12 weeks: cognitive training (CT; n = 16), conventional resistance training (RET; n = 23) and eccentric ergometer training (EET; n = 23). Subjects were tested for functional parameters and body composition. Biopsies were collected from M. vastus lateralis before and after the intervention for the assessment of fiber size and composition. Maximal isometric leg extension strength (MEL: +8.4 +/- 1.7%) and eccentric muscle coordination (COORD: -43 +/- 4%) were significantly improved with EET but not with RET (MEL: +2.3 +/- 2.0%; COORD: -13 +/- 3%) and CT (MEL: -2.3 +/- 2.5%; COORD: -12 +/- 5%), respectively. We observed a loss of body fat (-5.0 +/- 1.1%) and thigh fat (-6.9 +/- 1.5%) in EET subjects only. Relative thigh lean mass increased with EET (+2.5 +/- 0.6%) and RET (+2.0 +/- 0.3%) and correlated negatively with type IIX/type II muscle fiber ratios. It was concluded that both RET and EET are beneficial for the elderly with regard to muscle functional and structural improvements but differ in their spectrum of effects. A training frequency of only two sessions per week seems to be the lower limit for a training stimulus to reveal measurable benefits.

Automatic algorithm for monitoring systolic pressure variation and difference in pulse pressure

BACKGROUND: Difference in pulse pressure (dPP) reliably predicts fluid responsiveness in patients. We have developed a respiratory variation (RV) monitoring device (RV monitor), which continuously records both airway pressure and arterial blood pressure (ABP). We compared the RV monitor measurements with manual dPP measurements. METHODS: ABP and airway pressure (PAW) from 24 patients were recorded. Data were fed to the RV monitor to calculate dPP and systolic pressure variation in two different ways: (a) considering both ABP and PAW (RV algorithm) and (b) ABP only (RV(slim) algorithm). Additionally, ABP and PAW were recorded intraoperatively in 10-min intervals for later calculation of dPP by manual assessment. Interobserver variability was determined. Manual dPP assessments were used for comparison with automated measurements. To estimate the importance of the PAW signal, RV(slim) measurements were compared with RV measurements. RESULTS: For the 24 patients, 174 measurements (6-10 per patient) were recorded. Six observers assessed dPP manually in the first 8 patients (10-min interval, 53 measurements); no interobserver variability occurred using a computer-assisted method. Bland-Altman analysis showed acceptable bias and limits of agreement of the 2 automated methods compared with the manual method (RV: -0.33% +/- 8.72% and RV(slim): -1.74% +/- 7.97%). The difference between RV measurements and RV(slim) measurements is small (bias -1.05%, limits of agreement 5.67%). CONCLUSIONS: Measurements of the automated device are comparable with measurements obtained by human observers, who use a computer-assisted method. The importance of the PAW signal is questionable.