Lactate and glucose concentrations in brain interstitial fluid, cerebrospinal fluid, and serum during experimental pneumococcal meningitis

Metabolic abnormalities during bacterial meningitis include hypoglycorrhachia and cerebrospinal fluid (CSF) lactate accumulation. The mechanisms by which these alterations occur within the central nervous system (CNS) are still incompletely delineated. To determine the evolution of these changes and establish the locus of abnormal metabolism during meningitis, glucose and lactate concentrations in brain interstitial fluid, CSF, and serum were measured simultaneously and sequentially during experimental pneumococcal meningitis in rabbits. Interstitial fluid samples were obtained from the frontal cortex and hippocampus by using in situ brain microdialysis, and serum and CSF were directly sampled. There was an increase of CSF lactate concentration, accompanied by increased local production of lactate in the brain, and a decrease of CSF-to-serum glucose ratio that was paralleled by a decrease in cortical glucose concentration. Brain microdialysate lactate concentration was not affected by either systemic lactic acidosis or artificially elevated CSF lactate concentration. These data support the hypothesis that the brain is a locus for anaerobic glycolysis during meningitis, resulting in increased lactate production and perhaps contributing to decreased tissue glucose concentration.

Cerebral acid-base homeostasis after severe traumatic brain injury

OBJECT: Brain tissue acidosis is known to mediate neuronal death. Therefore the authors measured the main parameters of cerebral acid-base homeostasis, as well as their interrelations, shortly after severe traumatic brain injury (TBI) in humans. METHODS: Brain tissue pH, PCO2, PO2, and/or lactate were measured in 151 patients with severe head injuries, by using a Neurotrend sensor and/or a microdialysis probe. Monitoring was started as soon as possible after the injury and continued for up to 4 days. During the 1st day following the trauma, the brain tissue pH was significantly lower, compared with later time points, in patients who died or remained in a persistent vegetative state. Six hours after the injury, brain tissue PCO2 was significantly higher in patients with a poor outcome compared with patients with a good outcome. Furthermore, significant elevations in cerebral concentrations of lactate were found during the 1st day after the injury, compared with later time points. These increases in lactate were typically more pronounced in patients with a poor outcome. Similar biochemical changes were observed during later hypoxic events. CONCLUSIONS: Severe human TBI profoundly disturbs cerebral acid-base homeostasis. The observed pH changes persist for the first 24 hours after the trauma. Brain tissue acidosis is associated with increased tissue PCO2 and lactate concentration; these pathobiochemical changes are more severe in patients who remain in a persistent vegetative state or die. Furthermore, increased brain tissue PCO2 (> 60 mm Hg) appears to be a useful clinical indicator of critical cerebral ischemia, especially when accompanied by increased lactate concentrations.

Sodium thiosulfate prevents vascular calcifications in uremic rats

Accelerated vascular calcification is a severe complication of chronic kidney disease contributing to high morbidity and mortality in patients undergoing renal replacement therapy. Sodium thiosulfate is increasingly used for the treatment of soft tissue calcifications in calciphylaxis. Therefore, we determined whether it also prevents development of vascular calcifications in chronic kidney disease. We found that uremic rats treated by thiosulfate had no histological evidence of calcification in the aortic wall whereas almost three-fourths of untreated uremic rats showed aortic calcification. Urinary calcium excretion was elevated and the calcium content of aortic, heart, and renal tissue was significantly reduced in the thiosulfate-treated compared to non-treated animals. Sodium thiosulfate treatment transiently lowered plasma ionized calcium and induced metabolic acidosis. It also lowered bone strength in the treated animals compared to their normal controls. Hence, sodium thiosulfate prevented vascular calcifications in uremic rats, likely by enhancing acid- and/or chelation-induced urinary calcium loss. The negative impact on rat bone integrity necessitates a careful risk-benefit analysis before sodium thiosulfate can be used in individual human patients.

To stent or not to stent perioperatively the ureteroileal anastomosis of ileal orthotopic bladder substitutes and ileal conduits? Results of a prospective randomized trial

PURPOSE: We evaluated the impact of stenting the ureteroileal anastomosis on its competence, upper urinary tract dilatation, gastrointestinal recovery, metabolic parameters and patency rate after cystectomy with ileal bladder substitution or ileal conduit. MATERIALS AND METHODS: A total of 54 patients (37 with an ileal bladder substitute and 17 with an ileal conduit) were prospectively randomized into 2 groups, with (29) or without (25) perioperative stenting of the ureteroileal anastomosis. In all cases an end-to-side ureteroileal refluxing anastomosis was performed. The stents were removed after 5 to 10 days. The parameters assessed postoperative days 1, 3 and 7 were creatinine concentration from the wound drains, upper urinary tract dilatation, time to bowel function recovery, serum creatinine, as well as urea and incidence of metabolic acidosis. RESULTS: Median patient age was 68 years (range 45 to 85). Urine leak on postoperative day 1 was more frequent in those anastomoses without stents, and on postoperative days 3 and 7 the values were comparable. Stenting of the ureteroileal anastomosis resulted in significantly decreased early postoperative upper urinary tract dilatation, improved recovery of bowel function and decreased metabolic acidosis. In either group no patient had clinical evidence of ureteroileal anastomotic stricture during the early postoperative period. Three patients with perioperative stenting required surgical or endoscopic treatment for a stricture of the ureteroileal anastomosis during the 12-month followup. CONCLUSIONS: Stenting of the ureteroileal anastomosis allows for significantly less frequent incidence of early postoperative dilatation of the pelvicaliceal system, bowel activity resumes significantly earlier and metabolic acidosis is significantly less frequent.

Evaluation of anesthesia recovery quality after low-dose racemic or S-ketamine infusions during anesthesia with isoflurane in horses

OBJECTIVE: To compare anesthesia recovery quality after racemic (R-/S-) or S-ketamine infusions during isoflurane anesthesia in horses. ANIMALS: 10 horses undergoing arthroscopy. PROCEDURES: After administration of xylazine for sedation, horses (n = 5/group) received R-/S-ketamine (2.2 mg/kg) or S-ketamine (1.1 mg/kg), IV, for anesthesia induction. Anesthesia was maintained with isoflurane in oxygen and R-/S-ketamine (1 mg/kg/h) or S-ketamine (0.5 mg/kg/h). Heart rate, invasive mean arterial pressure, and end-tidal isoflurane concentration were recorded before and during surgical stimulation. Arterial blood gases were evaluated every 30 minutes. Arterial ketamine and norketamine enantiomer plasma concentrations were quantified at 60 and 120 minutes. After surgery, horses were kept in a padded recovery box, sedated with xylazine, and video-recorded for evaluation of recovery quality by use of a visual analogue scale (VAS) and a numeric rating scale. RESULTS: Horses in the S-ketamine group had better numeric rating scale and VAS values than those in the R-/S-ketamine group. In the R-/S-ketamine group, duration of infusion was positively correlated with VAS value. Both groups had significant increases in heart rate and mean arterial pressure during surgical stimulation; values in the R-/S-ketamine group were significantly higher than those of the S-ketamine group. Horses in the R-/S-ketamine group required slightly higher end-tidal isoflurane concentration to maintain a surgical plane of anesthesia. Moderate respiratory acidosis and reduced oxygenation were evident. The R-norketamine concentrations were significantly lower than S-norketamine concentrations in the R-/S-ketamine group. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with R-/S-ketamine, anesthesia recovery was better with S-ketamine infusions in horses.

[Mitochondrial dysfunction during sepsis, impact and possible regulating role of hypoxia-inducible factor-1alpha]

There is a direct correlation between the development of the multiple organ dysfunction syndrome (MODS) and the elevated mortality associated with sepsis. The mechanisms responsible for MODS development are being studied, however, the main efforts regarding MODS evaluation have focused on oxygen delivery optimization and on the modulation of the characteristic inflammatory cascade of sepsis, all with negative results. Recent studies have shown that there is development of tissue acidosis, even when there are normal oxygen conditions and limited presence of tissue cellular necrosis or apoptosis, which would indicate that cellular energetic dysfunction may be a central element in MODS pathogenesis. Mitochondrias are the main source of cellular energy, central regulators of cell death and the main source for reactive oxygen species. Several mechanisms contribute to mitochondrial dysfunction during sepsis, that is blockage of pyruvate entry into the Krebs cycle, oxidative phosphorylation substrate use in other enzymatic complexes, enzymatic complex inhibition and membrane damage mediated by oxidative stress, and reduction in mitochondrial content. Hypoxia-inducible factor-1alpha (HIF-1alpha) is a nuclear transcription factor with a central role in the regulation of cellular oxygen homeostasis. Its induction under hypoxic conditions is associated to the expression of hundreds of genes that coordinate the optimization of cellular oxygen delivery and the cellular energy metabolism. HIF-1alpha can also be stabilized under normoxic condition during inflammation and this activation seems to be associated with a prominent pro-inflammatory profile, with lymphocytes dysfunction, and to a reduction in cellular oxygen consumption. Further studies should establish a role for HIF-1alpha as a therapeutic target.

Association of arterial blood pressure and vasopressor load with septic shock mortality: a post hoc analysis of a multicenter trial

INTRODUCTION: It is unclear to which level mean arterial blood pressure (MAP) should be increased during septic shock in order to improve outcome. In this study we investigated the association between MAP values of 70 mmHg or higher, vasopressor load, 28-day mortality and disease-related events in septic shock. METHODS: This is a post hoc analysis of data of the control group of a multicenter trial and includes 290 septic shock patients in whom a mean MAP > or = 70 mmHg could be maintained during shock. Demographic and clinical data, MAP, vasopressor requirements during the shock period, disease-related events and 28-day mortality were documented. Logistic regression models adjusted for the geographic region of the study center, age, presence of chronic arterial hypertension, simplified acute physiology score (SAPS) II and the mean vasopressor load during the shock period was calculated to investigate the association between MAP or MAP quartiles > or = 70 mmHg and mortality or the frequency and occurrence of disease-related events. RESULTS: There was no association between MAP or MAP quartiles and mortality or the occurrence of disease-related events. These associations were not influenced by age or pre-existent arterial hypertension (all P > 0.05). The mean vasopressor load was associated with mortality (relative risk (RR), 1.83; confidence interval (CI) 95%, 1.4-2.38; P < 0.001), the number of disease-related events (P < 0.001) and the occurrence of acute circulatory failure (RR, 1.64; CI 95%, 1.28-2.11; P < 0.001), metabolic acidosis (RR, 1.79; CI 95%, 1.38-2.32; P < 0.001), renal failure (RR, 1.49; CI 95%, 1.17-1.89; P = 0.001) and thrombocytopenia (RR, 1.33; CI 95%, 1.06-1.68; P = 0.01). CONCLUSIONS: MAP levels of 70 mmHg or higher do not appear to be associated with improved survival in septic shock. Elevating MAP >70 mmHg by augmenting vasopressor dosages may increase mortality. Future trials are needed to identify the lowest acceptable MAP level to ensure tissue perfusion and avoid unnecessary high catecholamine infusions.

Evaluation of Proteferm® as a Nitrogen Supplement for Finishing Steers

Proteferm is a liquid by-product from the production of monosodium glutamate by fermentation that is 40% solids and contains 95% crude protein on a dry basis. Two trials were conducted with yearling steers to study the effects of different levels of Proteferm when added to 90% concentrate diets to replace corn and urea. Feeding Proteferm resulted in a decrease in urine pH, suggesting a metabolic acidosis that was probably caused by a negative cation–anion balance. Correcting the cation–anion imbalance resulted in an increase in feed intake and the performance of steers fed Proteferm as 1.5% of diet dry matter to be similar to the performance of control steers. Addition of sodium bicarbonate to the control diet or to the diet containing 1.5% Proteferm to produce a positive cation–anion balance did not improve performance. The results of these trials indicate that 1.5% Proteferm is the maximum that should be added to high concentrate diets fed to beef cattle without affecting performance or carcass value.

An Evaluation of Effective Fiber in Beef Feedlot Finishing Diets

A study was designed to collect a database of Iowa feedlot rations for determination of effective neutral detergent fiber (NDF) in complete diets from fiber analysis and particle size determination of individual feed ingredients and compare this with particle size determination of mixed wet rations. Seventy-one beef finishing total mixed rations were collected by ISU Extension Beef Field Specialists across Iowa. Producers were asked to complete a form assessing the acidosis risk associated with each ration. The average NDF of these diets was 25.9%. Of the total mixed rations 1.33 % remained in the top tray (>.75 in.), 47.27 % remained in the middle tray (>.31 in.), and 50.88 % was smaller than the .31 in screen. The effective NDF (eNDF) calculated from the eNDF of the ingredients averaged 10.56%. Estimated eNDF from total diet NDF and the percentage of the total diet in the top and middle trays averaged 12.47%. The calculated eNDF from non-grain sources alone averaged 3.6%. The percentage of digestive deads was weakly related to the percentage of the ration in the bottom tray (r=.19), the percentage in the top tray (r=- .46) and the effective NDF of the ration (r=-.23). The percentage of bloat was related to the total NDF of the diet (r=.28) and the effective fiber from non-grain sources (r=-.23). The number of off-feed incidences was related to the dry matter of the ration (r=.38), the apparent eNDF (r=-.28) and the percentage of ration in the bottom tray (r=.24). This study confirms that there is some relationship between effective NDF of the diet, effective NDF from non-grain sources or diet particle size; and acidosis indicators. These relationships are weak, however, indicating that other factors such as feedbunk management, feed processing, feed presentation and feed mixing likely also play a role in the incidence of acidosis in feedlot cattle.

Effects of beta-alanine supplementation and interval training on physiological determinants of severe exercise performance.

INTRODUCTION We aimed to manipulate physiological determinants of severe exercise performance. We hypothesized that (1) beta-alanine supplementation would increase intramuscular carnosine and buffering capacity and dampen acidosis during severe cycling, (2) that high-intensity interval training (HIT) would enhance aerobic energy contribution during severe cycling, and (3) that HIT preceded by beta-alanine supplementation would have greater benefits. METHODS Sixteen active men performed incremental cycling tests and 90-s severe (110 % peak power) cycling tests at three time points: before and after oral supplementation with either beta-alanine or placebo, and after an 11-days HIT block (9 sessions, 4 × 4 min), which followed supplementation. Carnosine was assessed via MR spectroscopy. Energy contribution during 90-s severe cycling was estimated from the O2 deficit. Biopsies from m. vastus lateralis were taken before and after the test. RESULTS Beta-alanine increased leg muscle carnosine (32 ± 13 %, d = 3.1). Buffering capacity and incremental cycling were unaffected, but during 90-s severe cycling, beta-alanine increased aerobic energy contribution (1.4 ± 1.3 %, d = 0.5), concurrent with reduced O2 deficit (-5.0 ± 5.0 %, d = 0.6) and muscle lactate accumulation (-23 ± 30 %, d = 0.9), while having no effect on pH. Beta-alanine also enhanced motivation and perceived state during the HIT block. There were no between-group differences in adaptations to the training block, namely increased buffering capacity (+7.9 ± 11.9 %, p = 0.04, d = 0.6, n = 14) and glycogen storage (+30 ± 47 %, p = 0.04, d = 0.5, n = 16). CONCLUSIONS Beta-alanine did not affect buffering considerably, but has beneficial effects on severe exercise metabolism as well as psychological parameters during intense training phases.

Anaesthesia with medetomidine, midazolam and ketamine in six gorillas after premedication with oral zuclopenthixol dihydrochloride

OBJECTIVE To evaluate the effects of medetomidine, midazolam and ketamine (MMK) in captive gorillas after premedication with oral zuclopenthixol. STUDY DESIGN Case series. ANIMALS Six gorillas, two males and four females, aged 9-52 years and weighing 63-155 kg. METHODS The gorillas were given zuclopenthixol dihydrochloride 0.2 ± 0.05 mg kg(-1) per os twice daily for 3 days for premedication. On the day of anaesthesia the dose of zuclopenthixol was increased to 0.27 mg kg(-1) and given once early in the morning. Anaesthesia was induced with medetomidine 0.04 ± 0.004 mg kg(-1) , midazolam 0.048 ± 0.003 mg kg(-1) and ketamine 4.9 ± 0.4 mg kg(-1) intramuscularly (IM). Upon recumbency, the trachea was intubated and anaesthesia was maintained on 1-2% isoflurane in oxygen. Physiological parameters were monitored every 10 minutes and arterial blood gas analysis was performed once 30-50 minutes after initial darting. At the end of the procedure, 42-115 minutes after initial darting, immobilisation was antagonized with atipamezole 0.21 ± 0.03 mg kg(-1) and sarmazenil 5 ± 0.4 μg kg(-1) IM. RESULTS Recumbency was reached within 10 minutes in five out of six animals. One animal required two additional darts before intubation was feasible. Heart rate ranged from 60 to 85 beats minute(-1) , respiratory rate from 17 to 46 breaths minute(-1) and temperature from 36.9 to 38.3 °C. No spontaneous recoveries were observed and anaesthetic level was stable. Blood gas analyses revealed mild respiratory acidosis, and mean PaO(2) was 24.87 ± 17.16 kPa (187 ± 129 mmHg) with all values being above 13.4 kPa (101 mmHg). Recovery was smooth and gorillas were sitting within 25 minutes. CONCLUSION AND CLINICAL RELEVANCE The drug combination proved to be effective in anaesthetizing captive gorillas of various ages and both sexes, with minimal cardio-respiratory changes.

Evaporation of free water causes concentrational alkalosis in vitro

BACKGROUND The development of metabolic alkalosis was described recently in patients with hypernatremia. However, the causes for this remain unknown. The current study serves to clarify whether metabolic alkalosis develops in vitro after removal of free water from plasma and whether this can be predicted by a mathematical model. MATERIALS AND METHODS Ten serum samples of healthy humans were dehydrated by 29 % by vacuum centrifugation corresponding to an increase of the contained concentrations by 41 %. Constant partial pressure of carbon dioxide at 40 mmHg was simulated by mathematical correction of pH [pH(40)]. Metabolic acid-base state was assessed by Gilfix' base excess subsets. Changes of acid-base state were predicted by the physical-chemical model according to Watson. RESULTS Evaporation increased serum sodium from 141 (140-142) to 200 (197-203) mmol/L, i.e., severe hypernatremia developed. Acid-base analyses before and after serum concentration showed metabolic alkalosis with alkalemia: pH(40): 7.43 (7.41 to 7.45) vs 7.53 (7.51 to 7.55), p = 0.0051; base excess: 1.9 (0.7 to 3.6) vs 10.0 (8.2 to 11.8), p = 0.0051; base excess of free water: 0.0 (- 0.2 to 0.3) vs 17.7 (16.8 to 18.6), p = 0.0051. The acidifying effects of evaporation, including hyperalbuminemic acidosis, were beneath the alkalinizing ones. Measured and predicted acid-base changes due to serum evaporation agreed well. CONCLUSIONS Evaporation of water from serum causes concentrational alkalosis in vitro, with good agreement between measured and predicted acid-base values. At least part of the metabolic alkalosis accompanying hypernatremia is independent of renal function.

Predictive oncology: a review of multidisciplinary, multiscale in silico modeling linking phenotype, morphology and growth.

Empirical evidence and theoretical studies suggest that the phenotype, i.e., cellular- and molecular-scale dynamics, including proliferation rate and adhesiveness due to microenvironmental factors and gene expression that govern tumor growth and invasiveness, also determine gross tumor-scale morphology. It has been difficult to quantify the relative effect of these links on disease progression and prognosis using conventional clinical and experimental methods and observables. As a result, successful individualized treatment of highly malignant and invasive cancers, such as glioblastoma, via surgical resection and chemotherapy cannot be offered and outcomes are generally poor. What is needed is a deterministic, quantifiable method to enable understanding of the connections between phenotype and tumor morphology. Here, we critically assess advantages and disadvantages of recent computational modeling efforts (e.g., continuum, discrete, and cellular automata models) that have pursued this understanding. Based on this assessment, we review a multiscale, i.e., from the molecular to the gross tumor scale, mathematical and computational "first-principle" approach based on mass conservation and other physical laws, such as employed in reaction-diffusion systems. Model variables describe known characteristics of tumor behavior, and parameters and functional relationships across scales are informed from in vitro, in vivo and ex vivo biology. We review the feasibility of this methodology that, once coupled to tumor imaging and tumor biopsy or cell culture data, should enable prediction of tumor growth and therapy outcome through quantification of the relation between the underlying dynamics and morphological characteristics. In particular, morphologic stability analysis of this mathematical model reveals that tumor cell patterning at the tumor-host interface is regulated by cell proliferation, adhesion and other phenotypic characteristics: histopathology information of tumor boundary can be inputted to the mathematical model and used as a phenotype-diagnostic tool to predict collective and individual tumor cell invasion of surrounding tissue. This approach further provides a means to deterministically test effects of novel and hypothetical therapy strategies on tumor behavior.

Perioperative use of crystalloids in patients undergoing open radical cystectomy: balanced Ringer's maleate versus a glucose 5%/potassium-based balanced solution: study protocol for a randomized controlled trial

BACKGROUND The optimal crystalloid solution to use perioperatively in patients undergoing open radical cystectomy remains unclear. Many of the fluids used for intravenous hydration contain supraphysiologic concentrations of chloride, which can induce hyperchloremia and metabolic acidosis, resulting in renal vasoconstriction and decreased renal function. In addition, patients receiving less fluid and less sodium show faster recovery of gastrointestinal (GI) function after colonic surgery. METHODS AND DESIGN This is an investigator-initiated, single-center, randomized, controlled, parallel group trial with assessor-blinded outcome assessment, in the Department of Urology, University Hospital Bern, Switzerland. The study will involve 44 patients with bladder cancer scheduled for radical cystectomy and urinary diversion. The primary outcome is the duration between the end of surgery and the return of the GI function (first defecation). Secondary outcomes are fluid balance (body weight difference postoperatively versus preoperatively) and the incidence of kidney function disorders according to the Risk-Injury-Failure-Loss-End Stage Renal Disease (RIFLE classification). An equal number of patients are allocated to receive Ringerfundin® solution or a glucose/potassium-based balanced crystalloid solution as baseline infusion during the entire time that intravenous administration of fluid is necessary during the perioperative period. The randomized crystalloid solution is infused at a rate of 1 ml/kg/h until the bladder has been removed, followed by 3 ml/kg/h until the end of surgery. Postoperative hydration is identical in both groups and consists of 1,500 ml of the randomized crystalloid solution per 24 hours. Postoperative patient care is identical in both groups; patients are allowed to drink clear fluids immediately after surgery, and liquid diet is started on postoperative day 1, as well as active mobilization and the use of chewing gum. Body weight is measured daily in the morning. Time of first flatus and first defecation are recorded. DISCUSSION This trial assesses the benefits and harms of two different balanced crystalloid solutions for perioperative fluid management in patients undergoing open radical cystectomy with urinary diversion, with regard to return of GI function and effects on postoperative renal function. TRIAL REGISTRATION Current Controlled Trials ISRCTN32976792 (registered on November 21 2013).

The Vacuolar H+-ATPase B1 Subunit Polymorphism p.E161K Associates with Impaired Urinary Acidification in Recurrent Stone Formers

Mutations in the vacuolar–type H+-ATPase B1 subunit gene ATP6V1B1 cause autosomal–recessive distal renal tubular acidosis (dRTA). We previously identified a single-nucleotide polymorphism (SNP) in the human B1 subunit (c.481G.A; p.E161K) that causes greatly diminished pump function in vitro. To investigate the effect of this SNP on urinary acidification, we conducted a genotype-phenotype analysis of recurrent stone formers in theDallas and Bern kidney stone registries. Of 555 patients examined, 32 (5.8%) were heterozygous for the p.E161K SNP, and the remaining 523 (94.2%) carried two wild–type alleles. After adjustment for sex, age, body mass index, and dietary acid and alkali intake, p.E161K SNP carriers had a nonsignificant tendency to higher urinary pH on a random diet (6.31 versus 6.09; P=0.09). Under an instructed low–Ca and low–Na diet, urinary pH was higher in p.E161K SNP carriers (6.56 versus 6.01; P,0.01). Kidney stones of p.E161K carriers were more likely to contain calcium phosphate than stones of wild-type patients. In acute NH4Cl loading, p.E161K carriers displayed a higher trough urinary pH (5.34 versus 4.89; P=0.01) than wild-type patients. Overall, 14.6% of wild-type patients and 52.4% of p.E161K carriers were unable to acidify their urine below pH 5.3 and thus, can be considered to have incomplete dRTA. In summary, our data indicate that recurrent stone formers with the vacuolar H+-ATPase B1 subunit p.E161K SNP exhibit a urinary acidification deficit with an increased prevalence of calcium phosphate– containing kidney stones. The burden of E161K heterozygosity may be a forme fruste of dRTA.