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MECCIAS trial: Metabolic consequences of continuous veno-venous hemofiltration on indirect calorimetry.
Jonckheer, J, Demol, J, Lanckmans, K, Malbrain, MLNG, Spapen, H, De Waele, E
Clinical nutrition (Edinburgh, Scotland). 2020;(12):3797-3803
Abstract
BACKGROUND and aims: Caloric prescription based on resting energy expenditure (REE) measured with indirect calorimetry (IC) improves outcome and is the gold standard in nutritional therapy of critically ill patients. Until now continuous renal replacement therapy (CRRT) precluded the use of IC due to several mechanisms. We investigated the impact of CRRT on V̇CO2, V̇O2 and REE to facilitate indirect calorimetry during CRRT. METHODS In 10 critically ill ventilated patient in need of continuous veno-venous hemofiltration (CVVH) using citrate predilution we performed IC in 4 different states: baseline, high dose, baseline with NaCl predilution and without CVVH. CO2 content of effluent fluid was measured by a point of care blood gas analyzer. Carbon dioxide production (V̇CO2) measured with IC was adapted by adding the CO2 flow of effluent and deducing CO2 flow in postdilution fluid to calculate a true V̇CO2. True REE was calculated with the Weir equation using the true V̇CO2. RESULTS CO2 removal in effluent during baseline, high dose and NaCl predilution was respectively 24 mL/min, 38 mL/min and 23 mL/min. Together with the CO2 delivery by the postdilution fluid this led to an adaptation of REE respectively by 34 kcal/d or 2% (p = 0,002), 44 kcal/d or 3% (p = 0,002) and 33 kcal/d or 2% (p = 0,002). Compared to the true REE during baseline of 1935 ± 921 kcal/d, true REE during high dose was 1723 ± 752 kcal/d (p = 0.65), during NaCl predilution it was 1604 ± 633 kcal/d (p = 0.014) and without CRRT it was 1713 ± 704 kcal/d (p = 0.193). CONCLUSIONS CO2 alterations due to CVVH are clinically of no importance so no correction factor of REE is needed with or without CVVH. IC must be performed during CVVH as CVVH seems to alter metabolism. These changes may be mainly explained by the use of citrate predilution.
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CO2 and O2 removal during continuous veno-venous hemofiltration: a pilot study.
Jonckheer, J, Spapen, H, Debain, A, Demol, J, Diltoer, M, Costa, O, Lanckmans, K, Oshima, T, Honoré, PM, Malbrain, M, et al
BMC nephrology. 2019;(1):222
Abstract
BACKGROUND Carbon dioxide (CO2) accumulation is a challenging issue in critically ill patients. CO2 can be eliminated by renal replacement therapy but studies are scarce and clinical relevance is unknown. We prospectively studied CO2 and O2 behavior at different sample points of continuous veno-venous hemofiltration (CVVH) and build a model to calculate CO2 removal bedside. METHODS In 10 patients receiving standard CVVH under citrate anticoagulation, blood gas analysis was performed at different sample points within the CVVH circuit. Citrate was then replaced by NaCl 0.9% and sampling was repeated. Total CO2 (tCO2), CO2 flow (V̇CO2) and O2 flow (V̇O2) were compared between different sample points. The effect of citrate on transmembrane tCO2 was evaluated. Wilcoxon matched-pairs signed rank test was performed to evaluate significance of difference between 2 data sets. Friedman test was used when more data sets were compared. RESULTS V̇CO2 in the effluent (26.0 ml/min) correlated significantly with transmembrane V̇CO2 (24.2 ml/min). This represents 14% of the average expired V̇CO2 in ventilated patients. Only 1.3 ml/min CO2 was removed in the de-aeration chamber, suggesting that CO2 was almost entirely cleared across the membrane filter. tCO2 values in effluent, before, and after the filter were not statistically different. Transmembrane tCO2 under citrate or NaCl 0.9% predilution also did not differ significantly. No changes in V̇O2 were observed throughout the CVVH circuit. Based on recorded data, formulas were constructed that allow bedside evaluation of CVVH-attributable CO2 removal. CONCLUSION A relevant amount of CO2 is removed by CVVH and can be quantified by one simple blood gas analysis within the circuit. Future studies should assess the clinical impact of this observation. TRIAL REGISTRATION The trial was registered at https://clinicaltrials.gov with trial registration number NCT03314363 on October 192,017.
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Shear-mediated dilation of the internal carotid artery occurs independent of hypercapnia.
Hoiland, RL, Smith, KJ, Carter, HH, Lewis, NCS, Tymko, MM, Wildfong, KW, Bain, AR, Green, DJ, Ainslie, PN
American journal of physiology. Heart and circulatory physiology. 2017;(1):H24-H31
Abstract
Evidence for shear stress as a regulator of carotid artery dilation in response to increased arterial CO2 was recently demonstrated in humans during sustained elevations in CO2 (hypercapnia); however, the relative contributions of CO2 and shear stress to this response remains unclear. We examined the hypothesis that, after a 30-s transient increase in arterial CO2 tension and consequent increase in internal carotid artery shear stress, internal carotid artery diameter would increase, indicating shear-mediated dilation, in the absence of concurrent hypercapnia. In 27 healthy participants, partial pressures of end-tidal O2 and CO2, ventilation (pneumotachography), blood pressure (finger photoplethysmography), heart rate (electrocardiogram), internal carotid artery flow, diameter, and shear stress (high-resolution duplex ultrasound), and middle cerebral artery blood velocity (transcranial Doppler) were measured during 4-min steady-state and transient 30-s hypercapnic tests (both +9 mmHg CO2). Internal carotid artery dilation was lower in the transient compared with steady-state hypercapnia (3.3 ± 1.9 vs. 5.3 ± 2.9%, respectively, P < 0.03). Increases in internal carotid artery shear stress preceded increases in diameter in both transient (time: 16.8 ± 13.2 vs. 59.4 ± 60.3 s, P < 0.01) and steady-state (time: 18.2 ± 14.2 vs. 110.3 ± 79.6 s, P < 0.01) tests. Internal carotid artery dilation was positively correlated with shear rate area under the curve in the transient (r2 = 0.44, P < 0.01) but not steady-state (r2 = 0.02, P = 0.53) trial. Collectively, these results suggest that hypercapnia induces shear-mediated dilation of the internal carotid artery in humans. This study further promotes the application and development of hypercapnia as a clinical strategy for the assessment of cerebrovascular vasodilatory function and health in humans.NEW & NOTEWORTHY Shear stress dilates the internal carotid artery in humans. This vasodilatory response occurs independent of other physiological factors, as demonstrated by our transient CO2 test, and is strongly correlated to shear area under the curve. Assessing carotid shear-mediated dilation may provide a future avenue for assessing cerebrovascular health and the risk of cerebrovascular events.
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Improved recurrence-free survival with ARCON for anemic patients with laryngeal cancer.
Janssens, GO, Rademakers, SE, Terhaard, CH, Doornaert, PA, Bijl, HP, van den Ende, P, Chin, A, Takes, RP, de Bree, R, Hoogsteen, IJ, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;(5):1345-54
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PURPOSE Anemia is associated with poor tumor control. It was previously observed that accelerated radiotherapy combined with carbogen breathing and nicotinamide (ARCON) can correct this adverse outcome in patients with head and neck cancer. The purpose of this study was to validate this observation based on data from a randomized trial. EXPERIMENTAL DESIGN Of 345 patients with cT2-4 laryngeal cancer, 174 were randomly assigned to accelerated radiotherapy and 171 to ARCON. Hemoglobin levels, measured before treatment, were defined as low when <7.5 mmol/L for women and <8.5 mmol/L for men. The hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. Data were analyzed 2 years after inclusion of the last patient. RESULTS Pretreatment hemoglobin levels were available and below normal in 27 of 173 (16%) accelerated radiotherapy and 27 of 167 (16%) ARCON patients. In patients with normal pretreatment, hemoglobin levels treatment with ARCON had no significant effect on 5-year loco-regional control (LRC, 79% versus 75%; P = 0.44) and disease-free survival (DFS, 75% vs. 70%; P = 0.46) compared with accelerated radiotherapy. However, in patients with low pretreatment, hemoglobin levels ARCON significantly improved 5-year LRC (79% vs. 53%; P = 0.03) and DFS (68% vs. 45%; P = 0.04). In multivariate analysis including other prognostic factors, pretreatment hemoglobin remained prognostic for LRC and DFS in the accelerated radiotherapy treatment arm. No correlation between pretreatment hemoglobin levels and pimonidazole uptake was observed. CONCLUSION Results from the randomized phase III trial support previous observations that ARCON has the potential to correct the poor outcome of cancer patients with anemia (ClinicalTrials.gov number, NCT00147732).
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An exploratory study of respiratory quotient calibration and association with postmenopausal breast cancer.
Prentice, RL, Neuhouser, ML, Tinker, LF, Pettinger, M, Thomson, CA, Mossavar-Rahmani, Y, Thomas, F, Qi, L, Huang, Y
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2013;(12):2374-83
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BACKGROUND The respiratory quotient (RQ), defined as the ratio of carbon dioxide exhaled to oxygen uptake, reflects substrate utilization when energy is expended. Fat and alcohol have RQ values of approximately 0.7, compared with 1.0 for carbohydrate, and approximately 0.8 for protein. Here, the association between RQ and postmenopausal breast cancer risk is studied. METHODS Paired RQ measurements were obtained, separated by approximately 6 months, for women in the reliability subset of a Women's Health Initiative (WHI) Nutrition and Physical Activity Assessment Study. Linear regression of the average of the paired log RQ assessments on a corresponding log food quotient (FQ) average and other study subject characteristics, including age, body mass index, race, and education, yielded calibration equations for predicting RQ. RESULTS Calibration equations, using any of food frequency, food record, or dietary recall data, explained an appreciable fraction of measured log RQ variation, and these were used to compute calibrated RQ estimates throughout WHI cohorts. Calibrated RQ estimates using 4-day food record (4DFR) data related inversely (P = 0.004) to (invasive) breast cancer risk in the WHI Dietary Modification trial comparison group, and corresponding RQ estimates using food-frequency data related inversely (P = 0.002) to breast cancer incidence in this cohort combined with the larger WHI observational study. CONCLUSION Although preliminary, these analyses suggest a substantially higher postmenopausal breast cancer risk among women having relatively low RQ. IMPACT RQ elevation could provide a novel target for breast cancer risk reduction.
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Necrosis predicts benefit from hypoxia-modifying therapy in patients with high risk bladder cancer enrolled in a phase III randomised trial.
Eustace, A, Irlam, JJ, Taylor, J, Denley, H, Agrawal, S, Choudhury, A, Ryder, D, Ord, JJ, Harris, AL, Rojas, AM, et al
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2013;(1):40-7
Abstract
BACKGROUND AND PURPOSE Addition of carbogen and nicotinamide (hypoxia-modifying agents) to radiotherapy improves the survival of patients with high risk bladder cancer. The study investigated whether histopathological tumour features and putative hypoxia markers predicted benefit from hypoxia modification. MATERIALS AND METHODS Samples were available from 231 patients with high grade and invasive bladder carcinoma from the BCON phase III trial of radiotherapy (RT) alone or with carbogen and nicotinamide (RT+CON). Histopathological tumour features examined were: necrosis, growth pattern, growing margin, and tumour/stroma ratio. Hypoxia markers carbonic anhydrase-IX and glucose transporter-1 were examined using tissue microarrays. RESULTS Necrosis was the only independent prognostic indicator (P=0.04). Necrosis also predicted benefit from hypoxia modification. Five-year overall survival was 48% (RT) versus 39% (RT+CON) (P=0.32) in patients without necrosis and 34% (RT) versus 56% (RT+CON) (P=0.004) in patients with necrosis. There was a significant treatment by necrosis strata interaction (P=0.001 adjusted). Necrosis was an independent predictor of benefit from RT+CON versus RT (hazard ratio [HR]: 0.43, 95% CI 0.25-0.73, P=0.002). This trend was not observed when there was no necrosis (HR: 1.64, 95% CI 0.95-2.85, P=0.08). CONCLUSIONS Necrosis predicts benefit from hypoxia modification in patients with high risk bladder cancer and should be used to select patients; it is simple to identify and easy to incorporate into routine histopathological examination.
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Effect of ingestion of medium-chain triacylglycerols on moderate- and high-intensity exercise in recreational athletes.
Nosaka, N, Suzuki, Y, Nagatoishi, A, Kasai, M, Wu, J, Taguchi, M
Journal of nutritional science and vitaminology. 2009;(2):120-5
Abstract
Medium-chain triacylglycerols (MCT) are known to hydrolyze readily and completely to fatty acids and to be metabolized more easily by beta-oxidation than long-chain triacylglycerols (LCT). Therefore, we investigated the effect of 2 wk of ingestion of food containing a small amount (6 g) of MCT on energy metabolism during moderate-intensity exercise and high-intensity exercise in recreational athletes. For comparison, the subjects were administered food containing MCT or LCT for 14 d, and were instructed to perform cycle ergometer exercise at a workload corresponding to 60% peak O(2) uptake (VO(2)) for 40 min followed by a workload corresponding to 80% peak VO(2) until exhaustion. Blood lactate concentration, VO(2), VCO(2), and rating of perceived exertion (RPE) were measured at rest and during exercise. The exercise time to exhaustion at a workload corresponding to 80% peak VO(2) was significantly (p<0.05) longer in the MCT trial (10.2+/-7.6 min; mean+/-SD) than in the LCT trial (5.8+/-3.3 min). Blood lactate concentration and RPE during exercise were significantly (p<0.05) lower after ingestion of MCT-containing food. Fat oxidation rate was higher and carbohydrate oxidation rate was lower during exercise in the MCT trial than in the LCT trial, but the differences were not significant. These results indicate that the ingestion of MCT-containing food may suppress utilization of carbohydrate for energy production because of increased utilization of fatty acids for generating energy. In conclusion, our data suggest that short-term ingestion of food containing a small amount of MCT suppresses the increase in blood lactate concentration and RPE during moderate-intensity exercise and extends the duration of subsequent high-intensity exercise, at levels higher than those achieved by ingestion of LCT-containing food.
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Carbogen and nicotinamide increase blood flow and 5-fluorouracil delivery but not 5-fluorouracil retention in colorectal cancer metastases in patients.
Gupta, N, Saleem, A, Kötz, B, Osman, S, Aboagye, EO, Phillips, R, Vernon, C, Wasan, H, Jones, T, Hoskin, PJ, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2006;(10):3115-23
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PURPOSE To examine whether carbogen and nicotinamide increases 5-fluorouracil (5-FU) delivery to colorectal cancer metastases. EXPERIMENTAL DESIGN Six patients were scanned using positron emission tomography. Two scans were done to coincide with the start of separate chemotherapy cycles. At the second positron emission tomography session, 60 mg/kg nicotinamide was given orally 2 to 3 hours before 10-minute carbogen inhalation. In the middle of carbogen treatment, [15O]H2O (to measure regional tissue perfusion) and then [18F]5-FU (to measure 5-FU tissue pharmacokinetics) were administered. RESULTS Regions of interest were drawn in 12 liver metastases, 6 spleens, 6 livers, and 12 kidneys. Nicotinamide and carbogen administration increased mean blood pO2 from 93 mm Hg (95% confidence interval, 79-198) to 278 mm Hg (95% confidence interval, 241-316; P = 0.031). Regional perfusion (mL(blood)/min/mL(tissue)) increased in metastases (mean change = 52%, range -32% to +261%, P = 0.024), but decreased in kidney (mean change = -42%, range -82% to -11%, P = 0.0005) and liver (mean change = -34%, range -43% to -26%, P = 0.031). 5-FU uptake at 3.75 minutes (m(2)/mL) increased in tumor (mean change = 40%, range -39% to +196%, P = 0.06) and decreased in kidney (mean change = -25%, range -71% to 12%, P = 0.043). 5-FU delivery measured as K1 increased in tumor (mean change = 74%, range -23% to +293%, P = 0.0039). No differences were seen in [18F]5-FU tumor exposure (net area under curve) and retention. CONCLUSION Nicotinamide and carbogen administration can increase 5-FU delivery to colorectal cancer liver metastases. Despite an increase in perfusion and 5-FU delivery, the effects were not directly related and did not increase 5-FU retention or tissue exposure.
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Acute and late morbidity in the treatment of advanced bladder carcinoma with accelerated radiotherapy, carbogen, and nicotinamide.
Hoskin, PJ, Rojas, AM, Phillips, H, Saunders, MI
Cancer. 2005;(11):2287-97
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BACKGROUND Accelerated radiotherapy combined with carbogen and nicotinamide (ARCON) to overcome tumor hypoxia and cell proliferation achieved high tumor control and survival in Phase II studies of patients with advanced head and neck and bladder carcinomas. Thus, morbidity and treatment outcomes from the latter study were analyzed to evaluate the therapeutic potential of ARCON. METHODS Acute and late morbidity was assessed in 105 patients with high-grade superficial or muscle-invasive bladder carcinoma who were given accelerated radiotherapy (50-55 grays in 4 weeks) with carbogen alone or with ARCON. Urinary dysfunction was scored based on daytime frequency, nocturia, incontinence, dysuria, hematuria, and urgency. Bowel morbidity was based on stool frequency and consistency, rectal discharge, blood loss, and medication. Endpoints for treatment outcome were overall survival, disease-free survival, and locoregional control. RESULTS Nearly all patients experienced reduced ability to retain urine beyond 2 hours, although 20-30% had almost normal function at night. Incidence of acute moderate or worse dysuria was 41% with ARCON and 56% with carbogen; 96% and 76% of patients, respectively, had bowel frequencies > or = 3 times per day. By 10-12 weeks from the start of radiotherapy, acute reactions returned to baseline levels. At 3 years, the daytime frequency < or = 2 times per hour was approximately 75% in both arms. Incidence of severe hematuria (< or = 25%) and urinary urgency (< or = 16%) was much lower. No more than 6% of patients had severe bowel morbidity. With most assays, the differences between schedules were not significant either for acute or late morbidity. Local tumor control and survival rates at 3 years were 53% and 43%, respectively, for ARCON, similar to the rates for carbogen alone. CONCLUSIONS Historical comparisons suggested no overt increase in normal tissue radiosensitivity when adding carbogen and nicotinamide. Although, for some endpoints, the incidence of late sequelae was higher than expected, overall morbidity was no worse than reported by others. The data indicated that ARCON could achieve a therapeutic gain in patients with advanced bladder carcinoma. A Phase III, randomized, multicenter trial is underway currently in the United Kingdom to evaluate these findings.
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Hematological and acid-base changes in men during prolonged exercise with and without sodium-lactate infusion.
Miller, BF, Lindinger, MI, Fattor, JA, Jacobs, KA, Leblanc, PJ, Duong, M, Heigenhauser, GJ, Brooks, GA
Journal of applied physiology (Bethesda, Md. : 1985). 2005;(3):856-65
Abstract
An emerging technique used for the study of metabolic regulation is the elevation of lactate concentration with a sodium-lactate infusion, the lactate clamp (LC). However, hematological and acid-base properties affected by the infusion of hypertonic solutions containing the osmotically active strong ions sodium (Na(+)) and lactate (Lac(-)) are a concern for clinical and research applications of LC. In the present study, we characterized the hematological and plasma acid-base changes during rest and prolonged, light- to moderate-intensity (55% Vo(2 peak)) exercise with and without LC. During the control (Con) trial, subjects were administered an isotonic, isovolumetric saline infusion. During LC, plasma lactate concentration ([Lac(-)]) was elevated to 4 meq/l during rest and to 4-7 meq/l during exercise. During LC at rest, there were rapid and transient changes in plasma, erythrocyte, and blood volumes. LC resulted in decreased plasma [H(+)] (from 39.6 to 29.6 neq/l) at the end of exercise while plasma [HCO(3)(-)] increased from 26 to 32.9 meq/l. Increased plasma strong ion difference [SID], due to increased [Na(+)], was the primary contributor to decreased [H(+)] and increased [HCO(3)(-)]. A decrease in plasma total weak acid concentration also contributed to these changes, whereas Pco(2) contributed little. The infusion of hypertonic LC caused only minor volume, acid-base, and CO(2) storage responses. We conclude that an LC infusion is appropriate for studies of metabolic regulation.