Cerebral lactate uptake during exercise is driven by the increased arterial lactate concentration.

Exercise facilitates cerebral lactate uptake, likely by increasing arterial lactate concentration and hence the diffusion gradient across the blood-brain barrier. However, nonspecific ß-adrenergic blockade by propranolol has previously reduced the arterio-jugular venous lactate difference (AVLac) during exercise, suggesting ß-adrenergic control of cerebral lactate uptake. Alternatively, we hypothesized that propranolol reduces cerebral lactate uptake by decreasing arterial lactate concentration. To test that hypothesis, we evaluated cerebral lactate uptake taking changes in arterial concentration into account. Nine healthy males performed incremental cycling exercises to exhaustion with and without intravenous propranolol (18.7 ± 1.9 mg). Lactate concentration was determined in arterial and internal jugular venous blood at the end of each workload. To take changes in arterial lactate into account, we calculated the fractional extraction (FELac) defined as AVLac divided by the arterial lactate concentration. Arterial lactate concentration was reduced by propranolol at any workload (P < 0.05), reaching 14 ± 3 and 11 ± 3 mmol·l-1 during maximal exercise without and with propranolol, respectively. Although AVLac and FELac increased during exercise (both P < 0.05), they were both unaffected by propranolol at any workload (P = 0.68 and P = 0.26) or for any given arterial lactate concentration (P = 0.78 and P = 0.22). These findings support that while propranolol may reduce cerebral lactate uptake, this effect reflects the propranolol-induced reduction in arterial lactate concentration and not inhibition of a ß-adrenergic mechanism within the brain. We hence conclude that cerebral lactate uptake during exercise is directly driven by the increasing arterial concentration with work rate.NEW & NOTEWORTHY During exercise the brain consumes lactate as a substitute for glucose. Propranolol has previously attenuated this cerebral lactate uptake, suggesting a ß-adrenergic transport mechanism. However, in the present study, we demonstrate that the fractional extraction of arterial lactate by the brain is unaffected by propranolol throughout incremental exercise to exhaustion. We conclude that cerebral lactate uptake during exercise is passively driven by the increasing arterial concentration, rather than by a ß-adrenergic mechanism within the brain.

Protocol for a multicentre retrospective observational cohort study in Denmark: association between the intraoperative peripheral perfusion index and postoperative morbidity and mortality in acute non-cardiac surgical patients.

INTRODUCTION: Perioperative haemodynamic instability is associated with postoperative morbidity and mortality. Macrocirculatory parameters, such as arterial blood pressure and cardiac output are associated with poor outcome but may be uncoupled from the microcirculation during sepsis and hypovolaemia and may not be optimal resuscitation parameters. The peripheral perfusion index (PPI) is derived from the pulse oximetry signal. Reduced peripheral perfusion is associated with morbidity in critically ill patients and in patients following acute surgery. We hypothesise that a low intraoperative PPI is independently associated with postoperative complications and mortality. METHODS AND ANALYSIS: We plan to conduct a retrospective cohort study in approximately 2300 patients, who underwent acute non-cardiac surgery (1 November 2017 to 31 October 2018) at two Danish University Hospitals. Data will be collected from patient records including patient demographics, comorbidity and intraoperative haemodynamic values with PPI as the primary exposure variable, and postoperative complications and mortality within 30 and 90 days as outcome variables. We primarily assess association between PPI and outcome in multivariate regression models. Second, the predictive value of PPI for outcome, using area under the receiver operating characteristics curve is assessed. ETHICS AND DISSEMINATION: Data will be reported according to the Strengthening the Reporting of Observational Studies in Epidemiology and results published in a peer-reviewed journal. The study is approved by the regional research ethics committee, storage and management of data has been approved by the Regional Data Protection Agency, and access to medical records is approved by the hospital board of directors (ClinicalTrials.gov registration no: NCT03757442).

Time Trial Performance Is Sensitive to Low-Volume Autologous Blood Transfusion.

PURPOSE: This study tested the hypothesis that autologous blood transfusion (ABT) of ~50% of the red blood cells (RBC) from a standard 450-mL phlebotomy would increase mean power in a cycling time trial. In addition, the study investigated whether further ABT of RBC obtained from another 450-mL phlebotomy would increase repeated cycling sprint ability. METHODS: In a randomized, double-blind, placebo-controlled crossover design (3-month wash-out), nine highly trained male subjects donated two 450-mL blood bags each (BT trial) or were sham phlebotomized (PLA trial). Four weeks later, a 650-kcal time trial (n = 7) was performed 3 d before and 2 h after receiving either ~50% (135 mL) of the RBC or a sham transfusion. On the following day, transfusion of RBC (235 mL) from the second donation or sham transfusion was completed. A 4 × 30-s all-out cycling sprint interspersed by 4 min of recovery was performed 6 d before and 3 d after the second ABT (n = 9). RESULTS: The mean power was increased in time trials from before to after transfusion (P < 0.05) in BT (213 ± 35 vs 223 ± 38 W; mean ± SD) but not in PLA (223 ± 42 vs 224 ± 46 W). In contrast, the mean power output across the four 30-s sprint bouts remained similar in BT (639 ± 35 vs 644 ± 26 W) and PLA (638 ± 43 vs 639 ± 25 W). CONCLUSIONS: ABT of only ~135 mL of RBC is sufficient to increase mean power in a 650-kcal cycling time trial by ~5% in highly trained men. In contrast, a combined high-volume transfusion of ~135 and ~235 mL of RBC does not alter 4 × 30-s all-out cycling performance interspersed with 4 min of recovery.

Elevated Renal Oxygen Extraction During Open Abdominal Aortic Aneurysm Repair Is Related to Postoperative Renal Dysfunction.

BACKGROUND: Open abdominal aortic aneurysm repair is often followed by elevated plasma creatinine, likely due to impaired renal blood flow. We evaluated whether postoperative elevation in creatinine relates to renal oxygen extraction during surgery as an index of renal blood flow and also monitored frontal lobe oxygenation. METHODS: For 19 patients (66 ± 10 years; mean ± SD) undergoing open infrarenal abdominal aortic aneurysm repair, renal oxygen extraction was determined by arterial and renal vein catheterization. Near-infrared spectroscopy determined frontal lobe oxygenation. RESULTS: During surgery mean arterial pressure (from 102 ± 14 to 65 ± 11 mm Hg; P < .0001), arterial hemoglobin (from 7.7 ± 0.7 to 6.6 ± 0.8 mmol/L; P < 0.0001), and frontal lobe oxygenation (from 74 ± 6% to 70 ± 6%; P = .0414) decreased, while renal oxygen extraction increased (from 5.3% [4.3-8.1]; median [interquartile range] to 10.8% [5.8-17.5]; P = .0405). Plasma creatinine became significantly elevated on the second day after the operation (from 83 [73-101] to 105 µmol/L [79-143]; P = .0062) with a peak increase observed after 2 days (1-2). The peak increase in creatinine correlated to intraoperative renal oxygen extraction ( r = 0.51; P = .026). CONCLUSION: Kidney function was affected after open abdominal aortic aneurysm repair likely related to limited renal blood flow. We take the increase in renal oxygen extraction and reduction in frontal lobe oxygenation to suggest that mean arterial pressure and hemoglobin were too low to maintain renal and cerebral circulation in vascular surgical patients.

Matrix Metalloproteinase Mediated Type I Collagen Degradation is an Independent Predictor of Increased Risk of Acute Myocardial Infarction in Postmenopausal Women.

Acute myocardial infarction (AMI) is often underdiagnosed in women. It is therefore of interest to identify biomarkers that indicate increased risk of AMI and thereby help clinicians to have additional focus on the difficult AMI diagnosis. Type I Collagen, a component of the cardiac extracellular matrix, is cleaved by matrix metalloproteinases (MMPs) generating the neo-epitope C1M. We investigated the association between serum-C1M and AMI and evaluated whether C1M is a prognostic marker for outcome following AMI. This study is based on The Prospective Epidemiological Risk Factor (PERF) Study including postmenopausal women. 316 out of 5,450 women developed AMI within the follow-up period (14 years, median). A multivariate Cox analysis assessed association between serum-C1M and AMI, and re-infaction or death subsequent to AMI. The risk of AMI increased by 18% (p = 0.03) when serum-C1M was doubled and women in the highest quartile had a 33% increased risk compared to those in the low quartiles (p = 0.025). Serum-C1M was, however not related to reinfarction or death subsequent to AMI. In this study C1M was be an independent risk factor for AMI. Measuring MMP degraded type I collagen could be useful for prediction of increased risk of AMI if replicated in other cohorts.

Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans.

BACKGROUND & AIMS: Fibroblast growth factor 21 (FGF-21) is a liver-derived metabolic regulator induced by energy deprivation. However, its regulation in humans is incompletely understood. We addressed the origin and regulation of FGF-21 secretion in humans. METHODS: By determination of arterial-to-venous differences over the liver and the leg during exercise, we evaluated the organ-specific secretion of FGF-21 in humans. By four different infusion models manipulating circulating glucagon and insulin, we addressed the interaction of these hormones on FGF-21 secretion in humans. RESULTS: We demonstrate that the splanchnic circulation secretes FGF-21 at rest and that it is rapidly enhanced during exercise. In contrast, the leg does not contribute to the systemic levels of FGF-21. To unravel the mechanisms underlying the regulation of exercise-induced hepatic release of FGF-21, we manipulated circulating glucagon and insulin. These studies demonstrated that in humans glucagon stimulates splanchnic FGF-21 secretion whereas insulin has an inhibitory effect. CONCLUSIONS: Collectively, our data reveal that 1) in humans, the splanchnic bed contributes to the systemic FGF-21 levels during rest and exercise; 2) under normo-physiological conditions FGF-21 is not released from the leg; 3) a dynamic interaction of glucagon-to-insulin ratio regulates FGF-21 secretion in humans.

Ischemic preconditioning of one forearm enhances static and dynamic apnea.

INTRODUCTION: Ischemic preconditioning enhances ergometer cycling and swimming performance. We evaluated whether ischemic preconditioning of one forearm (four times for 5 min) also affects static breath hold and underwater swimming, whereas the effect of similar preconditioning on ergometer rowing served as control because the warm-up for rowing regularly encompasses intense exercise and therefore reduced muscle oxygenation. METHODS: Six divers performed a dry static breath hold, 11 divers swam underwater in an indoor pool, and 14 oarsmen rowed "1000 m" on an ergometer. RESULTS: Ischemic preconditioning reduced the forearm oxygen saturation from 65% ± 7% to 19% ± 7% (mean ± SD; P < 0.001), determined using spatially resolved near-infrared spectroscopy. During the breath hold (315 s, range = 280-375 s), forearm oxygenation decreased to 29% ± 10%; and in preparation for rowing, right thigh oxygenation decreased from 66% ± 7% to 33% ± 14% (P < 0.05). Ischemic preconditioning prolonged the breath hold from 279 ± 72 to 327 ± 39 s, and the underwater swimming distance from 110 ± 16 to 119 ± 14 m (P < 0.05) and also the rowing time was reduced (from 186.5 ± 3.6 to 185.7 ± 3.6 s; P < 0.05). CONCLUSIONS: We conclude that while the effect of ischemic preconditioning (of one forearm) on ergometer rowing was minimal, probably because of reduced muscle oxygenation during the warm-up, ischemic preconditioning does enhance both static and dynamic apnea, supporting that muscle ischemia is an important preparation for physical activity.

Cerebral oxygenation during exercise in patients with terminal lung disease.

STUDY OBJECTIVES: In patients with terminal lung disease who were exercising, we assessed whether improved arterial O2 saturation with an increased fraction of inspired oxygen (FIO2) affects cerebral oxygenation. DESIGN: Randomized, crossover. PATIENTS AND METHODS: The cerebral changes in oxyhemoglobin (DeltaHbO2) and changes in deoxyhemoglobin (DeltaHb) levels were evaluated using near-infrared spectrophotometry and the middle cerebral artery (MCA) mean velocity (V(mean)) was determined by transcranial Doppler ultrasonography in 13 patients with terminal lung disease (New York Heart Association class III-IV). Patients were allocated to an FIO2 of either 0.21 or 0.35 during incremental exercise with 15 min between trials. RESULTS: Peak exercise intensity (mean [+/- SE], 26 +/- 4 W) reduced the arterial O2 pressure (at rest, 64 +/- 3 mm Hg; during exercise, 56 +/- 3 mm Hg) and the arterial oxygen saturation (SaO2) [at rest, 92 +/- 2%; 87 +/- 2%; p < 0.05], while the arterial CO2 pressure was not significantly affected. The MCA V(mean) increased from 49 +/- 5 to 63 +/- 7 cm/s (p < 0.05) as did the DeltaHb, while the DeltaHbO2 remained unaffected by exercise. With an elevated FIO2, the SaO2 level (at rest, 95.8 +/- 0.7%; during exercise, 96.0 +/- 1.0%) and arterial O2 pressure (at rest, 102 +/- 11 mm Hg; during exercise, 100 +/- 8 mm Hg) were not significantly affected by exercise, and the levels of blood oxygenation remained higher than the values established at normoxia (p < 0.05). The MCA V(mean) increased to a level similar to that achieved during control exercise (ie, to 70 +/- 11 cm/s). In contrast to control exercise, DeltaHb decreased while DeltaHbO2 increased during exercise with 35% O2 (p < 0.05). CONCLUSION: An O2-enriched atmosphere enabled patients with terminal lung disease to maintain arterial O2 saturation during exercise. An exercise-induced increase in cerebral perfusion was not affected by hyperoxia, whereby the enhanced availability of oxygenated hemoglobin increases cerebral oxygenation. The clinical implication of the study is that during physical activity patients with terminal lung disease are recommended to use an elevated FIO2 to protect cerebral oxygenation.

The effect of hepatectomy on glucose homeostasis in pig and in man.

BACKGROUND/AIMS: The liver is regarded the most important source of glucose production and it is common practice to administer glucose during human liver transplantations to avoid hypoglycaemia. The purpose of this study was to evaluate the importance of extra-hepatic contribution (kidney, gut and muscle) to the glucose homeostasis in the anhepatic pig and in man during the anhepatic phase of human liver transplantations. METHODS: Blood glucose and lactate were monitored in the anhepatic phase in 46 patients undergoing liver transplantation. Arterial-venous differences of lactate, glucose, glycerol, alanine and free fatty acids were measured over kidney, gut and hind leg in 18 pigs made anhepatic. RESULTS: Blood glucose did not change significantly and blood lactate increased only marginally during the anhepatic phase of human orthotopic liver transplantation. In the anhepatic pig, however, blood glucose decreased with a halflife of about 26 min and blood lactate increased. Kidney gluconeogenesis was 0.116+/-0.016 mmol min(-1). Fifty percent of kidney glucose output could be accounted for by lactate- and glycerol uptake. CONCLUSIONS: The results show that in humans extra hepatic gluconeogenesis is sufficient to maintain normal blood glucose in the anhepatic phase of orthotopic liver transplantation, while in the pig this was not the case.