Morten Zaar

Blood lactate is an important energy source for the human brain

Lactate is a potential energy source for the brain. The aim of this study was to establish whether systemic lactate is a brain energy source. We measured in vivo cerebral lactate kinetics and oxidation rates in 6 healthy individuals at rest with and without 90 mins of intravenous lactate infusion (36 μmol per kg bw per min), and during 30mins of cycling exercise at 75% of maximal oxygen uptake while the lactate infusion continued to establish arterial lactate concentrations of 0.89 ± 0.08, 3.9 ± 0.3, and 6.9 ± 1.3 mmol/L, respectively. At rest, cerebral lactate utilization changed from a net lactate release of 0.06 ± 0.01 to an uptake of 0.16 ± 0.07 mmol/min during lactate infusion, with a concomitant decrease in the net glucose uptake. During exercise, the net cerebral lactate uptake was further increased to 0.28 ± 0.16 mmol/min. Most 13C-label from cerebral [1-13C]lactate uptake was released as 13CO2 with 100% ± 24%, 86% ± 15%, and 87% ± 30% at rest with and without lactate infusion and during exercise, respectively. The contribution of systemic lactate to cerebral energy expenditure was 8% ± 2%, 19% ± 4%, and 27% ± 4% for the respective conditions. In conclusion, systemic lactate is taken up and oxidized by the human brain and is an important substrate for the brain both under basal and hyperlactatemic conditions.

Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain

Lactate is shuttled between organs, as demonstrated in the Cori cycle. Although the brain releases lactate at rest, during physical exercise there is a cerebral uptake of lactate. Here, we evaluated the cerebral lactate uptake and release in hypoxia, during exercise and when the two interventions were combined. We measured cerebral lactate turnover via a tracer dilution method ([1‐13C]lactate), using arterial to right internal jugular venous differences in 9 healthy individuals (5 males and 4 females), at rest and during 30 min of submaximal exercise in normoxia and hypoxia (Fio2 10%, arterial oxygen saturation 72±10%, mean±sd). Whole‐body lactate turnover increased 3.5‐fold and 9‐fold at two workloads in normoxia and 18‐fold during exercise in hypoxia. Although middle cerebral artery mean flow velocity increased during exercise in hypoxia, calculated cerebral mitochondrial oxygen tension decreased by 13 mmHg (P<0.001). At the same time, cerebral lactate release increased from 0.15 ± 0.1 to 0.8 ± 0.6 mmol min−1 (P<0.05), corresponding to ∼10% of cerebral energy consumption. Concurrently, cerebral lactate uptake was 1.0 ± 0.9 mmol min−1 (P<0.05), of which 57 ± 9% was oxidized, demonstrating that lactate oxidation may account for up to ∼33% of the energy substrate used by the brain. These results support the existence of a cell‐cell lactate shuttle that may involve neurons and astrocytes.— Overgaard, M., Rasmussen, P., Bohm, A. M., Seifert, T., Brassard, P., Zaar, M., Homann, P., Evans, K. A., Nielsen, H. B., Secher, N. H. Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain. FASEB J. 26, 3012–3020 (2012). www.fasebj.org

Initial administration of hydroxyethyl starch vs lactated Ringer after liver trauma in the pig

BACKGROUND This study tested the circulatory effectiveness of post-trauma administration of a large intravascular volume expander, hydroxyethyl starch 130/0.4 (HES), vs standard lactated Ringers solution (RL). METHODS Liver injury was inflicted in 14 pigs [31 (4) kg; mean (sd)] and treatment simulated an acute pre-hospital event: after a standard first-respond delay (7 min), volume administration was provided in three phases to simulate increasing intravascular access. In the first two phases, the fluid was administered either by HES or by RL and, during the last phase, all animals received HES to stabilize the intravascular volume. RESULTS The liver trauma severed an equal number of 1-3 mm diameter blood vessels [1.4 (0.6)] and after 7 min, the blood loss was 184 (127) ml and mean arterial pressure had decreased by 19 (13) mm Hg (P<0.01). The intravascular volume expansion effect was 115 (25)% for HES and 76 (21)% for RL (P<0.05), yet oxygen uptake was maintained in zero of seven vs three of seven pigs and the survival was three of seven vs seven of seven, respectively (P<0.05). In these animals, the initial administration of HES provoked uncontrolled bleeding, whereas the administration of RL was associated with attenuated bleeding: total blood loss 2455 (1919) vs 311 (208) ml, respectively (P<0.01), reflecting that bleeding ceased in six of the pigs administered RL. CONCLUSIONS After injury, the intravascular volume expanding effect of HES was larger than that for RL. However, initial administration of HES provoked uncontrolled haemorrhage, suggesting that prioritizing intravascular volume expansion did not result in stabilization of the circulation after haemorrhage.

Cardiac output during exercise: A comparison of four methods

Several techniques assessing cardiac output (Q) during exercise are available. The extent to which the measurements obtained from each respective technique compares to one another, however, is unclear. We quantified Q simultaneously using four methods: the Fick method with blood obtained from the right atrium (QFick‐M), Innocor (inert gas rebreathing; QInn), Physioflow (impedance cardiography; QPhys), and Nexfin (pulse contour analysis; QPulse) in 12 male subjects during incremental cycling exercise to exhaustion in normoxia and hypoxia (FiO2 = 12%). While all four methods reported a progressive increase in Q with exercise intensity, the slopes of the Q/oxygen uptake (VO2) relationship differed by up to 50% between methods in both normoxia [4.9 ± 0.3, 3.9 ± 0.2, 6.0 ± 0.4, 4.8 ± 0.2 L/min per L/min (mean ± SE) for QFick‐M, QInn, QPhys and QPulse, respectively; P = 0.001] and hypoxia (7.2 ± 0.7, 4.9 ± 0.5, 6.4 ± 0.8 and 5.1 ± 0.4 L/min per L/min; P = 0.04). In hypoxia, the increase in the Q/VO2 slope was not detected by Nexfin. In normoxia, Q increases by 5–6 L/min per L/min increase in VO2, which is within the 95% confidence interval of the Q/VO2 slopes determined by the modified Fick method, Physioflow, and Nexfin apparatus while Innocor provided a lower value, potentially reflecting recirculation of the test gas into the pulmonary circulation. Thus, determination of Q during exercise depends significantly on the applied method.

Extra‐cerebral oxygenation influence on near‐infrared‐spectroscopy‐determined frontal lobe oxygenation in healthy volunteers: a comparison between INVOS‐4100 and NIRO‐200NX

Frontal lobe oxygenation (ScO2) is assessed by spatially resolved near‐infrared spectroscopy (SR‐NIRS) although it seems influenced by extra‐cerebral oxygenation. We aimed to quantify the impact of extra‐cerebral oxygenation on two SR‐NIRS derived ScO2.

Nitrite and S-nitrosohemoglobin Exchange Across the Human Cerebral and Femoral Circulation; Relationship to Basal and Exercise Blood Flow Responses to Hypoxia

Background: The mechanisms underlying red blood cell (RBC)–mediated hypoxic vasodilation remain controversial, with separate roles for nitrite (![Graphic][1] ) and S -nitrosohemoglobin (SNO-Hb) widely contested given their ability to transduce nitric oxide bioactivity within the microcirculation. To establish their relative contribution in vivo, we quantified arterial-venous concentration gradients across the human cerebral and femoral circulation at rest and during exercise, an ideal model system characterized by physiological extremes of O2 tension and blood flow. Methods: Ten healthy participants (5 men, 5 women) aged 24±4 (mean±SD) years old were randomly assigned to a normoxic (21% O2) and hypoxic (10% O2) trial with measurements performed at rest and after 30 minutes of cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled simultaneously from the brachial artery and internal jugular and femoral veins with plasma and RBC nitric oxide metabolites measured by tri-iodide reductive chemiluminescence. Blood flow was determined by transcranial Doppler ultrasound (cerebral blood flow) and constant infusion thermodilution (femoral blood flow) with net exchange calculated via the Fick principle. Results: Hypoxia was associated with a mild increase in both cerebral blood flow and femoral blood flow ( P gradients reflecting consumption (arterial>venous; P arterial; P 0.05). Conclusions: These findings suggest that hypoxia and, to a far greater extent, exercise independently promote arterial-venous delivery gradients of intravascular nitric oxide, with deoxyhemoglobin-mediated ![Graphic][3] reduction identified as the dominant mechanism underlying hypoxic vasodilation. # Clinical Perspective {#article-title-44} [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gifBackground: The mechanisms underlying red blood cell (RBC)–mediated hypoxic vasodilation remain controversial, with separate roles for nitrite ( ) and S-nitrosohemoglobin (SNO-Hb) widely contested given their ability to transduce nitric oxide bioactivity within the microcirculation. To establish their relative contribution in vivo, we quantified arterial-venous concentration gradients across the human cerebral and femoral circulation at rest and during exercise, an ideal model system characterized by physiological extremes of O2 tension and blood flow. Methods: Ten healthy participants (5 men, 5 women) aged 24±4 (mean±SD) years old were randomly assigned to a normoxic (21% O2) and hypoxic (10% O2) trial with measurements performed at rest and after 30 minutes of cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled simultaneously from the brachial artery and internal jugular and femoral veins with plasma and RBC nitric oxide metabolites measured by tri-iodide reductive chemiluminescence. Blood flow was determined by transcranial Doppler ultrasound (cerebral blood flow) and constant infusion thermodilution (femoral blood flow) with net exchange calculated via the Fick principle. Results: Hypoxia was associated with a mild increase in both cerebral blood flow and femoral blood flow (P<0.05 versus normoxia) with further, more pronounced increases observed in femoral blood flow during exercise (P<0.05 versus rest) in proportion to the reduction in RBC oxygenation (r=0.680–0.769, P<0.001). Plasma gradients reflecting consumption (arterial>venous; P<0.05) were accompanied by RBC iron nitrosylhemoglobin formation (venous>arterial; P<0.05) at rest in normoxia, during hypoxia (P<0.05 versus normoxia), and especially during exercise (P<0.05 versus rest), with the most pronounced gradients observed across the bioenergetically more active, hypoxemic, and acidotic femoral circulation (P<0.05 versus cerebral). In contrast, we failed to observe any gradients consistent with RBC SNO-Hb consumption and corresponding delivery of plasma S-nitrosothiols (P>0.05). Conclusions: These findings suggest that hypoxia and, to a far greater extent, exercise independently promote arterial-venous delivery gradients of intravascular nitric oxide, with deoxyhemoglobin-mediated reduction identified as the dominant mechanism underlying hypoxic vasodilation.

Coupling between the blood lactate-to-pyruvate ratio and MCA Vmean at the onset of exercise in humans

Activation-induced increase in cerebral blood flow is coupled to enhanced metabolic activity, maybe with brain tissue redox state and oxygen tension as key modulators. To evaluate this hypothesis at the onset of exercise in humans, blood was sampled at 0.1 to 0.2 Hz from the radial artery and right internal jugular vein, while middle cerebral artery mean flow velocity (MCA V(mean)) was recorded. Both the arterial and venous lactate-to-pyruvate ratio increased after 10 s (P < 0.05), and the arterial ratio remained slightly higher than the venous (P < 0.05). The calculated average cerebral capillary oxygen tension decreased by 2.7 mmHg after 5 s (P < 0.05), while MCA V(mean) increased only after 30 s. Furthermore, there was an unaccounted cerebral carbohydrate uptake relative to the uptake of oxygen that became significant 50 s after the onset of exercise. These findings support brain tissue redox state and oxygenation as potential modulators of an increase in cerebral blood flow at the onset of exercise.

Hypoxia increases exercise heart rate despite combined inhibition of β-adrenergic and muscarinic receptors

Hypoxia increases the heart rate response to exercise, but the mechanism(s) remains unclear. We tested the hypothesis that the tachycardic effect of hypoxia persists during separate, but not combined, inhibition of β-adrenergic and muscarinic receptors. Nine subjects performed incremental exercise to exhaustion in normoxia and hypoxia (fraction of inspired O2 = 12%) after intravenous administration of 1) no drugs (Cont), 2) propranolol (Prop), 3) glycopyrrolate (Glyc), or 4) Prop + Glyc. HR increased with exercise in all drug conditions (P < 0.001) but was always higher at a given workload in hypoxia than normoxia (P < 0.001). Averaged over all workloads, the difference between hypoxia and normoxia was 19.8 ± 13.8 beats/min during Cont and similar (17.2 ± 7.7 beats/min, P = 0.95) during Prop but smaller (P < 0.001) during Glyc and Prop + Glyc (9.8 ± 9.6 and 8.1 ± 7.6 beats/min, respectively). Cardiac output was enhanced by hypoxia (P < 0.002) to an extent that was similar between Cont, Glyc, and Prop + Glyc (2.3 ± 1.9, 1.7 ± 1.8, and 2.3 ± 1.2 l/min, respectively, P > 0.4) but larger during Prop (3.4 ± 1.6 l/min, P = 0.004). Our results demonstrate that the tachycardic effect of hypoxia during exercise partially relies on vagal withdrawal. Conversely, sympathoexcitation either does not contribute or increases heart rate through mechanisms other than β-adrenergic transmission. A potential candidate is α-adrenergic transmission, which could also explain why a tachycardic effect of hypoxia persists during combined β-adrenergic and muscarinic receptor inhibition.

Early activation of the coagulation system during lower body negative pressure

We considered that a moderate reduction of the central blood volume (CBV) may activate the coagulation system. Lower body negative pressure (LBNP) is a non‐invasive means of reducing CBV and, thereby, simulates haemorrhage. We tested the hypothesis that coagulation markers would increase following moderate hypovolemia by exposing 10 healthy male volunteers to 10 min of 30 mmHg LBNP. Thoracic electrical impedance increased during LBNP (by 2·6 ± 0·7 Ω, mean ± SD; P < 0·001), signifying a reduced CBV. Heart rate was unchanged during LBNP, while mean arterial pressure decreased (84 ± 5 to 80 ± 6 mmHg; P < 0·001) along with stroke volume (114 ± 22 to 96 ± 19 ml min−1; P < 0·001) and cardiac output (6·4 ± 2·0 to 5·5 ± 1·7 l min−1; P < 0·01). Plasma thrombin–antithrombin III complexes increased (TAT, 5 ± 6 to 19 ± 20 μg l−1; P < 0·05), indicating that LBNP activated the thrombin generating part of the coagulation system, while plasma D‐dimer was unchanged, signifying that the increased thrombin generation did not cause further intravascular clot formation. The plasma pancreatic polypeptide level decreased (13 ± 11 to 6 ± 8 pmol l−1; P < 0·05), reflecting reduced vagal activity. In conclusion, thrombin generation was activated by a modest decrease in CBV by LBNP in healthy humans independent of the vagal activity.

Coagulation competence and fluid recruitment after moderate blood loss in young men.

The coagulation system is activated by a reduction of the central blood volume during orthostatic stress and lower body negative pressure suggesting that also a blood loss enhances coagulation. During bleeding, however, the central blood volume is supported by fluid recruitment to the circulation and redistribution of the blood volume. In eight supine male volunteers (24 ± 3 years, blood volume of 6.9 ± 0.7 l; mean ± SD), 2 × 450 ml blood was withdrawn over ∼30 min while cardiovascular variables were monitored. Coagulation was evaluated by thrombelastography, and fluid recruitment was estimated by red blood cell count. Withdrawing 900 ml blood increased heart rate (62 ± 7 to 69 ± 13 bpm, P < 0.05; mean ± SD) and reduced stroke volume (113 ± 12 to 96 ± 14 ml, P < 0.05) leaving cardiac output, mean arterial pressure, and total peripheral resistance unchanged and, furthermore, reduced red blood cell count (4.80 ± 0.33 to 4.64 ± 0.37 × 1012 cells l−1, P < 0.05) indicating that 218 ± 173 ml fluid was recruited to the circulation. Withdrawing 450 ml blood reduced the time until initial fibrin formation (R: 6.5 ± 0.9 to 5.1 ± 1.0 min, P < 0.01), whereas the rate of clot formation increased after withdrawal of 900 ml blood (&agr;-Angle: 66 ± 4 to 70 ± 3 deg, P < 0.01). Clot strength (maximal amplitude: 57 ± 4 mm), clot lysis 30 min after maximal amplitude (LY30: 0.8% [0–3.5%] (median [range])), and platelet count (218 ± 25 × 109 l−1) were unaffected. For supine males, ∼25% of a moderate blood loss is compensated by fluid recruitment to the circulation, which may explain the minor cardiovascular response. Yet, a blood loss of 450 ml accelerates coagulation, and this is further accentuated when blood loss is 900 ml.