Interstitial Lactate Concentrations Research Articles

Interstitial Glucose Metabolism Monitoring as an Additional Method for Objective Assessment of Donor Liver, Prediction and Immediate Diagnosis of Early Graft Dysfunction.

A retrospective observational single-center study included 32 cases of liver transplantation. Along with standard methods for assessing the initial function of grafts during the first week after surgery, interstitial (in the transplanted liver) concentrations of glucose and its metabolites were monitored. In 18 cases, the interstitial glucose metabolism was also studied during static cold storage (SCS). With the development of early allograft dysfunction (EAD), compared with the uneventful post-transplant period, statistically significantly higher interstitial lactate concentrations were observed as early as 3 h after reperfusion: 12.3 [10.1; 15.6] mmol/L versus 7.2 [3.9; 9.9] mmol/L (p=0.003). A value above 8.8 mmol/L may be considered as a criterion for the immediate diagnosis of EAD (sensitivity - 89%, specificity - 65%).Interstitial lactate concentration at the end of SCS and the area under the "lactate concentration-SCS duration" curve were associated with the initial graft function. Values of these parameters greater than 15.4 mmol/L and 76.1 mmol/L·h, respectively, with a sensitivity of 100% in both cases and a specificity of 77 and 85%, may be used to assess the risk of primary EAD. Monitoring of interstitial concentrations of glucose and its metabolites, primarily, lactate, is an objective additional method for the assessment of the donor liver viability both during SCS and in the early postoperative period.

Assessment and monitoring of liver graft viability and initial function using interstitial microdialysis

Assessing the viability and monitoring the function of liver graft in the early postoperative period are critical clinical tasks. One possible solution is to determine the changes in concentration of blood glucose, its metabolites and glycerol in the graft using interstitial microdialysis. Objective: to study the dynamics of interstitial glucose, lactate, pyruvate and glycerol in the early post-liver transplant period – depending on the initial graft function (IGF) – and to compare with the results of standard laboratory blood tests. Materials and methods. Four selected clinical observations of deceased donor liver transplantation are presented. Two of the observations showed normal IGF, one observation – early allograft dysfunction (EAD), complicated by hepatic artery thrombosis (HAT), while one observation demonstrated primary non-function (PNF). Collection of microdialysis samples began after arterial reperfusion of the liver graft and continued continuously for 7 days or until death. Standard blood biochemistry and coagulation tests were performed at least once a day. Results. With normal IGF and a smooth postoperative period, interstitial concentrations of glucose, lactate, pyruvate and glycerol remained stable throughout the observation period, ranging from 5 to 20 mmol/L, 1.1 to 7.5 mmol/L, 90 to 380 μmol/L, and 10–100 μmol/L, respectively. EAD was associated with initially higher levels of glucose, lactate, and pyruvate. With HAT development, there was a rapid (within 2–4 hours) five-fold increase in interstitial concentration of lactate with simultaneous decrease in glucose and pyruvate levels to 0.1 mmol/L and 11 μmol/L, respectively. In the case of PNF, there was an initially high concentration of interstitial lactate – 16.4 mmol/L, which increased further to 35.5 mmol/L. Glucose concentration was close to 0. Changes in interstitial glucose, its metabolites and glycerol concentrations chronologically preceded the corresponding changes in peripheral blood composition by 3–5 hours. Conclusion. Microdialysis measurement of interstitial glucose, lactate, pyruvate and glycerol concentrations facilitates real-time monitoring of liver graft viability and function. The high sensitivity of the method could help in accelerating diagnosis of vascular complications (HAT in particular), as well as graft dysfunction with other causes. Therefore, the method is feasible in clinical practice.

Na+,HCO3--cotransporter NBCn1 (Slc4a7) accelerates ErbB2-induced breast cancer development and tumor growth in mice.

Metabolic acid production challenges cellular pH homeostasis in solid cancer tissue, and mechanisms of net acid extrusion represent promising new targets for breast cancer therapy. Here, we used genetically engineered mice to investigate the contribution of the Na+,HCO3--cotransporter NBCn1 (Slc4a7) to intracellular acid-base regulation in ErbB2-induced breast cancer tissue and the consequences of NBCn1 knockout for breast tumor development and growth. We demonstrate an approximately 2-fold increase of NBCn1 protein abundance in ErbB2-induced breast cancer tissue compared to normal breast tissue despite a 4-fold decrease in the NBCn1 mRNA level. In congruence, we show that NBCn1 facilitates net acid extrusion and elevates steady-state intracellular pH in breast cancer tissue. Disruption of NBCn1 expression delayed ErbB2-induced breast carcinogenesis from a median tumor-free survival of 9.5 months in wild-type mice to 12 months in NBCn1-knockout mice and decelerated the tumor growth rate by approximately 1/3. Glycolytic metabolism-evaluated based on the interstitial concentrations of lactate and glucose measured in microdialysates-was increased in breast cancer tissue compared to normal breast tissue, but was unaffected by NBCn1 knockout. Disruption of NBCn1 expression inhibited cell proliferation-evaluated by staining for the proliferative marker Ki67-particularly in central tumor areas with predicted increase in acid loading from glycolytic metabolism. In conclusion, NBCn1 regulates intracellular pH in ErbB2-induced breast cancer tissue by providing a pathway for cellular uptake of HCO3-, which can neutralize metabolic acidic waste products. Disrupting NBCn1 expression delays ErbB2-induced breast cancer development, inhibits cancer cell proliferation, and decelerates tumor growth.

Microdialysis as a Part of Invasive Cerebral Monitoring During Porcine Septic Shock.

Metabolic changes in critically ill patients with endotoxin-induced septic shock are measured primarily by techniques that afford organ-specific metabolic monitoring based on interstitial fluid samples. The present study was designed to evaluate the role of cerebral microdialysis (MD) as a part of invasive neuromonitoring during endotoxemia in a porcine model. Continuous endotoxin infusion was administered to 7 female pigs and, in addition to hemodynamic monitoring and blood chemistry, interstitial lactate, pyruvate, glucose and glycerol concentrations in muscle, liver, and cerebral tissue were measured via in vivo MD for an observation period of 180 minutes. The cerebral concentrations of lactate and glycerol showed no significant increases, whereas the hepatic and muscular levels rose dramatically under endotoxemia. However, the lactate/pyruvate ratio and especially the lactate/glucose ratio showed a profound and significant increase in brain tissue as well. Cerebral perfusion pressure decreased from 77 to 50 mm Hg without reaching pathologic values. Although our results confirm the special protection of the brain during endotoxemia compared with other organs, early metabolic changes become evident by increasing lactate/pyruvate ratio and lactate/glucose ratio. MD appears to be a suitable additional technique in invasive neuromonitoring for obtaining early information about metabolic deterioration in the brain during septic shock.

A 3-day EGCG-supplementation reduces interstitial lactate concentration in skeletal muscle of overweight subjects

Green tea, particularly epigallocatechin-3-gallate (EGCG), may affect body weight and composition, possibly by enhancing fat oxidation. The aim of this double-blind, randomized placebo-controlled cross-over study was to investigate whether 3-day supplementation with EGCG (282mg/day) stimulates fat oxidation and lipolysis in 24 overweight subjects (age = 30 ± 2yrs, BMI = 27.7 ± 0.3 kg/m2). Energy expenditure, substrate metabolism and circulating metabolites were determined during fasting and postprandial conditions. After 6 h, a fat biopsy was collected to examine gene expression. In 12 subjects, skeletal muscle glycerol, glucose and lactate concentrations were determined using microdialysis. EGCG-supplementation did not alter energy expenditure and substrate oxidation compared to placebo. Although EGCG reduced postprandial circulating glycerol concentrations (P = 0.015), no difference in skeletal muscle lipolysis was observed. Fasting (P = 0.001) and postprandial (P = 0.003) skeletal muscle lactate concentrations were reduced after EGCG-supplementation compared to placebo, despite similar tissue blood flow. Adipose tissue leptin (P = 0.05) and FAT/CD36 expression (P = 0.08) were increased after EGCG compared to placebo. In conclusion, 3-day EGCG-supplementation decreased postprandial plasma glycerol concentrations, but had no significant effects on skeletal muscle lipolysis and whole-body fat oxidation in overweight individuals. Furthermore, EGCG decreased skeletal muscle lactate concentrations, which suggest a shift towards a more oxidative muscle phenotype.

Is microdialysis useful for early detection of acute rejection after kidney transplantation?

IntroductionAcute rejection following kidney transplantation (KTx) is still one of the challenging complications leading to chronic allograft failure. The aim of this study was to investigate the role of microdialysis (MD) in the early detection of acute graft rejection factor following KTx in porcine model. MethodsSixteen pigs were randomized after KTx into case (n = 8, without immunosuppressant) and control groups (n = 8, with immunosuppressant). The rejection diagnosis in our groups was confirmed by histopathological evidences as “acute borderline rejection”. Using MD, we monitored the interstitial concentrations of glucose, lactate, pyruvate, glutamate and glycerol in the transplanted grafts after reperfusion. ResultsIn the early post-reperfusion phase the lactate level in our case group was significantly higher comparing to the control group and remained in higher levels until the end of monitoring. The lactate to pyruvate ratio showed a considerable increase in the case group during the post-reperfusion phase. The other metabolites (glucose, glycerol, glutamate) were nearly at the same levels at the end of our monitoring in both study groups. ConclusionThe increase in lactate and lactate to pyruvate ratios seems to be an indicator for early detection of acute rejection after KTx. Therefore, MD as a minimally invasive measurement tool may help to identify the need to immunosuppression adjustment in the early KTx phase before the clinical manifestation of the rejection.

Cerebral metabolism during experimental endotoxin shock and after preconditioning with monophosphoryl lipid A

PurposePreconditioning with low doses of monophosphoryl lipid A (MPL) has been shown to induce endotoxin tolerance and to reduce the metabolic and hemodynamic consequences of endotoxin shock. However, no data are available about the effects of endotoxin preconditioning on cerebral metabolism during endotoxemia. The study was designed to determine the effects of endotoxin preconditioning with MPL on cerebral metabolism via microdialysis compared to muscle tissue metabolism during experimental endotoxemia. MethodsIn a controlled animal study, continuous endotoxin infusion (1μg/kg b.w. per h) was administrated to 7 female mixed-breed pigs after pretreatment with MPL in incremental doses of endotoxin during days 5–2 before the experiments. In the control group, 7 animals received a saline pretreatment. In addition to hemodynamic monitoring and blood gas analyses, interstitial lactate, pyruvate, glucose and glycerol concentrations in muscle and cerebral tissue were measured using in vivo microdialysis. ResultsThere were no significant differences between the two groups with respect to hemodynamic parameters, while mixed venous oxygen saturation (SvO2), arterial blood pH and mean pulmonary arterial pressure (MPAP) were significantly higher in the preconditioned group. Cerebral perfusion pressure (CPP) and brain tissue oxygen pressure (ptiO2) values stayed stable throughout the experiment with no inter-group differences. While interstitial concentrations of lactate and glycerol as well as the lactate/pyruvate (LP) and the lactate/glucose (LG) ratio in muscle tissues were significantly increased in control animals compared to those who had been pretreated with MPL; the results of cerebral microdialysis showed no significant changes in interstitial lactate or glycerol levels in both groups. However, the lactate/glucose (LG) ratio in the control group showed a significantly higher increase than in the preconditioned group. ConclusionsPreconditioning with low doses of MPL ameliorates the negative metabolic effects of endotoxin shock in muscle tissue. With regard to cerebral metabolism, the present study suggests that MLP preconditioning provides moderate advantages, at least in an experimental model of endotoxin shock.

Combined administration of hyperbaric oxygen and hydroxocobalamin improves cerebral metabolism after acute cyanide poisoning in rats

Hyperbaric oxygen therapy (HBOT) or intravenous hydroxocobalamin (OHCob) both abolish cyanide (CN)-induced surges in interstitial brain lactate and glucose concentrations. HBOT has been shown to induce a delayed increase in whole blood CN concentrations, whereas OHCob may act as an intravascular CN scavenger. Additionally, HBOT may prevent respiratory distress and restore blood pressure during CN intoxication, an effect not seen with OHCob administration. In this report, we evaluated the combined effects of HBOT and OHCob on interstitial lactate, glucose, and glycerol concentrations as well as lactate-to-pyruvate ratio in rat brain by means of microdialysis during acute CN poisoning. Anesthetized rats were allocated to three groups: 1) vehicle (1.2 ml isotonic NaCl intra-arterially); 2) potassium CN (5.4 mg/kg intra-arterially); 3) potassium CN, OHCob (100 mg/kg intra-arterially) and subsequent HBOT (284 kPa in 90 min). OHCob and HBOT significantly attenuated the acute surges in interstitial cerebral lactate, glucose, and glycerol concentrations compared with the intoxicated rats given no treatment. Furthermore, the combined treatment resulted in consistent low lactate, glucose, and glycerol concentrations, as well as in low lactate-to-pyruvate ratios compared with CN intoxicated controls. In rats receiving OHCob and HBOT, respiration improved and cyanosis disappeared, with subsequent stabilization of mean arterial blood pressure. The present findings indicate that a combined administration of OHCob and HBOT has a beneficial and persistent effect on the cerebral metabolism during CN intoxication.

Acute peripheral tissue effects of ghrelin on interstitial levels of glucose, glycerol, and lactate: a microdialysis study in healthy human subjects

Ghrelin is a gut-derived peptide and an endogenous ligand for the ghrelin receptor. Intravenous infusion of ghrelin induces insulin resistance and hyperglycemia and increases circulating levels of nonesterified free fatty acids. Our objective was to investigate whether the metabolic effects are mediated directly by ghrelin in skeletal muscle and adipose (peripheral and central) tissues. Ten healthy men (24.9 ± 1.3 yr) received 300 min of supraphysiological ghrelin administration by microdialysis catheters in skeletal muscle and adipose tissues in a randomized, single-blind, and placebo-controlled study. Microdialysis perfusates were analyzed every 30 min for glucose, glycerol, and lactate during both a basal period and a hyperinsulinemic euglycemic clamp. The primary outcome measures were interstitial concentrations of glucose, glycerol, and lactate in skeletal muscle and adipose tissues. Interstitial concentrations of glucose were similar in skeletal muscle, peripheral, and central adipose tissue in the basal period. During hyperinsulinemia, interstitial concentrations of glucose in skeletal muscle decreased in response to ghrelin exposure [2.84 ± 0.25 (ghrelin) vs. 3.06 ± 0.26 mmol/l (placebo), P = 0.04]. Ghrelin exposure did not impact on interstitial concentrations of glycerol and lactate. We conclude that ghrelin administration into skeletal muscle decreases interstitial concentrations of glucose during euglycemic hyperinsulinemia, which is indicative of increased insulin sensitivity without any effects on interstitial glycerol levels in either muscle or adipose tissue. These data contrast with the metabolic effects of ghrelin observed after systemic exposure and suggest the existence of a second messenger that remains to be identified.

The Selective Phosphodiesterase-5 Inhibitor Tadalafil Induces Microvascular and Metabolic Effects in Type 2 Diabetic Postmenopausal Females

The objective of the study was to explore the acute in vivo effects of the selective phosphodiesterase-5 inhibitor tadalafil on local microcirculation and regional metabolism in skeletal muscle and adipose tissue (AT). We studied eight postmenopausal female patients with type 2 diabetes (T2D) and eight nondiabetic controls (Ctrl) in the postabsorptive state and 180 min after the administration of tadalafil 10 mg. Intramuscular and sc microdialysis were combined with measurements of forearm (FBF) and AT blood flow as well as with arterial and deep venous blood sampling. Muscle capillary recruitment, as ascertained by the permeability surface area product for glucose (PS(glu)), forearm glucose uptake (FGU), interstitial lactate, and glycerol concentrations, was measured. When compared with Ctrl, T2D patients exhibited lower (P = 0.01) PS(glu) but similar FGU and FBF. After tadalafil, PS(glu) (P = 0.01) and muscle interstitial-arterial (I-A) lactate concentration gradient (P < 0.01) increased significantly in both groups, whereas FBF, FGU, and I-A glycerol remained unchanged. In AT, tadalafil did not significantly affect local blood flow, whereas the sc interstitial (I) lactate and I-A lactate concentrations increased (P < 0.01), and the I-A glycerol decreased in both groups. Finally, in multivariate analysis the PS(glu) was a strong and independent predictor of muscle glucose disposal (β: 0.737 and 0.963, P < 0.05, in Ctrl and T2D, respectively). Tadalafil emerges as an acutely acting modulator of microvascular recruitment and glucose metabolism in skeletal muscle and adipose tissue. We suggest that selective phosphodiesterase-5 blockade may provide a path forward to new therapeutics in the setting of insulin resistance.

Post‐conditioning with cyclosporine A fails to reduce the infarct size in an in vivo porcine model

Cyclosporine A has generated intense interest in the field of cardioprotection due to its ability to protect the mitochondria at reperfusion by blocking the opening of the mitochondrial permeability transition pore. The aim of our study was to examine the cardioprotective effect of Sandimmun, a clinically available formulation of cyclosporine A, in an in vivo large mammal model. Forty-eight pigs were randomly allocated to one of three groups: (i) Control group (Con, n=19), (ii) Cyclosporine group, (Cyclo, n=19) Sandimmun 10 mg/kg i.v. bolus 5 min before reperfusion and (iii) Pre-conditioning group (Precon, n=10) two cycles of 10 min ischemia interspersed with 30-min reperfusion. The study was further sub-divided into a metabolic protocol, evaluating myocardial metabolism by measuring changes in the interstitial lactate concentration, and a coronary flow protocol. All animals were subjected to 40 min of left anterior descending coronary artery occlusion, followed by 180 min of reperfusion before histochemical staining and assessment of infarct size by planimetry. Infarct sizes were measured as: Con 51.4 +/- 16.5%, Cyclo 47.3 +/- 15.7% and Precon 2.4 +/- 3.6%, with no significant difference between the Con and Cyclo groups but a highly significant difference between the Precon and Cyclo and Con groups (P<0.0001 for both comparisons). In the Cyclo group, the interstitial lactate concentration was significantly increased compared with the Con group at 6-min reperfusion, although significantly lower at 14 min presumably due to accelerated washout. In this large animal model, a 10 mg/kg bolus administration of Sandimmun 5 min before reperfusion did not reduce the infarct size.

Increased interstitial concentrations of pyruvate and lactate in the trapezius muscle of patients with fibromyalgia - a microdialysis study

The aim of this study was to compare the interstitial concentrations of pyruvate, lactate and glutamate in the trapezius muscle between patients with fibromyalgia syndrome and healthy controls. Comparative cross-sectional study. Patients with fibromyalgia (n = 19) and healthy controls (n = 19); all women. Subjects answered a questionnaire about different aspects of pain. Pressure pain thresholds over the trapezius and tibialis anterior muscles were determined. The inter-stitial concentrations of pyruvate, lactate and glutamate were determined in the resting trapezius muscle by the microdialysis technique, with samples collected every hour for 5 consecutive hours. Pain intensity was also rated. Significantly higher interstitial concentrations of pyruvate and lactate were found in patients with fibromyalgia- syndrome. The multivariate regression analyses of group membership and pressure pain thresholds of the trapezius confirmed the importance of pyruvate and lactate. Different mechanisms that may increase pyruvate and lactate in patients with fibromyalgia syndrome are discussed. Improved understanding of peripheral muscle alterations in patients with fibromyalgia syndrome could lead to mechanism-based rehabilitation.

Biochemical alterations in the trapezius muscle of patients with chronic whiplash associated disorders (WAD) – A microdialysis study

The mechanisms behind the development of chronic trapezius myalgia in patients with whiplash associated disorders (WAD) appear to involve both peripheral and central components, but the specific contribution of alterations in muscle is not clear. Female patients with WAD and involvement of trapezius ( N = 22) and female controls ( N = 20; CON) were studied during an experiment compromised of rest (baseline), 20 min repetitive low-force exercise and 120 min recovery. Their interstitial concentrations of serotonin (5-HT), glutamate, lactate, pyruvate, potassium, interleukin-6 (IL-6), and blood flow were determined in the trapezius muscle using a microdialysis technique. Pressure pain thresholds (PPT) over trapezius and tibialis anterior muscles were also assessed. In WAD, we found signs of generalized hypersensitivity according to PPT. The WAD group had significantly higher interstitial [IL-6] and [5-HT] in the trapezius than the CON. [Pyruvate] was overall significantly lower in WAD, and with lactate it showed another time-pattern throughout the test. In the multivariate regression analysis of pain intensity [5-HT] was the strongest regressor and positively correlated with pain intensity in WAD. In addition, blood flow, [pyruvate], and [potassium] influenced the pain intensity in a complex time dependent way. These findings may indicate that peripheral nociceptive processes are activated in WAD with generalized hypersensitivity for pressure and they are not identical with those reported in chronic work-related trapezius myalgia, which could indicate different pain mechanisms.

Transient but Profound Reduction of Bispectral Index Values After Tourniquet Deflation: Did the BIS Detect An Alteration of Brain Electrocortical Activity?

To the Editor: We (1) previously reported the occurrence of astroglial cell damage immediately after tourniquet deflation from bone cement. In a recent arthroscopic knee repair, tourniquet deflation was followed by a large, transient decrease in bispectral index (BIS), suggesting the release of circulating substances that altered the brain’s electrocortical activities. A 27-year-old softball player underwent video-assisted repair of the left anterior cruciate ligament. The surgery was aided by a pneumatic tourniquet on the proximal left thigh, inflated to a pressure of 250 mm Hg. When the tourniquet was deflated, the BIS abruptly decreased to lower values, <10, for approximately 10 min (Figs. 1a and b). Then, over the next 10 min, the BIS value gradually increased, until it returned to the previous value of approximately 60. His arterial blood pressure (110–130/70–80 mm Hg), heart rate (60–90 bpm), and pupil size (5–6 mm) were unchanged during this period. End-tidal CO2 transiently increased to 58 mm Hg upon deflation, and then returned to the baseline value of 28–35 mm Hg. Anesthetic emergence was rapid and unremarkable, with no suggestion of neurological deficit.Figure 1.: (a) BIS values plotted against time during the anesthesia. The horizontal bar denotes the duration (approximately 5 min) of low BIS values. The closed circle denotes the deflation of pneumatic tourniquet. (b) Recorded bipolar electroencephalograph (1–2 Hz) during the low BIS period. The configuration of waves does not show any apparent artifact components.Tourniquet-induced limb ischemia and exsanguination lead to production of H2O2 and free radicals (2,3). Skeletal muscle is highly vulnerable to ischemia (4). Increased pressure within an osteofascial compartment, found in both acute trauma and exercise-induced elevated compartment pressure, may result in circulatory compromise (5). Indicators of skeletal muscle ischemia, including interstitial concentrations of glucose, lactate, and hypoxanthine, increase more prominently after limb exsanguination than after circulatory occlusion alone (6). Tourniquet-induced exsanguination and ischemia during limb surgery may cause more severe ischemic changes in muscular, athletic patients than in patients of average physical condition. Glial cells and oligodendrocytes may be injured by ischemia-reperfusion events (7). These cells’ electrocortical activity is negatively correlated to the concentration of hypoxantine (8). We speculate that the transiently low BIS in this case was caused by the brain’s response to toxic substances, such as hypoxantine, produced during the tourniquet-generated exsanguination and ischemia. Manabu Shimogai, MD Hiroshi Iranami, MD Akinori Yamazaki, MD Japanese Red Cross Society of Wakayama Medical Center [email protected] Yoshio Hatano, MD Department of Anesthesiology Wakayama Medical University Wakayama City Wakayama, Japan

Lactate in rat skeletal muscle after hemorrhage measured by microdialysis probe calibrated in situ.

The interstitial lactate concentration in rat skeletal muscle was measured in the normal state and after hemorrhage using a microdialysis probe, and the values calculated by in vitro and in vivo calibration were compared. After withdrawal of 30% of the estimated total blood volume, the lactate concentration in the dialysate gradually increased and then maintained an almost constant level. It was found that interstitial lactate levels of skeletal muscle calculated by the in vitro calibration method were not significantly different from those calculated by in vivo calibration in both the normal state and after hemorrhage. These data indicate that the absolute lactate concentration in the muscle interstitium in the normal state and after acute hemorrhage can be practically measured by a microdialysis probe calibrated in vitro. From the comparison of lactate concentrations in blood and in the muscle interstitium, it was suggested that rat skeletal muscle functions as a lactate consumer, rather than as a lactate producer, after acute hemorrhage.

A single bout of exercise is followed by a prolonged decrease in the interstitial glucose concentration in skeletal muscle

The present study was performed to test the hypothesis that the interstitial glucose concentration in human skeletal muscle is decreased for a prolonged period following a single bout of exercise, while blood flow has returned to resting levels. Muscle interstitial concentrations of glucose, lactate, pyruvate and urea were monitored in six healthy individuals during 8 h following a 2-h one-leg exercise session by microdialysis at low perfusion flow rate. Simultaneously the blood flow was measured by the microdialysis ethanol technique. The blood glucose and the control leg interstitial glucose concentrations were stable during the experiment averaging 5.7 +/- 0.1 and 4.1 +/- 0.3 mm, respectively. In contrast, the interstitial glucose concentration in the exercise leg was markedly decreased, averaging 1.9 +/- 0.5 mm, during the first 5.5 h following exercise (P < 0.01), after which it returned towards normal values. Muscle blood flow at the site of the microdialysis catheter, measured as the ethanol outflow-to-inflow ratio, did not change significantly over time in the control or exercise leg and did not differ significantly between the two legs. Interstitial concentrations of lactate, pyruvate and urea were not significantly different between the control and exercise leg. The study shows that the interstitial glucose concentration in skeletal muscle is markedly decreased for several hours following a single exercise session. The decreased interstitial glucose concentration may serve to limit the rate of post-exercise muscle glucose uptake to a rate compatible with normal blood glucose levels and may also be speculated to have a positive long-term health implication by augmenting muscle insulin sensitivity.

From the Laboratory to the Bedside

From the Laboratory to the Bedside

Anaphylactic Shock

The pathophysiology of anaphylactic shock during anesthesia is incompletely characterized. It is described as distributive by analogy with septic shock (anaerobic metabolism, high tissue oxygen pressure [Ptio2] values). The Ptio2 profile and its metabolic consequences during anaphylaxis are not known. Ovalbumin-sensitized anaphylactic shock rats (n = 11) were compared to nicardipine-induced hypotension rats (n = 12) for systemic hemodynamics, Ptio2, sympathetic nervous system activation, skeletal muscle blood flow, and interstitial lactate and pyruvate concentrations using combined microdialysis and polarographic Clark-type oxygen probes. In both groups, the time course and the magnitude of arterial hypotension were similar. The ovalbumin group but not the nicardipine group displayed decreased skeletal muscle blood flow (from 45 +/- 6.2 ml x 100 g(-1) x min(-1) to 24.3 +/- 5 ml x 100 g(-1) x min(-1); P < 0.0001) and Ptio2 values (from 42 +/- 5 to 5 +/- 2; P < 0.0001). The ovalbumin group had more intense sympathetic nervous system activation with higher plasma epinephrine and interstitial norepinephrine concentrations. For the ovalbumin group, there was skeletal muscle anaerobic metabolism (lactate concentration increased from 0.446 +/- 0.105 to 1.741 +/- 0.459 mm; P < 0.05) and substrate depletion (pyruvate concentration decreased from 0.034 +/- 0.01 mm to 0.006 +/- 0.002 mm; P < 0.05) leading to increased interstitial lactate/pyruvate ratios (from 17 +/- 6 to 311 +/- 115; P < 0.05). This profile suggests decreased skeletal muscle blood flow and oxygen delivery. Persistent energy consumption results in decreased Ptio2 and substrate depletion through anaerobic glycolysis leading to complete failure of cellular energy production. This could explain rapid organ dysfunction and resuscitation difficulties.

Transmural Differences in Myocardial Function and Metabolism During Direct Left Ventricular to Coronary Artery Sourcing

We investigated the hypothesis that in the absence of collateral circulation, a left ventricle-coronary artery (LV-CA) bypass will maintain normal LV wall function and metabolism transmurally, both at rest and during stress, when the left anterior descending coronary artery (LAD) is acutely occluded proximally. In 18 anesthetized pigs (74 +/- 7 kg, mean +/- standard deviation), a covered stent was placed transmurally in the lateral wall of the beating LV and connected to the proximal LAD via an arterial graft. Subepicardial and subendocardial segmental shortening as well as interstitial lactate and glucose concentrations were measured regionally by sonomicrometry and microdialysis, respectively. When the LAD was occluded proximally, direct left ventricular sourcing decreased the net LAD flow to 64 +/- 25% of the native flow (n = 18, all animals). In the subepicardium, systolic shortening (SS) decreased to 87 +/- 18% of baseline (p = 0.124), with the appearance of minor postsystolic shortening (PSS), and minor changes in interstitial lactate and glucose levels. In the subendocardium, in contrast, SS decreased to 54 +/- 20% (p = 0.001). Marked PSS concurred with a sixfold increase in lactate (p = 0.008), and a 65 +/- 31% decrease in glucose (p = 0.003), indicating subendocardial anaerobic metabolism. Stress induced by infusion of dobutamine increased lactate and decreased glucose concentration in the subepicardium to subendocardial levels, indicating transmural anaerobic metabolism. In the anesthetized pig, direct sourcing by a LV-CA bypass distal to an acute coronary occlusion resulted in a 36% decrease in net forward coronary flow, subendocardial anaerobic metabolism, and loss of subendocardial contractile function at rest. These adverse effects extended into the subepicardium when the heart was stressed.

Local effect of vanadate on interstitial glucose and lactate concentrations in human skeletal muscle

The aim of this study was to investigate the local effect of the insulin-mimetic agent vanadate on glucose metabolism in human skeletal muscle in vivo. Interstitial concentrations of glucose and lactate were determined by microdialysis at a low flow rate in the quadriceps femoris muscle of 18 men. In the same leg two microdialysis catheters were inserted. In one catheter, the perfusion medium was supplemented with sodium metavanadate (10–100 mM) after a basal period, the other catheter served as control. In the catheter perfused with metavanadate, the interstitial glucose concentration was decreased by 13–50% compared to the control catheter (p < 0.05). The lactate concentration was higher in the 50 mM and 100 mM metavanadate catheters compared to control (39–89%, p < 0.05). There was no difference between control and metavanadate catheters in urea concentrations. Five of the subjects were insulin-resistant and for them the results were similar, although the effect was somewhat smaller. The decreased interstitial glucose concentration, and the increased lactate concentration, in the vicinity of the microdialysis catheter most likely reflects an increased cellular glucose uptake. The present study thus indicates that vanadate mimics the effect of insulin in human skeletal muscle in vivo.