Neonatal de-afferentation of capsaicin-sensitive sensory nerves increases in vivo insulin sensitivity in conscious adult rats

Sensory neuropeptides, released from the peripheral nervous system, might modulate glucose homeostasis by antagonizing insulin action. The effects of de-afferentation of functional small diameter unmyelinated C-fibres (sensory nerves) on in vivo insulin-mediated intracellular glucose metabolism were investigated by using euglycaemic insulin (6 and 18 mU/kg x min) clamps with [3-(3)H]-glucose infusion in 24 adult rats, treated neonatally with either capsaicin (CAP) (50 mg/kg) or vehicle (CON). Following the clamp, skeletal muscle groups, liver and adipose tissue were freeze-clamped. At plasma insulin levels of approximately 90 mU/l, CAP-rats showed a 21% increase in whole body glucose uptake compared with CON (24.4 +/- 1.6 vs 20.1 +/- 0.8 mg/kg min, p < 0.02), which was paralleled by a 20% increase in whole body glycolysis (12.6 +/- 0.8 vs 10.5 +/- 0.5 mg/ kg.min p < 0.05) (concentration of 3H2O in plasma). Whole body skeletal muscle glycogenesis was increased by 80% in CAP-rats (5.7 +/- 0.7 vs 3.1 +/- 0.7 mg/kg x min, p < 0.05) with increased muscle glycogen synthase activity. Whole body (muscle, liver and adipose tissue combined) de novo lipogenesis also was increased in CAP-rats compared with CON (0.69 +/- 0.10 vs 0.44 +/- 0.06 mg/kg x min, p < 0.05) (incorporation of [3-(3)H]-glucose counts into glycogen or fat). Hepatic glucose production was lower in CAP-rats compared with CON (0.6 +/- 0.6 vs 2.1 +/- 0.7 mg/kg x min, p < 0.05). Plasma glucagon, corticosterone, epinephrine and norepinephrine levels were reduced in CAP-rats: 43 +/- 2 compared with 70 +/- 6 pg/ml, 855 +/- 55 compared with 1131 +/- 138 nmol/l, 513 +/- 136 compared with 1048 +/- 164 pmol/l and 928 +/- 142 compared with 1472 +/- 331 pmol/l, respectively, p < 0.05. At plasma insulin levels of approximately 400 mU/l, CAP-rats showed no differences in peripheral and hepatic insulin action compared with CON. We conclude that the removal of endogenous sensory neuropeptides, by de-afferentation of capsaicin-sensitive sensory nerves, increases in vivo insulin sensitivity, but not responsiveness: 1) primarily through an increased sensitivity of skeletal muscle glycogen synthesis to insulin; 2) through a reduction in the levels of counter-regulatory hormones, thereby creating a milieu which favours overall in vivo insulin sensitivity with respect to glucose uptake, glucose production, glycolysis, glycogenesis and lipogenesis.     

Effect of diabetes, insulin, and glucose load on lipid peroxidation in the rat

Lipid peroxidative activity in rats made diabetic with streptozocin and rats made acutely hyperglycemic by intraperitoneal dextrose administration was determined by measurement of exhaled ethane during exposure in vivo to ethane-free air (EFA). Diabetic rats demonstrated increased ethane in the expired breath while breathing EFA (5.82 +/- 0.56 pmol/min/100 g) compared with control rats (4.02 +/- 0.23 pmol/min/100 g). Insulin treatment of diabetic rats attenuated the ethane produced (4.88 +/- 0.23 pmol/min/100 g). Acute hyperglycemia increased exhaled ethane to levels higher than those seen in diabetic rats (9.87 +/- 0.98 pmol/min/100 g). Saline injected intraperitoneally to control rats produced ethane levels similar to those of untreated nondiabetic controls (4.11 +/- 0.52 pmol/min/100 g). Chronic uncontrolled hyperglycemia and acute hyperglycemia are associated with increased in vivo ethane production.     

Exhaled nitric oxide (NO) is reduced shortly after bronchoconstriction to direct and indirect stimuli in asthma

Exhaled NO is increased in patients with asthma and may reflect disease severity. We examined whether the level of exhaled NO is related to the degree of airway obstruction induced by direct and indirect stimuli in asthma. Therefore, we measured exhaled NO levels before and during recovery from histamine and hypertonic saline (HS) challenge (Protocol 1) or histamine, adenosine 5'-monophosphate (AMP), and isotonic saline (IS) challenge (Protocol 2) in 11 and in nine patients with mild to moderate asthma, respectively. The challenges were randomized with a 2-d interval. Exhaled NO and FEV1 were measured before and at 4, 10, 20, and 30 min after each challenge. NO was measured during a slow VC maneuver with a constant expiratory flow of (0.05 x FVC)/s against a resistance of 1 to 2 cm H2O. Baseline exhaled NO levels were not significantly different between study days in Protocol 1 (mean +/- SD: 4.8 +/- 1.8 ppb [histamine] versus 5.4 +/- 2.1 ppb [HS], p = 0.4) or in Protocol 2 (7.9 +/- 4.7 ppb [histamine], 8.3 +/- 5.2 ppb [AMP], and 7.2 +/- 3.7 ppb [IS], p = 0.7). A significant reduction in exhaled NO was observed directly after HS (mean +/- SEM: 39.2 +/- 3.9 %fall) and AMP challenge (32.3 +/- 7.3 %fall) (MANOVA, p < 0.001), respectively, whereas exhaled NO levels tended to decrease after histamine challenge. Isotonic saline challenge did not induce changes in exhaled NO (p = 0.7). There was a positive correlation between %fall in FEV1 and the %fall in exhaled NO after histamine, HS, and AMP challenge as indicated by the mean slope of the within-subject regression lines (p <= 0.04). We conclude that acute bronchoconstriction, as induced by direct and indirect stimuli, is associated with a reduction in exhaled NO levels in asthmatic subjects. This suggests that airway caliber should be taken into account when monitoring exhaled NO in asthma.     

Effects of various flow types on maternal hemodynamics during fetal bypass: is there nitric oxide release during pulsatile perfusion?

OBJECTIVE: This study investigates the role of various flow conditions on maternal hemodynamics during fetal cardiopulmonary bypass. METHODS: Normothermic fetal bypass was conducted under pulsatile, or steady flow, for a 60-minute period. Fetal lamb preparations were randomly assigned to 1 of the 3 groups: steady flow (n=7), pulsatile flow (n=7), or pulsatile blocked flow bypass (n=7), where fetuses were perfused with Nomega-nitro-L-arginine after the first 30 minutes of pulsatile flow to assess the potential role of endothelial autacoids. RESULTS: Maternal oximetry and pressures remained unchanged throughout the procedure. Under fetal pulsatile flow, maternal cardiac output increased after 20 minutes of bypass and remained significantly higher than under steady flow at minute 30 (8.8+/-0.7 L x min(-1) vs 5.9+/-0.5 L x min(-1), P=.02). Maternal cardiac output in the pulsatile group also remained higher than in both steady and pulsatile blocked flow groups, reaching respectively 8.7+/-0.9 L x min(-1) vs 5.8+/-0.4 L x min(-1) (P=.02) and 5.9+/-0.3 L min(-1) (P=.01) at minute 60. Maternal systemic vascular resistances were significantly lower under pulsatile than under steady flow after 30 minutes and until the end of bypass (respectively, 9.1+/-0.6 IU vs 12.7+/-1.1 IU, P=.02 and 8.9+/-0.5 IU vs 12.9+/-1.2 IU, P=.01). Infusion of Nomega-nitro-L-arginine was followed by an increase in systemic vascular resistances from 9.3+/-0.7 IU, similar to that of the pulsatile group, to 13.5+/-1 IU at 60 minutes, similar to that of the steady flow group. CONCLUSIONS: Maternal hemodynamic changes observed under fetal pulsatile flow are counteracted after infusion of Nomega-nitro-L-arginine, suggesting nitric oxide release from the fetoplacental unit under pulsatile fetal flow conditions.     

Peri-operative benefits of beating-heart coronary revascularization in patients with triple vessel disease

OBJECTIVES: To compare the perioperative benefits of the offpump coronary artery surgery to conventional surgery with cardiopulmonary bypass (CPB) assistance. METHOD: Retrospective study comparing 50 consecutive patients with triple vessel disease (TVD) operated upon with CPB assistance to 50 consecutive patients with TVD operated on beating heart (BH) by the same surgeon between January 1996 and August 1997 at the Montreal Heart Institute. Matching criteria between the 2 groups were: first time operation, normal left ventricular ejection function (LVEF), and coronary TVD. RESULTS: Demographic data and risk factors were comparable in both groups. Unstable angina was the most common surgical indication (CBP: 72%, BH: 62%). The average number of grafts were comparable in both groups (CBP: 3.5 vs 0.6 vs BH: 3.3 +/- 0.4, p = 0.06) as well as the preoperative LVEF (CEC: 60 +/- 1% vs CB: 62 +/- 1.2%, p = 0.38). Arterial lactate count was lower in the BH group during the perioperative period (3.0 +/- 1.0 vs 3.9 +/- 1.7 mM) as well as the maximal CK-MB level (BH: 20 +/- 6.4 vs CBP: 40 +/- 3.5 IU/L, p = 0.003), transfusional needs (CB: 34% vs CEC: 66%, p = 0.003), and postoperative creatinin level (BH: 100 +/- 4.2 vs CBP: 120 +/- 7.1 mM, p = 0.001). Postoperative HB level was also higher in the BH group (110 +/- 14 vs 104 +/- 12, p = 0.001). CONCLUSION: Our data confirm potential benefits from BH surgery on patients affected with triple vessel disease relatively to transfusional needs, and myocardial as well as renal protection.     

Increased portal endothelin-1 level is associated with the liver function after cardiopulmonary bypass in rabbits: influence of hypothermia on the damage

The purpose of this study was to prove the hypothesis that ET-1 production is increased in the splanchnic-hepato circulation during cardiopulmonary bypass (CPB) with or without hypothermia and this greatly affects hepatocellular function after surgery. Twelve Japanese white rabbits were used. In group I (n = 6), the rectal temperature was kept at 37.0 degrees C during CPB (90 min). In group II (n = 6), the rectal temperature was lowered to 26 degrees C during the first 30 minutes and then increased to 37 degrees C for the following 60 minutes. In group I, surface liver tissue blood flow (LBF) remained stable during CPB. While, in group II, LBF was significantly reduced to 66.9% of baseline values during hypothermic CPB, but it increased during the rewarming phase to 84.3% of the baseline value (p = 0.0070). At the end of CPB, portal ET-1 levels were increased in both groups, but they were significantly higher in group II (7.32 +/- 0.50 pg/ml and 9.29 +/- 0.61 pg/ml, respectively). Serum GOT, GPT, LDH and arterial ammonia levels were also higher in group II. Portal ET-1 levels had a significant positive correlation with those liver enzymes. Histopathological examination after CPB showed severe damage of the hepatic parenchyma in zone 3 associated with microvesicular fatty infiltration in group II.     

Application of a new method for analysis of exhaled gas in critically ill patients

OBJECTIVE: Application of a new method for analysis of exhaled gas in critically ill patients. DESIGN: Open study. SETTING: Surgical intensive care unit of an university hospital. PATIENTS: Thirty-seven consecutive, critically ill, mechanically ventilated patients. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Chemical analysis of the patient's exhaled gas was based upon substance adsorption and concentration onto activated charcoal, microwave desorption and gas chromatographic separation. Patients with acute respiratory distress syndrome (ARDS) exhaled less isoprene than those without ARDS [9.8 (8.2-21.6) vs 21.8 (13.9-41.4) nmol/m2 per min [median (95% confidence interval)], p = 0.04]. In patients who developed pulmonary infection, pentane elimination increased from 0.4 (0.0-5.4) to 2.7 (0.6-6.1, p = 0.05) nmol/m2 per min and isoprene elimination decreased from 5.2 (0-33) to 5.0 (0-17, p = 0.05) nmol/m2 per min, resulting in a significant increase in pentane/isoprene ratio from 0.1 (0-0.3) to 0.4 (0-15, p = 0.007) when compared to patients without pulmonary infection. CONCLUSIONS: The new method allows quantitative analysis of human gas samples with low substance concentrations and is well suited for clinical studies which involve the investigation of metabolic processes in the lung and the body.     

Hypothermic modulation of cerebral ischemic injury during cardiopulmonary bypass in pigs

BACKGROUND: The aim of this study was to determine whether progressive levels of hypothermia (37, 34, 31, or 28 degrees C) during cardiopulmonary bypass (CPB) in pigs reduce the physiologic and metabolic consequences of global cerebral ischemia. METHODS: Sagittal sinus and cortical microdialysis catheters were inserted into anesthetized pigs. Animals were placed on CPB and randomly assigned to 37 degrees C (n = 10), 34 degrees C (n = 10), 31 degrees C (n = 11), or 28 degrees C (n = 10) management. Next 20 min of global cerebral ischemia was produced by temporarily ligating the innominate and left subclavian arteries, followed by reperfusion, rewarming, and termination of CPB. Cerebral oxygen metabolism (CMRO2) was calculated by cerebral blood flow (radioactive microspheres) and arteriovenous oxygen content gradient. Cortical excitatory amino acids (EAA) by microdialysis were measured using high-performance liquid chromatography. Electroencephalographic (EEG) signals were graded by observers blinded to the protocol. After CPB, cerebrospinal fluid was sampled to test for S-100 protein and the cerebral cortex was biopsied. RESULTS: Cerebral oxygen metabolism increased after rewarming from 28 degrees C, 31 degrees C, and 34 degrees C CPB but not in the 37 degrees animals; CMRO2 remained lower with 37 degrees C (1.8 +/- 0.2 ml x min[-1] x 100 g[-1]) than with 28 degrees C (3.1 +/- 0.1 ml x min[-1] x 100 g[-1]; P < 0.05). The EEG scores after CPB were depressed in all groups and remained significantly lower in the 37 degrees C animals. With 28 degrees C and 31 degrees C CPB, EAA concentrations did not change. In contrast, glutamate increased by sixfold during ischemia at 37 degrees C and remained significantly greater during reperfusion in the 34 degrees C and 37 degrees C groups. Cortical biopsy specimens showed no intergroup differences in energy metabolites except two to three times greater brain lactate in the 37 degrees C animals. S-100 protein in cerebrospinal fluid was greater in the 37 degrees C (6 +/- 0.9 microg/l) and 34 degrees C (3.5 +/- 0.5 microg/l) groups than the 31 degrees C (1.9 +/- 0.1 microg/l) and 28 degrees C (1.7 +/- 0.2 microg/l) animals. CONCLUSIONS: Hypothermia to 28 degrees C and 31 degrees C provides significant cerebral recovery from 20 min of global ischemia during CPB in terms of EAA release, EEG and cerebral metabolic recovery, and S-100 protein release without greater advantage from cooling to 28 degrees C compared with 31 degrees C. In contrast, ischemia during 34 degrees C and particularly 37 degrees C CPB showed greater EAA release and evidence of neurologic morbidity. Cooling to 31 degrees C was necessary to improve acute recovery during global cerebral ischemia on CPB.     

Attenuation of neutrophil and endothelial activation by intravenous morphine in patients with acute myocardial infarction

To investigate the effects of morphine on neutrophil and endothelial activation, we measured serum levels of intercellular adhesion molecule-1 (ICAM-1), L-selectin, and neutrophil endopeptidase 24.11 (NEP) in 38 patients with acute myocardial infarction (group 1) and 16 control subjects (group 2). In group 1, all the patients underwent blood sampling at initial presentation and 10 minutes later. Twenty of them had 3 mg of morphine administered intravenously immediately after the first sampling (group 1A) and the other 18 after a second sampling (group 1B). The serum levels of ICAM-1 and L-selectin were both significantly higher in groups 1A and 1B than in group 2. In group 1A, the ICAM-1 decreased significantly at second blood samplings (310 +/- 28 vs 368 +/- 30 ng/ml; p <0.001), whereas in group 1B there was no significant change in ICAM-1 (357 +/- 33 vs 359 +/- 26 ng/ml; p = NS). In group 1A, the L-selectin decreased significantly at second blood samplings (2.3 +/- 1.2 mg/L, p <0.001 vs baseline), whereas in group 1B there was no significant change in L-selectin (3.9 +/- 1.0 mg/L, p = NS vs baseline). There was no significant difference in baseline NEP activities between groups 1A and 1B (4.89 +/- 1.22 vs 5.14 +/- 1.57 nmol/mg protein; p = NS). However, the NEP activities at second blood samplings decreased significantly in group 1A (9.88 +/- 1.86 nmol/mg protein, p <0.001 vs baseline), whereas no significant changes were observed in group 1B (5.09 +/- 1.62 nmol/mg protein, p = NS vs baseline). In conclusion, morphine increased NEP activities and thus attenuated shedding of L-selectin and ICAM-1.     

Autoantibodies to tissue transglutaminase as predictors of celiac disease

Our aim was to study the prognostic value of growth hormone (GH) -stimulated insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) generation in patients with compensated [group 1 (N = 8) with a Child-Pugh (CP) score of 5-8] and decompensated postnecrotic liver cirrhosis [group 2 (N = 7) with a CP score of 9-12]. Serum levels of IGF-I, GH-binding protein (GHBP), and IGFBP-3 were measured before and 24 hr after a single subcutaneous injection of recombinant human GH (rhGH, 0.14 units/kg). Patients (mean age 56 years) were followed prospectively for three years. Six patients (40%) died during the follow-up period, of whom half had a CP score <9. Mean serum IGF-I levels 24 hr after rhGH injection (group 1 vs group 2, 17.4 +/- 6.8 vs 7.4 +/- 0.7 nmol/liter) predicted survival with 93% accuracy. Levels <10 nmol/liter portended a poor prognosis, with 15% survival at one year, whereas levels >10 nmol/liter had a 100% survival rate at one and two years, respectively. Baseline IGF-I (9.98 +/- 2.0 vs 6.38 +/- 0.8 nmol/liter), GHBP (9.2 +/- 3 vs 5.7 +/- 0.8%/50 microl), and IGFBP-3 serum levels at baseline (1.7 +/- 0.3 vs 0.86 +/- 0.2 mg/liter) and at 24 hr (2.04 +/- 0.38 vs 0.99 +/- 0.3 mg/liter) did not add to the predictive value of stimulated IGF-I levels at 24 hr and were less accurate in predicting the outcome in comparison to CP score (80%). We conclude that stimulated IGF-1 <10 nmol/liter may be a true predictor of a negative prognosis in patients with liver cirrhosis.     

Human isosporiasis in an AIDS patient--report of first case in Malaysia

Splanchnic and systemic hemodynamics and plasma levels of aldosterone, glucagon and plasma renin were investigated in 12 patients with advanced cirrhosis before and 2 wk (14.6 +/- 2.8 days) and 2 mo (60.8 +/- 10.5 days) after orthotopic liver transplantation. Liver transplant was followed by significant (p < 0.01) changes in systemic hemodynamics at 2 wk, with a marked reduction in cardiac index (4.9 +/- 0.8 vs. 3.7 +/- 0.7 L/min.m2) and increases in mean arterial pressure (79 +/- 8 vs. 101 +/- 11 mm Hg) and peripheral vascular resistance (721 +/- 149 vs. 1,274 +/- 253 dyn.sec.cm-5). Two months after liver transplant, we saw further significant increases in peripheral vascular resistance (1,700 +/- 341 dyn.sec.cm-5; p < 0.05) without changes in cardiac index. Hepatic venous pressure gradient, very high before transplantation, was normal 2 wk after liver transplant (18.7 +/- 3.0 vs. 2.1 +/- 0.8 mm Hg; p < 0.01). Hepatic blood flow rose markedly from 1.03 +/- 0.46 to 2.25 +/- 0.79 L/min (p < 0.01) and was still elevated at 2 mo (1.84 +/- 0.74 L/min). Azygos blood flow had not changed after 2 wk with respect to pretransplant values (0.65 +/- 0.26 vs. 0.69 +/- 0.39 L/min) but had decreased significantly at 2 mo (0.39 +/- 0.16 L/min; p < 0.05). The elevated aldosterone, plasma renin and glucagon levels found in our cirrhotic patients before transplantation decreased to near-normal values 2 wk after the procedure. These results suggest that most of the hemodynamic and humoral abnormalities characteristic of advanced cirrhosis are reversed after liver transplant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanism of the diabetogenic action of cyclosporin A

To investigate the mechanism of diabetogenic action of cyclosporin A (CsA), 7 male Wistar albino rats received 10 mg/kg/day of the drug for 4 weeks (CsA). The results were compared with controls (C); blood CsA levels measured weekly remained stable throughout the experiment (mean +/- SEM) (X = 2657.9+/-155.1 ng/ml). Intravenous glucose load (0.75 g/kg) performed after 2 weeks of CsA therapy showed glucose intolerance in treated animals as evaluated by the glucose area under the curve (CsA = 409.2+/-17.8 vs. C = 313.3+/-12.6 umol x ml(-1) x min(-1)) (p < 0.05) with insulin levels being similar in the two groups (CsA = 8603.9+/-1645.5 vs. C = 9571.9+/-828.5 pmol x ml(-1) x min(-1)). After 4 weeks of CsA administration, glucose intolerance was maintained (CsA = 398.6+/-35.6 vs. C = 301.7+/-23.0 umol x ml(-1) x min(-1)) (p < 0.05) associated with a significant decrease in insulin secretion (CsA = 4404.9+/-2392.0 vs. C = 10075.9+/-2861.0 pmol x ml(-1) x min(-1) (p < 0.05). These results suggest that CsA induced a state of insulin resistance preceding the failure of insulin secretion. After 4 weeks, the pancreatic insulin content was also decreased (CsA = 0.7+/-0.1 vs. C = 1.4+/-0.5 mU/mg) (p < 0.05). Maximal insulin binding to isolated adipocytes was not affected by CsA (CsA = 7.4+/-2.6 vs. C = 6.4+/-2.0%), although glucose transport and oxidation decreased after CsA treatment (p < 0.05). In conclusion, glucose intolerance induced by CsA in Wistar albino rats is due to decreased insulin production and impaired insulin action by a post-binding mechanism.     

Redefining cardiovascular performance during resuscitation: ventricular stroke work, power, and the pressure-volume diagram

OBJECTIVES: (1) To compare left ventricular stroke work index (SW) and left ventricular power output (LVP), hemodynamic variables that encompass blood pressure as well as blood flow, with the purely flow-derived hemodynamic and oxygen transport variables as markers of perfusion and outcome in critically injured patients during resuscitation. (2) To use the ventricular pressure-volume diagram to define characteristic hemodynamic patterns in the determinants of SW and LVP that are associated with survival. METHODS: This was a cohort study at a university Level I trauma center during the course of 1 year. A consecutive series of patients was monitored with a volumetric pulmonary artery catheter during the initial 48 hours of resuscitation. Heart rate, SW, LVP, cardiac index, and oxygen delivery and consumption during resuscitation were compared using multivariate logistic regression analysis with regard to the ability to clear lactate in less than 24 hours and survival. Receiver operating characteristic curves were constructed to determine threshold values for SW and LVP. Ventricular pressure-volume diagrams were used to describe characteristic patterns in the determinants of SW and LVP in survivors and nonsurvivors. Preload was expressed as left ventricular end-diastolic volume index, afterload as aortic input impedance (Ea), and contractility as ventricular end-systolic elastance (Ees). The ratio of Ea/Ees (RATIO) was used as a measure of ventricular-arterial coupling, which describes the efficacy of energy transfer from the heart to the vascular system. RESULTS: One hundred eleven patients (87 survivors, 24 nonsurvivors) met study criteria. Survivors had a significantly higher SW (4,510 +/- 1,070 vs. 3,440 +/- 980 mm Hg x mL x m(-2); p < 0.0001) and LVP (370 +/- 94 vs. 270 +/- 81 mm Hg x L x min(-2) x m(-2); p < 0.0001) than nonsurvivors. Heart rate, SW, and LVP were the only studied variables that were significantly related to lactate clearance and survival by logistic regression. Threshold values determined by the receiver operating characteristic curves were 4,000 mm Hg x mL x m(-2) for SW and 320 mm Hg x L x min(-1) x m(-2) for LVP. Survivors had better ventricular-arterial coupling than nonsurvivors, indicated by a lower RATIO (0.32 +/- 0.22 vs. 0.54 +/- 0.38; p = 0.003). This lower RATIO was attributable to lower levels of Ea (2.7 +/- 0.7 vs. 3.4 +/- 0.8 mm Hg x mL(-1) x m(-2); p = 0.0003) and a trend toward higher levels of Ees (13 +/- 11 vs. 9.9 +/- 7.3 mm Hg x mL(-1) x m(-2); p = 0.12). CONCLUSION: Thermodynamic perfusion variables that encompass both pressure and flow, such as SW and LVP, are more closely related to perfusion and outcome than the purely flow-derived variables. The higher SW and LVP in survivors is related to better ventricular-arterial coupling, and therefore more efficient cardiac function. Cutoff values for LVP of 320 mm Hg x L x min(-1) x m(-2) and for SW of 4,000 mm Hg x mL x m(-2) may be useful thresholds for evaluating hemodynamic performance during resuscitation.     

Cardiovascular and metabolic responses to adrenaline infusion in patients with short-term hypothyroidism

OBJECTIVE: The relation between the clinical manifestations of thyroid disease (both hypo and hyper-thyroidism) and tissue sensitivity to catecholamines remains uncertain. It has been suggested that tissue adrenergic responsiveness is decreased in hypothyroidism, but the reports have been conflicting and have invariably focused on a single physiological response. Therefore the aim of the present study was to determine in patients with moderate, short-term, symptomatic hypothyroidism the responses of heart rate, systolic and diastolic blood pressure, forearm blood flow and metabolic rate to adrenaline infused at a rate known to achieve plasma concentrations in the middle of the physiological range. PATIENTS: Ten subjects (5M, age 43 +/- 3 years, mean +/- SEM) were studied. All were on thyroxine replacement for hypothyroidism following either thyroidectomy or radioactive iodine and had been biochemically euthyroid for at least 6 months. DESIGN: Studies were performed in random order. One study was undertaken on full replacement therapy and the other after 50 micrograms thyroxine daily for 2 weeks. After basal, supine measurements adrenaline was infused at 25 ng/kg/min for 30 minutes. MEASUREMENTS: Heart rate, blood pressure, blood glucose, metabolic rate and forearm blood flow were measured at rest and at 10-minute intervals throughout the adrenaline infusion. RESULTS: Free T4 (10.6 +/- 1.3 vs 17.6 +/- 2.0 pmol/l, P < 0.001) and free T3 (3.6 +/- 0.2 vs 4.6 +/- 0.3 pmol/l, P < 0.01) concentrations were significantly lower on 50 micrograms thyroxine than full replacement therapy. Fasting blood glucose concentrations (4.7 +/- 0.2 vs 4.7 +/- 0.1 mmol/l) were similar. The resting adrenaline concentrations were comparable, 0.29 +/- 0.18 and 0.24 +/- 0.14 nmol/l on 50 micrograms thyroxine and full replacement therapy respectively, and increased to a similar level (2.36 +/- 0.39 and 2.36 +/- 0.35 nmol/l) throughout the adrenaline infusion. The resting heart rate and metabolic rate were significantly lower on 50 micrograms thyroxine than full replacement therapy (68 +/- 2 vs 72 +/- 3 beats/min, P < 0.01; and 4.48 +/- 0.35 vs 4.88 +/- 0.39 kJ/min, P < 0.01) respectively, but the increase in heart rate (7 +/- 2 vs 8 +/- 2 beats/min) and metabolic rate (0.43 +/- 0.09 vs 0.43 +/- 0.06 kJ/min) did not differ on the two study days. Resting systolic blood pressure, diastolic blood pressure and forearm blood flow were comparable on 50 micrograms thyroxine and full replacement therapy as were the changes in systolic blood pressure (1 +/- 1 vs 1 +/- 1 mmHg), diastolic blood pressure (-7 +/- 2 vs -7 +/- 1 mmHg), forearm blood flow (1.4 +/- 0.1 vs 1.7 +/- 0.2 ml/min/100ml forearm) and blood glucose concentration (0.7 +/- 0.1 vs 0.7 +/- 0.1 mmol/l). CONCLUSIONS: Patients with short-term hypothyroidism appear to have a normal response to adrenaline infusion despite reduced baseline heart rate and metabolic rate. Thus, under physiological and mild pathophysiological conditions there appears to be no evidence of any synergy between thyroid status and sensitivity to catecholamines.     

Inflammatory reaction and capillary leak syndrome related to cardiopulmonary bypass in neonates undergoing cardiac operations

We studied the inflammatory reaction related to cardiopulmonary bypass in 24 neonates (median age 6 days) undergoing the arterial switch operation for simple transposition of the great arteries, with respect to the development of postoperative capillary leak syndrome. Complement proteins, leukocyte count, tumor necrosis factor-alpha, and histamine levels were determined before, during, and after cardiopulmonary bypass. Additionally, protein movement from the intravascular into the extravascular space during cardiopulmonary bypass was assessed by the measurement of plasma concentrations of proteins with molecular weights ranging from 21,200 to 718,000. Capillary leak syndrome developed in 13 of the 24 neonates. Patients with capillary leak syndrome, as compared with those without, had preoperatively higher C5a levels (C5a, 3.0 +/- 0.6 microgram/L vs 0.9 +/- 0.2 microgram/L) (mean +/- standard error of the mean) (p < 0.05) and higher leukocyte counts (leukocytes, 17.9 +/- 2.1 X 10(3) cells/ml versus 11.7 +/- 0.8 X 10(3) cells/ml) (p < 0.05), suggesting in these neonates a preoperative inflammatory state. Preoperative clinical and operative data were identical in both patient groups. Before cardiopulmonary bypass, serum protein concentrations were similar in all patients. Ten minutes after institution of cardiopulmonary bypass, protein concentrations fell to significantly lower values in patients with capillary leak syndrome than in those without: albumin (19% +/- 1.5% vs 30% +/- 6% of the prebypass value, p < 0.05), immunoglobulin G (17% +/- 1.5% vs 29% +/- 5.5%, p < 0.001), and alpha 2-macroglobulin (15% +/- 1.2% vs 25% +/- 4%, p < 0.02). During cardiopulmonary bypass, albumin concentrations remained significantly lower in patients with capillary leak syndrome than in those without, whereas hematocrit values were similar in both groups. During cardiopulmonary bypass, patients with capillary leak syndrome also had lower concentrations of complement proteins C3 and C4 but not C1 inhibitor. C3d/C3 ratio and C5a levels were similar in both patient groups. In contrast, histamine liberation during cardiopulmonary bypass was significantly more pronounced in patients with capillary leak syndrome than in those without (725.2 +/- 396.7 pg/ml vs -54.1 +/- 58.4 pg/ml, p < 0.05). Tumor necrosis factor-alpha levels after protamine administration were also significantly higher in patients with capillary leak syndrome (38.1 +/- 10.0 pg/ml vs 15.3 +/- 3.4 pg/ml, p < 0.05). Leukocyte count during and after cardiopulmonary bypass was similar in both patient groups. This study demonstrates increased protein leakage as early as 10 minutes after initiation of.     

Assessment of insulin sensitivity and secretion with the labelled intravenous glucose tolerance test: improved modelling analysis

A new modelling analysis was developed to assess insulin sensitivity with a tracer-modified intravenous glucose tolerance test (IVGTT). IVGTTs were performed in 5 normal (NGT) and 7 non-insulin-dependent diabetic (NIDDM) subjects. A 300 mg/kg glucose bolus containing [6,6-(2)H2]glucose was given at time 0. After 20 min, insulin was infused for 5 min (NGT, 0.03; NIDDM, 0.05 U/kg). Concentrations of tracer, glucose, insulin and C-peptide were measured for 240 min. A circulatory model for glucose kinetics was used. Glucose clearance was assumed to depend linearly on plasma insulin concentration delayed. Model parameters were: basal glucose clearance (Cl(b)), glucose clearance at 600 pmol/l insulin concentration (Cl600), basal glucose production (Pb), basal insulin sensitivity index (BSI = Cl(b)/basal insulin concentration); incremental insulin sensitivity index (ISI = slope of the relationship between insulin concentration and glucose clearance). Insulin secretion was calculated by deconvolution of C-peptide data. Indices of basal pancreatic sensitivity (PSIb) and first (PSI1) and second-phase (PSI2) sensitivity were calculated by normalizing insulin secretion to the prevailing glucose levels. Diabetic subjects were found to be insulin resistant (BSI: 2.3 +/- 0.6 vs 0.76 +/- 0.18 ml x min(-1) x m(-2) x pmol/l(-1), p < 0.02; ISI: 0.40 +/- 0.06 vs 0.13 +/- 0.05 ml x min(-1) x m(-2) x pmol/l(-1), p < 0.02; Cl600: 333 +/- 47 vs 137 +/- 26 ml x min(-1) x m(-2), p < 0.01; NGT vs NIDDM). Pb was not elevated in NIDDM (588 +/- 169 vs 606 +/- 123 micromol x min(-1) x m(-2), NGT vs NIDDM). Hepatic insulin resistance was however present as basal glucose and insulin were higher. PSI1 was impaired in NIDDM (67 +/- 15 vs 12 +/- 7 pmol x min x m(-2) x mmol/l(-1), p < 0.02; NGT vs NIDDM). In NGT and in a subset of NIDDM subjects (n = 4), PSIb was inversely correlated with BSI (r = 0.95, p < 0.0001, log transformation). This suggests the existence of a compensatory mechanism that increases pancreatic sensitivity in the presence of insulin resistance, which is normal in some NIDDM subjects and impaired in others. In conclusion, using a simple test the present analysis provides a rich set of parameters characterizing glucose metabolism and insulin secretion, agrees with the literature, and provides some new information on the relationship between insulin sensitivity and secretion.     

Renal lactate metabolism and gluconeogenesis during insulin-induced hypoglycemia

The contribution of gluconeogenic precursors to renal glucose production (RGP) during insulin-induced hypoglycemia was assessed in conscious dogs. Ten days after surgical placement of sampling catheters in the right and left renal veins and femoral artery and an infusion catheter in the left renal artery, systemic and renal glucose and glycerol kinetics were measured with peripheral infusions of [6-3H]glucose and [2-13C]glycerol. Renal blood flow was determined with a flowprobe, and the renal balance of lactate, alanine, and glycerol was calculated by arteriovenous difference. After baseline, six dogs received 2-h simultaneous infusions of peripheral insulin (4 mU x kg(-1) x min(-1)) and left intrarenal [6,6-2H]dextrose (14 micromol x kg(-1) x min(-1)) to achieve and maintain left renal normoglycemia during systemic hypoglycemia. Arterial glucose decreased from 5.3 +/- 0.1 to 2.2 +/- 0.1 mmol/l; insulin increased from 46 +/- 5 to 1,050 +/- 50 pmol/l; epinephrine, from 130 +/- 8 to 1,825 +/- 50 pg/ml; norepinephrine, from 129 +/- 6 to 387 +/- 15 pg/ml; and glucagon, from 52 +/- 2 to 156 +/- 12 pg/ml (all P < 0.01). RGP increased from 1.7 +/- 0.4 to 3.0 +/- 0.5 (left) and from 0.6 +/- 0.2 to 3.2 +/- 0.2 (right) micromol x kg(-1) x min(-1) (P < 0.01). Whole-body glycerol appearance increased from 6.0 +/- 0.5 to 7.7 +/- 0.7 micromol x kg(-1) x min(-1)(P < 0.01); renal conversion of glycerol to glucose increased from 0.13 +/- 0.04 to 0.30 +/- 0.10 (left) and from 0.11 +/- 0.03 to 0.25 +/- 0.05 (right) micromol x kg(-1) x min(-1), (P < 0.05). Net renal gluconeogenic precursor uptake increased from 1.5 +/- 0.4 to 5.0 +/- 0.4 (left) and from 0.9 +/- 0.2 to 3.8 +/- 0.4 (right) micromol x kg(-1) x min(-1) (P < 0.01). Renal lactate uptake could account for approximately 40% of postabsorptive RGP and for 60% of RGP during hypoglycemia. These results indicate that gluconeogenic precursor extraction by the kidney, particularly lactate, is stimulated by counterregulatory hormones and accounts for a significant fraction of the enhanced gluconeogenesis induced by hypoglycemia.     

Transgenic overexpression of human islet amyloid polypeptide inhibits insulin secretion and glucose elimination after gastric glucose gavage in mice

Islet amyloid polypeptide (IAPP) is synthesized in islet beta cells and has been implicated in diabetes pathogenesis because it can inhibit insulin secretion and action and form fibrils leading to islet amyloidosis. Its physiological function has, however, not been established. We therefore examined insulin secretion and glucose elimination after i.v. or gastric gavage of glucose in transgenic mice overexpressing human IAPP (hIAPP) resulting in considerably increased circulating IAPP concentrations. The insulin response to and the glucose elimination after i.v. glucose (1 g/kg) were not different in transgenic mice compared with wild type animals, neither in males nor in females. In contrast, the insulin response to gastric glucose (150 mg/mouse) was reduced and the glucose elimination was inhibited in both male and female transgenic mice. The area under the 30 min insulin curve (AUCinsulin) was 21 +/- 2 nmol/l in 30 min in transgenic males (n = 24) vs 43 +/- 3 nmol/l in 30 min in wild type males (n = 26; p < 0.001) and the respective areas under the glucose curve (AUCglucose) were 1.90 +/- 0.12 and 1.62 +/- 0.09 mol/l in 120 min (p < 0.05). Similarly, in females, the AUCinsulin was 17 +/- 2 nmol/l in 30 min in transgenic mice vs 25 +/- 3 nmol/l in 30 min in wild type mice (p < 0.05) and the respective AUCglucose was 1.62 +/- 0.7 and 1.12 +/- 0.07 mol/l in 120 min (p < 0.001). Hence, endogenous hIAPP inhibits insulin secretion and glucose elimination after gastric glucose gavage in both male and female mice, indicating that overexpression of hIAPP could be a diabetogenic factor, via effects on the intestinal tract or the gut-islet axis or both.     

Cardiopulmonary bypass-induced changes in plasma concentrations of propofol and in auditory evoked potentials

Unbound, rather than total, plasma concentrations may be related to the anaesthetic action of propofol. Therefore, we measured plasma concentrations of propofol and recorded Nb wave latencies of auditory evoked potentials (AEP) during continuous infusion of propofol in 15 patients undergoing coronary artery bypass grafting (CABG) surgery. After induction of anaesthesia with fentanyl, propofol was infused continuously at a rate of 10 mg kg-1 h-1 for 20 min, and then the rate was reduced to 3 mg kg-1 h-1. Administration of heparin before cardiopulmonary bypass (CPB) did not affect total or unbound propofol concentration. Initiation of CPB decreased mean total propofol concentration from 2.6 to 1.7 micrograms ml-1 (P < 0.01). Simultaneously, mean unbound propofol concentration remained at 0.06 micrograms ml-1 because of a slight increase in the mean free fraction of plasma propofol (from 2.3 to 3.5%; P > 0.05). During hypothermic CPB, mean total propofol concentration increased to concentrations measured before bypass (to 2.1 micrograms ml-1; P > 0.05 vs value before CPB) and the mean unbound propofol concentration was at its highest (0.07 microgram ml-1; P < 0.05 vs value before heparin). After CPB and administration of protamine, the mean total propofol concentration remained lowered (1.7 micrograms ml-1; P < 0.05 vs value before heparin) and the mean unbound propofol concentration returned to the level measured before heparin (P < 0.001 vs value during hypothermia). The latency of the Nb wave from recordings of AEP increased after induction of anaesthesia, reached its maximum during hypothermia and was prolonged during the subsequent phases of the study. The latency of the Nb wave did not correlate with total or unbound propofol concentration. We conclude that the changes in total and unbound concentrations of plasma propofol were not parallel in patients undergoing CABG. During CPB or at any other time during the CABG procedure, the unbound propofol concentration did not decrease and Nb wave latency was prolonged compared with baseline values measured after induction of anaesthesia before the start of CPB.     

Mechanisms of worsening gas exchange during acute exacerbations of chronic obstructive pulmonary disease

This study was undertaken to investigate the mechanisms that determine abnormal gas exchange during acute exacerbations of chronic obstructive pulmonary disease (COPD). Thirteen COPD patients, hospitalized because of an exacerbation, were studied after admission and 38+/-10 (+/-SD) days after discharge, once they were clinically stable. Measurements included forced spirometry, arterial blood gas values, minute ventilation (V'E), cardiac output (Q'), oxygen consumption (V'O2), and ventilation/perfusion (V'A/Q') relationships, assessed by the inert gas technique. Exacerbations were characterized by very severe airflow obstruction (forced expiratory volume in one second (FEV1) 0.74+/-0.17 vs 0.91+/-0.19 L, during exacerbation and stable conditions, respectively; p=0.01), severe hypoxaemia (ratio between arterial oxygen tension and inspired oxygen fraction (Pa,O2/FI,O2) 32.7+/-7.7 vs 37.6+/-6.9 kPa (245+/-58 vs 282+/-52 mmHg); p=0.01) and hypercapnia (arterial carbon dioxide tension (Pa,CO2) 6.8+/-1.6 vs 5.9+/-0.8 kPa (51+/-12 vs 44+/-6 mmHg); p=0.04). V'A/Q' inequality increased during exacerbation (log SD Q', 1.10+/-0.29 vs 0.96+/-0.27; normal < or = 0.6; p=0.04) as a result of greater perfusion in poorly-ventilated alveoli. Shunt was almost negligible on both measurements. V'E remained essentially unchanged during exacerbation (10.5+/-2.2 vs 9.2+/-1.8 L x min(-1); p=0.1), whereas both Q' (6.1+/-2.4 vs 5.1+/-1.7 L x min(-1); p=0.05) and V'O2 (300+/-49 vs 248+/-59 mL x min(-1); p=0.03) increased significantly. Worsening of hypoxaemia was explained mainly by the increase both in V'A/Q' inequality and V'O2, whereas the increase in Q' partially counterbalanced the effect of greater V'O2 on mixed venous oxygen tension (PV,O2). We conclude that worsening of gas exchange during exacerbations of chronic obstructive pulmonary disease is primarily produced by increased ventilation/perfusion inequality, and that this effect is amplified by the decrease of mixed venous oxygen tension that results from greater oxygen consumption, presumably because of increased work of the respiratory muscles.