Lactate Extraction Research Articles

Effects of intracoronary calcium chloride on the postischemic heart in pigs

Whether calcium chloride (CaCl2) should be used to reverse myocardial dysfunction during cardiac operations remains a controversial issue. Calcium chloride may reduce, rather than increase, myocardial contractility and may produce exaggerated vasoconstriction in postischemic vessels in which the endothelium has been damaged. These possibilities were investigated in an open-chest porcine model that allowed control of systemic hemodynamics. Incremental doses of CaCl2 (1, 3, and 10 mg/min) were infused directly into a coronary artery before and after 10 or 15 minutes of ischemia followed by 15 minutes of reperfusion. Calcium chloride increased regional contraction, coronary blood flow, and oxygen consumption before ischemia, whereas oxygen and lactate extraction were unchanged. After ischemia and reperfusion, contraction was impaired and lactate extraction was reduced, but a similar response to CaCl2 was observed. Contraction returned to baseline values promptly after CaCl2. Thus, CaCl2 exerts a positive inotropic effect both in normal and in postischemic myocardium. Calcium chloride does not cause direct coronary constriction nor does it worsen myocardial stunning after a short period of normothermic myocardial ischemia.

The Efficacy of Amrinone or Adrenaline on Low Cardiac Output Following Cardiopulmonary Bypass in Patients with Coronary Artery Disease Undergoing Preoperative ß-Blockade

We examined 20 patients undergoing coronary bypass grafting for coronary artery disease with NYHA classifications of II and III who had been treated with beta-blocking agents. Patients were randomised for administration of either adrenaline (0.1 microgram/kg/min) or amrinone (bolus 1 mg/kg, continuous infusion of 5-10 micrograms/kg/min), if following cardiopulmonary bypass their cardiac index was < 2.4 L/min/m2 with normal peripheral resistance and normal or increased right- or left-ventricular filling pressures. Over a period of 1 hour, the hemodynamic parameters mean arterial pressure (MAP), cardiac index (CI), heart rate (HR), coronary perfusion pressure (CPP), total peripheral resistance (TPR), as well as the pressure-work index (PWI) were registered or calculated. By means of a coronary sinus catheter myocardial arterio-venous oxygen content difference (AVDO2cor), myocardial blood flow (MBF), using the thermodilution method, and myocardial oxygen consumption (MVO2) could be measured or calculated. Simultaneously, arterial and myocardial lactate concentrations and, using the arterio-venous lactate ratio, myocardial lactate extraction or production were quantified. Using a transseptal approach, the left-ventricular pressure curve was measured and used to differentiate for myocardial contractility (dp/dtmax). Following induction of anesthesia and after cardiopulmonary bypass, plasma levels of the used beta-blocking agent were determined. Both substances caused a significant increase in myocardial contractility, with adrenaline showing a more potent effect than amrinone. Both substances caused a significant increase in CI with a mild increase in HR. Amrinone caused a significant drop in TPR, while MAP remained practically constant.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac and skeletal muscle myoglobin release after reperfusion of injured myocardium in dogs with systemic hypotension.

Myoglobin (Mb) is an intramyocardial protein that is released into the systemic circulation and rapidly cleared via the kidneys after myocardial injury. Arterial Mb concentration-time curves have been studied in humans and dogs in the setting of acute coronary artery occlusion, and the rate of rise of Mb is both sensitive and specific as an indicator of successful coronary artery reperfusion. Systemic hypotension may alter Mb kinetics and impact on the utility of this method by causing Mb release from ischemic skeletal muscle and by decreasing renal Mb clearance. This study was undertaken to determine whether analysis of Mb kinetics remains accurate in identifying coronary reperfusion in the setting of systemic hypotension. Eighteen chronically instrumented dogs were made hypotensive by being bled via a large-bore femoral artery catheter into a reservoir adjusted to maintain a constant mean arterial pressure of 50 mm Hg for 8 hours. After the first hour of hypotension, each dog was studied under one of the following three protocols: group 1, 2 hours of mid-left anterior descending artery (LAD) occlusion followed by 5 hours of unlimited reperfusion; group 2, 7 hours of mid-LAD occlusion without reperfusion; or group 3, 7 additional hours of hypotension alone. Systemic lactate extractions demonstrated a shift to anaerobic metabolism in skeletal muscle and confirmed that shock was established in all animals. Regional arteriovenous Mb differences in group 1 animals demonstrated release of large amounts of Mb from reperfused myocardium; in contrast, smaller amounts of Mb were released both from skeletal muscle rendered ischemic by hypotension and from myocardium rendered ischemic by coronary occlusion without reperfusion. In group 1 dogs, arterial Mb rose rapidly immediately after reperfusion, with peak Mb occurring 108 +/- 24 minutes (mean +/- SEM) after vessel reopening. In group 2 and group 3 dogs, arterial Mb rose more slowly, such that peak Mb was not reached within 8 hours in 11 of 12 animals. The linear rate of rise of arterial Mb over the first hour of reperfusion in group 1 dogs was 51 +/- 16 ng.mL-1.min-1. This slope was significantly greater than slopes determined over the same time period in dogs occluded and not reperfused (group 2, 1.2 +/- 0.6 ng.mL-1.min-1) and in those hypotensive alone (group 3, 0.8 +/- 0.5 ng.mL-1.min-1). All the slopes of group 2 and group 3 dogs fell below the range of slopes of group 1 dogs. In contrast to slopes of the Mb concentration-time curves, linear creatine kinase slopes were significantly less sensitive in predicting reperfusion. Analysis of plasma Mb kinetics allows early identification of coronary reperfusion after myocardial injury even in the presence of significant systemic hypotension.

931-108 Parasympathetic Intervention Affects Ischemia by Increasing Coronary Flow in Normal, but not in Impaired Left Ventricular Function. A New Approach to Antiischemic Therapy?

Cardiovascular parasympathetic control reportedly is reduced in left ventricular (LV) dysfunction and in heart-failure. To evaluate whether parasympathetic intervention differentially affects coronary flow and ischemia in normal (N) vs impaired (I = ejection fraction &lt; 40%) LV-function, 17 pts in N and 7 pts in I received atropine before ischemia was induced by incremental atrial pacing. Placebo was administered to a matching control group (CN and CI, resp.). All pts had &gt; 70% left CAD. During maximal pacing, heart rate and rate pressure product (myocardial oxygen demand) where 7% and 12% higher in N, compared to CN, but were comparable in I and CI. Moreover, 1 minute post pacing these values were 8% and 12% higher, resp., N vs CN. Vasoconstrictive circulating neurohormones (norepinephrine) increased similarly in all groups. Coronary flow increased 23% more in N than in CN and to a similar extent in I and CI. Myocardial ischemia, as indicated by changes in myocardial lactate metabolism, was less in N [lactate extraction +10% (N) vs -21% (CN), -18% (I) and -19% (CI)]. Fifteen minutes after pacing, coronary flow was still decreased by 11% and coronary vascular resistance increased by 15% in CN, as compared to N. Thus, reduction of parasympathetic tone improves coronary flow and reduces myocardial ischemia in the latter, despite similar sympathetic activation and more pronounced myocardial oxygen demand in N. This supports a greater role for cardiovascular parasympathetic control of (diseased) coronary arterial system in normal LV-function and, possibly, a new area of intervention in antiischemic therapy in the latter.

979-31 Intravenous Infusion of ATP Increases Coronary Blood Flow and Improves Ischemia via Elevation of Myocardial Adenosine Levels due to Degradation of ATP

Adenosine is known to be cardioprotective for the ischemic heart, however, an intravenous administration of adenosine can not increase coronary blood flow (CBF) because of its rapid degradation. To test if an intravenous ATP administration is timely degraded to adenosine at the heart, we measured CBF of the left anterior descending coronary artery and coronary arteriovenous differences of adenosine concentration (Ado) in the canine hearts. Infusions of ATP (5, 10, 20, and 40 μg/kg/min) into the systemic vein increased Ado from 7 ± 4 to 19 ± 7, 38 ± 7, 68 ± 11 and 112 ± 15 pmol/ml, although ATP, ADP and AMP concentrations in the coronary venous blood were not increased. An intravenous infusions of ATP increased CBF from 93 ± 5 to 127 ± 6, 149 ± 5, 168 ± 78 and 195 ± 6 ml/100 g/min, which was blunted by 8-sulfophenyltheophylline. Aortic pressure was decreased by 12 ± 5 mmHg from 107 ± 5 mmHg during 40 μg/kg/min of ATP infusion. During ischemia due to reduction of perfusion pressure by 56 ± 4%, an intravenous infusion of 40 μg/kg/min of ATP increased CSF (56 ± 3 to 66 ± 5 ml/100 g/min) with increased fractional shortening (9 ± 2 vs 14 ± 3) and lactate extraction ratio (-34 ± 5 vs. -17 ± 6%). We conclude that an intravenous administration of ATP can elevate myocardial adenosine levels, and improve myocardial contractile and metabolic function in the ischemic heart. Intravenous ATP administration may be promising for cardioprotection in the patients with acute ischemic heart diseases.

744-1 Endogenous Nitric Oxide Attenuates Myocardial Inotropic Responses in Ischemic Myocardium of the Canine Heart

Nitric oxide (NO) is reported to attenuate myocardial contraction, raising the possibility that endogenous NO decreases the inotropic response of ischemic myocardium. In 42 dogs, the left anterior descending coronary artery was perfused with blood from the left carotid artery. During reduction of perfusion pressure (1 03 ± 6 to 53 ± 4 mmHg) so that coronary blood flow (CBF) decreases to 60% of the control, fractional shortening (FS) of the perfused area decreased from 23.3 ± 3.3 to 8.4 ± 1.3%. Intravenous infusions of isoproterenol (ISO, 75 and 150 ng/kg/min) increased FS to 15.9 ± 33 and 22.5 ± 2.5%, respectively. An infusion of L-NAME, an inhibitor of NO synthase, did not alter FS in the non-ischemic condition (24.5 ± 2.1%). However, changes in FS due to reduction of C8F to 60% (FS:14.3 ± 1.3%), and intravenous infusions of ISO during coronary hypoperfusion (FS:23.3 ± 3.3 and 32.3 ± 2.8%) were augmented in the L-NAME group compared with the untreated group. Lactate extraction ratio (-4.1 ± 2.2 vs -15.6 ± 4.2%), and pH in the coronary venous blood (7.32 ± 0.03 vs 7.27 ± 0.03) in the L-NAME group were lower than the untreated group during coronary hypoperfusion. Furthermore, L-arginine restored metabolic dysfunction due to L-NAME in the ischemic myocardium. These results indicate that endogenous NO attenuates myocardial contractile function in the ischemic heart and improves myocardial metabolic function. NO and NO donors such as nitrates in the ischemic heart disease may play an importrant role for myocardial energysparing effect as well as coronary vasodilation.

744-4 Evidence for Downward-Shift of Coronary Pressure-Flow Relationship Following a Brief Period of Ischemia in Dogs

This study was undertaken to test whether a brief period of ischemia affects the coronary pressure-flow relationship during reduction of coronary perfusion pressure (CPP). The left anterior descending coronary artery was cannulated and perfused with blood from the left carotid artery in 40 open-chest dogs. Coronary blood flow (CBF) was measured during intracoronary administrations of papaverine and adenosine. Coronary pressure-flow relationship was assessed during transient reduction of CPP from 100 to 30 mmHg with 10 mmHg intervals. Coronary hyperemic flow due to adenosine and papaverine was attenuated at 30 min of reperfusion following 10 and 15 min of ischemia. In the group of transient 10 min ischemia, both fractional shortening (FS) and CBF returned to the pre-ischemic values at 30 and 60 min of reperfusion, however, marked decreases in CBF (35 ± 5 vs 56 ± 4 ml/100 g/ml at CPP = 60 mmHg, p &lt; 0.01) during graded reductions in CPP were observed. Furthermore, both FS (6 ± 1 vs 14 ± 1% at CPP = 60 mmHg. p &lt; 001) and lactate extraction ratio (–41 ± 15 vs 1 ± 6% at CPP = 60 mmHg, p &lt; 0.05) were decreased. The endocardial vs. epicardial flow ratio was reduced relative to the control condition. The downward-shift of the coronary perfusion pressure-flow relationship and the deterioration of myocardial contractile and metabolic function during reduction of CPP were restored at 60 min of reperfusion. In contrast, in the group of transient 15 min ischemia, although both baseline FS and coronary hyperemic flow due to adenosine and papaverine remained to be at 30 and 60 min of reperfusion, the coronary perfusion pressure-flow relationship was not shifted. Transient brief period of ischemia can reversibly affect the coronary pressure-flow relationship due to the reduced capability of vascular relaxation, however, the downward-shift of coronary pressure-flow relationship can be blunted by the reduced myocardial contractile force against the coronary resistance vessels.

979-36 Role of Endogenous Adenosine in Coronary Pressure-Flow Relationship In Dogs

There have been conflicting evidence for the role of adenosine in coronary pressure flow relationship; although adenosine release increases when coronary perfusion pressure (CPP) is reduced, adenosine deaminase does not affect changes in coronary blood flow (CBF). To examine the role of endogenous adenosine in coronary pressure flow relationship, responses of CBF were observed during a stepwise reduction of CPP by 10 mmHg with and without 8-phenyltheophylline (8PT). In 32 dogs, the left anterior descending coronary artery was perfused from the carotid artery, where CBF was measured. According to the reduction of CPP, adenosine concentration detected in coronary venous blood was increased (CPP = 100 mmHg:7 ± 2, 8O mmHg:25 ± 3, 70 mmHg:53 ± 5, 40 mmHg:165 ± 11 pmollml), Administration of 8PT reduced CBF by 8 ± 3% at CPP = 100 – 70 mmHg, and by 34 ± 7% at CPP = 60-40 mmHg. When CPP was altered between 100 and 70 mmHg, 8PT markedly reduced (p &lt; 0,001) fractional shortening (FS) and lactate extraction ratio (LER) (FS:9,8 ± 1.2 vs. 23.6 ± 1.2%, LER:-6,5 ± 1.9 vs. 26.7 ± 1.9% at CPP = 70 mmHg). Interestingly, 8PT markedly reduced End/Epi flow ratio by 35 ± 4% at CPP = 70 mmHg. Thus we conclude that when CPP is reduced, endogenous adenosine favors endocardial myocardial flow and preserves myocardial contractile and metabolic function.

Effects of contrast media on coronary hemodynamics and myocardial metabolism.

This study was designed to compare the effects of ionic contrast medium (CM), Renografin-76 (R76), and nonionic CM, Omnipaque-350 (OM350), on coronary hemodynamics and myocardial metabolism. In 10 open-chest, atrial-paced dogs, 4 mL of R76 and OM350 were injected into the left anterior descending coronary artery. Coronary blood flow (CBF), myocardial oxygen consumption (MVO2), lactate extraction (LE), left ventricular (LV) dp/dt, and aortic systolic pressure (AOP) were measured. The maximal CBF changes caused by OM350 and R76 were 23.7 +/- 3.3 mL/minute and 18.3 +/- 3.3 mL/minute (NS), respectively. OM350 produced an increase in LV dp/dt by 378 +/- 85 mm Hg/second, which was different from -244 +/- 65 mm Hg/second by R76 (P < .05). The changes in MVO2 and LE after OM350 injection were 2.6 +/- 0.6 mL/minute and 10.2 +/- 5 microM/minute, respectively; those were different from -0.1 +/- 0.4 mL/minute, and -7.7 +/- 5.1 microM/minute after R76 injection (P < .05). Although both agents increased CBF, they appeared to act by different mechanisms. That a direct coronary vasodilator effect is the main action of R76 on coronary vascular response is suggested by decreasing myocardial contractility and oxygen consumption. However, OM350, by enhancing both parameters, may augment CBF at least in part by autoregulation.

Relation between shock-related myocardial injury and defibrillation efficacy of monophasic and biphasic shocks in a canine model.

Certain biphasic waveforms with specific time ratios of positive and negative components require less energy for successful defibrillation of the fibrillating ventricles than monophasic waveforms. However, if more efficient waveforms were also to be associated with more injurious effects on myocardial function, they might not provide a true biological advantage. This study investigates the relation between defibrillation efficacy and potential toxicity of monophasic and asymmetric, single capacitor, biphasic waveforms with equal durations of positive and negative components. The myocardial lactate extraction rate (LER) was used to measure the injurious effects on myocardial oxidative metabolism of two synchronized 35-J shocks in sinus rhythm. LER, mean arterial pressure (MAP) and, in a subset of experiments, cardiac output (CO) and coronary blood flow (CBF) were measured at baseline, 30 seconds, 60 seconds, 90 seconds, 150 seconds, 300 seconds, and 600 seconds after the shocks. In 12 dogs, three different waveforms (M 10: monophasic 10 milliseconds; BI 10: biphasic 10 milliseconds; BI 20: biphasic 20 milliseconds) were tested as series of two consecutive shocks (60 seconds apart) resulting in a total of 36 sets of data. At baseline, LER was 25 +/- 11%. After monophasic shocks, LER decreased significantly more than after biphasic shocks (LER at 150 seconds: M 10: -6 +/- 31% versus BI 10: 21 +/- 15% versus BI 20: 21 +/- 16%; M 10 versus BI 10 and M 10 versus BI 20, P < .05) and showed also a slower recovery (LER at 300 seconds: M 10: 1 +/- 24% versus BI 10: 20 +/- 11% versus BI 20: 20 +/- 15%; M 10 versus BI 10 and M 10 versus BI 20, P < .05). The maximal decrease in LER was 41 +/- 27% for M 10 compared with 18 +/- 15% for BI 10 and 15 +/- 11% for BI 20 (both, M 10 versus BI 10 and M 10 versus BI 20, P < .05). There was a similar decrease in CO and MAP, with the lowest MAP after monophasic shocks. The maximal decrease in MAP was significantly greater after M 10 compared with BI 20 (-29 +/- 15 mm Hg versus -13 +/- 11 mm Hg, P < .05). The defibrillation threshold was 18.6 +/- 8 J for M 10 compared with 11.5 +/- 4.0 J for BI 10 (P < .05) and 15.0 +/- 6.1 J for BI 20, respectively (P = NS). Our results suggest that these specific biphasic waveforms are associated with less injurious effects on myocardial oxidative metabolism and hemodynamic performance. Given their higher defibrillation efficacy as well, biphasic waveforms may provide important long-term benefits in patients receiving frequent shocks from implantable cardioverter-defibrillators.

Coronary sinus oxygen content and lactate extraction during hyperventilation in patients with coronary artery disease

Coronary sinus oxygen content and lactate extraction during hyperventilation in patients with coronary artery disease

AICA riboside improves myocardial ischemia in coronary microembolization in dogs

This study was undertaken to examine whether 5-amino-4-imidazolecarboxamide (AICA) riboside (acadesine), which augments adenosine release in ischemic myocardium, further attenuates ischemic injury after acute coronary microembolization. The left anterior descending coronary artery was cannulated and perfused with blood from the left carotid artery in 46 dogs, and coronary blood flow (CBF) of the perfused area was measured. In 12 dogs, 15-microns microspheres (5.0 x 10(4)/ml) were injected repeatedly until CBF approached zero. Changes in CBF, fractional shortening, lactate extraction ratio, and adenosine release were measured with and without administration of AICA riboside. In the control group (n = 7), CBF increased to 154 +/- 11 ml.100 g-1.min-1 at 16-30% of total coronary embolization, and adenosine release was 6.1 +/- 1.0 nmol.100 g-1.min-1. Administration of AICA riboside (n = 5) enhanced coronary hyperemia (187 +/- 8 ml.100 g-1.min-1, P < 0.05), adenosine release (11.9 +/- 0.9 nmol.100 g-1.min-1, P < 0.001), and myocardial adenosine content (0.434 +/- 0.069 vs. 0.118 +/- 0.019 nmol/mg wet wt, P < 0.01) and attenuated decreases in fractional shortening and lactate extraction ratio. AICA riboside preserved myocardial tissue ATP content of the embolized area. The administrations of 8-phenyltheophylline (n = 12) and alpha,beta-methyleneadenosine 5'-diphosphate (n = 10) abolished the beneficial effects of AICA riboside. Furthermore, AICA riboside increased ectosolic and cytosolic 5'-nucleotidase activity of the embolized myocardium (n = 12). Thus we conclude that AICA riboside attenuates contractile and metabolic dysfunction by enhancing adenosine release via activation of ectosolic 5'-nucleotidase and inducing local hyperemia in acute coronary microembolization.

Eicosanoid biosynthesis in patients with stable angina: Beneficial effects of very low dose aspirin

Objectives. We assessed the production of eicosanoids and the effects of very low dose aspirin in patients with stable angina under basal conditions and during rapid atrial pacing.Background. Platelet activation occurs in acute ischemic syndromes but is still controversial in stable angina. Very low dose aspirin is known to be platelet selective and can be used to test the hypothesis of the platelet origin of increased thromboxane production in stable angina.Methods. Urinary excretion of eicosanoids was measured in 42 patients, including 24 patients with and 18 patients without coronary artery disease. The effects of 50 mg/day of aspirin were measured at rest and during pacing-induced ischemia in 10 patients with stable angina and were compared with a similar group of patients not treated by aspirin.Results. Excretion of 11-dehydro-thromboxane B2was 2.6 times higher in patients with stable angina than in healthy subjects (mean [±SEM] 74.8 ± 13.0 [24 patients] vs. 29.0 ± 5.4 [18 patients] ng/mmol of creatinine, p < 0.01). Urinary prostacyclin metabolite levels did not differ between the two groups. Treatment for 8 days with 50 mg/day of aspirin inhibited platelet cyclooxygenase, as reflected by the 97% reduction of in vitro serum thromboxane production. This aspirin regimen normalized the level of urinary thromboxane metabolites in patients with angina (17.3 ± 3.4 ng/mmol of creatinine [10 patients], p < 0.001 from baseline level before treatment) and did not change prostacyclin metabolite levels. Atrial pacing in patients with angina not treated with aspirin caused lactate and thromboxane release into the coronary sinus. In patients with very low dose aspirin therapy, pacing did not cause thromboxane release despite inducing myocardial ischemia. However, fractional lactate extraction decreased less sharply in patients with than without aspirin therapy.Conclusions. Thromboxane production is greatly increased in patients with stable angina. Very low dose aspirin administered to these patients reduces thromboxane synthesis to normal levels, preserves prostacyclin biosynthesis and prevents acute thromboxane release into the coronary circulation during pacing-induced ischemia. Our data suggest that platelets (not monocytes/ macrophages) are activated in stable angina to produce thromboxane.

Nonglucose substrates increase glycogen synthesis in vivo in dog heart

The effects of circulating nonglucose substrates on insulin-stimulated cardiac glycogen synthesis were studied in the dog heart in vivo using 13C-nuclear magnetic resonance (-NMR) and arteriovenous difference techniques. [1-13C]glycogen was monitored in hearts during an intravenous infusion of 20 mU/min insulin and glucose while [1-13C]glucose (10 mg/min) was infused into the left anterior descending coronary artery. When 1 mmol/min of lactate, pyruvate, or beta-hydroxybutyrate was added to the venous infusion, the measured rate of glycogen synthesis was increased, on average, sixfold. It was not increased further after a subsequent 10-min infusion of 5 micrograms/min epinephrine. Lactate extraction increased from 0.18 +/- 0.05 to 0.62 +/- 0.11 mumol.min-1.g wet wt-1 during lactate infusion, whereas glucose extraction did not change significantly (0.15 +/- 0.05 mumol.min-1.g wet wt-1 at 45 min of insulin and glucose infusion to 0.09 +/- 0.02 mumol.min-1.g wet wt-1 at 45 min of the lactate infusion). Therefore, the uptake and oxidation of circulating nonglucose substrates redirects the fate of extracted glucose from glycolysis to glycogen synthesis in the dog heart in vivo.

Midazolam's effects on myocardial load and coronary perfusion: Reduced regional O 2 consumption and lactate production during ischemia in dogs

It is hypothesized that because of its potential to increase coronary flow and simultaneously decrease myocardial performance and O 2 consumption, midazolam would minimize regional metabolic impairment during myocardial ischemia. Therefore, the hemodynamic and regional metabolic effects of systemic midazolam administration were compared during moderate and severe constrictions of the left anterior descending artery (LADa) to nontreated but ischemic animals in a canine model of acute coronary occlusion. In 16 anesthetized, ventilated, surgically prepared, and catheterized dogs, resting flow in the LADa was decreased by 50% and 75% for 15 minutes with 1 hour of normal flow in between. By arbitrary assignment, 7 dogs received midazolam (0.3 mg/kg and then 0.05 mg/kg/min) before thoracotomy. In all dogs, heart rate, electrocardiogram, LADa flow, left ventricular (LV) first time-derivative, and aortic, pulmonary artery, LADa, and LV pressures were measured continuously. Before and during constrictions, cardiac output by thermodilution and regional myocardial blood flow by microspheres were measured and blood was sampled for analysis. Data (mean ± SEMI were compared within and between groups using ANOVA. Before placement of the LADa ligature, mid-azolam decreased heart rate and mean aortic pressure. Before ischemia, heart rate and LADa pressure were lower with midazolam than without it, but baseline metabolic variables were similar between the two groups (except for O 2 consumption in the ischemic zone, which was lower with midazolam than without it). During 75% constriction with midazolam, LV end-diastolic pressure, coronary resistance, and ischemic zone O 2 consumption were lower than without midazolam. Ischemic zone O 2 delivery/consumption ratio was higher. Also, ischemic zone lactate consumption, consumption rate (flux consumption/heart rate), and extraction values were less negative compared with those values without midazolam. Based on these hemodynamic and metabolic changes, it is concluded that midazolam improved the relationship of supply to demand and decreased ischemic lactate production before and after ischemia was induced. This should be further explored clinically for potential use in patients with ischemic heart disease, in whom midazolam is used as an adjuvant or as a main anesthetic.

Improved hemodynamic function and mechanical efficiency in congestive heart failure with sodium dichloroacetate

Objectives. The purpose of this study was to determine whether sodium dichloroacetate improves hemodynmic performance and mechanical efficiency in congestive heart failure.Background. Congestive heart failure is associated with impaired hemodynamic performance and reduced mechanical efficiency. Dichloroacetate stimulates pyruvate dehydrogenase activity by inhibition of pyruvate dehydrogenase kinase, which results in inhibition of free fatty acid metabolism and stimulation of high respiratory quotient glucose and lactate consumption by the heart. Facilitation of glucose and lactate consumption with dichloroacetate should improve mechanical efficiency of the failing ventricle.Methods. Ten patients with New York Heart Association functional class III to IV congestive heart failure were studied. Dichloroacetate (50 mg/kg body weight) was administered intravenously for 30 min, with measurements of hemodynamic variables, coronary sinus blood flow and blood gas, glucose and lactate levels for 2 h. The same patients were also given dobutamine (5 to 12.5 mg/kg per min) for comparison.Results. Therapeutic levels of dichloroacetate were achieved (100 to 160 μg/liter of plasma). Myocardial consumption of lactate was stimulated from 29% to 37.4%. Forward stroke volumes increased (+5.3 ml/beat, p < 0.02), as did left ventricular stroke work (+1.8 g-m/m2per beat, p < 0.02) and left ventricular minute work (from 1.38 to 1.55 kg-m/m2per min, p < 0.01). Myocardial oxygen consumption decreased (from 19.3 to 16.3 ml/min, p = 0.06) as left ventricular minute work increased. Left ventricular mechanical efficiency thus improved from 15.2% to 20.6% (p = 0.03).Dobutamine administration resulted in the opposite trend with respect to myocardial lactate extraction (from 34% to 15.3%, p < 0.02). Stroke volume increased (+7.4 ml/beat, p = NS vs. dichloroacetate), as did left ventricular minute work (from 1.29 to 1,59 g-m/m2per min, p < 0.01 vs. dichloroacetate) and myocardial oxygen consumption (from 18.6 to 21.0 ml/min, p = 0.06 vs. dichloroacetate). Left ventricular mechanical efficiency did not change with dobutamine administration (from 16.4% to 15.8%, p = NS).Conclusions. Dichloroacetate administration stimulates myocardial lactate consumption and improves left ventricular mechanical efficiency. Forward stroke volume and left ventricular minute work increase significantly, with a simultaneous reduction in myocardial oxygen consumption. Dobutamine administration results in similar hemodynamic improvements but with no change in left ventricular mechanical efficiency and with opposite effects on lactate metabolism. The opposing metabolic actions, yet similar hemodynamic responses, of dichloroacetate and dobutamine suggest that these agents may be complementary in the treatment of congestive heart failure.

Hemodynamic and metabolic correlates of dipyridamole-induced myocardial thallium-201 perfusion abnormalities in multivessel coronary artery disease

The mechanisms responsible for the development of reversible thallium-201 (Tl-201) defects with dipyridamole stress in patients with coronary artery disease (CAD) is not well understood. Previous experimental animal studies have demonstrated coronary steal characterized by an absolute decrease in subendocardial flow distal to a stenosis in response to dipyridamole infusion. Accordingly, the purpose of this study was to determine if reversible Tl-201 defects in response to dipyridamole infusion are reflective of myocardial ischemia or secondary to regional differences in flow reserve. Dipyridamole (0.56 mg/kg) Tl-201 imaging was performed in 23 patients in whom serial electrocardiographic, hemodynamic, aortic and coronary sinus lactate, and coronary sinus adenosine measurements were obtained. All patients with CAD had Tl-201 redistribution (3.8 ± 2.0 defects/patient), and all patients without CAD had normal scans. Mean aortic pressure was similar in both groups and did not change in response to dipyridamole (non-CAD 103 ± 11 vs CAD 99 ± 15 mm Hg, p = NS). Pulmonary capillary wedge pressure was similar at baseline (non-CAD 11 ± 4 vs CAD 13 ± 5 mm Hg, p = NS) and did not change in response to the drug (non-CAD 14 ± 3 vs CAD 15 ± 7 mm Hg, p = NS). Lactate extraction fraction was similar at baseline (non-CAD 0.22 ± 0.09 vs CAD 0.17 ± 0.14, p = NS) and decreased similarly in both groups (non-CAD 0.08 ± 0.06 vs CAD 0.05 ± 0.12, p = NS). Coronary sinus adenosine concentration was significantly higher at baseline in patients with CAD (non-CAD 16 ± 4 vs CAD 35 ± 13 ng/ml, p = 0.034), presumably to maintain resting coronary blood flow, and increased significantly with a comparable percent increase in both groups after dipyridamole (non-CAD 35 ± 10 vs CAD 69 ± 35 ng/ml, p = 0.0001). In this group of patients with multivessel CAD, dipyridamole-induced Tl-201 perfusion abnormalities were not associated with significant myocardial ischemia by hemodynamic and metabolic criteria and appeared to be more indicative of abnormal flow reserve.

Improved exercise hemodynamic status in dilated cardiomyopathy after beta-adrenergic blockade treatment

Objectives. This study was performed to investigate exercise hemodynamic status in a double-blind, placebo-controlled trial and was a substudy in the Metoprolol in Dilated Cardiomyopathy Trial.Background. Previous open studies have shown beneficial effects on exercise hemodynamic status after beta-adrenergic blocking agent therapy in patients with congestive heart failure.Methods. The study included 41 patients with idiopathic dilated cardiomyopathy with ejection fraction <0.40 (metoprolol, 20 patients; placebo, 21 patients) whose hemodynamic status was investigated at rest and during supine submaximal exercise, at baseline and after 6 and 12 months of treatment. Myocardial metabolism was evaluated in a subset of 19 patients.Results. Metoprolol-treated patients responded favorably, as expressed by improved exercise cardiac index ([mean ± SD] placebo 4.8 ± 1.6 to 4.7 ± 1.8 liters/min per m2, metoprolol 4.3 ± 1.1 to 5.4 ± 1.9 liters/min per m2, p = 0.0001) and stroke work index (placebo 44 ± 20 to 41 ± 27 gm/m2, metoprolol 35 ± 16 to 58 ± 28 gm/m2, p < 0.0001). Exercise systolic arterial pressure increased (placebo 161 ± 25 to 151 ± 23 mm Hg, metoprolol 155 ± 29 to 165 ± 37 mm Hg, p = 0.0003) as well as exercise oxygen consumption index (placebo 463 ± 194 to 474 ± 232 ml/min per m2, metoprolol 406 ± 272 to 507 ± 298 ml/min per m2p = 0.045). There was a significant increase in exercise duration in the metoprolol group (63 ± 38 s) compared with the placebo group (−24 ± 42 s) (p = 0.01). Net myecardial lactate extraction increased in the metoprolol group, suggesting less myocardial ischemia (placebo 17 ± 22 to 9.5 ± 6.4 mmol/min, metoprolol −32 ± 100 to 42 ± 45 mmol/min, p = 0.03). Peripheral levels of norepinephrine leaded to decrease at rest and during exercise, whereas myocardial net spillover was unchanged.Conclusions. Metoprolol improved hemodynamic status in patients with dilated cardiomyopathy at rest and had a more pronounced effect during exercise. These positive effects were achieved along with improved or stable myocardial metabolic data.

Anaesthesia for Myocardial Revascularisation

We studied the effects on myocardial performance and metabolism of fentanyl/propofol and fentanyl/enflurane anaesthesia in 20 patients before coronary artery bypass grafting. Anaesthesia was induced with fentanyl 20 micrograms.kg-1 and pancuronium 0.15 mg.kg-1. Patients received, by random allocation, either propofol by infusion, 6 mg.kg-1.h-1 reduced by half after 10 min then adjusted as necessary (mean rate 2.8 mg.kg-1.h-1), or enflurane 0.8% inspired concentration for 10 min reduced to 0.6% and adjusted as required (mean 0.7%). Measurements were made before induction, after tracheal intubation, after skin incision and after sternotomy. There were no significant differences between the groups in any haemodynamic variables during the study. Following intubation both groups showed a rise in heart rate (p < 0.01) and cardiac index (p < 0.05). Systemic vascular resistance decreased after intubation (p < 0.05) then returned to baseline during surgery; stroke index was unchanged after intubation but was reduced during surgery (p < 0.01) as systemic vascular resistance increased. Regional and global coronary blood flow were maintained in both groups, as were myocardial oxygen consumption and lactate extraction ratio. However, lactate production did occur in one patient receiving enflurane and Holter monitoring confirmed ischaemia. One patient receiving propofol showed lactate production not accompanied by any ECG changes. This study suggests that propofol may be a suitable alternative to enflurane as an adjunct to opioids in anaesthesia for coronary artery bypass grafting.

Intracoronary propofol does not decrease myocardial contractile function in the dog

The intravenous administration of propofol is associated with a considerable decrease in arterial blood pressure. The present study was undertaken to test the hypothesis that myocardial function is not affected by propofol and therefore does not contribute to the hypotensive effect of this anaesthetic agent. Propofol was administered in anaesthetized, open-chest dogs by direct arterial infusion into the left anterior descending coronary artery (LAD). Mean arterial blood pressure, heart rate, left ventricular pressure, dP/dt, regional lactate and oxygen extraction, as well as coronary blood flow were measured. Diastolic function was determined by calculation of the time constant of isovolumetric relaxation from the left ventricular pressure measurement and dP/dt. Contractility was evaluated by measuring regional systolic shortening in an area of the myocardium supplied by the LAD. This was compared with systolic shortening in the distribution of the circumflex (CIRC) artery and with the effects obtained with the intracoronary administration of thiopentone. Intracoronary infusions of propofol and thiopentone did not produce any change in systemic arterial blood pressure, heart rate, or left ventricular end diastolic pressure. Propofol, at a concentration of 5 or 10 micrograms.ml-1 did not decrease systolic shortening in the area perfused by the LAD while thiopentone (40 micrograms.ml-1) reduced systolic shortening by 33% (P < or = 0.05). Neither drug had an effect on systolic shortening in the CIRC area, LAD blood flow or diastolic function. The results of this study suggest that propofol does not have an effect on myocardial contractility. The hypotension associated with the intravascular administration of propofol is more likely due to either a direct vascular or a central effect.