Environmental factors promoting the effective use of a computer-assisted clinical case for second-year osteopathic medical students.

Computer-aided clinical cases (CACC) have the potential to complement and/or supplement other types of problem-based learning exercises in modern medical curricula. Deploying a CACC learning experience requires institutional commitment to technology and a belief by administration, faculty, and students that "climbing a steep growth curve" is worth the effort. Several aspects of the institutional environment at the Kirksville College of Osteopathic Medicine (KCOM) led to the development of the CACC exercise described in this article, including the need to design a uniform, supplemental, Internet-based learning experience and assessment exercises for students doing clinical rotations at off-site facilities. The CACC learning experience was enthusiastically accepted by second-year medical students as an integrative and clinically relevant educational experience. The success of this CACC exercise has helped to promote the development of other innovative applications of technology of medical education at KCOM.

Increased oxyhemoglobin affinity by carbamylation: coronary autoregulation and O2 transport.

Hemoglobin carbamylation with sodium cyanate was used to study myocardial O2 delivery during increased oxyhemoglobin affinity. A group of control dogs was compared with a group of dogs, in which their hemoglobin had been carbamylated by daily ingestion of sodium cyanate over a period of 6-8 wk. The O2 tension at 50% saturation of hemoglobin (P50) averaged 23 mmHg in the carbamylated group compared with an average P50 of 31 mmHg in the control group. The left main coronary artery was cannulated and perfused via an extracorporeal, pressure-controlled reservoir. Coronary pressure, coronary flow, and blood gas measurements were made at coronary perfusion pressures spanning the autoregulatory range. The increased oxyhemoglobin affinity produced no significant difference in convective O2 transport to the coronary capillaries, although the carbamylated group had a significantly higher arterial O2 content and significantly lower coronary flow. The autoregulatory process was not significantly altered by carbamylation-induced shifts in the O2 dissociation curve. Despite a significantly lower coronary sinus PO2 in the carbamylated group, the increase in oxyhemoglobin affinity was associated with significantly lower O2 extractions in the carbamylated group. Significant extraction reserve was present in both the control and carbamylated groups as demonstrated by the fact that O2 extraction could still increase well above control levels when perfusion pressure was lowered. We conclude that there is no significant vasodilatory compensation for moderate increases in oxyhemoglobin affinity, despite the continued presence of autoregulatory vasodilatory reserve.

Myocardial oxygen transport during leftward shifts of the oxygen dissociation curve by carbamylation or hypothermia.

An isolated dog heart preparation was used to study the effect of left-shifting the O2 dissociation curve by carbamylation or hypothermia. The two interventions had a similar effect on the variables of O2 delivery. There were significant decreases in myocardial O2 consumption, coronary sinus PO2, and O2 extraction. There was no compensatory increase in O2 transport. Coronary flow autoregulation was somewhat blunted by hypothermia but not by carbamylation. We conclude that an increase in hemoglobin-O2 affinity is capable of limiting myocardial O2 delivery and that increases in convective O2 transport play a minor role at best in the coronary adaptation to small decreases in P50.

Maximum myocardial oxygen transport during anemia and polycythemia in dogs.

The purpose of this study was to determine the effect of hematocrit changes on coronary pressure-flow relations during maximum vasodilation to define the relative importance of changes in hemoglobin concentration, blood viscosity, and perfusion pressure in determining maximum myocardial oxygen transport. An anemic group and a polycythemic group of dogs were studied under halothane anesthesia at the hematocrit extremes and after serial exchange transfusions to intermediate hematocrits. Circumflex pressure-flow relations were generated at each hematocrit during maximum pharmacological vasodilation (adenosine 20 micrograms X kg-1 X min-1 or chromonar 8 mg/kg). Maximal coronary vascular conductance (incremental conductance) decreased in an approximately linear fashion with increasing hematocrit. Maximum myocardial oxygen transport showed an "inverted U-shape" relation to hematocrit with the peak occurring at or slightly above normal hematocrit. Hemoglobin concentration, viscosity, and perfusion pressure were all found to be physiologically important determinants of maximal myocardial oxygen transport. Given normal perfusion pressure, arterial oxygen saturation, and myocardial oxygen extraction, we found that maximum myocardial oxygen delivery greatly exceeds the level necessary to supply basal myocardial oxygen needs at all hematocrits studied.

Pulmonary injury depresses cardiac systolic function through Starling mechanism.

To determine whether pulmonary microvascular injury or lung hyperinflation changes left ventricular (LV) performance and whether ventricular interaction plays a role in mediating such changes, we studied seven open-chest, closed-pericardium, anesthetized dogs before and after right ventricular (RV) injections of 150- to 200-micron glass beads. Because people with pulmonary disease are often treated with positive end-expiratory pressure, we also hyperinflated the lungs before and after creating the pulmonary microvascular injury. Measurements of LV and RV pressures and dimensions were taken at end expiration during the basal state, during lung hyperinflation, and after microvascular injury at RV end-diastolic pressures of 5, 10, and 15 mmHg produced by volume loading. Acute volume loading produced upward shifts in the LV diastolic pressure-size curve both before and after microvascular injury. Neither microvascular injury nor lung hyperinflation substantially affected the LV diastolic pressure-size relationship. LV end-diastolic size determined LV stroke work with no consistent independent influence of microvascular injury or lung hyperinflation. Neither microvascular injury nor lung hyperinflation depressed systolic performance beyond that associated with changes in end-diastolic heart size.

Regulation of transmural myocardial blood flow.

A major problem in understanding how myocardial blood flow is regulated is the common occurrence of subendocardial ischemia in many diseases, with or without coronary arterial disease. Two commonly held explanatory hypotheses were that high systolic intramyocardial pressures prevented flow to deep but not superficial muscle, or that in diastole tissue pressures were highest subendocardially. Neither hypothesis is tenable today, and the likeliest hypothesis is that retrograde systolic flow from the deeper muscle produces a longer time constant for diastolic flow in deep than in superficial muscle.

Pulmonary artery constriction produces a greater right ventricular dynamic afterload than lung microvascular injury in the open chest dog.

Investigators model noncardiogenic pulmonary hypertension by constricting the pulmonary artery to increase right ventricular afterload. To investigate this model's validity, we compared the right ventricular afterload, quantified as pulmonary input impedance, created by constricting the pulmonary artery and by inducing a pulmonary microvascular injury (with glass beads infused into the pulmonary circulation). The pulmonary injury constriction produced a different right ventricular afterload than the microvascular injury. The constriction increased both the input resistance and the characteristic impedance. Microvascular injury increased only input resistance. Physiological levels of lung inflation did not influence pulmonary impedance, but lung hyperinflation increased input resistance both before and while constricting the pulmonary artery or after producing microvascular injury. Total right ventricular power output and stroke work were unchanged during each vascular intervention. Pulmonary artery constriction did not affect power output distribution, whereas microvascular injury decreased oscillatory power and its relative contribution to total power. Lung hyperinflation dramatically reduced right ventricular power and left ventricular stroke work. These effects appeared mediated by right ventricular afterload increase uncompensated for by right ventricular preload increase. These observations help explain the hemodynamic consequences of acute pulmonary hypertension and the effects of lung hyperinflation with positive end-expiratory pressure respiration in such patients.

Effects of pressure gradients between branches of the left coronary artery on the pressure axis intercept and the shape of steady state circumflex pressure-flow relations in dogs.

When steady state pressure-flow relations are studied in the circumflex coronary artery, pressure gradients develop between it and other branches of the left coronary artery. To assess the effects of these pressure gradients, we compared the pressure axis intercept and shape of steady state circumflex pressure-flow relations in the presence and absence of gradients after autoregulation was abolished, both in the beating heart and during long diastoles in dogs. We used peripheral coronary pressures and radionuclide-labeled microspheres to assess arterial collateral flow. In the beating heart, interarterial pressure gradients reduced the curvature at low circumflex pressures, and overestimated the mean pressure axis intercept by 7.8 mm Hg (P less than 0.05). The results were similar for the pressure-flow relations derived during long diastoles. This overestimation exaggerates the difference between the pressure axis intercept and coronary sinus pressure. The peripheral coronary pressure and microsphere results indicate that these effects are mediated largely by arterial collateral flow.

The effects of cardiopulmonary bypass on coronary blood flow in the dog.

The effects of cardiopulmonary bypass on autoregulation, maximum coronary flow, and regional blood flow in the heart were investigated in 25 dogs. A Gregg cannula was inserted into the left main coronary artery, and pressure-flow relations were then measured in the autoregulating state or with vasodilation produced by intracoronary adenosine infusion before, during, and after cardiopulmonary bypass. Seventeen of the dogs had radioactive microspheres injected to investigate regional blood flow changes at the same times. (1) Autoregulation was not present after bypass for at least 3 hours. (2) Blood flow was shifted toward the subendocardium on bypass (increased subendocardial/subepicardial ratio) and tended to return to prebypass distribution following bypass. (3) Blood flow after bypass was not significantly different to the subendocardium and subepicardium. (4) Response to a coronary vasodilator (maximum coronary flow) was significantly affected by cardiopulmonary bypass: blood flow to all layers of the heart could be increased with adenosine after bypass. (5) Global lactate and oxygen metabolism were not adversely affected by bypass. We conclude that cardiopulmonary bypass abolished the normal autoregulation of coronary flow; this may predispose the incompletely revascularized patient to a "coronary steal" syndrome. However, the heart with normal coronary arteries is not underperfused in any layer after bypass. Thus, the bypass technique is not the cause of the subendocardial ischemia that sometimes complicates cardiac operations.

Arterial and venous coronary pressure-flow relations in anesthetized dogs. Evidence for a vascular waterfall in epicardial coronary veins.

The coronary circulation of anesthetized dogs was tested for the presence of vascular waterfalls by manipulating coronary arterial and coronary venous pressures. The left main coronary artery and the coronary sinus were cannulated, and relationships between coronary artery pressure, coronary sinus pressure, and coronary flow were studied. Experiments were conducted during diastolic arrests, under steady state conditions, in the absence of autoregulation. Relations of coronary flow to coronary sinus pressure at constant coronary artery pressure were consistent with the presence of a vascular waterfall in the coronary sinus. When the great cardiac vein was cannulated, relations of great vein flow to great vein pressure at constant coronary artery pressure were consistent with the presence of a vascular waterfall in the great vein, indicating that waterfall behavior can occur in epicardial veins other than the coronary sinus. In dogs on right heart bypass, with the coronary sinus and great vein uncannulated, the relationship between right atrial pressure and coronary sinus pressure showed a waterfall pattern, indicating that the waterfall is not an artifact of venous cannulation. In the right heart bypass experiments, venous waterfall behavior was seen in beating hearts as well as during diastolic arrests. We conclude that a vascular waterfall is present in epicardial coronary veins which can significantly influence coronary blood flow.

Instantaneous renal arterial pressure-flow relations in anesthetized dogs.

Instantaneous renal arterial pressure-flow (P/ Qra ) relations were investigated in 11 anesthetized dogs using the nonpulsatile fall in aortic pressure and renal arterial flow ( Qra ) during cardiac arrest caused by vagal stimulation. We found that P/ Qra relations were linear with an extrapolated zero flow intercept (Ped, effective downstream pressure) of 20.8 +/- 1.9 mmHg and the reciprocal of the slope (Ra, arterial resistance) of 0.6 +/- 0.04 mm Hg X ml-1 X min. These values are markedly lower than the values found in similar experiments in coronary and femoral arteries. Raising renal venous pressure (5 dogs) decreased Qra and elevated Ra and Ped in the ipsilateral renal artery while decreasing Qra and elevating Ra but not Ped in the contralateral renal artery. Carotid artery occlusion (6 dogs) decreased Qra and elevated Ra and Ped. Alpha-Adrenergic blockade (4 dogs) lowered Ped and Ra. Arterial resistance seems to be more important for change in P/Q relations in the renal arterial bed than it is in other arterial beds investigated so far. We suggest that the effective downstream pressure to renal arterial flow is downstream from the glomerular capillaries. The location of the "vascular waterfall " phenomenon appears to be between the intrarenal veins and the veins outside the capsule.

Increased number of myocardial blood flow measurements with radionuclide-labeled microspheres.

We evaluated the use of a least-squares radionuclide separation technique to allow an increased number of myocardial blood flow measurements with radionuclide-labeled microspheres in dogs. Two sets of labeled microspheres were studied: a set of eight labeled with 125I, 153Gd, 57Co, 51Cr, 113Sn, 85Sr, 95Nb, and 46Sc; and a set of nine in which 125I and 46Sc were replaced with 114In, 54Mn, and 65Zn. For each microsphere label the nuclide activities determined by least-squares separation compared favorably with those actually added to in vitro samples containing a fixed amount of the other nuclides in the set. For the set of eight radionuclide-labeled microspheres, myocardial flow measurements made with the least-squares separation technique and the reference sample method were usually within 15% and almost all within 20% of direct measurements of coronary venous outflow in a right heart bypass preparation. Serial left atrial injections of 15-micron microspheres totaling 48 X 10(6) caused no significant changes in systemic hemodynamics, regional myocardial flows, or coronary pressure-flow relations, whether the coronary bed was autorelating or vasodilated with chromonar. We conclude that at least nine myocardial blood flow measurements can be made in dogs with acceptable accuracy and without evidence of dysfunction due to embolization of the coronary vascular bed. With appropriate validation, this method should be applicable to other organs and animal models as well.

A canine model of acute coronary artery stenosis: effects of deliberate hypotension.

Coronary artery disease is considered a contraindication to inducing hypotension during surgery because the combined effects of stenosis and hypotension in reducing distal coronary artery perfusion pressure might produce myocardial ischemia. To study the effect of deliberate hypotension (mean systemic pressure, 50 mmHg) on regional myocardial perfusion, oxygenation, and lactate extraction, we constricted the left-anterior descending coronary artery (LADCA) in dogs. Two degrees of stenosis were studied: "critical" stenosis, which reduced resting coronary blood flow from 34.4 to 31.2 ml/min and abolished reactive hyperemia of the LADCA in response to 10 s of total coronary artery occlusion; and a more "severe" stenosis, which reduced resting coronary blood flow by 40%. LADCA pressure was measured distal to the stenosis, and LADCA perfusion pressure was obtained by subtracting the left ventricular end-diastolic pressure from the coronary artery diastolic pressure measured past the stenosis. Hypotension was induced by administering sodium nitroprusside, halothane at a high concentration, or trimethaphan. Lactate extraction and oxygen consumption were measured across the myocardium distal to the stenosis (from the coronary artery to the great cardiac vein) and across the whole heart (from the coronary artery to the coronary sinus). Regional myocardial blood flow was measured using radioactive microspheres. A transmural electrocardiogram was obtained from electrodes implanted in the subendocardium and the subepicardium in the distribution of the LADCA distal to the stenosis. Although the combination of critical stenosis and hypotension reduced regional myocardial blood flow and lowered LADCA perfusion pressure to 27 +/- 3 (SE) mmHg, myocardial ischemia did not occur, as evidenced by continued lactate extraction and no redistribution of transmural blood flow or change in ST segment. On the other hand, the combination of severe stenosis and hypotension reduced LADCA perfusion pressure to 17 +/- 2 (SE) mmHG and produced evidence of ischemia by regional lactate production, reduction of the subendocardial/subepicardial flow ratio, and depression of the ST segment.

Direct measurement of left ventricular interstitial adenosine.

Characterization of adenosine's role as a regulator of coronary blood flow requires accurate measurement of endogenous adenosine concentration in the left ventricular (LV) interstitial compartment. Existing techniques for determining adenosine in this compartment are indirect, requiring the acceptance of major assumptions before conclusions can be drawn. We describe a new technique utilizing a LV epicardial diffusion well that allows us to make rapid, direct measurement of LV interstitial adenosine concentration, avoiding many problems inherent in existing techniques. Our results show adenosine concentrations of 555 pmol/ml in resting anesthetized dogs, indicating a resting adenosine level well within the vasoactive range. Further experiments using intramyocardial bolus injections of methylene blue dye and [8-14C]adenosine indicate that the epicardial well receives adenosine from a transmural distribution of LV interstitium and not from epicardial sources only. The transmural interstitial adenosine is transported via small lymphatics to the epicardial surface of the heart where diffusion occurs into the epicardial well. We also examined diffusion characteristics of the parietal pericardial membrane and found that the rate constant of adenosine diffusion for this and the visceral pericardium are of the same order of magnitude, indicating that the extensively used standard pericardial superperfusate method probably underestimates cardiac interstitial adenosine concentration by 50% or more. The influence of the parietal pericardium adequately explains why our resting adenosine concentrations using the epicardial well are higher than those recently reported using the standard pericardial superperfusate method.

Acute and chronic microsphere loss from canine left ventricular myocardium.

We determined the effects of time, type of anesthesia, and myocardial infarction on loss of radioactive microspheres averaging 9 or 15 micrometers diameter from left ventricular myocardium. The principle used to compute losses was comparison of the number of microspheres injected directly into coronary arteries to the numbers remaining in myocardium, appearing within 2-4 min in the coronary sinus, or trapped in the lungs. Losses of 9-micrometers microspheres within 2 min of injection were significantly greater for halothane (mean 6.3%) than nitrous oxide anesthesia (mean 3.3%), and in the next 2 h increased to 11.7 and 7.9%, respectively. Over 5 wk in conscious dogs losses were as high as 40 and 11% for 9 and 15 micrometers microspheres, respectively. Losses were not greater for infarcted than normal muscle, and negligible radioactivity appeared in paracardiac lymph nodes. Microspheres leaving the heart were almost all below 10.3 micrometers diameter, so that microspheres with diameters 10-14 (mean 12) micrometers might be the best size to use for myocardial studies.

Effect of coronary sinus occlusion on coronary pressure-flow relations.

We studied the effect of transient occlusion of the coronary sinus on the relationship between aortic pressure and circumflex coronary blood flow in open-chest anesthetized dog preparations during artificially prolonged diastoles. The coronary pressure-flow relation was linear, and flow stopped at an arterial pressure (Pf = 0) that always exceeded coronary venous pressure (Pcv). During reactive hyperemia, Pf = 0 was 31 mmHg when Pcv was 5 mmHg and increased to 52 mmHg when the coronary sinus was occluded (Pcv, 38 mmHg). Elevation of Pcv translated the coronary pressure-flow relation to a higher Pf = 0 without altering the slope of the relation. Pf = 0 increased by about two-thirds of the increase in Pcv. We found no evidence that there existed a level of Pcv below which changes in Pcv had no effect on the coronary pressure-flow relation. These data are not compatible with the existence of a vascular waterfall mechanism in the coronary circulation unless it is assumed that Pcv is one of the determinants of Pf = 0.