Digital ischemia and gangrene due to red blood cell aggregation induced by acquired dysfibrinogenemia.

Digital gangrene was observed in a patient who had angiographic findings of digital arterial occlusion. The patient's blood showed a marked red blood cell aggregation with rouleaux formation in long chains, which could not be dispersed at shear rates up to 200 sec-1. Studies of the patient's blood revealed the presence of an abnormal fibrinogen capable of aggregating normal red blood cells. This fibrinogen was found by Raman spectroscopy to have an increased alpha-helical content, whereas the beta-sheet content was decreased. Defibrinogenation therapy with ancrod resulted in a dramatic symptomatic relief. The disappearance of the abnormal fibrinogen 6 months later and an absence of a family history indicate that this dysfibrinogenemia was acquired.

Effect of jet ventilation on heart failure: decreased afterload but negative response in left ventricular end-systolic pressure-volume function.

OBJECTIVE: To examine the mechanism of cardiac assist with systolic jet ventilation, specifically effects on loading conditions and left ventricular pressure-volume function. Both systolic and diastolic jet ventilation were compared in the absence and presence of heart failure. DESIGN: Prospective, two-factor, repeated-measures study. SETTING: Animal laboratory. SUBJECTS: Ten anesthetized, closed-chest dogs. INTERVENTIONS: The measurement protocol consisted of two phases: a) apnea, randomized jet ventilation (systole- and diastole-synchronized); b) postjet ventilation apnea, before and after heart failure, induced with a propranolol-imipramine-plasma expansion treatment. MEASUREMENT AND MAIN RESULTS: Systolic and diastolic jet ventilation was associated with mean airway pressures of approximately 7 mm Hg and intrapleural pressures of approximately 3 mm Hg in both heart conditions. In normal hearts, jet ventilation (either mode) decreased transmural left ventricular end-diastolic pressure by 40% to 60% (p < .05), left ventricular end-diastolic volume 25 +/- 8%, and stroke volume by 28% to 30%. Heart failure was associated with decreases (41 +/- 6%) in end-systolic pressure-volume function (i.e., pressure change/volume change or elastance), transmural left ventricular end-systolic pressure (22 +/- 3%), and stroke volume (16 +/- 4%), and increased transmural left ventricular end-diastolic pressure (139 +/- 6%). Application of jet ventilation (either mode) during heart failure did not affect stroke volume but significantly (p < .05) attenuated transmural left ventricular end-diastolic pressure by 30% to 40%, left ventricular end-diastolic volumes by 33 +/- 9%, and transmural left ventricular end-systolic pressure by 11% to 19% (p < .05). After jet ventilation, left ventricular elastance was decreased 36 +/- 8% in normal hearts and 35 +/- 11% in failing hearts. Stroke volume, however, returned to baseline levels because of increases in transmural left ventricular end-diastolic pressure in both heart conditions, and also in failing hearts, because transmural left ventricular end-systolic pressure remained decreased approximately 30% (p < .05). CONCLUSIONS: Jet ventilation did not decrease stroke volume in failing hearts because of the afterload-reducing benefit (decreased transmural left ventricular end-systolic pressure) of increased intrapleural pressure in dilated ventricles. Moreover, jet ventilation did not have positive effects on myocardial function and had negative effects on left ventricular elastance in the postjet ventilation period in both normal and failing hearts. Cardiac assist by jet ventilation was not cycle specific, suggesting no selective benefit of jet ventilation over conventional positive-pressure ventilation during heart failure. These studies demonstrate a negative inotropy associated with jet ventilation that, during heart failure, may compromise the general benefit of positive-pressure-mediated increases in intrapleural pressure.

Tourniquet-induced exsanguination in patients requiring lower limb surgery. An ischemia-reperfusion model of oxidant and antioxidant metabolism.

BACKGROUND: Surgically induced ischemia and reperfusion is frequently accompanied by local and remote organ injury. It was hypothesized that this procedure may produce injurious oxidants such as hydrogen peroxide (H2O2), which, if unscavenged, will generate the highly toxic hydroxyl radical (.OH). Accordingly, it was proposed that tourniquet-induced exsanguination for limb surgery may be a useful ischemia-reperfusion model to investigate the presence of oxidants, particularly H2O2. METHODS: In ten patients undergoing knee surgery, catheters were placed in the femoral vein of the limb operated on for collection of local blood and in a vein of the arm for sampling of systemic blood. Tourniquet-induced limb exsanguination was induced for about 2 h. After tourniquet release (reperfusion), blood samples were collected during a 2-h period for measurement of H2O2, xanthine oxidase activity, xanthine, uric acid (UA), glutathione, and glutathione disulfide. RESULTS: At 30 s of reperfusion, H2O2 concentrations increased (approximately 90%) from 133 +/- 5 to 248 +/- 8 nmol.ml-1 (P < 0.05) in local blood samples, but no change was evident in systemic blood. However, in both local and systemic blood, xanthine oxidase activity increased approximately 90% (1.91 +/- 0.07 to 3.93 +/- 0.41 and 2.19 +/- 0.07 to 3.57 +/- 0.12 nmol UA.ml-1.min-1, respectively) as did glutathione concentrations (1.27 +/- 0.04 to 2.69 +/- 0.14 and 1.27 +/- 0.03 to 2.43 +/- 0.13 mumol.ml-1, respectively). At 5 min reperfusion, in local blood, H2O2 concentrations and xanthine oxidase activity peaked at 796 +/- 38 nmol.ml-1 (approximately 500%) and 11.69 +/- 1.46 nmol UA.ml-1.min-1 (approximately 520%), respectively. In local blood, xanthine and UA increased from 1.49 +/- 0.07 to 8.36 +/- 0.33 nmol.ml-1 and 2.69 +/- 0.16 to 3.90 +/- 0.18 mumol.ml-1, respectively, whereas glutathione and glutathione disulfide increased to 5.13 +/- 0.36 mumol.ml-1 and 0.514 +/- 0.092 nmol.ml-1, respectively. In systemic blood, xanthine oxidase activity peaked at 4.75 +/- 0.20 UA nmol.ml-1.min-1. At 10 min reperfusion, local blood glutathione and UA peaked at 7.08 +/- 0.46 mumol.ml-1 and 4.67 +/- 0.26 mumol.ml-1, respectively, while the other metabolites decreased significantly toward pretourniquet levels. From 20 to 120 min, most metabolites returned to pretourniquet levels; however, local and systemic blood xanthine oxidase activity remained increased 3.76 +/- 0.29 and 3.57 +/- 0.37 nmol UA.ml-1.min-1, respectively. Systemic blood H2O2 was never increased during the study. During the burst period (approximately 5-10 min), local blood H2O2 concentrations and xanthine oxidase activities were highly correlated (r = 0.999). CONCLUSIONS: These studies suggest that tourniquet-induced exsanguination for limb surgery is a significant source for toxic oxygen production in the form of H2O2 and that xanthine oxidase is probably the H2O2-generating enzyme that is formed during the ischemia-reperfusion event. In contrast to the reperfused leg, the absence of H2O2 in arm blood demonstrated a balanced oxidant scavenging in the systemic circulation, despite the persistent increase in systemic xanthine oxidase activity.

Comparison of hemodynamic responses to pipecuronium and doxacurium in patients undergoing valvular surgery while anesthetized with fentanyl.

Hemodynamic responses to pipecuronium bromide or doxacurium chloride were compared in patients undergoing valvular heart surgery. Thirty ASA class III-IV patients of either sex, mean age 62 +/- 3 years (+/- SD), weight 70 +/- 3 kg, were randomly selected to receive either doxacurium (0.08 mg/kg) or pipecuronium (0.15 mg/kg). Hemodynamic parameters were determined at preinduction, induction, 2 minutes and 6 minutes following administration of the muscle relaxant. Anesthetic induction consisted of midazolam, 0.10 mg/kg, followed by fentanyl, 5 micrograms/kg. Measured or calculated parameters were as follows: mean arterial pressure, heart rate, cardiac index, mean pulmonary artery pressure, systemic vascular resistance index, central venous pressure, pulmonary capillary wedge pressure, stroke volume index, left and right stroke work indices, and pulmonary vascular resistance index. Awake patients who had been randomly assigned to the pipecuronium group had significantly higher pulmonary capillary wedge pressures (22 +/- 2 v 15 +/- 2 mmHg; P < 0.05) and heart rates (86 +/- 3 v 64 +/- 5 beats/min; P < 0.05) than awake patients in the doxacurium group. Following induction, both wedge pressure and heart rate were not significantly different between the two groups. Compared to hemodynamics at induction, there were no clinically significant changes following administration of pipecuronium or doxacurium.

Urine hydrogen peroxide during adult respiratory distress syndrome in patients with and without sepsis.

BACKGROUND: The lung injury in adult respiratory distress syndrome (ARDS) has been associated with increased expiratory hydrogen peroxide (H2O2) concentrations. Furthermore, patients with sepsis and ARDS are reported to have greater serum scavenging of H2O2 than patients with ARDS only. We hypothesized that the systemic presence of H2O2 would be detectable in the urine of these two groups of patients and that, in the case of ARDS sepsis, the relative contribution of each disease to the production this analyte would be discernible. Accordingly, we used an in vitro radioisotope assay to follow the weekly course of urine H2O2 levels in ARDS patients with and without sepsis, and in samples from control non-ARDS patients with sepsis with indwelling urinary catheters and in samples provided by healthy volunteers. METHODS: Thirty patients with ARDS were included in the study: 23 had sepsis and 7 were sepsis free. An indwelling catheter was used to collect urine from each patient over a 24-h period, first within 48 h of ICU admission and then every seventh day over the course of their illness. Urine H2O2 was measured by competitive decarboxylation of 1-14C-alpha-ketoglutaric acid by H2O2. Urine samples were provided by 20 healthy volunteers while, in 10 non-ARDS patients with sepsis, urine was collected over one 24-h period following a 5-day minimum with an indwelling urinary catheter. RESULTS: Urine H2O2 concentration in healthy control subjects (88 +/- 4 mumol/L) and non-ARDS patients with urinary catheters (96 +/- 5 mumol/L) was not significantly different. During the first 48 h in the ICU, urine H2O2 in patients with ARDS only (295 +/- 29 mumol/L) was significantly lower (p < 0.05) than patients with ARDS and sepsis (380 +/- 13 mumol/L); however, the lung injury scores of these two groups did not differ. Furthermore, within the first 48 h, the urine H2O2 of the patients with ARDS and sepsis who did not survive (427 +/- 19 mumol/L; n = 7) was significantly higher than that in patients who survived sepsis (352 +/- 14 mumol/L; n = 15). Thereafter, the lung injury scores and urine H2O2 levels of the nonsurvivor ARDS-sepsis group remained significantly higher compared with the other two groups. At lung injury scores of 3 and 2, regardless of days in ICU, the patients with ARDS only had significantly lower urine H2O2 (266 +/- 30 mumol/L and 167 +/- 24 mumol/L, respectively) compared with the survivor ARDS-sepsis group (376 +/- 19 mumol/L and 250 +/- mumol/L). When the patients with ARDS (both ARDS only and with sepsis) recovered, their urine H2O2 concentration did not differ from the control groups (healthy donors and patients without ARDS). CONCLUSION: Lung injury scores did not differentiate patients with ARDS and sepsis from patients with ARDS only during the first 10 days in the ICU; however, urine H2O2 levels were significantly greater in the patients with ARDS and sepsis. Moreover, despite no initial difference in lung injury, patients who did not survive ARDS and sepsis had consistently greater urine H2O2 concentration than patients who survived sepsis. The urine H2O2 level in the ARDS-only group was about 70 percent of the level in the survivor ARDS and sepsis group, suggesting that ARDS alone is the major contributor to the H2O2 oxidant processes during combined ARDS and sepsis. Furthermore, these studies demonstrate that urine H2O2 may be a useful analyte to differentiate the severity of oxidant processes in patients with ARDS and sepsis albeit the prognosis appears to be survival or nonsurvival.

Separation of myocardial versus peripheral effects of calcium administration in normocalcemic and hypocalcemic states using pressure-volume (conductance) relationships.

This study used left ventricular pressure-volume (conductance) relationships to separate the effects of calcium administration on myocardial performance and peripheral vasoconstriction in normocalcemic and hypocalcemic states. Hypocalcemia was produced in anesthetized dogs with intravenous citrate-phosphate-dextrose until serum [Ca2+] was approximately 0.7 mmol/L. Calcium (CaCl2) bolus (5 mg/kg) was administered during normocalcemia (n = 6) and hypocalcemia (n = 6), and data were collected at 1, 5 and 10 min after CaCl2 administration. During normocalcemia, CaCl2 administration increased [Ca2+] 19% at 1 min and was accompanied by a 47% (P < 0.05) decrease in left ventricular contractility (i.e., end-systolic elastance or E(lves)) and a 13% (P < 0.05) increase in systemic vascular resistance. At 5 and 10 min, serum [Ca2+] and the hemodynamic variables began to return to the baseline values. During hypocalcemia, E(lves) decreased 25% (P < 0.05), but after CaCl2 bolus, it increased to baseline levels and remained there during the 10-min period. Hypocalcemia and the CaCl2 bolus did not significantly affect SVR. In conclusion, these studies suggest that the indications for the use of calcium should depend on the initial serum level of ionized calcium.

Hemodilution with oxyhemoglobin. Mechanism of oxygen delivery and its superaugmentation with a nitric oxide donor (sodium nitroprusside).

BACKGROUND: Hemodilution (HD) with oxyhemoglobin colloid (oxyHb) provides a greater arterial oxygen content (CaO2) than HD with conventional colloids; however, oxygen delivery (DO2) is essentially the same, because, in contrast to conventional HD, cardiac output (CO) is not augmented. This study seeks to elucidate the mechanism that limits CO during oxyHb-HD and to test whether infusion of a nitric oxide (NO) donor would augment DO2, because oxyHb is known to inactivate in vitro endothelial-derived NO. METHODS: Anesthetized dogs were isovolemically hemodiluted with 10% oxyHb, 8% albumin, or 10% methemoglobin (weak NO inactivator) to 20% hematocrit. After HD, sodium nitroprusside (SNP) was titrated intravenously until decreases (> 10 mmHg) in mean aortic pressure (Pao) indicated the presence of exogenous NO. Systemic hemodynamics and regional blood flows (microsphere method) were measured. RESULTS: Albumin-HD and metHb-HD produced typical HD-mediated responses: increased CO (63-65%), slight decreases (13-15%) in DO2, decreases in systemic vascular resistance (SVR) proportional to the decreases (49-52%) in blood viscosity of all three groups, and increased regional blood flows (RBF). Responses to oxyHb-HD were atypical: CO and its determinants were not changed, DO2 decreased (23%) proportional to CaO2, and SVR and most RBF were not changed except for a net redistribution of CO to myocardium and skeletal muscle. In albumin-HD or metHb-HD, SNP (2-5 micrograms.kg-1.min-1) induced comparable decreases in mean Pao (29-37%) and SVR (39-41%); however, CO, RBF, and DO2 were not affected. In oxyHb-HD, exceptionally large doses of SNP (54 +/- 5 micrograms.kg-1.min-1) decreased mean Pao only 19 +/- 1%; however, CO increased 78 +/- 5% and decreases (61 +/- 3%) in SVR were slightly greater than viscosity reductions. Other determinants of CO were not affected. Most RBF increased proportional to CO; there was, however, preferential distribution to myocardium and skeletal muscle. Consequently, the augmented CO, and CaO2 of oxyHb-HD, produced large increases in DO2, 77 +/- 5% from HD alone and 43 +/- 3% from prehemodilution values. CONCLUSIONS: This study indicates that the limited CO and DO2 of oxyHb-HD resulted from opposing changes in two determinants of flow, i.e., reduced blood viscosity and increased arterial resistance (vasoconstriction). The vasoconstriction was not evident with metHb-HD and was reversed by the SNP infusion, indicating that oxyHb inactivated in vivo endothelial-derived NO. The ability of the NO donor (SNP) to facilitate large viscosity-mediated increases in DO2 during oxyHb-HD is an important finding that could potentially render oxyHb colloids more useful than conventional colloids, particularly for the individual with a compromised circulation who would benefit from an increased oxygen supply.

Effects of fentanyl on coronary blood flow distribution and myocardial oxygen consumption in the dog.

Little data exist on the effects of fentanyl on coronary blood flow (CBF), myocardial oxygen balance, and the regional distribution of blood flow. These studies were designed to determine whether fentanyl had any intrinsic effects on myocardial oxygen consumption (MVO2) and blood flow distribution. In anesthetized dogs, fentanyl was administered in a dose of 50 micrograms/kg and various measurements were made at 5 and 20 minutes. After hemodynamic recovery from the fentanyl, the animals were treated with atropine to block the known vagomimetic effect of fentanyl and challenged with acetylcholine (3.5 micrograms/kg); then fentanyl (50 micrograms/kg) was again administered and measurements made at 5 and 20 minutes. In the untreated dogs at 5 minutes post-fentanyl, heart rate (HR) decreased 30% and at 20 minutes decreased 29%. Treatment with atropine essentially eliminated HR changes at both time periods. Mean arterial pressure (MAP) fell by 20% and 22% at 5 minutes and 20 minutes, respectively, in the untreated group, but when atropine was administered, MAP was observed to be intermediate between baseline and the untreated animals. Left ventricular MVO2 at 5 minutes in the untreated group was modestly but not significantly reduced. However, at 20 minutes post-fentanyl, MVO2 decreased significantly. MVO2 was essentially unchanged after atropine. Regional CBF (measured by radiolabelled microspheres) was unchanged at 5 minutes, but all layers exhibited significant reductions at 20 minutes. In the atropine group, only the LV epicardial area appeared to show decreases in flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggressive hydration during continuous positive-pressure ventilation restores atrial transmural pressure, plasma atrial natriuretic peptide concentrations, and renal function.

BACKGROUND AND METHODS: The correlations between continuous positive-pressure ventilation-induced antidiuresis/antinatriuresis, atrial transmural pressure, and atrial natriuretic peptide concentrations have not been clarified. The purpose of the present study was to use aggressive hydration to restore atrial transmural pressure during continuous positive-pressure ventilation and to test for correlations of atrial transmural pressure, atrial natriuretic peptide concentration, diuresis, and natriuresis during this intervention. An intrapleural catheter was used to measure atrial transmural pressure in three ways: a) right atrial pressure minus intrapleural pressure, b) left ventricular end-diastolic pressure minus intrapleural pressure, and c) pulmonary artery occlusion pressure minus intrapleural pressure. Hemodynamic, atrial natriuretic peptide concentrations, and renal measurements were made in 12 anesthetized closed-chest dogs during baseline (intermittent positive-pressure ventilation), during continuous positive-pressure ventilation), during continuous positive-pressure ventilation with 10 cm H2O end-expiratory pressure, and during continuous positive-pressure ventilation plus aggressive hydration (approximately 60 mL/kg lactated Ringer's solution). Pearson's correlation matrix was used to generate all possible correlation coefficients between the three atrial transmural pressures, atrial natriuretic peptide concentrations, urine output, and urine sodium excretion. RESULTS: Application of continuous positive-pressure ventilation resulted in a 60% decrease in right atrial transmural pressure (p less than .05), a 51% decrease in left ventricular end-diastolic transmural pressure (p less than .05), and a 26% decrease in pulmonary artery occlusion transmural pressure (p less than .05) from baseline. Plasma atrial natriuretic peptide concentration decreased from 80 +/- 12 (SEM) pg/mL at baseline to 49 +/- 8 pg/mL during continuous positive-pressure ventilation (p less than .05). Both urine output and sodium excretion decreased by 81% (p less than .05). After aggressive hydration with lactated Ringer's solution during continuous positive-pressure ventilation, to restore atrial transmural pressure to baseline, plasma atrial natriuretic peptide concentration returned to baseline values (81 +/- 12 pg/mL) as did urine output and sodium excretion. Correlation indices (r2 values) between transmural pressure, atrial natriuretic peptide concentration, urine output, and sodium excretion ranged from .835 to .994. Multivariate analysis of covariance demonstrated significant (p less than .05) temporal dependence between the three transmural pressures, atrial natriuretic peptide concentration, urine output, and sodium excretion. CONCLUSIONS: The results demonstrate that aggressive hydration during continuous positive-pressure ventilation will restore diuresis and natriuresis and that this response correlates significantly with atrial transmural filling pressure and plasma atrial natriuretic peptide concentration.

On the interaction of the liposomal membrane with blood components.

Liposome-encapsulated hemoglobin (LEH) has been shown to be a viable candidate as a blood replacement. However, few data have been presented as to how LEH interacts with normal blood components. Liposomes were prepared from egg lecithin, cholesterol, and dicetyl phosphate or phosphatidic acid, and mixed with fresh blood plasma or whole blood. Erythrocyte osmotic fragility, prothrombin time (extrinsic coagulation efficiency), activated partial thromboplastin time (intrinsic coagulation efficiency), plasma clot stability in urea (fibrin stabilizing factor), and clot retraction (platelet activation) were measured. Although liposomes were found to bind extensively to erythrocytes, all tests indicated that the liposomes had no significant adverse effects, provided that normal levels of plasma Ca++ were maintained. The ability of liposomes to absorb Ca++ from the plasma was related directly to the amount of dicetyl phosphate or phosphatidic acid present and thus, presumably, to the presence of negatively charged species in the membrane. The mechanics of deformation of the LEH membrane were investigated by encapsulating Hemoglobin S in liposomes. Liposomes containing Hemoglobin S were found to sickle when deoxygenated, but not liposomes containing normal hemoglobin. Shape analysis of sickled liposomes yielded a deforming stress of 10(6) dynes/cm2, about 50 times greater than the reported limit for shear elasticity of the erythrocyte membrane.

Lack of increased cardiac output during hemoglobin hemodilution can be reversed with sodium nitroprusside.

To investigate a possible connection between EDRF or nitric oxide (NO) and the unchanged cardiac output (CO) during hemoglobin-hemodilution we infused nitroprusside (NP) in eight Hb-diluted dogs (Hct approximately 20%). Normal hypotensive doses of NP were not effective and supranormal doses (133.0 micrograms/kg/min) were needed to induce even a modest decrease in mean AoP (approximately 25 mmHg). With these NP doses, cardiac output increased 177%, diastolic AoP (afterload) decreased 30%, while systolic AoP and LVEDP (preload) were unchanged. Heart rate, LV contractility (pressure-volume function) and blood volume were not changed throughout the study. Normally, NP alone decreases both preload and afterload resulting in unchanged CO. In the Hb + NP dogs, CO increased because only afterload decreased suggesting a selective effect of Hb on venous and arterial smooth muscle relaxation. In hemodilution with nonhemoglobin colloids, CO increases primarily because the diluted blood offers less viscous resistance to ventricular ejection. It appears that in order for cardiac output to increases in the presence of Hb, some decrease in arteriolar resistance is needed, presumably to unmask the effects of reduced viscosity. These results suggest the unchanged CO during Hb-dilution is related to a selective effect of Hb on venous and arteriolar nitric oxide (EDRF) function.

Skeletal muscle blood flow and O2 uptake during intravenous nicotine with and without hypertension.

The mechanism by which nicotine causes peripheral vasoconstriction and its relationship to the increased risk of peripheral vascular disease in smokers are unknown. To study the peripheral vascular effects of nicotine, we measured hemodynamic responses and oxygen consumption of the in situ gracilis muscle during intravenous (i.v.) nicotine infusions in anesthetized dogs. Nicotine 36.0 micrograms/kg/min increased gracilis artery pressure (Pga) 91 +/- 17% and muscle vascular resistance (MVR) 96 +/- 18% whereas muscle blood flow (MBF) and oxygen consumption (MVO2) were unchanged from baseline. In dogs with extracorporeal-controlled normotension during nicotine infusion, however, Pga was held at baseline levels but similar increases in MVR were observed (95 +/- 11%) as flows decreased 52 +/- 9%. Oxygen consumption decreased in direct proportion (53 +/- 5%) to MBF, indicating complete impairment of oxygen extraction (A-VO2). Thus impaired oxygen extraction was masked in dogs in which Pga was allowed to increase because of sustained pressure-dependent flows. Phenoxybenzamine block of muscle alpha-adrenoceptors increased MBF and MVO2 in both normotensive and hypertensive dogs. Combined alpha- and beta-blockade effectively neutralized all sympathoadrenal responses in the muscle. All the above results occurred regardless of innervation. Plasma levels of norepinephrine (NE) and epinephrine (EPI) increased greater than 1,000% during nicotine infusion. Apparently, these levels were high enough to (a) override dilator effects of plasma EPI and (b) cause vasoconstriction in muscle independent of nerve supply. Infusion of nicotine in the gracilis artery had no effect on muscle hemodynamics. Nicotine-induced increase in plasma catecholamines resulted in a powerful constriction of both resistance and oxygen-exchange vessels of skeletal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Norepinephrine and phenylephrine effects on right ventricular function in experimental canine pulmonary embolism.

In a canine model of pulmonary embolism (PE) produced by infusion of autologous blood clots, mean arterial blood pressure (MAP) decreased to 73 +/- 4 mm Hg while cardiac output (CO) decreased to less than 50 percent of baseline. Intravenous infusion of phenylephrine (PHEN) and norepinephrine (NE) restored MAP to somewhat above baseline values. However, only NE restored CO to control levels. The right ventricular myocardial blood flow increased 15 percent in the PE group with PHEN and 229 percent with NE at equipressor concentrations. The right ventricular myocardial oxygen consumption (RVMVo2) was not significantly different between PE and PE + PHEN while PE + NE increased RVMVO2 by 144 percent to 20.2 +/- 1.8 ml/min/100 g. The RV output was not adequately restored with PE, but when RV contractility was augmented with NE, RV output was restored to baseline. Right ventricular minute work increased 100 percent with NE and was maintained with a 100 percent increase in oxygen consumption. Calculated pulmonary vascular resistance (PVR) was decreased during PE by 36 percent with PE + PHEN while PVR in NE-treated dogs decreased by 59 percent. In NE-treated animals, systemic vascular resistance (SVR) was restored to control levels while in PHEN-treated animals SVR increased about 75 percent from baseline. We conclude that the salutary effects of NE on RV output are due to both alpha and beta receptor stimulation, which increased contractility, RVMBF, and RVMVo2, and decreased both PVR and SVR. In the PHEN-treated dogs, our indices of minute-work, RVMBF, and RVMVo2 suggest that coronary autoregulation was intact; however, there was no apparent benefit to RV output. This study suggests that in the clinical setting of acute PE, the judicious use of NE, rather than PHEN, may be more beneficial in restoring RV function and systemic hemodynamics.

Effect of fast vs slow intralipid infusion on gas exchange, pulmonary hemodynamics, and prostaglandin metabolism.

Intralipid (20 percent, 500 ml) was infused fast (5 h) or slow (10 h) randomly in patients with lung injury to relate changes in plasma prostaglandin (PG) concentrations to gas exchange and pulmonary hemodynamics. Data were collected at baseline, midpoint of infusion, and 2 h following infusion. Vasodilator and vasoconstrictor PG metabolites, 6-keto-PGF1 alpha, and thromboxane B2, respectively, were measured in radial arterial blood samples. Slow Intralipid infusion increased shunt fraction (QS/QT) without changing mean pulmonary artery pressure (MPAP), whereas fast Intralipid infusion increased MPAP without changing QS/QT. Prostaglandin levels did not change significantly during either infusion. However, in both groups when the PG substrate was removed, hemodynamic and metabolite values decreased in parallel. In conclusion, we were unable to demonstrate a cause and effect relationship between plasma levels of 6-keto-PGF1 alpha and thromboxane B2 and the observed pulmonary hemodynamic response to slow or fast Intralipid infusion.

Influence of nifedipine on systemic and regional hemodynamics during adenosine-induced hypotension in dogs.

Previous pharmacologic studies indicating competitive interactions between adenosine and nifedipine at the adenosine vascular receptor suggest that adenosine may be a less effective hypotensive drug after pretreatment with nifedipine. This hypothesis was tested in 18 pentobarbital-anesthetized, open-chest dogs by evaluating the hypotensive effects and regional hemodynamic responses to 60-minute intravenous adenosine infusions before and after bolus injection of nifedipine (20 micrograms/kg, IV). Regional blood flow was measured with 15-microns radioactive microspheres. Before nifedipine, infusion of adenosine at a rate of 126 +/- 30 mumol/min caused a 50% reduction in mean aortic pressure that in the presence of no change in aortic blood flow was attributable to a proportional decrease in systemic vascular resistance. These systemic effects were associated with heterogeneous changes in regional blood flow; blood flow decreased in the renal cortex (-68%), pancreas (-50%), spleen (-77%), and skin (-61%); increased in the left (+112%) and right (+265%) ventricular myocardium; and did not change significantly in the duodenum, liver, skeletal muscle, or brain. Nifedipine did not alter the dose requirement or time course of the adenosine-induced hypotensive response or affect the associated systemic hemodynamic changes. Furthermore, nifedipine caused only minor alterations in the regional blood flow changes during adenosine-induced hypotension. Apparently the high plasma levels of adenosine required for controlled hypotension in the present study were sufficient to overcome the blocking influence of nifedipine at the adenosine vascular receptor. The study demonstrates that the hypotensive action of adenosine remains unimpaired after pretreatment with nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional hemodynamics and oxygen supply during isovolemic hemodilution in the absence and presence of high-grade beta-adrenergic blockade.

Studies were performed in 16 pentobarbital-anesthetized dogs to evaluate regional circulatory effects of isovolemic hemodilution in the absence (group 1) and presence (group 2) of high-grade beta-adrenergic blockade with propranolol. Regional blood flow measured with 15 microm radioactive microspheres was used to calculate regional oxygen supply. In group 1, hemodilution with 5% dextran (40,000 molecular weight) reduced arterial hematocrit and oxygen content by approximately one half and had heterogeneous effects on regional blood flows. Blood flow was unchanged in the renal cortex, liver, and spleen, and it increased in the pancreas, duodenum, brain, and myocardium; however, only in the brain and myocardium were increases in blood flow sufficient to maintain oxygen supply at baseline (pre-hemodilution) levels. In group 2, intravenous administration of propranolol (1 mg/kg) itself decreased blood flow in the spleen and myocardium and had no other regional effects. Hemodilution after propranolol caused regional circulatory changes that were essentially similar to those in the absence of propranolol. It is concluded that (1) during isovolemic hemodilution, oxygen supply to the brain and myocardium is maintained at the expense of oxygen supply to less critical organs, and (2) this pattern of regional circulatory response during hemodilution remains intact in the presence of high-grade beta-adrenergic blockade with propranolol.

Myocardial blood flow and oxygen consumption during isovolemic hemodilution alone and in combination with adenosine-induced controlled hypotension.

Recent reports have proposed combining isovolemic hemodilution and controlled hypotension to limit blood loss during surgery. Before such a technique can be considered for clinical use, it must be demonstrated that it does not endanger maintenance of adequate myocardial oxygenation. Accordingly, measurements of left ventricular myocardial blood flow and oxygen consumption were obtained during isovolemic hemodilution alone and in combination with adenosine-induced controlled hypotension in ten pentobarbital-anesthetized, open chest dogs with normal coronary circulation. Hemodilution to a hematocrit of 21.7% was produced by isovolemic exchange of whole blood for 5% dextran. In the presence of hemodilution, adenosine was infused intravenously at a rate sufficient to decrease mean aortic pressure to 51 mm Hg. Myocardial blood flow was measured with radioactive microspheres and used to calculate global left ventricular myocardial oxygen consumption and oxygen supply. Hemodilution alone increased aortic blood flow (+43%) but had no effect on aortic pressure, left atrial pressure, heart rate, or left ventricular dP/dtmax; an increase in myocardial blood flow (+130%) maintained oxygen supply and consumption at the baseline level. Adenosine-induced hypotension during hemodilution decreased heart rate (-35%), left ventricular dP/dt max (-28%), and aortic blood flow (-14%). These systemic responses were accompanied by reduced myocardial oxygen consumption (-29%) and increased myocardial blood flow (+54%) and myocardial oxygen supply (+72%). These latter effects resulted in reduction in the coronary arteriovenous oxygen content difference and in an attendant rise in coronary sinus Po2 (+66%), which are signs of luxuriant myocardial perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional hemodynamics and oxygen supply during isovolemic hemodilution alone and in combination with adenosine-induced controlled hypotension.

Studies were performed in ten pentobarbital-anesthetized, open chest dogs to evaluate regional circulatory effects of isovolemic hemodilution alone, and in combination with adenosine-induced controlled hypotension. Regional blood flow measured with 15-microns radioactive microspheres was used to calculate regional oxygen supply. Hemodilution with 5% dextran (40,000 molecular weight) reduced arterial hematocrit and oxygen content by approximately one-half and caused heterogeneous changes in regional blood flows; flow decreased in the spleen, was unchanged in the renal cortex, liver, skeletal muscle and skin, and increased in the duodenum, pancreas, brain and myocardium; however, only in the brain and myocardium were increases in flow sufficient to preserve oxygen supply. Intravenous infusion of adenosine reduced aortic pressure by 50% and reduced flow in most tissues (renal cortex, pancreas, liver, spleen, skin, and brain), with the result that oxygen deficits were produced or accentuated in these organs. The magnitude of flow reductions in the renal cortex (-73%) and cerebral cortex (-37%) were noteworthy. In the myocardium, direct coronary vasodilation by adenosine caused parallel increases in blood flow and oxygen supply to levels exceeding prevailing metabolic requirements. It is concluded that 1) during isovolemic hemodilution alone, oxygen supply to the brain and myocardium is maintained at the expense of oxygen supply to less critical organs and, 2) during combined isovolemic hemodilution and adenosine-induced hypotension, oxygen is oversupplied to the myocardium but undersupplied to the brain and kidney. These latter effects suggest the need for extensive clinical monitoring of patients in whom combined isovolemic hemodilution and adenosine-induced hypotension is utilized.

Oxygenated cholesterols synergistically immobilize acyl chains and enhance protein helical structure in human erythrocyte membranes.

Fourier transform infrared spectroscopy revealed that insertion of 20 alpha-hydroxycholesterol into human erythrocyte membranes (10% of total membrane sterol) immobilized the lipid acyl chains to a degree equivalent to enriching total membrane cholesterol by 50% (Rooney, M.W., Lange, Y. and Kauffman, J.W. (1984) J. Biol. Chem. 259, 8281-8285). Raman spectroscopy showed that the amount of acyl chain rotamers was not significantly altered by the presence of 20 alpha-hydroxycholesterol, indicating that acyl chain immobilization was limited to an inhibition of lateral motion. The presence of 20 alpha-hydroxycholesterol may synergistically enhance the acyl-chain-immobilizing behavior of membrane cholesterol. In addition, protein helical structure was not altered by 20 alpha-hydroxycholesterol. The insertion of 7 alpha-hydroxycholesterol into erythrocyte membranes resulted in an increase in protein helical structure which was comparable to that observed for erythrocyte membranes enriched with pure cholesterol by 50%. However, both acyl chain mobility and conformation were unchanged. These results suggest a synergistic behavior between oxysterols and cholesterol in modifying erythrocyte membrane packing.

Acyl chain organization and protein secondary structure in cholesterol-modified erythrocyte membranes.

Fourier transform infrared and Raman spectroscopies are used to study the effects of cholesterol on human erythrocyte membrane acyl chain organization (mobility and conformation) and protein secondary structure. Compared to normal red cell membranes (approximately equal to 0.8 mol of cholesterol/mol of phospholipid) (C/P), acyl chain mobility is greater for the depleted (C/P approximately equal to 0.6) and less for the enriched (C/P approximately equal to 1.2) membranes as monitored by shifts of the IR symmetric methylene C-H stretching band (2852 wave numbers, cm-1) over the temperature range 5 to 40 degrees C. There is a continuous first order trend to the IR shifts, but no evidence of a phase change for any of the three cholesterol contents. Raman scattering of C-C stretching vibrations (1065-1130 cm-1) revealed that acyl chain conformation in the three membrane preparations is in a similar state of high disorder; however, compared to depleted and control membranes, the enriched membrane acyl chains display higher order lattice packing. The alpha-helical content of membrane proteins is correlated with the relative intensity of the Raman peptide backbone C-C stretching band (940 cm-1). Spectra of cholesterol-enriched erythrocyte membranes indicate a substantial increase in protein helical structure compared to those of the cholesterol-depleted membranes.