Biomedical subjects

R M Prewitt

Publications and source records attributed to R M Prewitt.

At least 37 records · Page 2Linked to original sources

PubMed1991

Principles of thrombolysis in pulmonary embolism.

A canine model of pulmonary embolism, induced by injection of autologous radioactive blood clots, was used to investigate principles of thrombolysis in pulmonary embolism. One study compared recombinant tissue plasminogen activator (rtPA) with heparin in the treatment of pulmonary embolism. This study also compared the efficacy of rtPA (1 mg/kg) given over 15 min (rtPA15) to the same total dose infused over 90 min. Compared with heparin, both rtPA regimens induced marked pulmonary thrombolysis. During drug infusion, the rate of thrombolysis was increased 2-fold with rtPA15. A 2nd canine study investigated the physiologic mechanism of the decrease in pulmonary artery pressure with rtPA. The pattern of hemodynamic improvement with rtPA indicated that pulmonary thrombolysis predominantly occurred in partially, rather than totally, obstructed vascular units. A 3rd canine study compared rtPA and high-dose urokinase (UK) in treatment of pulmonary embolism. Both rtPA regimens were superior to UK in inducing pulmonary thrombolysis and improving pulmonary hemodynamics. Most recently, the effects of flow dynamics on rtPA-induced pulmonary thrombolysis were investigated, and it was demonstrated that an increase in cardiac output markedly enhanced rtPA-induced pulmonary thrombolysis. Most likely, the increase in cardiac output increased thrombolysis by enhancing delivery of rtPA to thrombus in partially obstructed vascular units.

Fibrinolysis↗

PubMed1990

Pulmonary vascular pressure-flow characteristics in canine pulmonary embolism.

We tested the hypothesis that, in canine embolic pulmonary hypertension, upstream transmission of increased left atrial pressure (LAP) is inversely related to the level of the pressure intercept (PI) obtained by extrapolation from the linear pulmonary vascular pressure-flow (P-Q) plot. P-Q coordinates were obtained by varying Q through systemic fistulas. Seven group 1 dogs were embolized with autologous blood clot to produce marked pulmonary hypertension and mean pulmonary arterial pressure (PAP), and PI increased from 15 to 41 mmHg (P less than 0.001) and from 8.8 to 31 mmHg (P less than 0.001), respectively. Before and after embolization we assessed effects of increased LAP, produced by inflation of a left atrial balloon, on PAP at constant Q. Embolization depressed the mean slope of this relationship from 0.78 to 0.16 (P less than 0.001). Subsequently, six group 2 dogs were embolized to produce moderate pulmonary hypertension with a mean PI of 22 mmHg. This value was significantly less than PI in group 1 (P less than 0.01). After embolization, the slope of the PAP-LAP relationship was greater in group 2 than group 1: 0.47 vs. 0.16 (P less than 0.01). We conclude that the upstream transmission of left atrial pressure is inversely related to PI and that marked embolic pulmonary hypertension produces an effective vascular waterfall.

Animals↗

PubMed1990

Thrombolytic therapy in canine pulmonary embolism. Comparative effects of urokinase and recombinant tissue plasminogen activator.

We compared thrombolytic and pulmonary hemodynamic effects of recombinant tissue plasminogen activator (rtPA) and urokinase (UK) in canine micropulmonary thromboembolism. Dogs were embolized with radioactive autologous blood clot to increase mean pulmonary artery pressure (from 13 to 34 mm Hg, p less than 0.005) and decrease cardiac output (2.5 to 1.6 L min, p less than 0.005). Four groups of six dogs were treated. We employed two doses of UK, 30,000 U/kg (UK30) and 60,000 U/kg (UK60), and two doses of rtPA, 1 mg/kg (rtPA1) and 2 mg/kg (rtPA2). Drugs were infused over 15 min. Rate and extent of pulmonary thrombolysis were assessed by continuously counting over both lung fields with a gamma camera. Compared with treatment with UK, both rtPA regimes significantly increased thrombolysis. Mean total pulmonary thrombolysis was 14 and 23% with UK30 and UK60, respectively, and 35 and 43% with rtPA1 and rtPA2. Corresponding to the increased thrombolysis, pulmonary hemodynamics improved most with rtPA. From 90 min to 3 h, pulmonary artery pressure was significantly lower with both rtPA regimes than with either UK regime. These results indicate, at least in the model employed, that compared with treatment with UK, pulmonary thrombolysis and corresponding hemodynamic improvement are greatest with rtPA.

Animals↗

PubMed1990

Hemodynamic management in pulmonary embolism and acute hypoxemic respiratory failure.

Management of patients with the adult respiratory distress syndrome should be directed toward maintaining adequate cardiac output and tissue oxygenation without exacerbating pulmonary edema. The aim of therapy should be to maintain low left ventricular filling pressure, which will tend to decrease the rate of edema formation. If cardiac output is low or decreases as a function of therapy, flow may be increased with inotropic agents. When a marked decline in cardiac output complicates pulmonary embolism, norepinephrine may be an excellent drug for at least short-term maintenance of hemodynamic stability. When a moderate decrease in cardiac output complicates an increase in right ventricular afterload, isoproterenol or dobutamine may be used to increase flow. Rapid administration of recombinant tissue plasminogen activator may be the treatment of choice of pulmonary thromboembolism associated with a low output state.

Acute Disease↗

PubMed1989

Recombinant tissue-type plasminogen activator in canine embolic pulmonary hypertension. Effects of bolus versus short-term administration on dynamics of thrombolysis and on pulmonary vascular pressure-flow characteristics.

We used a canine model of embolic pulmonary hypertension, induced by injection of autologous radioactive blood clots, to investigate effects of recombinant tissue-type plasminogen activator (rt-PA) on dynamics of thrombolysis and on pulmonary pressure-flow (PQ) characteristics. Over 5 (rt-PA5) or 15 (rt-PA15) minutes, 1 mg/kg rt-PA was infused. Rate and extent of thrombolysis were assessed by counting over both lung fields with a gamma camera. Emboli increased mean pulmonary artery pressure from 14 to 36 mm Hg (p less than 0.005). This change was predominantly due to an increase in the effective outflow pressure (PI) (from 9 to 29 mm Hg, p less than 0.001), obtained by extrapolation from the linear PQ relation. While pulmonary hemodynamics improved with rt-PA5 and rt-PA15, the change was greatest with rt-PA15. For example, the increase in PI that occurred with embolization was abolished with rt-PA15. Also, the decrease in pulmonary artery pressure was greatest with rt-PA15. While not significantly different, extent of total clot lysis tended to be greatest with rt-PA15 (p less than 0.07). Also, while during infusion, the concentration of rt-PA5 was threefold that of rt-PA15, the corresponding rate of thrombolysis was similar with rt-PA5 and rt-PA15. These results indicate that the improvement in pulmonary hemodynamics with rt-PA is primarily explained by a decrease in PI. Furthermore, they suggest an upper limit to the dose-thrombolytic rate relation with rt-PA.

Animals↗

PubMed1989

The cardiopulmonary and renal hemodynamic effects of norepinephrine in canine pulmonary embolism.

Autologous blood clot was injected into six dogs to produce a graduated decrease in cardiac output (CO). The effects of an infusion of norepinephrine, titrated to specific end points, were recorded before embolization and at two levels of pulmonary hypertension. Simultaneous measurements of systemic and renal hemodynamics were made. Sequential blood clot injection increased (p less than .01) pulmonary vascular resistance (PVR) from 1.3 to 13 to 33 mm Hg.L-1.min and reduced CO 45 percent and 75 percent (p less than .01). Norepinephrine increased both stroke volume and CO (p less than .01) in each condition and did not increase PVR. Since the biventricular filling pressures remained constant or fell slightly with norepinephrine, the increase in CO is best explained by an improvement in pump performance. There was no deterioration in renal blood flow or creatinine clearance with norepinephrine. The data suggested that in this model of right ventricular dysfunction, norepinephrine consistently improved myocardial performance without provoking further vasoconstriction in either the pulmonary or renal circulations.

Animals↗

PubMed1988

Effects of altered left atrial pressure on pulmonary vascular pressure-flow relationships.

We studied the effects of changes in pulmonary capillary wedge pressure (PCWP) on the slope (incremental resistance) and the extrapolated pressure intercept (PI) of the mean pulmonary artery pressure (PAP)-cardiac output (CO) relationship. Multipoint plots of PAP against CO were obtained in intact anesthetized dogs. Group 1 consisted of six dogs entirely in West zone 3 and group 2 of four dogs with mixed West zone 2-3. The four conditions studied were the following: 1) fixed low PCWP, 2) fixed high PCWP, 3) variable PCWP, and 4) time-control repeat of condition 1. The PI significantly exceeded PCWP at fixed low PCWP (group 1, 9.3 vs. 11.1 mmHg, group 2, 6.6 vs. 3.9 mmHg). PI became identical to PCWP only at fixed high PCWP in group 1 (19 +/- 2.0 vs. 19 +/- 1.1 mmHg). Thus PCWP reflects the effective vascular outflow pressure when PCWP is fixed and high. For both groups of dogs in condition 3, when PCWP was varied with CO, the slope of the resulting PAP-CO plot was significantly greater than when PCWP was constant. Also in 9 of 10 dogs, PI was less than PCWP when PCWP was varied. These findings demonstrate that when changes in PCWP are allowed to occur during the generation of a pulmonary artery pressure-flow plot, the resulting slope and intercept, as defined by a Starling resistor model, do not accurately represent the incremental resistance and outflow pressure of the pulmonary vasculature.

Analysis of Variance↗

PubMed1988

Treatment of canine embolic pulmonary hypertension with recombinant tissue plasminogen activator. Efficacy of dosing regimes.

We investigated effects of two dosing regimes of recombinant tissue plasminogen activator (rt-PA) and sodium heparin on pulmonary thrombolysis in a canine model of pulmonary hypertension, induced by injection of radioactive blood clots. By continuously counting over both lung fields with a mobile gamma camera, we correlated rate and extent of pulmonary thrombolysis with corresponding pulmonary hemodynamics. Treatment with heparin, over a 3-hour interval, did not result in significant thrombolysis or in a decrease in mean pulmonary artery pressure (PAP). In contrast, rt-PA caused marked pulmonary thrombolysis. While total clot lysis was similar when 1 mg/kg rt-PA was infused over 15 (rt-PA15) or 90 (rt-PA90) minutes (47% and 42%, respectively), rate of lysis during infusion was markedly increased with rt-PA15 (56% vs. 27%/hr, p less than 0.001). Corresponding to the increased rate of thrombolysis with rt-PA15, relative PAP decrease was greater at 15 and 30 minutes. At 4 hours, PAP decreased most with rt-PA90. However, two of the six dogs given rt-PA15 had an increase in PAP and lung radioactivity 1 hour after rt-PA. This was associated with dislodgment of a previously trapped clot. These results suggest that rt-PA may be appropriate therapy for pulmonary embolism and support further studies designed to optimize dosing regimes.

Animals↗

PubMed1987

Treatment of canine pulmonary hypertension: effects of norepinephrine and isoproterenol on pulmonary vascular pressure-flow characteristics.

Pulmonary vascular flow resistive properties may be described by mean pulmonary arterial pressure (PAP)-cardiac output (CO) plots. The slope of the PAP-CO relationship defines the incremental resistance and the extrapolated pressure intercept defines the effective outflow pressure. We investigated effects of norepinephrine (11 dogs) and isoproterenol (seven dogs) on the pulmonary vascular PAP-CO relationship in a model of pulmonary hypertension produced by injection of autologous blood clots. Multiple PAP-CO coordinates were obtained with and without drug infusion. CO was varied by opening systemic arteriovenous fistulas. PAP-CO relationships were well described by a linear equation (mean r value .964 +/- .032). Isoproterenol increased mean CO by 61% (p less than .01), and calculated pulmonary vascular resistance (PVR) decreased by 31% (p less than .05), corresponding to a 35% decrease (5.1 +/- 2.0 to 3.3 +/- 0.9 mm Hg X liter X min-1; p less than .01) incremental resistance. In the first seven dogs to receive norepinephrine, despite a 25% increase in blood pressure (p less than .01) no significant effects on CO, PAP, PVR, or PAP-CO relationship were observed. In the next four dogs, norepinephrine was infused at a lower dose to increase blood pressure 50% and a higher dose to ensure an increase in CO. In both conditions, calculated PVR fell (p less than .05) compared with that before norepinephrine. However, measured incremental resistance and effective outflow pressure did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Pathophysiology and therapy of right ventricular dysfunction due to pulmonary embolism.

When shock complicates an acute increase in RV afterload, initial therapy should be directed toward restoration of an adequate BP (RV coronary perfusion pressure) and CO. Current results indicate that norepinephrine, a drug with direct inotropic and pressor effects, may be an excellent agent for acute resuscitation and short-term maintenance of hemodynamic stability when frank circulatory instability complicates pulmonary embolism. Following hemodynamic stabilization, thrombolytic therapy should be initiated. Recent evidence suggests that the lytic agent can be given by bolus technique, but more work is required to determine the optimum dosing regimen. In the absence of shock, when a moderate decrease in CO complicates pulmonary embolism, isoproterenol or hydralazine may be used to improve flow. However, both of these agents may decrease systemic vascular resistance and BP. Accordingly, the latter parameter should be carefully monitored to ensure that excessive falls in BP and RV coronary perfusion pressure do not occur. Whereas in certain conditions volume expansion is appropriate therapy to increase CO, in acute pulmonary hypertension with excessive RV afterload, volume expansion may worsen RV function. Recent canine studies indicate that an increase in vascular closing pressure is the predominant mechanism explaining the increase in PAP and apparent increase in PVR complicating pulmonary embolism. Accordingly, in addition to decreasing vascular resistance, therapy to decrease RV afterload could be directed toward decreasing the vascular response producing excessive closing pressures.

Animals↗

PubMed1986

Pulmonary vascular pressure-flow relationship in canine oleic acid pulmonary edema.

We tested the hypothesis that the increased impedance to flow in canine oleic acid (OA) lung injury is predominantly due to an increase in effective downstream pressure (EDP), obtained by extrapolating to zero flow the linear portion of the pulmonary artery pressure (PAP)/flow (Q) relationship. PAP-Q coordinates were obtained in eight anesthetized, O2-ventilated dogs by varying Q through systemic arteriovenous fistulae. PAP-Q lines were obtained before and approximately 5 h after injection of OA. A second group of six dogs served as a time control (TC) group. There was a linear relationship between PAP and Q in both experimental and control groups (mean r value 0.948). The presence of pulmonary edema in the OA group caused the EDP to almost double, from 7 to 12 mmHg (P less than 0.01). In contrast, EDP remained constant in TCs. Incremental vascular conductance (IVC), slope of the PAP/Q line, decreased (P less than 0.05) a similar amount in both groups. The above findings are consistent with the modeling of the pulmonary circulation according to a Starling resistor in that large amounts of edema changed EDP but not incremental conductance.

Animals↗

PubMed1986

Pulmonary vascular effects of hydralazine in a canine preparation of pulmonary thromboembolism.

Pulmonary arterial pressure (PAP)-flow coordinates were obtained in 14 anesthetized dogs before and after pulmonary hypertension was induced with autologous blood clots. Cardiac output (CO) was altered by systemic arteriovenous fistulas. The PAP-CO coordinates were always rectilinear. Before emboli, the mean vascular closing or outflow pressure (the pressure intercept of the PAP-CO line) was 8.8 +/- 2.1 (SD) mm Hg. Emboli increased PAP (15.1 +/- 1.6 to 36.5 +/- 3.5 mm Hg; p less than .001) and decreased CO (3.8 +/- 0.6 to 2.4 +/- 0.8 liters X min-1; p less than .001). Incremental resistance (the slope of the PAP-CO line) only increased slightly. On the other hand, the marked increase in PAP was predominantly due to an increase in effective outflow pressure (from 8.8 +/- 2.1 to 28.6 +/- 3.6; p less than .001). Hydralazine was administered in a dose sufficient to double CO. This did not affect PAP and caused an inconsistent and small decrease in incremental resistance. However, a consistently significant decrease in effective outflow pressure, averaging 23%, was observed. In this canine preparation of pulmonary hypertension the predominant effect of hydralazine appears to be a decrease in the mean vascular closing or outflow pressure.

Animals↗

PubMed1986

Hemodynamic management in clinical acute hypoxemic respiratory failure. Dopamine vs dobutamine.

We investigated short-term hemodynamic effects of dopamine and dobutamine in eight patients with acute hypoxemic respiratory failure. We tested the hypothesis that for a similar increase in cardiac output, left ventricular filling pressure (pulmonary capillary wedge pressure [PCWP]) would increase with dopamine and decrease with dobutamine. Dopamine increased cardiac output (p less than 0.05), stroke volume (p less than 0.05), and PCWP (p less than 0.01). Cardiac output increased almost 20 percent when PCWP increased 50 percent with dopamine. In contrast, despite a mean 30 percent increase in cardiac output with dobutamine (p less than 0.01), PCWP decreased. In six of these patients, left ventricular end-diastolic volumes and end-systolic volumes were measured using scintigraphic techniques. In all patients, end-diastolic volume increased with dopamine (p less than 0.05); and in four of six, end-systolic volume increased. In contrast, with dobutamine, in five of six patients, end-diastolic volume decreased; and in all six patients, end-systolic volume decreased. There was a small increase in intrapulmonary shunt with both drugs. We conclude that if an inotropic agent is required to increase cardiac output in patients with acute hypoxemic respiratory failure, dobutamine is probably preferred over dopamine.

Acute Disease↗

PubMed1985

Acute cardiopulmonary effects of nitroglycerin in canine oleic acid pulmonary edema.

In a canine model of acute respiratory failure, the authors investigated acute cardiopulmonary effects of nitroglycerin (TNG) and compared the results with those obtained after phlebotomy. Oleic acid increased intrapulmonary shunt (Qs/Qt) from 7.4 to 31% (P less than 0.001) and decreased (P less than 0.01) cardiac output (CO). In the presence of assumed low-pressure pulmonary edema, TNG was infused to decrease mean blood pressure (BP) by 40%; this was associated with a 26% decrease (P less than 0.05) in CO. Qs/Qt increased from 31 to 42% (P less than 0.01). There was a slight increase (P less than 0.01) in pulmonary vascular resistance (PVR) with TNG, and mean pulmonary artery pressure (PAP) decreased (P less than 0.05). In contrast, when CO was decreased by a similar amount with phlebotomy, mean Qs/Qt did not significantly change. There were similar changes in PVR and PAP and mixed venous O2 tension with TNG and phlebotomy. Accordingly, current results rule out increased flow, increased PVO2, and mechanical alterations in pulmonary vascular pressures as contributory to the increase in Qs/Qt with TNG. Alternatively, the increase in Qs/Qt with TNG may be explained by a direct pharmacologic decrease in pulmonary hypoxic vasoconstriction and/or by nonspecific pharmacologic effects.

Animals↗

PubMed1985

Effects of reduced resistive afterload on left ventricular pressure-volume relationship.

In seven anesthetized, beta-blocked dogs, we investigated the effects of a reduction in systemic vascular resistance (SVR) on left ventricular (LV) systolic mechanics. LV pressure and volumes (scintigraphic techniques) were measured in base-line condition, after opening one and then two arteriovenous fistulas (AVF). Volume was infused to maintain LV end-systolic pressure (LVESP). Despite a constant ESP, the mean end-systolic volume (LVESV) fell from 42 to 31 ml (P less than 0.025) when the SVR fell from 81 to 48 units (P less than 0.0025), and the LVESV fell further to 24 ml (P less than 0.0025) when the SVR was decreased to 30 units (P less than 0.025). In six similarly prepared dogs, aortic flow was measured, and when resistive afterload decreased, instantaneous flow increased. Since end-diastolic volume was not significantly changed when resistive afterload decreased, instantaneous LV volume decreased despite constant systolic LV pressure. In two of these dogs, LV pressure-volume (PV) trajectories were drawn for the ejection period. When SVR decreased there was a marked leftward shift of the PV trajectory as the end of ejection was approached. It is concluded that at a given contractile state and ventricular pressure, alterations in resistive load directly affect rate and extent of ventricular shortening.

Animals↗

PubMed1985

Treatment of canine permeability pulmonary edema: short-term effects of dobutamine, furosemide, and hydralazine.

The effects of treatment of oleic acid pulmonary edema with dobutamine, furosemide, and hydralazine on cardiopulmonary function in 24 dogs were investigated. Pulmonary capillary wedge pressure (PCWP) was adjusted to approximately 7 mm Hg; 45 min after oleic acid (0.08 ml/kg), dogs were randomly divided into a control group, in which PCWP was maintained at approximately 7 mm Hg, and into treatment groups as described above. Mean time-averaged PCWP was 2.3 mm Hg in dogs treated with dobutamine, 4.1 mm Hg with furosemide, and 4.4 mm Hg with hydralazine. Four hours of treatment with dobutamine and furosemide significantly (p less than .01) reduced accumulation of lung water compared with the control and hydralazine groups. Qs/Qt was lower (p less than .05) with dobutamine and furosemide compared with the other groups. In dogs given hydralazine, cardiac output (CO) and systemic vascular resistance (SVR) remained constant over the 4 hr treatment interval. In contrast, in all other groups, SVR increased and CO decreased (both p less than .05). The short-term pulmonary effects of the above drugs are probably explained by differences in PCWP and/or by regional pulmonary vascular effects.

Analysis of Variance↗

PubMed1985

Effects of vasodilators on canine cardiopulmonary function when a decrease in cardiac output complicates an increase in right ventricular afterload.

In canine oleic acid pulmonary edema, we investigated acute cardiopulmonary effects of nitroprusside (NP) before (NP1), and after (NP2) pulmonary vascular resistance (PVR) was increased via glass bead embolization. In the setting of increased PVR and reduced cardiac output (CO), acute cardiopulmonary effects of NP and hydralazine were compared. Oleic acid increased (p less than 0.05) pulmonary shunt (Qs/Qt) from 15 to 24%, but did not alter PVR. Cardiac output decreased (p less than 0.01) 31% with oleic acid from 4.2 to 2.9 1 X min-1 and systemic vascular resistance (SVR) increased (p less than 0.01). When PVR was normal, NP reduced (p less than 0.05) blood pressure (BP) from 148 to 123 mmHg, decreased SVR 31%, and increased (p less than 0.05) CO and Qs/Qt. Glass bead embolization increased (p less than 0.001) PVR from 2.2 to 20 mgHg X 1-1 X min and reduced (p less than 0.01) CO 23%, from 2.6 to 2 L/min. The Qs/Qt did not increase with embolization. In contrast to effects of NP1, when RV afterload was increased, CO fell (p less than 0.05) with NP2 from 2 to 1.6 1 X min-1. Alternatively, hydralazine improved cardiopulmonary function. In the setting of increased RV afterload, SVR and PVR decreased (p less than 0.01) 48 and 29%, respectively, with hydralazine. Corresponding to the decrease in resistance, CO increased (p less than 0.001) 84% with hydralazine, from 1.9 to 3.5 1 X min-1. Also, BP and Qs/Qt remained constant and arterial O2 tension increased (p less than 0.05) with hydralazine, from 113 to 152 mmHg.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMed1985

Effects of noradrenaline and isoproterenol on cardiopulmonary function in a canine model of acute pulmonary hypertension.

The authors investigated acute cardiopulmonary effects of noradrenaline and isoproterenol infusion in a canine model of increased pulmonary vascular resistance (PVR) and decreased cardiac output (CO). In six anesthetized, ventilated dogs, autologous blood clots were injected over approximately two hours to increase right ventricular (RV) afterload and decrease CO. After CO had decreased 40 percent dogs were treated with noradrenaline or isoproterenol in alternate sequence. Both drugs increased stroke volume but only isoproterenol affected CO. Flow increased from 1.3 to 3.0 L X min-1 (p less than .01) with isoproterenol infusion. Corresponding to the increase in CO, RV filling pressure and PVR decreased, from 9 to 5 mm Hg, and from 36 to 16 mm Hg X L-1 X min (p less than .01) respectively. When a moderate decrease in CO complicates an acute increase in PVR, isoproterenol may be an excellent drug to treat the decrease in flow.

Animals↗