Biomedical subjects

R M Prewitt

Publications and source records attributed to R M Prewitt.

At least 19 recordsLinked to original sources

PubMed1995

An increase in low aortic pressure increases coronary artery flow and coronary thrombolysis induced by intravenous administration of recombinant tissue plasminogen activator.

PURPOSE: Our study investigated the effects of an increase in aortic pressure, induced by norepinephrine (NE) administration on coronary artery flow in a clotted artery, and rate of coronary thrombolysis induced by intravenous (i.v.) administration of recombinant tissue plasminogen activator (rtPA). METHODS: A canine model of coronary thrombosis, induced by intracoronary injection of radioactive autologous blood clots, was used to test the hypothesis that an increase in aortic blood pressure will increase coronary artery flow and the rate of clot lysis induced by i.v. administration of rtPA. RESULTS: After clot injection, 11 dogs were phlebotomized to decrease systolic aortic pressure to 75 mm Hg. Subsequently, .25 mg/kg of rtPA was administered intravenously over two 15-minute intervals, one during hypotension, and the other after NE infusion had increased systolic blood pressure to 130 mm Hg. In six dogs the hypotensive condition was studied first, and in five dogs the NE-induced normotensive condition was studied first. In all dogs, coronary artery flow and the rate of clot lysis were significantly increased in the normotensive condition. CONCLUSIONS: These results indicate that an increase in a low coronary artery perfusion pressure may enhance coronary artery flow and the rate of thrombolysis.

Animals↗

PubMed1995

Effects of progressive vascular occlusion on slope and intercept of the pulmonary artery pressure-flow relationship.

Pulmonary hemodynamics may be described by mean pulmonary arterial pressure (PAP)-cardiac output (CO) plots. The slope of the PAP-CO relationship may define the incremental resistance (IR), and the extrapolated pressure intercept (P(I)), the effective outflow pressure. The authors investigated the effects of progressive pulmonary vascular occlusion on the IR and P(I) of the PAP-CO plot. Nine experimental and nine time control dogs were studied. In the former group, PAP-CO plots were obtained in three conditions: (1) Baseline, (2) following occlusion of the right pulmonary artery, and (3) following occlusion of the right pulmonary artery and blood flow to the left upper lobe. Following progressive occlusion, there was a corresponding increase in the IR of the PAP-CO plot, from 1.95 to 3.62 to 5.16 mmHg.1-1.min (all P < 0.05). In contrast to the increase in IR, P(I) remained constant. Over the same interval, there were no changes in IR or P(I) in the time control group. These findings indicate that changes in the slope of the PAP-CO plot correspond to changes in the number of parallel vascular units.

Animals↗

PubMed1995

Intravenous administration of recombinant tissue plasminogen activator. Optimizing the rate of coronary thrombolysis.

Although many studies have confirmed the efficacy of thrombolytic therapy in treatment of acute myocardial infarction, few studies have been designed to determine which dose regimen optimizes the rate of coronary thrombolysis. This study was designed to compare the efficacy of coronary thrombolysis obtained with intravenous administration of three dose regimens of recombinant tissue plasminogen activator (rtPA). The same total dose was administered as a bolus, over 30 min, or over 90 min. A canine model was employed. Coronary thrombosis was induced by injection of radioactive blood clot through a catheter placed in the left anterior descending coronary artery. Subsequently, 18 dogs were randomized into 3 groups of 6 dogs each. In group 1 dogs, 0.5 mg/kg of rtPA was administered intravenously as a bolus; in the group 2 dogs, rtPA was administered intravenously over 30 min (rtPA30); in the group 3 dogs, the drug was administered over 90 min (rtPA90). Coronary thrombolysis was assessed with a gamma camera. While at 100 min, the extent of clot lysis was similar between groups, 15 and 30 min after the start of rtPA administration, coronary thrombolysis was significantly less in the rtPA90 group. These results indicate that for a given total dose of rtPA, the rate of intravenous administration may significantly affect the rate of coronary thrombolysis.

Animals↗

PubMed1995

Thrombolytic therapy in cardiogenic shock: effect of increased aortic pressure and rapid tPA administration.

OBJECTIVES: To investigate the effect of an increase in aortic pressure combined with rapid tissue plasminogen activator infusion on hemodynamic stability and patency of the infarct-related artery in patients with acute myocardial infarction complicated by profound hypotension or cardiogenic shock. BACKGROUND: Thrombolytic therapy improves mortality in relatively stable patients with acute myocardial infarction but not in patients with cardiogenic shock. Recent canine studies have demonstrated that a moderate increase in low aortic pressure improves thrombolysis. Conceivably, then, decreased thrombolytic efficacy in cardiogenic shock is due, at least in part, to a low aortic pressure impairing delivery of the thrombolytic agent. PATIENTS AND METHODS: For patients presenting within 6 h of an acute myocardial infarction complicated by profound hypotension or cardiogenic shock, an inotropic agent was rapidly administered to increase the systolic aortic pressure to approximately 110 mmHg, and 100 mg of tissue plasminogen activator was administered intravenously over 45 to 60 mins. RESULTS: Eight consecutive patients meeting the study criteria were treated over 18 months. In six of eight patients, the inotropic agent increased systolic blood pressure over 10 mins, from a mean of 64 +/- 12 mmHg to 102 +/- 12 mmHg. In the two patients whose blood pressure did not increase, early angiography in one demonstrated occlusion of the infarct-related artery, and both of the patients died. In the other six patients there was clinical and hemodynamic evidence of early reperfusion, and infarct-related arteries were patent on angiography. These six patients survived at least 30 days, with four having a favourable clinical outcome and two having a functional limitation due to heart failure. CONCLUSIONS: These results are consistent with experimental data indicating that an increase in aortic pressure combined with rapid tissue plasminogen activator infusion may increase thrombolytic efficacy when an acute myocardial infarction is complicated by profound hypotension or cardiogenic shock.

Adult↗

PubMed1994

Effect of rate of administration of recombinant tissue plasminogen activator on efficacy of coronary thrombolysis.

The authors employed a canine model of coronary thrombosis, induced by injection of radioactive blood clot, via a catheter placed in the left anterior descending (LAD) coronary artery, to compare effects of different rates of administration of recombinant tissue plasminogen activator (rtPA) on efficacy of coronary thrombolysis. In one group of dogs 0.75 mg/kg of rtPA was administered via the catheter placed in the LAD coronary artery over fifteen minutes. In a second group of dogs the same dose of rtPA was administered over forty-five minutes. Compared with the group in which the drug was administered over forty-five minutes, by thirty and forty-five minutes after onset of treatment, the extent of coronary thrombolysis was significantly greater (P < 0.05) in the group who received the drug over fifteen minutes. These results demonstrate that the rate of intracoronary administration of rtPA may significantly affect thrombolytic efficacy.

Animals↗

PubMed1992

Marked systemic hypotension depresses coronary thrombolysis induced by intracoronary administration of recombinant tissue-type plasminogen activator.

OBJECTIVES: This study was designed to test the hypothesis that the level of aortic blood pressure affects the rate and extent of coronary thrombolysis induced by intracoronary administration of recombinant tissue-type plasminogen activator (rt-PA). BACKGROUND: Although many studies have confirmed the efficacy of thrombolytic therapy in the treatment of acute myocardial infarction, the effects of altered blood pressure on coronary thrombolysis have not been studied. Because the aortic pressure represents the coronary artery inflow pressure, first principles predict that changes in blood pressure will affect the delivery of the thrombolytic agent and thus affect thrombolysis. METHODS: The effects of large changes in blood pressure on coronary thrombolysis were studied in a canine model. Coronary thrombosis was induced by injection of radioactive blood clot through a catheter placed in the left anterior descending coronary artery. Subsequently, 24 dogs were classified into three groups of 8 dogs each: Group 1 dogs underwent phlebotomy to adjust systolic blood pressure to 130 mm Hg; Group 2 dogs underwent phlebotomy to decrease systolic blood pressure to 75 mm Hg. Dogs in Group 3 also underwent phlebotomy to achieve a systolic blood pressure of 75 mm Hg and then received norepinephrine to increase this pressure to 130 mm Hg. After adjustment in blood pressure, all dogs received an infusion of rt-PA (0.25 mg/kg body weight) over 30 min through the left anterior descending artery catheter. In a fourth group of six dogs, the effect of altered blood pressure on the rate of coronary thrombolysis was assessed. RESULTS: In dogs in Groups 1 and 3, the rate and extent of coronary thrombolysis were significantly increased compared with values in Group 2. In each of the six Group 4 dogs the rate of coronary thrombolysis increased when norepinephrine increased systolic blood pressure from 75 to 130 mm Hg. CONCLUSIONS: These results indicate that a moderate increase in coronary inflow pressure increases the rate and extent of coronary thrombolysis compared with values during marked systemic hypotension.

Animals↗

PubMed1992

Pulmonary vascular pressure-flow characteristics. Effects of dopamine before and after pulmonary embolism.

We compared the general hemodynamic effects of dopamine and dobutamine in dogs with acute pulmonary hypertension complicated by a decrease in cardiac output (CO). The pulmonary hypertension was induced by injection of autologous blood clot. Emboli markedly increased mean pulmonary artery pressure (Ppa) and decreased CO (both p < 0.001). Both dopamine and dobutamine increased CO 50% (p < 0.05) and decreased pulmonary vascular resistance (PVR) (p < 0.05), calculated as (PAP - left ventricular end diastolic pressure)/CO. Mean PVR (mm Hg/L/min) decreased from 16.1 to 12.4 with dopamine and from 16. to 11.9 with dobutamine, both p < 0.05. Ventricular filling pressures were not affected. In another 12 dogs we investigated the effects of both drugs on pulmonary pressure-flow (P-Q) characteristics. P-Q characteristics were determined in dogs with normal Ppa values and in those with embolic pulmonary hypertension. The slope of the P-Q relationship defines the incremental vascular resistance and the extrapolated pressure intercept, the effective vascular outflow pressure. All P-Q relationships were described well by a linear equation. Despite significant systemic effects in both groups and despite a decrease in PVR with both drugs in embolized dogs, neither drug significantly affected pulmonary P-Q characteristics. The discrepancy between PVR and incremental resistance is explained by an incorrect assumption in PVR that the left ventricular filling pressure is the effective vascular outflow pressure. We conclude that both before and after the induction of pulmonary hypertension, both dopamine and dobutamine improve CO without affecting pulmonary vascular tone.

Animals↗

PubMed1992

Coronary thrombolysis. Comparative effects of intracoronary administration of recombinant tissue plasminogen activator and urokinase.

We employed a canine model of coronary thrombosis, induced by injection of radioactive blood clot, via a catheter placed in the left anterior descending coronary artery, to compare effects of intracoronary administration of recombinant tissue plasminogen activator (rtPA) and urokinase (UK) on rate and extent of coronary thrombolysis. Two doses of UK, 15,000 U/kg (UK15) and 30,000 U/kg (UK30) and two doses of rtPA, 0.25 mg/kg (rtPA.25) and 0.75 mg/kg (rtPA.75) were given. Drugs were infused over 45 min. Compared with the other regimens, rate and extent of coronary thrombolysis were significantly increased with rtPA.75. Also, despite a much higher dose of UK, coronary thrombolysis was similar with UK30 and rtPA.25. Compared with UK15, rate and extent of coronary thrombolysis were increased with rtPA.25. These results indicate that intracoronary administration of rtPA is superior to intracoronary UK in inducing thrombolysis.

Animals↗

PubMed1991

Effects of left atrial pressure on the pulmonary vascular response to hypoxic ventilation.

We investigated the effects of hypoxic ventilation on the pulmonary arterial pressure- (P) flow (Q) relationship in an intact canine preparation. Mean pulmonary P-Q coordinates were obtained during hypoxic ventilation and during ventilation with 100% O2 at normal and at increased left atrial pressure. Specifically, we tested the hypothesis that, over a wide range, changes in left atrial pressure would alter the effects of hypoxic ventilation on pulmonary P-Q characteristics. Seven dogs were studied. When left atrial pressure was normal (5 mmHg), the mean value of the extrapolated intercept (PI) of the linear P-Q relationship was 10.9 mmHg and the slope (incremental vascular resistance, IR) of the P-Q relationship was 2.2 mmHg.l-1.min. Hypoxic ventilation increased PI to 18 mmHg (P less than 0.01) but did not affect IR. Subsequently, during ventilation with 100% O2, when left atrial pressure was increased to 14 mmHg by inflation of left atrial balloon, PI increased to 18 mmHg. IR was 1.6 mmHg.l-1.min. Again, hypoxic ventilation caused an isolated change in PI. Hypoxia increased PI from 18 to 28 mmHg (P less than 0.01). As in the condition of normal left atrial pressure, hypoxic ventilation did not affect IR. We conclude that, in an anesthetized intact canine preparation, hypoxic ventilation causes an isolated increase in the extrapolated pressure intercept of the pulmonary P-Q relationship. Furthermore the effects of hypoxic ventilation on pulmonary P-Q characteristics are not affected by the resting left atrial pressure.

Animals↗

PubMed1991

Effects of flow on recombinant tissue plasminogen activator-induced pulmonary thrombolysis.

We employed a canine model of pulmonary embolism induced by injection of radioactive blood clots to investigate effects of changes in cardiac output (CO) on recombinant tissue plasminogen activator- (rtPA) induced pulmonary thrombolysis. Rate and extent of thrombolysis were assessed with a gamma camera. Eighteen dogs were studied. Emboli increased mean pulmonary arterial pressure and decreased CO from 2.6 to 1.9 l/min (P less than 0.001). Subsequently, dogs were randomly divided into three groups: group 1 received 0.5 mg/kg of rtPA over 30 min; 30 min before the same dose regimen of rtPA, in the six group 2 dogs, mean CO was increased to approximately 3.25 l/min by opening one systemic arteriovenous fistula; in the six group 3 dogs, before rtPA, mean CO was increased to approximately 4.5 l/min by opening two or three fistulas. After embolization, CO remained low in group 1; the mean 2-h time-averaged CO was 1.8 l/min. CO was much higher in groups 2 and 3 (3.3 and 4.6 l/min, respectively; both P less than 0.001 compared with group 1; and P less than 0.001, group 2 vs. group 3). Compared with group 1, corresponding to the increased flow in groups 2 and 3, rate and extent of pulmonary thrombolysis significantly increased. These results indicate that an increase in flow per se augments rtPA-induced pulmonary thrombolysis. Also, because thrombolysis was similar between groups 2 and 3, these results define an upper limit to the flow-thrombolytic relationship with rtPA.

Animals↗

PubMed1991

Coronary thrombolysis with recombinant tissue plasminogen activator. Intracoronary vs intravenous administration.

We employed a canine model of coronary thrombosis, induced by injection of radioactive blood clot, via a catheter placed in the left anterior descending coronary artery, to compare effects of recombinant tissue plasminogen activator (rtPA) administered intravenously and administered directly into the coronary circulation. A control group did not receive rtPA. Compared with controls, both rtPA regimens induced coronary thrombolysis. However, compared with intravenous administration, rate and extent of coronary thrombolysis were increased with intracoronary administration. Most likely, the enhanced thrombolysis with intracoronary administration is explained by an increase in delivery of the drug to the thrombus.

Animals↗

PubMed1991

Effect of low-molecular-weight heparin on recombinant tissue plasminogen activator-induced thrombolysis in canine pulmonary embolism.

We employed a canine model of pulmonary embolism induced by radioactive blood clots to determine if low-molecular-weight heparin augments recombinant tissue plasminogen activator (rtPA)-induced thrombolysis. Following embolization, dogs were randomized: group 1 dogs received heparin; group 2 dogs received low-molecular-weight heparin; group 3 dogs received 1.5 mg/kg of rtPA over 45 minutes; group 4 dogs received rtPA 3 mg/kg over 45 minutes; and group 5 dogs received 1.5 mg/kg of rtPA plus low-molecular-weight heparin. Over three hours, little thrombolysis occurred in groups 1 and 2. In contrast, significant thrombolysis occurred in groups 3 to 5, 46 percent, 49 percent, and 46 percent, respectively (all p less than 0.01 compared with groups 1 and 2). We conclude that there is an upper limit to the dose-thrombolytic rate relationship with rtPA, and that low-molecular-weight heparin does not augment rtPA-induced thrombolysis.

Animals↗

PubMed1991

Effects of hydralazine and increased cardiac output on recombinant tissue plasminogen activator-induced thrombolysis in canine pulmonary embolism.

We employed a canine model of pulmonary embolism, induced by injection of autologous radiolabelled blood clots, to investigate effects of hydralazine and an increase in cardiac output per se on recombinant tissue plasminogen activator-induced thrombolysis. Emboli increased pulmonary artery pressure (PAP) and decreased CO from 2.7 to 1.8 L/min-1. Following embolization, dogs were randomly divided into three groups. Group 1 received .5 mg/kg of rtPA over 30 minutes. Group 2 received the same dose of rtPA and were pretreated with hydralazine to increase CO approximately 50 percent. In the group 3 dogs, CO was increased by opening a systemic A-V fistula. Following embolization, CO remained low in group 1, the mean 2 h time-averaged CO was 1.9 L/min-1. The CO was 2.9 and 3.1 L/min-1 in groups 2 and 3, respectively. Corresponding to the increased flow in groups 2 and 3, rate and extent of pulmonary thrombolysis significantly increased. These results indicate that an increase in CO augments rtPA-induced pulmonary thrombolysis.

Animals↗

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↗