Richard M. Prewitt

Volume Expansion versus Norepinephrine in Treatment of a Low Cardiac Output Complicating an Acute Increase in Right Ventricular Afterload in Dogs

The authors investigated the effects of treatment on ventricular performance when cardiac output (CO) was reduced significantly because of an acute increase in pulmonary vascular resistance (PVR). In eight anesthetized, ventilated dogs, the effects of volume expansion (100 ml 6% dextran) on ventricular performance were determined before and after PVR was elevated. Resistance was increased by microembolization of the pulmonary vascular bed with glass beads (80–100 μm). When PVR was normal, volume expansion increased (P < 0.05) stroke volume (SV) and mean blood pressure (BP). Alternatively, when RV afterload was increased, volume resulted in RV failure, i.e., decrease in SV (P < 0.01) from 9.1 to 6.3 ml and a decrease (P < 0.05) in mean BP from 97 to 65 mmHg, despite increased right ventricular end diastolic pressure (RVEDP) (P < 0.05). Right ventricular dysfunction occurred with volume expansion, despite constant PVR and a decrease (P < 0.01) in mean pulmonary artery pressure (PAP). In contrast to volume, norepinephrine infusion decreased biventricular filling pressures (P < 0.01) and increased (P < 0.01) SV from 6.2 to 11.3 ml. Accordingly, when RV afterload is increased significantly, even a relatively small increase in blood volume may result in RV dysfunction. Alternatively, inotropic agents with pressor effects may be the treatment of choice to increase CO when RV afterload is increased.

Intraaortic balloon counterpulsation enhances coronary thrombolysis induced by intravenous administration of a thrombolytic agent

OBJECTIVES This study was designed to test the hypothesis that in the presence of moderate hypotension, intraaortic balloon counterpulsation would enhance coronary thrombolysis induced by intravenous administration of recombinant tissue-type plasminogen activator (rt-PA). BACKGROUND Although many studies have confirmed the efficacy of thrombolytic therapy in acute myocardial infarction, few have systematically investigated the effects of alterations in aortic pressure on coronary thrombolysis, and none have previously investigated the effects of intraaortic balloon counterpulsation on thrombolysis. METHODS The effects of intraaortic balloon counterpulsation on aortic pressure, coronary blood flow and coronary thrombolysis were studied in a canine model. Coronary thrombosis was induced in eight dogs by injection of radioactive blood clot through a catheter placed in the left anterior descending coronary artery. Subsequently, dogs underwent phlebotomy to decrease systolic aortic pressure to approximately 90 mm Hg. After phlebotomy, during a 15-min interval of intravenous administration of rt-PA, coronary thrombolysis and coronary flow were determined during and in the absence of counterpulsation. RESULTS Intraaortic balloon counterpulsation significantly increased aortic diastolic pressure. Corresponding to the increase in pressure, intraaortic balloon counterpulsation significantly increased the rate of rt-PA-induced coronary thrombolysis. Although not statistically significant, peak diastolic coronary flow tended to increase with counterpulsation. CONCLUSIONS These results indicate that in the presence of moderate systemic hypotension, intraaortic balloon counterpulsation enhances the rate of rt-PA-induced coronary thrombolysis.

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.

Cardiovascular management in acute hypoxemic respiratory failure

This paper reviews recent data concerning the interactions among pulmonary edema, intrapulmonary shunt and cardiac output in acute hypoxemic respiratory failure. In canine oleic acid edema, a 5 mm Hg reduction in pulmonary wedge pressure significantly reduces edema, but a corresponding increase in colloid osmotic pressure does not. When pulmonary wedge pressure is lowered, cardiac output can be maintained with infusions of nitroprusside, dopamine or dobutamine. Each vasoactive agent improves ventricular pumping function, and the increase in cardiac output is due in part to peripheral circulatory actions of the drugs. Although pulmonary shunt increases with these vasoactive agents, increased shunt is due to their pulmonary vasoactivity but to the associated increase in pulmonary blood flow. Positive end-expiratory pressure reduces venous return by raising right atrial pressure, and it does not depress ventricular pumping function. Rather, positive end-expiratory pressure increases ventricular filling pressure t a given end-diastolic volume; it does not reduce and probably increases edema, yet it reduces shunt by redistributing the edema. These interpretations suggest several goals for cardiovascular management in acute hypoxemic respiratory failure: (1) the lowest pulmonary wedge pressure consistent with adequate cardiac output; and (2) the least positive end-expiratory pressure consistent with saturation of adequate circulating hemoglobin on nontoxic inspired oxygen.

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.

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.

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.

Effects of hydralazine and nitroprusside on cardiopulmonary function when a decrease in cardiac output complicates a short-term increase in pulmonary vascular resistance.

We investigated the short-term cardiopulmonary effects of nitroprusside and hydralazine when cardiac output (CO) was reduced by a short-term increase in pulmonary vascular resistance (PVR). In six anesthetized, ventilated dogs, small autologous blood clots, injected over 1 to 2 hr, increased right ventricular afterload. When CO had fallen approximately 40%, dogs were treated with nitroprusside and subsequently with hydralazine. Both drugs reduced biventricular filling pressures (p less than .05), but only hydralazine increased CO and stroke volume (p less than .05). Although mean blood pressure and pulmonary artery pressure remained constant with hydralazine, systemic vascular resistance and PVR decreased (p less than .01). In contrast, although nitroprusside reduced blood pressure and systemic vascular resistance (p less than .01), it did not affect PVR and pulmonary artery pressure. When CO is significantly reduced because of a short-term increase in PVR, hydralazine may be superior to nitroprusside in improving cardiopulmonary function.

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.

Increased cardiac output increases lung water in canine permeability pulmonary edema

We investigated the effects of increased cardiac output (CO) on oleic acid pulmonary edema in 14 open-chest, anesthetized, mechanically ventilated dogs. Pulmonary artery wedge pressure (Pawp) was adjusted to approximately 9 mm Hg via a left atrial balloon and CO to 1.7 L · m−1 via systemic arteriovenous fistulas (AVF); five minutes after oleic acid (0.08 mL · kg−1), dogs were randomly divided into two groups, high CO and low CO. In the high CO group, CO was increased by opening the AVFs. Pawp was maintained at 9 mm Hg for four hours in all dogs. The average CO time in the high CO group was 3.9 L · min−1 and 1.3 L · min−1 in the low CO group (P < .01). Lung water accumulation was significantly increased in the high CO group with a wet weight/ body weight ratio of 29 g o kg−1v 21 g · kg −1 in the low CO group (P < .004). With time, mean pulmonary artery pressure increased significantly (P < .05) in both groups, but was not different between groups at any time. While pulmonary vascular resistance remained constant in the high CO group, it increased markedly (P < .05) in the low CO group, possibly due to a decrease in pulmonary vascular surface area. The increase in lung water accumulation in the high CO group is probably due to prevention of pulmonary vascular derecruitment and therefore a greater perfused pulmonary vascular surface area.