David S Kirby

Treatment of ethanol-induced acute pulmonary hypertension and right ventricular dysfunction in pigs, by sildenafil analogue (UK343-664) or nitroglycerin

In patients at risk for sudden ethanol (ETOH) intravascular absorption, prompt treatment of pulmonary hypertension (PHTN) will minimise the risk of cardiovascular decompensation. We investigated the haemodynamic effects of intravenous ETOH and the pulmonary vasodilatory effects of a sildenafil analogue (UK343-664) and nitroglycerin (NTG) during ETOH-induced PHTN in pigs. We studied pulmonary and systemic haemodynamics, and right ventricular rate or time derivate of pressure rise during ventricular contraction ( =dP/dT), as an index of contractility, in 23 pigs. ETOH was infused at a rate of 50 mg/kg/min, titrated to achieve a twofold increase in mean pulmonary arterial pressure (MPAP), and then discontinued. The animals were randomised to receive an infusion of 2 ml/kg ( n = 7) normal saline, a 500-microg/kg bolus of UK343-664 ( n = 8), or NTG 1 microg/kg ( n = 8); each was given over 60 seconds. Following ETOH infusion, dP/dT decreased central venous pressure (CVP), and MPAP increased significantly, resulting in significantly increased pulmonary vascular resistance (PVR). Within 2 minutes after treatment with either drug, CVP, heart rate (HR), and the systemic vascular resistance-to-pulmonary vascular resistance (SVR/PVR) ratio returned to baseline. However, at that time, only in the UK343-664 group, MPAP and dP/dT partially recovered and were different from the respective values at PHTN stage. NTG and UK343-664 decreased PVR within 2 minutes, from 1241+/-579 and 1224+/-494 dyne . cm/sec 5 , which were threefold-to-fourfold increased baseline values, to 672+/-308 and 538+/-203 dyne . cm/sec 5 respectively. However, only in the UK343-664 group, changes from baseline PVR values after treatment were significant compared to the maximal change during target PHTN. Neither drug caused a significant change in SVR. In this model of ETOH-induced PHTN, both UK343-664 and NTG were effective pulmonary vasodilators with a high degree of selectivity. However, the changes from baseline values of PVR, and the partial recovery of systemic pressure and RV contractility compared to the maximal change during target PHTN, were significant only in the sildenafil analogue group.

Effects of Sildenafil Analogue UK 343-664 on a Porcine Model of Acute Pulmonary Hypertension

BACKGROUND Sildenafil (Pfizer Pharmaceuticals, Sandwich, Kent, UK) has been associated with pulmonary vasorelaxation. A more potent Sildenafil analogue (UK 343-664 [Pfizer Pharmaceuticals]) has been developed, but its effects in vivo have not been studied. This study evaluated the effects of UK 343-664 (Pfizer) during acute pulmonary hypertension. METHODS Fourteen adult swine were anesthetized with 1 minimum alveolar concentration isoflurane and were mechanically ventilated with an FIO(2) of 50%. End tidal CO(2) was maintained between 32 and 36 mm Hg. Micromanometer tipped catheters were placed in the ascending aorta, pulmonary artery, and right ventricle. Pulmonary flow was measured with a perivascular probe using transit time ultrasound. RESULTS Pulmonary hypertension was induced with a continuous infusion of the thromboxane analogue U46619. Animals were randomized into two groups. Group 1 (n = 9) received 500 microg of UK 343-664 (Pfizer) intravenously for more than 2 minutes. Group 2 (n = 5) served as the control group. Data were recorded continuously for 60 minutes. Statistical analyses were performed with the analysis of variance and t tests. A p less than 0.05 was considered significant.Pulmonary hypertension was achieved in all animals. The administration of UK 343-664 (Pfizer) was associated with a significant decrease in pulmonary artery pressure (30.3%; p < 0.05) and pulmonary vascular resistance (42%; p < 0.05) with mild systemic vasodilatation. These effects were partially maintained at 30 minutes (a 17.3% and 39% decrease, respectively; p < 0.05). CONCLUSIONS The administration of UK 343-664 (Pfizer) was associated with predominant pulmonary vasodilatation without systemic hypotension. This may represent a significant advance in the treatment of acute pulmonary hypertension. Potential clinical implications for this new phosphodiesterase enzyme type V (PDEV) inhibitor merit further study.

Treating myocardial stunning randomly, with either propofol or isoflurane following transient coronary occlusion and reperfusion in pigs.

Propofol and isoflurane may be used during fast track anesthesia for off-pump bypass, where transient ischemia is common. The purpose of this study was to compare the effects of propofol vs isoflurane in a porcine model of acute coronary occlusion. Twenty five pigs were randomized to receive general anesthesia with either isoflurane, 1 MAC (n = 13), or propofol, 3 mg/kg bolus followed by 200 microg/ kg/min infusion (n = 12). Pressure-tipped catheters were placed in the left ventricle (LV) and carotid artery; cardiac output was measured by ultrasound; two pairs of ultrasonic dimension catheters were placed in the subendocardium of LV. The slope of LV end-systolic pressure-volume relationship (Emax) was calculated. Reversible ischemia for 15 mins was accomplished with an occluder around the left anterior descending artery followed by reperfusion period. Measurements were done at baseline, end ischemia, early (5 min) and late (30 min) reperfusion. The data collected included systemic hemodynamics, LV end-diastolic pressure (LVEDP), dP/dt, Emax, and the presence of ventricular arrhythmias. The number of animals studied to completion was 19 (n = 11 in the isoflurane group; n = 8 in propofol group). There was a significant difference in Emax between isoflurane and propofol during early and late reperfusion [3.4 (0.5) and 4.0 (0.3) vs 2.6 (0.4) and 3.2 (0.5) mmHg/sec, respectively; P < 0.05]. Postreperfusion ventricular fibrillation occurred in 54% animals in the propofol group vs none in the isoflurane group ( P 0.05). Isoflurane administration was found to be cardioprotective against ventricular depression and arrhythmias compared to propofol.

Ethanol-induced acute pulmonary hypertension and right ventricular dysfunction in pigs

Editor—Absolute ethyl alcohol (ETOH) is used with increased frequency in the treatment of conditions such as percutaneous ablation of unresectable hepatic tumours, sclerotherapy of oesophageal varices, ventricular septal ablation, and i.v. embolization of arteriovenous malformations. – 3 Although the incidence of complications with the use of ETOH is relatively low, episodes of cardiopulmonary collapse have been described. The postulated mechanism is severe pulmonary vasoconstriction from the sudden passage of ETOH into the pulmonary circulation, causing pulmonary hypertension (PHTN) and right ventricular (RV) strain. However, there is limited information on the effects of i.v. ETOH on heart function, pulmonary and systemic haemodynamics, and in clinical conditions similar to those encountered during therapeutic procedures. We have studied the causal relationship between the i.v. administration of ETOH and alterations in systemic and pulmonary haemodynamics, and examined the duration of such changes in an intact porcine model. An additional purpose was to create a basis for investigating possible treatment in such catastrophes. After approval by the University of Florida Institutional Animal Care and Use Committee, eight domestic pigs (45–50 kg) were studied and handled according to NIH guidelines. The animals were anaesthetized with isoflurane in O2 50%. Animals were mechanically ventilated to maintain normocarbia. A 7-French (Fr), pressure-tipped, flotation pulmonary artery catheter (Millar Instruments Inc., Houston, TX, USA) was inserted via the right internal jugular vein into the main pulmonary artery. A 7-Fr, triple lumen, central venous catheter was placed through the left internal jugular vein. The left carotid artery was exposed, and a 5-Fr pressure-tipped catheter (Millar Instruments Inc.) was placed and advanced into the ascending aorta for continuous arterial pressure monitoring. A median sternotomy was then performed and the heart placed in a pericardial cradle. A 5-Fr pressure-tipped catheter was inserted via a small stab wound into the RV cavity for measurement of RV pressure (RVP) and RV dP/ dT. Cardiac output (CO) was measured with a 10 mm perivascular ultrasound probe placed in the main pulmonary artery. All animals were allowed to stabilize (arterial pressure, temperature) for 60 min after the surgical preparation before data collection. Haemodynamic measurements included systemic mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), RVP, central venous pressure (CVP), pulmonary artery occlusion pressure (PAOP), and CO. Pulmonary and systemic haemodynamics and RV dP/dT, as an index of contractility, were measured. PVR and systemic vascular resistance (SVR) were calculated using standard formulas. Undiluted ETOH was infused via a central venous catheter at a rate of 2 ml min (approximately 50 mg kg min) until a two-fold increase in MPAP was reached or a maximum of 20 ml were infused. Two previous animals (not included in this study) suffered from acute cor pulmonale when a dose of 5 ml of ETOH was administered as a rapid i.v. bolus (as is frequently administered for ablation procedures) and could not be resuscitated. Therefore, we decided to proceed with the slower infusion of ETOH. When the target MPAP was reached, the infusion was discontinued and the animals observed until haemodynamics returned to within 10% of baseline. Data were collected at baseline, when the target MPAP was achieved, and after discontinuation of the infusion until haemodynamics returned to within 10% of baseline. After discontinuation of ETOH, the animals received only an infusion of 2 ml kg of normal saline (NS). At the end of the experiment, the animals were euthanized. Data were expressed as mean (SD). A two-way analysis of variance was used, followed by Student–Newman–Keuls test for multiple comparisons. A P-value of ,0.05 was considered significant. A rate of 50 mg kg (approximately 2.5 ml of ETOH per min) was sufficient to induce significant PHTN within 3 min. The infusion of ETOH achieved a two-fold elevation in MPAP at a mean dose of 188 (22) mg kg. During the ETOH infusion, CO was maintained (Table 1), heart rate (HR) increased, and stroke volume remained stable. After ETOH infusion, CVP and MPAP increased significantly (Table 1), resulting in significantly increased PVR [from 289 (94) to 564 (118) dyn s cm; P,0.05], although MAP and PAOP (Table 1) and SVR remained relatively unchanged. The SVR/PVR ratio decreased by

Administration of milrinone before ischemia, in the presence of β-blockade, to treat metabolic impairment and myocardial stunning in pigs

Background: We examined effects of phosphodiesterase type III inhibition on regional myocardial metabolism and global left ventricular function, during ischemia, in the presence of β‐blockade.

Treating pulmonary hypertension post cardiopulmonary bypass in pigs: milrinone vs. sildenafil analog

Procedures using cardiopulmonary bypass (CPB) and aortic cross-clamping are associated with a variable degree of ischemia/reperfusion of the lungs, leading to acute pulmonary hypertension (PHT). The purpose of this study was to compare the effects of the sildenafil analog (UK343-664), a phosphodiesterase type V(PDEV) inhibitor, with milrinone, a PDE type III inhibitor, in a porcine model of acute PHT following CPB. After the pigs were anesthetized, pressure-tipped catheters were placed in the right ventricle and carotid and pulmonary arteries. Cardiac output was measured with an ultrasound probe on the ascending aorta. After heparinization and placement of aortic and right atrial cannulae, non-pulsatile CPB was instituted and cardioplegia administered following aortic cross-clamping. After 30 minutes, the clamp was removed and the animals re-warmed and separated from CPB in sinus rhythm. The animals were randomized to 3 groups, and 16 animals were studied to completion: milrinone (n=5) 50 μg/kg; sildenafil-analog (n=5) 500 μg/kg; and normal saline (NS) (n=6). Hemodynamic data were collected at baseline pre-CPB and, following termination of CPB, at baseline, 5, 10 and 30 minutes after administration of the drug. Pulmonary hypertension was present in all groups following CPB. After administration of the drugs, mean pulmonary artery pressure decreased in all 3 groups; however, only in the sildenafil-analog group did pulmonary vascular resistance(PVR) decrease by 35%, from 820 to 433 dynes · cm · sec-5 at 5 minutes (p<0.05), and continued to be decreased at 10 minutes by 26% (P<0.05). Pulmonary selectivity was demonstrated with sildenafil-analog, because there were no similar changes in systemic vascular resistance(SVR) and no significant changes in systemic hemodynamics. Sildenafil-analog, a PDEV inhibitor, shows a promising role for managing the PVR increases that occur following CPB.

Inhaled Amyl Nitrite Effectively Reverses Acute Catastrophic Thromboxane-Mediated Pulmonary Hypertension in Pigs

Acute catastrophic pulmonary vasoconstriction frequently leads to cardiovascular collapse. Rapid and selective pulmonary vasodilation is desired in order to restore haemodynamic stability. This pilot study examined the effectiveness of inhaled amyl nitrite as a selective pulmonary vasodilator. Nine adult swine were anaesthetized. Acute pulmonary hypertension with haemodynamic collapse was induced with a bolus administration of a thromboxane analogue, U46619. Six animals then received a capsule of amyl nitrite. The administration of inhaled amyl nitrite decreased mean pulmonary artery pressure from 42 +/- 3 to 22 +/ 3 mmHg at five minutes (p < 0.05), with a concomitant increase in cardiac output and mean arterial pressure. Pulmonary vascular resistance decreased from 4889 +/- 1338 to 380 +/- 195 dyne. sec. cm(-5) (by 92% from the maximal pulmonary hypertension change), with significant improvement in systemic haemodynamics. During acute thromboxane-mediated pulmonary hypertension with cardiovascular collapse, prompt administration of inhaled amyl nitrite was effective in restoring pulmonary and systemic haemodynamics within five minutes.

Treating Metabolic Impairment and Myocardial Stunning with Phosphodiesterase Inhibitor Type III, Milrinone, Administered Prior to Coronary Artery Occlusion in the Presence of Calcium Channel Blockade in Pigs

This study examined milrinone effects on ischaemic myocardial metabolism and function with calcium blockade. We studied 15 pigs in 3 groups: group C received no drugs; group D received diltiazem 5 mg bolus followed by infusion; group D+M received diltiazem and milrinone (50microg/Kg). The left anterior descending (LAD) artery was then occluded for 15 minutes. Left ventricular (LV) function data obtained included rate, pressures, output, Emax, and dP/dT. Blood lactate was obtained from the LAD and circumflex vessels at baseline, end of occlusion, early (15 min) and late (1 hour) reperfusion. In group D+M, less depression of LV function occurred during ischaemia and early reperfusion. Lactate extraction in the LAD region was less negative in D+M group than in the group without milrinone during ischaemia and late reperfusion. We conclude the preemptive administration of milrinone prior to ischaemia added to calcium blockade improved myocardialfunction and ischaemic metabolic effects.