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Background: Right ventricular failure remains an important cause of early morbidity and death after heart transplantation and is commonly related to preexistent recipient chronic pulmonary hypertension, which occurs as a result of long-standing congestive heart failure. In this study, the hemodynamic and inotropic effects of milrinone were assessed after bicaval heart transplantation in the setting of monocrotaline pyrrole-induced recipient chronic pulmonary hypertension., Methods: Twenty dogs were used for 10 successfully completed transplantation experiments. Recipient animals underwent right atrial injection of 3 mg/kg monocrotaline pyrrole 4 months before transplantation. Hemodynamic and functional data were taken 1 hour after termination of cardiopulmonary bypass and after milrinone infusion. Myocardial function was assessed with load-insensitive means (preload-recruitable stroke work) and pulmonary vascular impedance was calculated with Fourier analysis., Results: At the time of transplantation, before cardiopulmonary bypass, pulmonary hemodynamic indexes in recipient animals were significantly increased when compared with donors and were further significantly increased after cardiopulmonary bypass. Two animals died after transplantation as a result of acute right ventricular failure. In surviving animals milrinone infusion led to significant increases in right ventricular function, which occurred in association with significant improvements in pulmonary vascular impedance and transpulmonary efficiency., Conclusions: In the setting of monocrotaline pyrrole-induced recipient pulmonary hypertension, milrinone was associated with significant improvements in pulmonary vascular impedance, right ventricular function, and transpulmonary efficiency. These data suggest that milrinone is an effective means to improve right ventricular dysfunction and pulmonary vascular efficiency after bicaval heart transplantation in the setting of recipient chronic pulmonary hypertension.

Right ventricular failure following cardiac transplantation is most commonly related to pre-existent recipient pulmonary hypertension secondary to chronic congestive heart failure. Although nitric oxide has had some role clinically in improving pulmonary hemodynamics and right ventricular function in this setting, an appropriate large-animal model of stable pulmonary hypertension has not been available for basic investigation of this problem. This study was designed to examine the hemodynamic and inotropic effects of inhaled nitric oxide using a canine model of monocrotaline pyrrole-induced chronic pulmonary hypertension. Eight mongrel dogs (22-25 kg) were used. All animals underwent percutaneous pulmonary artery catheterization to measure right heart hemodynamics prior to and 8 weeks after a right atrial injection of monocrotaline pyrrole. Eight weeks post-injection, all hearts were instrumented with a pulmonary artery flow probe, sonomicrometric dimension transducers, and micromanometers. Data were collected at baseline and following nitric oxide administration. Eight weeks post-monocrotaline pyrrole injection, significant increases were observed in the pulmonary hemodynamics compared to pre-injection. Nitric oxide led to significant decreases in pulmonary vascular impedance. Significant improvements in pulmonary blood flow, transpulmonary efficiency, and right ventricular contractility were also observed. This investigation demonstrates the well-known clinical effects of nitric oxide in improving pulmonary hemodynamics which were also associated with an increase in pulmonary blood flow, transpulmonary efficiency, and right ventricular contractility in the setting of monocrotaline pyrrole-induced pulmonary hypertension.

Right ventricular (RV) failure, which is a leading cause of early morbidity and mortality following cardiac transplantation, is attributed to the inability of the donor RV to acutely compensate for the recipient's elevated pulmonary vascular resistance (PVR). Furthermore, the effect of donor brain death (BD) on RV function is unclear. The purpose of this study was to investigate the effects of donor BD on RV function in the setting of elevated PVR. The interactions of the RV and its afterload, the pulmonary vasculature, and left atrial pressure were assessed by measurements of pulmonary vascular energetics and their oscillatory nature using proximal ultrasonic pulmonary artery (PA) flow probe and micromanometers in the proximal and distal PA in 20 mongrel dogs (25.8 +/- 0.4 kg, five control animals). A band was placed around the distal PA (PA-systolic gradient > 15 mm Hg). BD was induced by rising intracranial pressure and was validated neuropathologically. Data were collected at 0, 2, 4, and 6 h after BD in both banded and control animals. Fourier analysis was used to calculate RV oscillatory power, mean power, and total power (TP). Comparison of changes due to banding were made to baseline measurements using multivariate analysis and paired Student's t test (p < 0.05). A significant twofold to fourfold increase in pulmonary impedance and PVR occurred with an acute rise in PA gradient. Control animals tolerated acute increases in PVR without significant changes in TP. There was a significant increase of RV TP from 73 (+/-11) to 98 (+/-10) mW at baseline after the acute rise in PVR and impedance. After BD, the response to increased PVR and impedance was abolished significantly compared with baseline and control animals, suggesting a significant loss of compensatory TP to sustain pulmonary vascular blood flow. The data indicate that BD is detrimental to RV mechanical function.

This study was designed to examine the effects of both nitric oxide and milrinone on pulmonary hemodynamics and right ventricular function using a newly established model of monocrotaline pyrrole-induced chronic pulmonary hypertension. Sixteen mongrel dogs (23-25 kg) were used. All animals underwent percutanous pulmonary artery catheterization to measure right heart hemodynamics prior to and 8 weeks after a right atrial injection of either monocrotaline pyrrole (MCTP, n=8) or placebo (CTL, n=8). Eight weeks postinjection, all hearts were instrumented with a pulmonary artery flow probe and intracavitary micromanometers. Data were collected at baseline as well as following both nitric oxide and milrinone administration. There was no significant difference in the baseline hemodynamic measurements between the two groups. Eight weeks postinjection, significant increases in the pulmonary artery pressure and pulmonary vascular resistance were observed in MCTP compared with CTL. Both nitric oxide and milrinone resulted in significant improvements in pulmonary vascular resistance, pulmonary blood flow, and right ventricular contractility. In addition, nitric oxide caused a significant improvement in pulmonary artery pressure and transpulmonary efficiency, while milrinone led to a significant increase in right ventricular hydraulic power. This study demonstrates the well-known clinical effects of nitric oxide and milrinone in improving pulmonary hypertension, which were also associated with an increase in pulmonary blood flow, transpulmonary efficiency, and right ventricular hydraulic power in the setting of monocrotaline pyrrole-induced chronic pulmonary hypertension.

Objective: To examine the hormonal and hemodynamic changes in a validated animal model of brain death., Design: Prospective, controlled study., Setting: Experimental research laboratory., Subjects: Adult male mongrel dogs (n = 10)., Interventions: Brain death was induced by inflation of a subdural balloon in ten mongrel dogs weighing 23 to 30 kg and validated neuropathologically. The hearts were instrumented with micromanometers and ultrasonic flow probes to measure cardiovascular changes. No inotropic or vasoactive support was given. Hemodynamic stability was maintained with intravenous fluids. Blood samples and hemodynamic readings were collected before and after the induction of brain death., Measurements and Main Results: A Cushing reflex, followed by a hyperdynamic response and diabetes insipidus, occurred in every animal following brain death. Mean arterial pressure, heart rate, contractility, and cardiac output increased to > 350 mm Hg, 230 beats/min, 4200 mm Hg/sec, and 2.8 L/min, respectively, at the peak of this phenomenon before returning to baseline. A plasma catecholamine surge was observed in every animal 15 mins after brain death, while the circulating concentrations of the pituitary gland hormones vasopressin and adrenocorticotrophic hormone decreased significantly after 15 and 45 mins of brain death, respectively, and continued to decrease throughout the experiments. Circulating triiodothyronine, thyroxine, and glucagon concentrations decreased significantly (p < .01) from 0.58 +/- 0.05 ng/mL, 2.20 +/- 0.15 micrograms/dL, and 49.7 +/- 9.1 pg/mL, respectively, to 0.34 +/- 0.03 ng/mL, 1.14 +/- 1.14 micrograms/dL, and 6.9 +/- 1.4 pg/mL, respectively, 420 mins after brain death. The hematocrit increased significantly 15 mins after brain death and then gradually decreased throughout the duration of the experiments., Conclusions: In a validated animal model of brain death, significant decreases in the circulating concentrations of stress hormones, as well as hemodynamic instability, occurred after brain death. Measurements of plasma adrenocorticotrophic hormone and vasopressin values may be useful as diagnostic predictors of brain death. Furthermore, the observed changes may contribute to organ dysfunction after brain death and may necessitate hormonal as well as inotropic and vasoactive support to maintain donor organ function in the clinical setting.

Purpose: Nitric oxide (NO) is a major regulator of vascular tone, blood pressure, and blood flow, and plays a significant role in disease states associated with hemodynamic alterations. However, the role of NO in association with the effects of brain death (BD) has not yet been evaluated., Methods: In 17 mongrel dogs (23 to 31 kg), right atrial serum measurements of nitrite and L-arginine as well as NO ex vivo tissue nitrite extraction were performed at baseline (0), and 120, 240, and 360 minutes after BD. The hearts were instrumented with micromanometers, transonic flow probes, and ultrasonic dimension transducers to determine systolic function and to analyze the pulmonary vasculature flow characteristics by Fourier analysis. Brain death was induced by inflation of a subdurally placed balloon and validated neuropathologically. The results are expressed as mean and standard error of the mean (+/- SEM) (P < .05, paired t-test)., Results: Right and left ventricular function deteriorated significantly (P < .001) by 37% (+/- 10) and 22% (+/- 7) respectively following BD. Pulmonary and systemic vascular resistance as well as pulmonary impedance decreased significantly over 6 hours after BD. Pulsatile flow, a potent stimulant of NO release, converted significantly to more steady flow. Myocardial NO extraction values remained unchanged after BD and serum L-arginine decreased from 12.84 mu g/L (+/- 0.60) to 11.77 mu g/L (+/- 0.55)., Conclusions: The decreases in pulmonary and systemic vascular resistance, pulmonary impedance, and cardiac function associated with BD are not related to major changes in the NO pathway. NO may not play a key role in the early changes after BD.

Deterioration of donor lung function contributes to the shortage of donor organs and early postoperative failure after transplantation. A decrease in donor pulmonary function is associated with opacification of lung fields on radiographs, rendering the lungs unsuitable for transplantation, which may be related to the effects of brain death (BD) on pulmonary hemodynamics. Twenty mongrel canines (25.5 +/- 0.7 kg) underwent 20 BD experiments using a previously validated BD organ donor model. An ultrasonic flowmeter was applied on the pulmonary artery and micromanometers were inserted into the right ventricle, pulmonary artery, and left atrium to measure, which allowed the hemodynamic assessment and impedance profile analysis of the pulmonary vasculature by Fourier transformation. Characteristic impedance (Zo) was compared with input resistance (RIN) and with calculated pulmonary vascular resistance (PVR), the conventional index. Right ventricular hydraulic power was analyzed and divided in its components oscillatory and steady power. The results are expressed as means and SEM (analysis of variance, paired two-tailed t tests). Cushing reflex, hemodynamic response, and diabetes insipidus were consistent findings following BD. PVR, Zo, and RIN decreased significantly (p < 0.05) from 367 +/- 40 dyne.s.cm-5, 226 +/- 13 dyne.s.cm-5, and 771 +/- 52 dyne.s.cm-5 to 261 +/- 25 dyne.s.cm-5, 159 +/- 10 dyne.s.cm-5, and 651 +/- 69 dyne.s.cm-5 6 h after BD. Pulmonary artery blood flow increased significantly from 1,499 +/- 107 mL/min to 2,064 +/- 209 mL/min (p < 0.05) after BD. Hydraulic power increased from 69 +/- 6 mW to 104 +/- 13 mW (p < 0.05) and the oscillatory power to steady power ratio of 33%/67% changed to 23%/77% following BD. Extravascular pulmonary water content increased significantly by 10% after BD. BD causes a significant change in pulmonary vascular hemodynamics. The decrease in impedance and right ventricular afterload may lead to significant pulmonary overflow injury and edema. The increase in steady power represents an important reserve of the right ventricle to sustain pulmonary blood flow following BD.

Microcirculatory forearm cutaneous blood flow was monitored continuously and non-invasively by laser-doppler-flowmetry (LDF) in 10 patients treated with the Berlin Heart biventricular assist device (BVAD) system for end-stage heart failure (BVAD-pts). Ten normal human subjects served as controls (C). The cutaneous blood flow was measured before, during, and after external brachial artery occlusion to evaluate the postocclusive reactive hyperemia (PORH) as a standardized response. To examine micro-vasculatory responses to macro-hemodynamic changes the cardiac output (CO) was decreased by reducing the BVAD-pump rate by 20%. No significant differences in base-line LDF measurements were ascertained in the two groups. After sudden cuff pressure release (1 min later) a statistically significant (p less than 0.004) three- to fourfold blood flow increase (PORH) occurred in both groups. The period of the PORH response was altered in all BVAD-pts. The time to peak PORH values were significantly diminished (p less than 0.05) A markedly delayed return to base-line level occurred in the BVAD-pts. The 20% reduction in the BVAD-pump rate significantly decreased CO (p 0.05) and increased systemic vascular resistance (SVR) (p less than 0.01), whereas LDF levels remained unchanged.