Inhaled Pulmonary Vasodilators and Thoracic Organ Transplantation: Does Evidence Support Its Use and Cost Benefit?

In heart transplantation, pulmonary hypertension and increased pulmonary vascular resistance followed by donor right ventricular dysfunction remain a major cause of perioperative morbidity and mortality. In lung transplantation, primary graft dysfunction remains a major obstacle because it can cause bronchiolitis obliterans and mortality. Pulmonary vasodilators have been used as an adjunct therapy for heart or lung transplantation, mainly to treat pulmonary hypertension, right ventricular failure, and associated refractory hypoxemia. Among pulmonary vasodilators, inhaled nitric oxide is unique in that it is selective in pulmonary circulation and causes fewer systemic complications such as hypotension, flushing, or coagulopathy. Nitric oxide is expected to prevent or attenuate primary graft dysfunction by decreasing ischemia-reperfusion injury in lung transplantation. However, when considering the long-term benefit of these medications, little evidence supports their use in heart or lung transplantation. Current guidelines endorse inhaled vasodilators for managing immediate postoperative right ventricular failure in lung or heart transplantation, but no guidance is offered regarding agent selection, dosing, or administration. This review presents the current evidence of inhaled nitric oxide in lung or heart transplantation as well as comparisons with other pulmonary vasodilators including cost differences in consideration of economic pressures to contain rising pharmacy costs.

Pre-clinical assessment of a water-in-fluorocarbon emulsion for the treatment of pulmonary vascular diseases.

Hypoxic pulmonary vasoconstriction (HPV) is a well-characterized vascular response to low oxygen pressures and is involved in life-threatening conditions such as high-altitude pulmonary edema (HAPE) and pulmonary arterial hypertension (PAH). While the efficacy of oral therapies can be affected by drug metabolism, or dose-limiting systemic toxicity, inhaled treatment via pressured metered dose inhalers (pMDI) may be an effective, nontoxic, practical alternative. We hypothesized that a stable water-in-perfluorooctyl bromide (PFOB) emulsion that provides solubility in common pMDI propellants, engineered for intrapulmonary delivery of pulmonary vasodilators, reverses HPV during acute hypoxia (HX). Male Sprague Dawley rats received two 10-min bouts of HX (13% O2) with 20 min of room air and drug application between exposures. Treatment groups: intrapulmonary delivery (PUL) of (1) saline; (2) ambrisentan in saline (0.1 mg/kg); (3) empty emulsion; (4) emulsion encapsulating ambrisentan or sodium nitrite (NaNO2) (0.1 and 0.5 mg/kg each); and intravenous (5) ambrisentan (0.1 mg/kg) or (6) NaNO2 (0.5 mg/kg). Neither PUL of saline or empty emulsion, nor infusions of drugs prevented pulmonary artery pressure (PAP) elevation (32.6 ± 3.2, 31.5 ± 1.2, 29.3 ± 1.8, and 30.2 ± 2.5 mmHg, respectively). In contrast, PUL of aqueous ambrisentan and both drug emulsions reduced PAP by 20-30% during HX, compared to controls. IL6 expression in bronchoalveolar lavage fluid and whole lung 24 h post-PUL did not differ among cohorts. We demonstrate proof-of-concept for delivering pulmonary vasodilators via aerosolized water-in-PFOB emulsion. This concept opens a potentially feasible and effective route of treating pulmonary vascular pathologies via pMDI.

Chronic Right Heart Failure: Expanding Prevalence and Challenges in Outpatient Management.

Right heart failure is caused by right heart dysfunction resulting in suboptimal stroke volume to supply the pulmonary circulation. Therapeutic developments mean that patients with acute right heart failure survive to hospital discharge and live with chronic right heart failure. Chronic right heart failure management aims to reduce afterload, optimize preload, and support contractility, with the best evidence available in vascular targeted therapy for pulmonary arterial hypertension. However, the management of chronic right heart failure relies on adapting therapies for left ventricular heart failure to the right. We review right heart failure management in the ambulatory setting and its challenges.

The role of inhaled prostacyclin in treating acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a syndrome of acute lung injury that is characterized by noncardiogenic pulmonary edema and severe hypoxemia second to a pathogenic impairment of gas exchange. Despite significant advances in the area, mortality remains high among ARDS patients. High mortality and a limited spectrum of therapeutic options have left clinicians searching for alternatives, spiking interest in selective pulmonary vasodilators (SPVs). Despite the lack of robust evidence, SPVs are commonly employed for their therapeutic role in improving oxygenation in patients who have developed refractory hypoxemia in ARDS. While inhaled epoprostenol (iEPO) also impacts arterial oxygenation by decreasing ventilation-perfusion (V/Q) mismatching and pulmonary shunt flow, this effect is not different from inhaled nitric oxide (iNO). The most effective and safest dose for yielding a clinically significant increase in PaO2 and reduction in pulmonary artery pressure (PAP) appears to be 20-30 ng/kg/min in adults and 30 ng/kg/min in pediatric patients. iEPO appears to have a ceiling effect above these doses in which no additional benefit may be derived. iNO and iEPO have shown similar efficacy profiles; however, they differ with respect to cost and ease of therapeutic administration. The most beneficial effects of iEPO have been seen in adult patients with secondary ARDS as compared with primary ARDS, most likely due to the difference in etiology of the two disease states, and in patients suffering from baseline right ventricular heart failure. Although iEPO has demonstrated improvements in hemodynamic parameters and oxygenation in ARDS patients, due to the limited number of randomized clinical trials and the lack of studies investigating mortality, the use of iEPO cannot be recommended as standard of care in ARDS. iEPO should be reserved for those refractory to traditional therapies.

Effects of terlipressin on pulmonary artery pressure in a septic cooled infant: an echocardiographic assessment.

Experience with terlipressin (TP) in the neonatal field is scarce. We describe the effects of TP on pulmonary circulation, studied with echocardiography, in an asphyxiated septic cooled infant with pulmonary hypertension (PH) who developed catecholamine-resistant hypotension and exacerbation of PH shortly after the beginning of the rewarming. TP was added to norephinephine and adrenaline infusions at the dose of 0.02 mg kg(-1) every 6 h, because of refractory hypotension and oliguria. After 10 min, blood pressure dramatically and definitely increased, and urinary output was re-established after 60 min. Echocardiographic evaluation 30 min after the second bolus of TP showed unchanged velocity of the tricuspidal valve regurgitation and improved biventricular functional indexes respect to the pre-treatment assessment. TP was continued for 12 h (three doses) without significant adverse effect except for a transient increase in troponin levels. Addition of TP boluses to catecholamine infusion in our newborn was effective in increasing systemic vascular resistance without increasing pulmonary vascular resistance, successfully reversing the hemodynamics of severe PH, and suggesting a potential primary vasodilator effect on pulmonary circulation. Transient increase of troponin levels during TP treatment confirms the risk of excessive coronary vasoconstriction when TP boluses are added to high dose catecholamines.

Noninvasive assessment of acute cardiopulmonary effects of an oral single dose of sildenafil in patients with idiopathic pulmonary hypertension.

We aimed to assess the acute cardiopulmonary effects of a 100-mg oral single dose of sildenafil in patients with idiopathic pulmonary hypertension (IPAH) using a well-validated but less-used noninvasive echocardiographic method for the measurement of both systolic and diastolic pulmonary artery pressure (PAP), by tricuspid regurgitation (TR) velocity curve analysis. We studied 12 consecutive patients with IPAH (10 patients with New York Heart Association functional class III, and 2 patients with functional class II). A 100-mg oral single dose of sildenafil was added to previous medications of all patients and its immediate effects were evaluated 1, 5, and 12 h after treatment. Using paired analysis, administration of a 100-mg oral single dose of sildenafil led to a significant reduction in mean PAP and a remarkable increase in pulmonary acceleration time (PAT) 1 h after treatment (P = 0.000; 95% confidence interval [CI] 18.99-26.00 and P = 0.005; 95% CI -12.89 to -2.95, respectively). In addition, although the right heart dimensions (right atrium and right ventricle) showed a trend toward improvement, the differences were not statistically significant (P = 0.13 and P = 0.08, respectively). Our results demonstrated that Doppler examination of TR alone can be easily used for the estimate of systolic and diastolic PAP in patients with IPAH. This study also shows that sildenafil is the only drug given orally that can evaluate the vasodilatory capacity of the pulmonary vascular bed in patients with IPAH, with promising effects on mPAP and PAT in these patients.

Assessment of acute pulmonary vascular reactivity in portopulmonary hypertension.

The role of acute pulmonary vasodilator testing in portopulmonary hypertension (PoPH), a current contraindication for orthotopic liver transplantation (OLT), has not been thoroughly elucidated. The purpose of this work was to analyze the results of acute vasodilator testing with inhaled nitric oxide (NO), to compare them with intravenous epoprostenol (PGI(2)), and to investigate the acute effects of the oral vasodilator isosorbide-5-mononitrate (Is-5-MN), in patients with PoPH. A total of 19 patients with PoPH (male/female = 9/10) were studied. Pulmonary hemodynamic measurements were performed at baseline and during NO inhalation (40 ppm); additionally, 15 patients were tested with PGI(2) (2-12 mug/kg/minute) and 8 were tested with Is-5-MN (20-40 mg). Inhaled NO reduced pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) by 5.7% and 11.0%, respectively. PGI(2) elicited greater reductions in PAP (11.8%) and PVR (-24.0%), and produced a 28% drop in systemic vascular resistance (SVR) and a 17% increase in the cardiac index (CI). Is-5-MN reduced PAP by 25.6% and PVR by 21.5%, without systemic changes. There was good agreement between the response to PGI(2) and Is-5-MN: 6 patients of the whole series (32%) decreased PAP >20% from baseline, reaching a final value < or = 35 mmHg, the current limit for OLT. In conclusion, acute vasodilator testing has a relevant role in PoPH, as it identifies one-third of patients able to reach a more favorable hemodynamic situation, which can be determinant for their management. For vasodilator testing, PGI(2) is more suitable than NO in PoPH. Is-5-MN exerts a selective effect on pulmonary circulation in patients who had already responded to PGI(2).

The effects of inhaled nitric oxide on the levels of cGMP plasma and lung tissue in a canine model of smoke inhalation injury.

The effects of inhaled nitric oxide (NO) on pulmonary hypertension and their mechanisms were studied in a canine model of smoke inhalation injury. Twenty-one dogs were randomly divided into three groups: four dogs constituted the normal control group, eight dogs subjected to smoke inhalation followed by O(2) inhalation (FiO(2)=0.45) constituted the injury control group, and nine dogs inhaling a mixture of O(2) and 45ppm nitric oxide after smoke exposure served as the treatment group. The levels of cyclic guanosine monophosphate (cGMP) in arterial plasma of the treatment group were higher than that of the control group at 5, 8, and 12h after smoke exposure, while the levels of cGMP in lung tissue were also significantly higher compared with that of the control group (P<0.01). The levels of cGMP of injury control group were decreased significantly compared with normal controls (P<0.05). Pulmonary vasoconstriction following smoke inhalation was significantly attenuated by inhalation of NO (P<0.05), which exerted no apparent effect on the systemic circulation (P>0.05). Inhalation of NO may lower pulmonary hypertension induced by smoke inhalation injury in dogs. The selective effect of NO on pulmonary circulation may be attributed to an increase in level of cGMP in smooth muscle cells of the lung tissue after inhalation of NO.

ADAR1 is involved in the development of microvascular lung injury.

Deamination of adenosine on pre-mRNA to inosine is a recently discovered process of posttranscription modification of pre-mRNA, termed A-to-I RNA editing, which results in the production of proteins not inherent in the genome. The present study aimed to identify a role for A-to-I RNA editing in the development of microvascular lung injury. To that end, the pulmonary expression and activity of the RNA editase ADAR1 were evaluated in a mouse model of endotoxin (15 mg/kg IP)-induced microvascular lung injury (n=5) as well as in cultured alveolar macrophages stimulated with endotoxin, live bacteria, or interferon. ADAR1 expression and activity were identified in sham lungs that were upregulated in lungs from endotoxin-treated mice (at 2 hours). Expression was localized to polymorphonuclear and monocytic cells. These events preceded the development of pulmonary edema and leukocyte accumulation in lung tissue and followed the local production of interferon-gamma, a known inducer of ADAR1 in other cell systems. ADAR1 was found to be upregulated in alveolar macrophages (MH-S cells) stimulated with endotoxin (1 to 100 microg/mL), live Escherichia coli (5x10(7) colony-forming units), or interferon-gamma (1000 U/mL). Taken together, these data suggest that ADAR1 may play a role in the pathogenesis of microvascular lung injury possibly through induction by interferon.

Anticoagulation management clinics for the outpatient control of oral anticoagulants.

Oral anticoagulant therapy has a high risk-benefit profile and is labor intensive to manage. A better understanding of the indications for anticoagulation and of prothrombin time monitoring has led to improved outcomes. The development of anticoagulation management services has also improved the overall management of anticoagulation and the resulting clinical outcomes. By reducing adverse events, anticoagulation management services also result in more cost-effective therapy. Although these results have been generated by mostly nonrandomized observational studies, until better quality investigations are available, the preponderance of current clinical evidence strongly supports the value of a coordinated approach to care by an anticoagulation management service.

A comparison of inhaled nitric oxide with intravenous vasodilators in the assessment of pulmonary haemodynamics prior to cardiac transplantation.

OBJECTIVE: Elevated pulmonary vascular resistance and transpulmonary gradient are predictors of increased perioperative mortality in patients undergoing orthotopic heart transplantation. Sodium nitroprusside and prostacyclin PGI2 are routinely used to assess the reversibility of pulmonary vascular resistance and transpulmonary gradient in heart transplant candidates, but their use is limited by their systemic vasodilatory effect. The aim of this study was to evaluate the systemic and pulmonary haemodynamic effects of low concentration (10 and 20 parts per million) inhaled nitric oxide in patients with severe heart failure with elevated transpulmonary gradient and pulmonary vascular resistance undergoing assessment for cardiac transplantation, and to compare the haemodynamic effects of inhaled nitric oxide with those of sodium nitroprusside and prostacyclin PGI2. METHOD: In 10 consecutive patients with elevated transpulmonary gradient (16+/-2 mm Hg) and pulmonary vascular resistance (3.6 +/-0.3 Wood units (WU)) nitric oxide (10 and 20 parts per million in 23% inspired oxygen (O2) via a tight fitting facemask) and increasing doses of intravenous sodium nitroprusside and prostacyclin were administered in a random, single-blinded fashion. RESULTS: Inhalation of nitric oxide (10 ppm) reduced the transpulmonary gradient (-7+/-2 mm Hg; P<0.01) and pulmonary vascular resistance (-1.8+/-0.4 WU; P<0.001) but did not affect the systemic vascular resistance (-0.3+/-1 WU) or mean systemic arterial pressure (-1.3 5 mm Hg). Sodium nitroprusside and prostacyclin reduced the transpulmonary gradient (-4.5+/-2 mm Hg; P<0.01 and -3.6+/-2 mm Hg; P<0.05), pulmonary vascular resistance (-1.5+/-0.4 WU; P<0.001 and -1.3+/-0.4 WU; P<0.01), systemic vascular resistance (-7+/-2 WU; P<0.01 and -7.2+/-2 WU; P<0.01) and mean systemic arterial pressure (-15+/-5 mm Hg; P<0.01 and -18+/-4 mm Hg; P<0.01). CONCLUSION: Low-concentration inhaled nitric oxide is as effective as sodium nitroprusside and prostacyclin in reducing transpulmonary gradient and pulmonary vascular resistance, and is highly pulmonary vasoselective.

Effect of inhaled nitric oxide on hemodynamics and VA/Q inequalities in patients with chronic obstructive pulmonary disease.

Nitric oxide (NO) has been reported to be an endothelium-derived relaxing factor, and hypoxic pulmonary vasoconstriction seems to be enhanced by inhibitors of endothelially dependent vascular relaxation. We examined the circulatory effects of inhalation of 15 ppm NO in air in 14 hypoxic patients suffering from chronic obstructive pulmonary disease (COPD). Of these patients 4 breathed 100% O2 before NO. The effects of NO inhalation on pulmonary gas exchange were also studied in 12 of these patients using the multiple inert gas elimination technique, 3 of whom breathed air, 100% O2, and 15 ppm NO in air in succession. Under baseline conditions, both mean +/- SD pulmonary artery pressure and pulmonary vascular resistance were increased (Ppa = 24.3 +/- 10.4 mm Hg and PVR = 3.3 +/- 1.1 mm Hg/L/min, respectively). Although the pulmonary circulatory effects were not immediate, with no detectable changes after 1 min NO inhalation, Ppa and PVR fell significantly (-19.1 +/- 10.5%, p < 0.02 and -29.3 +/- 15.1%, p < 0.02, respectively) after 10 min NO inhalation. Moreover, the extent of the NO-induced reduction in Ppa was found to depend on the level of baseline pulmonary arterial hypertension. No systemic circulatory effects were observed. The mean VA/Q ratio and the dispersion of ventilation and blood flow distributions were not altered by NO inhalation, although there was a significantly higher percentage of ventilation (7.3 +/- 7.3%, p < 0.05) in poorly and unperfused areas (VA/Q > 10).(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative assessment of increased airway microvascular permeability to 125I-labelled plasma fibrinogen induced by platelet activating factor and bradykinin.

1. We have used 125I-labelled fibrinogen (I-FN) in experiments monitoring plasma extravasation from vessels within guinea-pig trachea and peripheral lung tissue in response to platelet activating factor (PAF) and bradykinin (BK). Retained tissue radioactivity derived from I-FN was detected by direct measurement and by autoradiography. 2. Both PAF and BK caused concentration-dependent increases in radioactivity in trachea and peripheral lung, with PAF being approximately 1000 times more potent than BK at both sites. On a wet weight basis, mean tracheal leakage responses to PAF and BK were approximately 6 times and 2 times greater respectively than those in peripheral lung. Furthermore, in trachea, the maximal response to PAF was nearly twice that to BK, although they were approximately equiactive in peripheral lung. The dipeptidyl carboxypeptidase inhibitor, enalapril (1 mg kg-1, i.v.), increased the potency of BK by approximately 40 fold. 3. In trachea, PAF (50 ng kg-1, i.v.)-induced leakage was selectively inhibited by the PAF receptor antagonist, WEB 2086 (5-50 micrograms kg-1), while responses to BK (50 micrograms kg-1, i.v.) were selectively inhibited by the BK2 receptor antagonist NPC 349 (0.5-1 mg kg-1). Neither PAF nor BK-induced leakage were significantly altered by pretreatment with the histamine H1-receptor antagonists mepyramine (10 micrograms kg-1) or ketotifen (50 micrograms kg-1) or the leukotriene receptor antagonist SKF 104353. These data indicate that both agonists caused direct, specific receptor operated increases in tracheal vascular permeability to plasma macromolecules.The alpha/beta1-adrenoceptor agonist adrenaline (100 pgkg-1) caused modest inhibition of leakage induced by BK, but not of the leakage response to PAF.4. Peripheral airway leakage responses to both PAF and BK were also detected by light microscopic autoradiography in paraffin-embedded tissue sections. This was possible since a significant amount of extravasated I-FN was apparently precipitated and fixed in the extravascular space as 125-labelled fibrin. Autoradiograms showed that both agonists caused increases in peripheral bronchial circulation microvascular permeability to I-FN. No evidence for leakage in alveolar wall capillaries or in pulmonary blood vessels was observed. Quantitation of such autoradiographic data will allow a comprehensive evaluation of the effects of putative asthma mediators on microvascular permeability throughout the respiratory tree.

How does posture influence the haemodynamic assessment of a cardiovascular drug? Experience with nicardipine.

The extent to which posture altered the haemodynamic response to slow calcium channel blocker nicardipine was evaluated in 22 male patients with angiographically confirmed coronary artery disease. Patients were randomly allocated to supine or upright posture and an otherwise identical protocol performed in each group. At rest, following a control saline period, four doses of the drug (log cumulative dosage: 1.25, 2.5, 5.0, and 10.0 mg) were administered by i.v. infusion over a total period of 40 min; haemodynamic indices were recorded during the 3-5 min following each 5 min infusion. The exercise effects of the drug, in each posture, were determined by comparison of a control predrug exercise with observations at the same workload following the maximal cumulative dose. Nicardipine reduced resting mean blood pressure (MBP) and systemic vascular resistance index (SVRI) in both postures, the decrease being more pronounced when upright (MBP, -12%, -18%; p less than 0.01: SVRI, -30%, -46%; p less than 0.01). The increases in cardiac index (CI) and stroke volume index (SVI) were higher when upright (29 and 54% vs. 10 and 27%; p less than 0.01). Pulmonary artery occluded pressure (PAOP) increased by 29% when upright, without change when supine. On exercise, the effects for HR, MBP, CI, SI, and SVRI responses were independent of posture; however, a qualitative difference was apparent for PAOP (-17% vs. +14%; p less than 0.05). Thus, although the actions of nicardipine were qualitatively similar, quantitative differences related to posture were confirmed. These differences appeared to relate to posture-related baseline haemodynamic differences between the groups but with similar postnicardipine absolute values.

Quantitative radionuclide assessment of total pulmonary vascular volume changes.

Current techniques do not permit continuous and noninvasive assessments of changes in total pulmonary intravascular volume. Hence, the present study was undertaken to determine whether quantitative radionuclide imaging can be used to determine the direction and estimate the magnitude of total pulmonary vascular volume changes. The pulmonary circulation was separately perfused at a constant rate via the pulmonary artery and drained at a constant pressure via the left atrium in nine dogs. Changes in pulmonary intravascular volume were recorded as reciprocal changes in extracorporeal reservoir volume during phenylephrine or isoproterenol administration, a 20% increase in pulmonary artery flow or a 5 mmHg (1 mmHg = 133.32 Pa) decrease in left atrial pressure. Erythrocytes were labeled with technetium-99m and pulmonary volume changes were determined from tissue attenuation, blood radioactivity, and changes in total pulmonary radioactivity obtained with a gamma-camera. During each of the interventions, count changes correlated with volume changes (r greater than or equal to 0.75). The technique reliably detected volume changes as small as 10 mL. For all 531 individual pairs of radionuclide- and reservoir-determined volume changes, the correlation between reservoir-determined and radionuclide-estimated pulmonary intravascular volume changes was 0.87. The standard error of the radionuclide estimate was 21 mL. Hence, the present study demonstrates that quantitative radionuclide imaging can be used to continuously and noninvasively determine total pulmonary vascular volume changes.

Assessment and follow-up of patients with ventricular septal defect and elevated pulmonary vascular resistance.

Cardiac catheterization was undertaken in 87 patients (for a total of 89 studies) with ventricular septal defects, including 58 patients with moderate or severe elevation of pulmonary arteriolar resistance. When resting resistance was less than or equal to 7.9 U . m2, it always decreased with isoproterenol and no postoperative problems were experienced with pulmonary vascular obstructive disease. In 36 patients resting resistance measured greater than or equal to 8 U . m2. In 17 of these patients it decreased to less than 7 U . m2 with isoproterenol. Fifteen patients were operated on and postoperative problems with pulmonary vascular disease were experienced only in the single patient whose repair broke down. Surgery was undertaken in 4 of 19 patients in whom resistance did not decrease to less than 7 U . m2 with isoproterenol and advanced pulmonary vascular disease was evident in the 3 patients with follow-up observation. Correlation between measured resistance and other hemodynamic parameters was only fair. A pulmonary to systemic resistance ratio greater than or equal to 0.75 always indicated high absolute resistance but resistance ratios less than 0.75 were found quite frequently in the group with limited response to isoproterenol. These data argue that a reliable estimate of resistance, less than 7 U . m2, with a vasodilator predicts a good postoperative response regardless of measurements at rest or other hemodynamic parameters. Although observations on postoperative progress of patients with resistance greater than 7 U . m2 with a vasodilator are limited, a good postoperative course is unlikely unless resistance can be lowered to a level close to 7 U . m2.

Prostaglandin E1 in the adult respiratory distress syndrome. Benefit for pulmonary hypertension and cost for pulmonary gas exchange.

Prostaglandin E1 (PGE1) has been reported to improve survival in patients with the adult respiratory distress syndrome (ARDS). However, the effects of this pulmonary vasodilating compound on gas exchange have been little documented. We therefore measured hemodynamics, blood gases, and the distributions of ventilation-perfusion ratios (VA/Q), using the multiple inert gas elimination technique, at baseline and during infusion of PGE1 0.02 to 0.04 microgram.kg-1.min-1 in six patients with pulmonary hypertension secondary to ARDS ventilated with 10 cm H2O positive end-expiratory pressure. PGE1 decreased systemic arterial mean pressure (-16%) and pulmonary arterial mean pressure (-15%) and increased cardiac index (+20%) and heart rate (+11%). Arterial PO2 decreased from 99 +/- 6 to 77 +/- 8 mm Hg (p less than 0.01, mean +/- SEM) with no change in mixed venous PO2 and in O2 consumption. PGE1 increased true shunt from 21 +/- 4 to 32 +/- 5% of total blood flow (p less than 0.01) with no significant modification in the pattern of VA/Q distribution. Thus, in ARDS, pulmonary hypertension is reduced by PGE1 at the price of a deterioration in pulmonary gas exchange. The clinical relevance of these findings remains to be evaluated.

Short-term assessment of left ventricular function, coronary hemodynamics, and catecholamine balance in severe congestive heart failure after a single oral dose of milrinone.

Systemic and coronary hemodynamics were measured before and every 10 min after oral milrinone (10 mg) administration for 50 min, together with the drug plasma level in 14 patients with congestive heart failure. Left ventricular pressure (tip manometry), volume (angiography), and derived indexes were simultaneously assessed before and 60 min after milrinone treatment. Peak positive dP/dt, Vmax, and peak velocity of contractile element significantly increased 30 min after milrinone administration by 15%, 37%, and 30%, respectively. An increase in cardiac output (25%) with a consistent decrease in systemic vascular resistance (20%) occurred after 40 min without major changes in heart rate and aortic pressure. Right atrial pressure and minimal and end-diastolic left ventricular pressures decreased significantly after 50 min, by 30%, 25%, and 20%, respectively. Peak -dP/dt increased despite a slight change in end-systolic pressure. The time constants of relaxation, tau 1 and tau 2, significantly decreased by 15% after 50 min and by 16%. A transient but significant increase of 40% in coronary sinus blood flow was observed after 30 min, while myocardial oxygen consumption was unchanged 50 min after milrinone treatment. No changes were observed in catecholamine balance with milrinone. Ejection fraction increased significantly (22%) after milrinone administration, as well as the net work of left ventricle (27%). The increase of inotropism in failing hearts with a parallel reduction in preload and afterload makes milrinone a drug potentially useful in the oral treatment of severe heart failure.