INTRODUCTION

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Acute respiratory distress syndrome (ARDS) causes alveolar collapse resulting in intrapulmonary venous admixture of blood and severe arterial hypoxemia. Mechanical ventilation with positive end-expiratory pressure (PEEP) and low tidal volumes is applied during ARDS to recruit collapsed alveoli for gas exchange without hyperinflation of the lungs (1, 2).

Inhalation of nitric oxide (NO) in low concentrations has been shown to induce pulmonary vasodilation limited to ventilated lung areas, resulting in a redistribution of blood flow from nonventilated to ventilated lung units and in improved pulmonary oxygen transfer in patients with ARDS (3, 4). In contrast, intravenous administration of vasodilatory prostacyclin (PGI₂) (3, 5) and prostaglandin E₁ (PGE₁) (6) has been observed to release regional hypoxic pulmonary vasoconstriction, increase pulmonary blood flow to shunt units, and reduce arterial blood oxygenation.

Inhalation of aerosolized prostaglandins may cause vasodilation selectively in ventilated lung units, provided that the vasodilatory prostaglandin does not diffuse from ventilated to nonventilated lung units and that it is inactivated before reaching the systemic circulation (7). Because PGE₁ is deactivated rapidly within the lungs (8, 9), aerosolized PGE₁ should cause selective pulmonary vasodilation and improve gas exchange as does NO inhalation in patients with ARDS.

We hypothesize that inhalation of aerosolized PGE₁ provides vasodilation selectively in ventilated lung units and improves gas exchange equal to that of NO inhalation in low concentrations. To test this hypothesis we examined the cardiopulmonary function during inhalation of aerosolized PGE₁ and NO in patients with ARDS.

	METHODS

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After approval by the Innsbruck University ethics committee, 10 mechanically ventilated patients with ARDS were studied. The criteria of the American-European Consensus Conference were used to define ARDS (10). Patients were not included in the study if they had chronic lung or heart disease, bronchopleural fistula, or tricuspid insufficiency. Organ Failure Score (11) and Simplified Acute Physiologic Score (12) were recorded at inclusion in the study. Although all patients were hemodynamically stable, some received inotropic or vasoactive drugs (Table 1). During the study, fluid replacement and infusion of all drugs remained unchanged.

Cardiovascular Measurements

Heart rate (HR) was obtained from the electrocardiogram. Systemic blood pressure (Psa), central venous, pulmonary artery, and pulmonary artery occlusion pressures were continuously transduced (P50; Gould, Oxnard, CA) and recorded. Cardiac output and right ventricular ejection fraction (RVEF) were estimated with the thermal dilution technique using an algorithm based on an exponential curve analysis (Explorer; Baxter Edwards Critical-Care, Irvine, CA) (13).

Ventilatory and Lung Mechanics Measurements

Gas flow and airway pressure (Paw) were measured at the proximal end of the tracheal tube with a heated pneumotachograph (No. 2; Fleisch, Lausanne, Switzerland) connected to a differential pressure transducer (P130; Statham, Oxnard, CA). Tidal volume (VT) was derived from the integrated gas flow signal. Esophageal pressure (Pes) was measured with a balloon catheter as described previously (14).

Gas Analysis

Arterial and mixed venous blood gases and pH were determined immediately after sampling in duplicate with standard blood gas electrodes (STAT5Profil; Nova Biomedical, Waltham, MA). Each sample had oxygen saturation, hemoglobin, and methemoglobin analyzed using spectrophotometry (OSM3; Radiometer, Copenhagen, Denmark). Inspired and expired O₂ and CO₂ fractions were continuously measured (Datex, Helsinki, Finland).

Data Analysis

Transmural central venous pressure (Pcv_tm), pulmonary artery pressure (Ppa_tm), and pulmonary artery occlusion pressure (Pao_tm) were derived by subtracting Pes from the respective pressures. Standard formulas were used to calculate cardiac index (CI), stroke volume index (SVI), right ventricular end-diastolic volume index (RVEDVI), right ventricular end-systolic volume index (RVESVI), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), venous admixture (VA/T), oxygen delivery (DO₂), and oxygen extraction ratio (O₂ER). Alveolar dead space (VAD) was calculated as VT · (1  Pet_CO2/Pa_CO2) (4).

Administration and Measurement of NO

Nitric oxide was obtained as a mixture of 900 ppm NO in pure N₂ and administered with a NO delivery system (Pulmonox; MesserGriesheim, Gumpoldskirchen, Austria). Inspired NO and NO₂ were continuously measured with a chemiluminescence-type NO detector (CLD 700AL; EcoPhysics, Dürnten, Switzerland).

Administration of Aerosolized PGE₁

A PGE₁ solution (1 to 10 µg/ml) was prepared from 500 µg synthetic PGE₁ dissolved in 1 ml ethanol (Upjohn, Puurs, Belgium) by dilution in 0.9% saline (15). Aerosols of PGE₁ with a mean particle size of 2 µm were generated with a jet nebulizer (Dräger, Lübeck, Germany) which was powered during inspiration by a gas flow of 4 L/min from the ventilator.

Protocol

Mechanical ventilation was provided with PEEP set at 2 cm H₂O above the inflection pressure on a static pressure/volume curve and a tidal volume adjusted to correspond to the highest compliance (1, 2). Ventilator rate was titrated to achieve a Pa_CO2 between 50 and 60 mm Hg. Fraction of inspired oxygen (FI_O2) was set to maintain Pa_O2 above 60 mm Hg. Ventilator settings were held constant throughout the study.

After obtaining baseline measurements, increasing concentrations of aerosolized PGE₁ and NO were applied. The concentration of aerosolized PGE₁ was increased by 1 ng/kg/min and that of inhaled NO by 1 ppm at 10-min intervals. The lowest concentrations of inhaled PGE₁ and NO effecting a maximal increase in Pa_O2 compared with baseline conditions were used during the interventions. Intravenous PGE₁ infusion was titrated to achieve a similar decrease in Ppa_tm as observed with inhaled aerosolized PGE₁ and NO compared with baseline conditions. Patients not responding to PGE₁ or NO inhalation were excluded from the study.

Patients then received, in random order, NO, aerosolized PGE₁ in the inspiratory gas, infusion of PGE₁, or no intervention (control). A 60-min equilibration period followed each intervention before measurements. Before beginning each intervention, at least 30 min were allowed for cardiopulmonary variables to return to baseline values (± 10%).

Statistical Analysis

Results are expressed as mean ± standard error of the mean (SE). Data were analyzed with Friedman's two-way analysis of variance. When a significant F ratio was obtained, differences between the means were isolated with Wilcoxon's signed rank test. Differences were considered to be statistically significant if p < 0.05.

	RESULTS

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Patients were ventilated with VT of 390 to 610 ml (485 ± 19 ml), ventilator rate of 15-26/min (23 ± 1/min), PEEP of 14 to 20 cm H₂O (16 ± 1 cm H₂O), and FI_O2 of 0.80 to 0.97 (0.9 ± 0.02). Resulting mean airway pressure (Paw) of 20 to 32 cm H₂O (25 ± 2 cm H₂O) and peak Paw 24 to 42 cm H₂O (33 ± 2 cm H₂O) remained unchanged throughout the study. Concentrations of 6 to 15 ng/kg/min (10 ± 1 ng/kg/min) aerosolized PGE₁ or 2 to 10 ppm (7 ± 2 ppm) NO in the inspiratory gas were required to achieve a maximal increase in Pa_O2. Infusion of 8 to 16 ng/kg/min (12 ± 2 ng/kg/min) PGE₁ was administered to produce a similar decrease in Ppa_tm as observed during aerosolized PGE₁ and NO inhalation.

Changes in cardiovascular variables are shown in Table 2. Mean Ppa_tm and PVR decreased and RVEF increased with aerosolized PGE₁ and NO inhalation, and with intravenous PGE₁ infusion (p < 0.05). Aerosolized PGE₁ and NO inhalation were associated with a decrease in RVEDVI and RVESVI (p < 0.05) at a constant CI. Cardiac index was highest during intravenous PGE₁ (p < 0.05). Aerosolized PGE₁ and NO inhalation had no effect on mean Psa and SVR. Infusion of PGE₁ decreased mean Psa and SVR (p < 0.05). Heart rate, Pcv_tm, and Pao_tm did not change significantly between interventions.

Average and individual values of Pa_O2 and VA/T are shown in Figure 1. Inhalation of aerosolized PGE₁ and NO was associated with an increase in Pa_O2, DO₂, and P_O2 (p < 0.05), and a decrease in VA/T and O₂ER (p < 0.05) (Table 3). PGE₁ infusion decreased Pa_O2 and VA/T (p < 0.05). Hemoglobin, methemoglobin, pH, Pa_CO2, and VAD remained unchanged.

View larger version (17K): [in this window] [in a new window]   Figure 1.   Mean ± SE and individual values of PaO2 and venous admixture ( VA/ T) at baseline and during NO inhalation, aerosolized PGE1, PGE1 infusion, and control (no intervention). *p < 0.05 compared with control.

	DISCUSSION

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This study was designed to evaluate the effects of aerosolized PGE₁ and NO inhalation on cardiopulmonary function during optimized mechanical ventilation in patients with ARDS. PGE₁ and NO inhalation effected a comparable reduction in PVR while improving pulmonary gas exchange, as reflected by decreases in VA/T. Neither caused systemic vasodilation.

PGE₁ is present in the normal pulmonary epithelial lining fluid and like PGI₂ causes relaxation of the vascular smooth muscle and vasodilation. In a sheep model with induced pulmonary arterial hypertension, a larger decrease in PVR was observed during PGE₁ than PGI₂ infusion (16). In accordance with our findings, in patients infusion of PGE₁ in low concentrations reduced elevated PVR while systemic vasodilation was mild (6, 8). This presumably results from an almost complete first-pass deactivation of intravenously administered PGE₁ in the lung endothelium (8, 9).

Inhalation of aerosolized PGE₁ and NO lowered equally the elevated Ppa_tm and PVR. In contrast to measurements of pulmonary artery pressure the observed decrease in transmural Ppa should reflect release of the pulmonary vascular tone independent of ventilation-induced changes in intrathoracic pressure. Inhalation of 1 to 80 ppm NO has previously been shown to produce selective pulmonary vasodilation (3, 4). A similar phenomenon has been observed when PGI₂ was added in the inspiratory gas of mechanically ventilated ARDS patients (7, 17). Inhalation of aerosolized PGE₁ and NO did not affect mean Psa and SVR in our patients. This is in agreement with the concept of a selective dilator effect of inhaled PGE₁ and NO on the pulmonary vasculature (3, 4, 7, 17). Lack of systemic vasodilation during NO inhalation is explained by high-affinity binding of NO to hemoglobin (3, 4). Absence of systemic vascular effects during PGE₁ inhalation might be explained by rapid deactivation of PGE₁ in the lung endothelium (8, 9). In contrast, inhaled PGI₂ may spill over into the systemic circulation and is deactivated in the liver (17, 18). This is supported by the observed improvement in splanchnic oxygenation during aerosolized PGI₂ in low concentrations when compared with NO inhalation (18). In agreement with our results, inhalation of up to 5 mg PGE₁ in a sheep model increased the PGE₁ concentration in the epithelial lining fluid without changes in the plasma PGE₁ concentrations and systemic hypotension (15). Significantly lower doses of inhaled PGE₁ were required in our patients to achieve pulmonary vasodilation comparable to that during PGE₁ infusion. These results are in accordance with previous observations made with aerosolized PGI₂ (7, 17) and reflect the efficiency of alveolar prostaglandin delivery.

Pulmonary vasodilation induced by inhalation of PGE₁ and NO was accompanied by an increase of reduced RVEF and a decrease in enlarged right ventricular volumes at a constant CI. Our findings are supported by Rossaint and coworkers (19) who observed similar changes in cardiac volumes and function during selective relief of pulmonary hypertension with NO inhalation. Dilation of the right ventricle and decreased RVEF noted during pulmonary hypertension may reflect compensatory mechanisms to maintain stroke volume (19, 20). Therefore, reduced after-loading of the right ventricle during selective pulmonary vasodilation with PGE₁ and NO inhalation may explain the increase in RVEF without affecting SVI and CI as a normal physiologic response. Consistent with previous investigations (19, 21) PGE₁ infusion produced a comparable pulmonary vasodilation and rise in RVEF associated with an increased CI at unchanged right ventricular volumes. This increase in CI may be attributed to systemic vasodilation (19).

The observed improvement in pulmonary gas exchange during inhalation of aerosolized PGE₁ and NO contrasts with findings of ventilation-perfusion mismatch and reduced arterial blood oxygenation induced by PGE₁ or PGI₂ infusion in patients with ARDS. Infusion of vasodilatory prostanoids results in an overperfusion of already non- or poorly ventilated lung areas presumably by release of hypoxic pulmonary vasoconstriction (3, 5, 6, 22). Apparently the effects of vasodilatory prostanoids on ventilation-perfusion matching depend on the administration route of the substance (7, 17). Despite similar pulmonary vasodilation, aerosolized PGI₂ in low concentrations has been observed to improve intrapulmonary shunting and gas exchange (7, 17). Similar to these observations (7, 17) VA/T and Pa_O2 in our patients improved during aerosolized PGE₁, even though reduction of PVR was comparable to that during intravenous PGE₁ and NO inhalation. These findings indicate that PGE₁, when aerosolized in low concentrations, like PGI₂ or NO inhalation selectively dilates blood vessels in ventilated lung areas, leaving regional vasoconstriction in non- or poorly ventilated lung units unaffected, and improves arterial blood oxygenation by redistributing blood flow from essentially nonventilated to ventilated lung units (3, 4, 7, 17). The higher P_O2 during PGE₁ or NO inhalation may have further contributed to improved Pa_O2.

Recent developments in the treatment of ARDS have introduced inhalation of vasodilatory prostaglandins to improve pulmonary gas exchange and decrease PVR. The results of this study demonstrate that inhalation of aerosolized PGE₁ or NO in low concentrations equally decrease PVR and improve gas exchange by selective vasodilation in ventilated areas in patients with ARDS. Controlled long-term investigations are warranted to evaluate the therapeutic value of aerosolized PGE₁ inhalation in critically ill patients.