INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Acute respiratory distress syndrome (ARDS) has diverse causes and carries high morbidity and mortality rates (1, 2). It is characterized by profound hypoxemia, pulmonary hypertension, and poor lung compliance. Pulmonary hypertension in ARDS results from the combined effects of hypoxic pulmonary vasoconstriction, the release of mediators, and microthrombosis of the pulmonary circulation (3). A physiologic mechanism of improvement in ventilation-perfusion (A/) mismatch is hypoxic pulmonary vasoconstriction in lung areas with low A/ ratios. However, there are some completely consolidated regions associated with normally ventilated ones with similar variation in perfusion. Hypoxemia in these patients is primarily a result of shunting through consolidated lung. In the absence of definitive therapy, management involves supportive care using mechanical ventilation with increased inspired oxygen concentration and PEEP.

The mechanisms of action of NO on pulmonary circulation have been studied extensively. It has been suggested that inhaled NO, through its lipophilic properties, diffuses directly into the smooth muscle of the pulmonary resistance vessels in the proximity of the alveoli and activates soluble guanylate cyclase, which produces an increase in intracellular guanosine 3 ',5'-cyclic monophosphate and causes smooth-muscle relaxation. Inhaled NO is absorbed from ventilated alveoli, induces local vasodilation, and is rapidly inactivated in the blood by binding to hemoglobin. Therefore, the dilatory effect of low concentrations of inhaled NO is restricted to the pulmonary vasculature. Because the vasodilating effect of inhaled NO should be limited to the ventilated regions of the lung, NO is thought to improve the perfusion of ventilated regions, thus reducing intrapulmonary shunting and improving arterial oxygenation.

Marshall and colleagues (4) have suggested that a positive oxygen content change is only seen with NO when some constriction in addition to hypoxic pulmonary vasoconstriction is present in small arteries or veins or both. Therefore, the gain in PO₂ observed with NO should be enhanced when combined with an infused vasoconstrictor. The vasoconstrictor used in combination with NO should mimic or enhance hypoxic vasoconstriction. Norepinephrine, a catecholamine with predominant -adrenergic effects, was first used three decades ago for the treatment of hypotensive states before the development of the synthetic catecholamines, dopamine and dobutamine. Nowadays, norepinephrine is commonly used in the treatment of septic shock to restore arterial pressure when fluid infusion fails to restore an acceptable arterial pressure. We have previously performed a dose-response study comparing patients with ARDS and septic shock necessitating continuous intravenous infusion of norepinephrine with patients with septic ARDS not requiring norepinephrine (5). We found that the dose-response profile of the two populations was similar (5).

Almitrine bismesylate is a peripheral chemoreceptor stimulant that has been reported to improve oxygenation in patients presenting with ARDS. It has been hypothesized that this improvement in gas exchange resulted from enhancement of hypoxic pulmonary vasoconstriction. Because the vasoconstrictor effect of almitrine bismesylate should be predominant in the nonventilated regions of the lung, almitrine bismesylate should improve the matching between ventilation and perfusion of the lung. If almitrine bismesylate constriction is more potent at hypoxic vessels than at normoxic vessels in the lungs, it is expected to improve systemic oxygenation by reducing the perfusion of poorly oxygenated lung areas, particularly in ARDS lung with severe A/ mismatching.

We therefore presumed that the combination of an intravenous vasoconstrictor agent (almitrine bismesylate and/or norepinephrine) and NO inhalation in patients with ARDS could provide a beneficial effect in redistributing pulmonary blood flow from nonventilated to well-ventilated lung regions by constricting the vessels in nonventilated lung areas with almitrine bismesylate and/or norepinephrine, thus adding shunt control to NO-enhanced vasodilation in ventilated lung regions.

The aim of the present study was to investigate the response to a nonselective vasoconstrictor agent (norepinephrine), a selective pulmonary vasoconstrictor agent (almitrine bismesylate), and to inhaled NO, separately and combined, in a group of patients with ARDS, to determine whether these agents alone would improve PO₂ and whether their combination would have an additive or a synergistic effect on PO₂.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Study Population

During a 6-mo period, 16 consecutive patients (14 male, two female) not requiring inotropic and/or vasopressor agent and presenting with ARDS diagnosed on or after admission to the polyvalent ICU of Sainte-Marguerite University Hospital in Marseille, France were prospectively investigated early in the course of their respiratory disease after written informed consent was obtained from each patient's next of kin. The study was approved by our Ethics Committee (Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale de Marseille) and supported by l'Assistance Publique Hôpitaux de Marseille. ARDS was defined according to the recommendations of the American-European Consensus Conference (6). Among the 16 patients enrolled in the study, nine were admitted for an acute medical illness, five were admitted with postoperative complications after major surgery, and two were admitted to the ICU after multiple trauma. ARDS was related to nosocomial bronchopneumonia (eight patients), lung contusion (three patients), community-acquired pneumonia (two patients), aspiration pneumonia (two patients), or acute pancreatitis (one patient). The duration of mechanical ventilation preceding the study was 6 ± 5 d. All patients were tracheostomized, sedated, and paralyzed with a continuous infusion of sufentanil, midazolam, and vecuronium bromide, and the lungs were ventilated using conventional volume-controlled mechanical ventilation (7200 series; Puritan Bennett, Carlsbad, CA).

Instrumentation and Measurements

Hemodynamic parameters. All patients had a radial artery catheter (Seldicath; Plastimed, Saint Leu la Forêt, France) and a pulmonary artery catheter equipped with a fast-response thermistor (Model 93 A-434H-7.5F; Baxter Healthcare Corp., Irvine, CA), which was inserted percutaneously through the right jugular or the left axillar vein and positioned so that the distal port was in the pulmonary artery and the proximal port in the right atrium, just above the tricuspid valve.

Systolic arterial pressure, diastolic arterial pressure, systolic pulmonary arterial pressure, diastolic pulmonary arterial pressure, pulmonary artery occluded pressure (Ppao), and right atrial pressure (PRA) were measured at end-expiration. The supine zero reference level was the midaxilla. Cardiac output was measured by thermodilution using three 10-ml boluses of glucose solution between 6° and 10° C, injected via a closed system (Co-set; Baxter Healthcare) at end-inspiration to improve the reproducibility of the measurement and also to minimize the influence of changes in intrathoracic pressure. Injection temperature was measured by a thermistor located at the proximal port of the right atrial lumen. The mean of three measurements is reported. Cardiac index, oxygen delivery index (DO₂I), oxygen consumption index, oxygen extraction ratio, and venous admixture VA/T) were calculated using standard formulas. Systemic vascular resistance (SVRI) and pulmonary vascular resistance (PVRI) were calculated using the following standard formulas: SVRI = (-PRA) × 79.9/cardiac index; PVRI = (  Ppao) × 79.9/cardiac index. No paper recordings of hemodynamic parameters were performed.

On inclusion, no patient was receiving cardiovasoactive drugs. Fluid support was limited to 30 to 35 ml/kg/d of glucose 10%.

Blood gas analysis. Systemic and pulmonary arterial blood samples were simultaneously withdrawn within 3 min before the measurement of cardiac output. Arterial pH, PO₂, Pv_O2, and PCO₂ were measured using a blood gas analyzer (278-blood gas system; Ciba Corning, Medfield, MA). Hemoglobin concentration, arterial and mixed venous oxygen saturations (SO₂ and Sv_O2), and methemoglobin levels were measured using a calibrated hemoximeter (270-CO-oxymeter; Ciba Corning).

Respiratory parameters. The following respiratory parameters were recorded: exhaled tidal volume (measured with a pneumotachograph connected to a differential pressure transducer), peak inspiratory pressure, mean inspiratory pressure, and respiratory rate. Respiratory dynamic compliance was calculated as tidal volume/(peak inspiratory pressure  positive end-expiratory pressure).

Nitric Oxide Administration

Nitric oxide was released from a tank containing nitric oxide in nitrogen at a concentration of 450 ppm (Air Liquide, Meudon, France) and was administered sequentially during inspiration within the inspiratory limb of the ventilator just after the humidifier via a delivery system (Opti-NO; Taema, Antony, France). Intratracheal gas was sampled using continuous aspiration through the endotracheal tube permitting continuous determination of inspiratory, expiratory, and mean concentrations of nitric oxide and NO₂ using a chemiluminescence apparatus (NOX 4000; Sérès, Aix-en-Provence, France). For each patient, tidal volume, respiratory rate, and FI_O2 were adjusted to maintain minute ventilation constant throughout the study period. To detect changes in FI_O2 induced by inhalation of NO, FI_O2 was monitored continuously using an O₂ analyzer (NOX 4000; Sérès).

Procedure

The protocol consisted of seven consecutive phases (Figure 1). Baseline measurements were made after 1 h of steady-state conventional mechanical ventilation. After these measurements, norepinephrine was administered in order to obtain an increase in mean pulmonary arterial pressure () of 3 mm Hg. Measurements were performed after 30 min under norepinephrine. Then, the following two periods were randomized (NO alone or in association with norepinephrine) and measurements were performed after 30 min of each phase. Inhaled NO was administered at an inspiratory concentration of 20 ppm. The last three phases were performed under almitrine bismesylate (16 µg/kg/min) (Vectarion; Euthérapie, Neuilly, France). We decided to perform the therapeutic interventions with almitrine bismesylate at the end of the study period because of the prolonged half-life of almitrine bismesylate. The sequences necessitating almitrine bismesylate (almitrine bismesylate + inhaled NO, norepinephrine + inhaled NO, and almitrine bismesylate + norepinephrine + inhaled NO) were also randomized. Measurements were performed after 30 min of administration of these combinations of treatments.

View larger version (9K): [in this window] [in a new window]   Figure 1.   Study design.

Volume-controlled mechanical ventilation settings (except adjustments to keep constant minute ventilation) remained constant throughout the study.

Statistical Methods

All the statistics were performed by an experienced statistician (X.T.). Data are expressed as the mean ± SD. A response to inhaled NO and/ or almitrine bismesylate and/or norepinephrine was defined by an increase of the PO₂/FI_O2 ratio of at least 20% when compared with baseline.

Statistical calculations were performed using the SPSS 7.5 package (SPSS Inc., Chicago, IL). The distribution was analyzed in order to verify that it was normal. General factorial analysis of variance was performed to analyze the different times, and comparison between two times was performed by Student's t test for paired samples. A p value below 0.05 indicated significance.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Patients

The severity of ARDS was assessed by a Lung Injury Score (LIS) greater than 2.5 in all patients. Characteristics of the patients and respiratory parameters are summarized in Table 1. Of the 16 patients included in the study, nine subsequently died. The other patients survived and were discharged from the hospital.

Evolution of PO₂/FI_O2

General factorial analysis of variance taking into account all phases showed that inhaled NO increased oxygenation (p < 0.0001). Almitrine bismesylate also improved oxygenation significantly (p < 0.0001 by general factorial analysis of variance). Norepinephrine (given at a mean infusion rate of 0.21 ± 0.10 µg/kg/min) had no effect on oxygenation. A synergistic effect between inhaled NO and almitrine bismesylate was found (p < 0.05), whereas norepinephrine did not affect the response to inhaled NO.

The effect on oxygenation of each treatment (NO, norepinephrine, almitrine bismesylate) or the combination of these treatments was compared with control value of PO₂/FI_O2 using Student's t test. The results are reported in Table 2. Norepinephrine had no effect on oxygenation, even in the presence of inhaled NO. Furthermore, we observed a significant decrease in PO₂/FI_O2 when norepinephrine was added to the association between inhaled NO and almitrine bismesylate (p < 0.01 by Student's t test). When the number of responders was considered, 13 patients (81%) responded to the association between inhaled NO and almitrine bismesylate, whereas 11 responders (69%) were observed when norepinephrine was added to inhaled NO and almitrine bismesylate. The individual responses of the patients receiving inhaled NO associated with almitrine bismesylate with those observed with the association of these two therapeutics with norepinephrine are compared in Figure 2. The adjunction of norepinephrine to inhaled NO had no effect on oxygenation in nonresponders, and increased PO₂/FI_O2 significantly in only one NO responder (Figure 3). On the other hand, almitrine bismesylate induced an increase in PO₂/FI_O2 greater than 25 mm Hg in five of nine NO nonresponders and in five of seven NO responders (Figure 3).

View larger version (28K): [in this window] [in a new window]   Figure 2.   PO2/FIO2 data for individual patients under inhaled NO + almitrine bismesylate and inhaled NO + almitrine bismesylate + norepinephrine (n = 16).

View larger version (19K): [in this window] [in a new window]   Figure 3.   Variation of PO2/FIO2 in NO responders (n = 7) and in NO nonresponders (n = 9) with the adjunction of norepinephrine and almitrine bismesylate (while patients were receiving inhaled NO).

Evolution of Hemodynamic and Respiratory Parameters

Nitric oxide produced a significant decrease in (p < 0.0001 by general factorial analysis of variance). Both almitrine bismesylate and norepinephrine induced an increase in (p < 0.0001 by general factorial analysis of variance). Pulmonary vascular resistances exhibited a significant decrease with NO (p < 0.0001 by general factorial analysis of variance), whereas norepinephrine increased PVRI (p < 0.002 by general factorial analysis of variance). No effect of almitrine bismesylate on PVRI was found by analysis of variance. Almitrine bismesylate induced a slight but significant decrease in right ventricular ejection fraction, whereas right ventricular end-systolic volume index and right ventricular end-diastolic volume index did not change. Cardiac index was affected neither by almitrine bismesylate nor by norepinephrine. An increase in oxygen delivery was observed when inhaled NO was combined to almitrine bismeslyate, confirming the potential advantages of this association. A slight increase of mean arterial pressure was induced by norepinephrine (21 ± 12 mm Hg).

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

This study showed that a combination of almitrine and inhaled nitric oxide could markedly increase PO₂/FI_O2 in patients with ARDS. The maximum effect of the combination on arterial oxygenation was better than those obtained with nitric oxide or almitrine alone. However, when norepinephrine, almitrine bismesylate, and NO were administered together, the increase in PO₂ was less significant than when inhaled NO was associated only with almitrine bismesylate.

In 1993, Rossaint and colleagues (7) showed that inhaled NO improves oxygenation and decreases pulmonary arterial hypertension in patients with ARDS. Inhaled NO dilates vessels of ventilated lung areas, thereby redistributing blood flow from nonventilated to ventilated lung regions (7). It has been shown that the NO-induced decrease in PVRI is more pronounced when baseline PVRI is high (8, 9). This effect is due at least in part to the extent of hypoxic pulmonary vasoconstriction in nonventilated lung areas. Inhaled NO dilates only preconstricted pulmonary vessels and does not affect pulmonary vessels with normal tone (10). Moreover, studies of inhaled NO in patients with ARDS have shown that a certain number of patients have no response or only a minor response to inhaled NO (8, 11, 12). This has increased interest in therapies that could be an alternative or a complement to inhaled NO. The balance between the preexisting vascular tone and the amount and thus effect of inhaled NO reaching the lung via ventilation could be modified when vasoactive agents such as norepinephrine or almitrine bismesylate are added to inhaled NO.

Some studies (4, 13) suggest that even a nonselective vasoconstrictor, given alone, may improve PO₂ in the presence of a significant shunt. For example, Putensen and colleagues (14) found that the systemic administration of a NO-synthase inhibitor in the canine oleic acid lung injury model augmented the improvement of PO₂ related to inhaled NO. Such an effect would reflect an increase in hypoxic pulmonary vasoconstriction. Moreover, inhaled NO would reverse local vasoconstrictor, such that the combination may reduce shunt, and increase PO₂ more than either drug alone. However, Kobayashi and colleagues (15) did not find improvement in oxygenation when intravenous prostaglandin PGF₂ (which enhanced hypoxic pulmonary vasoconstriction) was associated with inhaled NO. On the other hand, Marshall and colleagues (13) found that the increase of PO₂ observed with the combination of inhaled NO and PGF₂ was not different from the increase of PO₂ observed when PGF₂ was administered alone.

Norepinephrine, a predominantly -receptor agonist (also with 1 properties), has pulmonary and systemic vasoconstrictor effects. Norepinephrine is nonselective (compared with almitrine bismesylate) and is routinely used in ICUs. The interactions between norepinephrine and NO have been experimentally explored. Using N^G-monomethyl-L-arginine (L-NMMA), Julou-Schaeffer and colleagues (16) showed that this specific inhibitor of NO formation increased the sensitivity to norepinephrine in control aortic rings only when a functional endothelium was present. In an experimental model of hemorragic shock, Thiemermann and colleagues (17) showed that the vascular hyporeactivity to vasoconstrictor agents (including norepinephrine) is mediated by NO, demonstrating the potential negative effect of NO on norepinephrine-induced vasoconstriction. Studying responders to inhaled NO, Mourgeon and colleagues (18) compared eight patients with ARDS with eight patients with ARDS associated with septic shock requiring norepinephrine and found that the use of norepinephrine was associated with a greater increase in PO₂/FI_O2. In a previous study (5), we were unable to confirm this hypothesis. Other nonspecific vasoconstrictor agents could be used. For example, Doering and colleagues (19) have studied the effects of phenylephrine on oxygenation, given alone or associated with inhaled NO. The results of this latter study suggested that inhaled NO is able to reverse phenylephrine-induced vasoconstriction in well-ventilated areas. The investigators emphasized in their discussion section that phenylephrine increased significantly in phenylephrine responders but not in nonresponders. They suggested that regional pulmonary vasoconstriction may be necessary and sufficient to improve oxygenation. The present study did not support this hypothesis. Indeed, whereas an increase in 3 mm Hg in under norepinephrine was targeted in our study. PO₂ did not increase in 12 of 16 patients. The differences between the two studies could be explained in several ways. First of all, we chose norepinephrine and not phenylephrine because norepinephrine is used much more in ICUs. Norepinephrine is a predominant -receptor agonist with some activity on -receptor, whereas phenylephrine is a pure -receptor agonist. In the present study, the determination of the amount of norepinephrine given was based on , whereas in the study of Doering and colleagues (19), phenylephrine infusion rate was adapted from a systemic parameter (mean arterial pressure). At baseline, hypoxemia was also more pronounced in our patients than in those in the study of Doering and colleagues (57 ± 12 versus 96 ± 10 mm Hg). Moreover, in order to determine if a patient responded to the treatment, we chose an increase of at least 20% in PO₂/FI_O2, whereas Doering and colleagues (19) chose an increase of 10 mm Hg in PO₂. One of the results of the study of Doering and colleagues (19) is crucial: indeed, PO₂ under NO (141 ± 16 mm Hg) was not statistically different from PO₂ under the combination of NO and phenylephrine (152 ± 17 mm Hg). In the present study, we also observed a comparable PO₂/FI_O2 ratio under inhaled NO (68.0 ± 18.6 mm Hg) and under the combination between inhaled NO and norepinephrine (73.2 ± 22.1 mm Hg). The absence of improvement of PO₂/ FI_O2 in the presence of norepinephrine observed in the present study may reflect a nonspecific diffuse vasoconstriction in response to norepinephrine.

Almitrine bismesylate, a selective pulmonary arterial vasoconstrictor, stimulates peripheral chemoreceptors and has been shown to reduce venous admixture, to improve oxygenation, and to increase in patients with ARDS. This suggests that almitrine bismesylate increases hypoxic pulmonary vasoconstriction, diverting blood away from the most hypoxic lung regions (20). It has also been shown that almitrine bismesylate increases the respiratory response to inhaled NO (21, 22), perhaps because they have complementary mechanisms of redirecting blood flow away from hypoxic lung regions, suggesting that redistribution of blood flow toward better ventilated lung units during administration of NO is increased by hypoxic pulmonary vasoconstriction in nonventilated lung areas. The results of the present study support the hypothesis that these two agents act by complementary mechanisms to improve PO₂. In the present study, a strong effect on oxygenation related to almitrine bismesylate was found by analysis of variance. The comparison of the effect of almitrine bismesylate given alone with control value of PO₂/FI_O2 was at the limit of significance (p = 0.055). This could be explained in part by the wide distribution of PO₂/FI_O2 values under almitrine bismesylate and by the relatively small size of the study population. However, the latter statistical test may not obliterate the beneficial effects of almitrine bismeslyate on oxygenation given alone or in combination with inhaled NO.

The lack of significant effect of almitrine bismesylate on RVPI could be explained in part by the variations of the three components taken into account in the calculation of this parameter. Indeed, the increase in Ppao and cardiac index, even if they were not significant, lessened the weight of the increase of in the calculation of RVPI. The lack of significant increase of RVPI in patients with ARDS observed in the present study is not surprising when one looks at the literature. Indeed, whereas increased significantly and cardiac index was unchanged, PVRI was not modified significantly in most of these clinical studies (20). Lu and colleagues (22) reported a significant increase of 16% in PVRI from 455 ± 185 to 527 ± 176 dyne · s · cm⁵ · m². The same group (25) recently reported a 10% increase in PVRI. The main difference with the two latter studies is probably the basal level of PVRI, which was markedly more elevated than in the present work and which could explain at least in part the apparent variable effect of almitrine bismesylate on PVRI.

Reversible peripheral neuropathy has been reported after prolonged administration of almitrine. Although no serious side effects have been described, the lowest dose of almitrine should be administered to critically ill patients. However, the minimum dose at which almitrine improves arterial oxygenation is not known. All previous animal and human studies of almitrine alone (23, 26, 27) and almitrine combined with nitric oxide (21, 28) have been performed using doses of almitrine of approximately 15 /kg/min, thus explaining why we chose this dose regimen.

Wysocki and colleagues (21) suggested that patients who did not respond to NO also do not respond to the combination of almitrine bismesylate and nitric oxide. This was not the case in the present study where an increase in PO₂ was observed in nitric oxide nonresponders. This could be explained by the increase in , which was greater in the study of Wysocki and coworkers (21) than in the present study (30 ± 5 mm Hg versus 26 ± 7 mm Hg). In in vivo studies in dogs and in isolated lung studies, the effect of almitrine bismesylate on hypoxic pulmonary vasoconstriction has been described as enhancement or inhibition (29). Gottschall and colleagues (32) suggested that almitrine bismesylate in low doses potentiates hypoxic constriction, whereas in high doses (> 20 µg/kg/min) it causes pulmonary vasoconstriction and renders the pulmonary vessels unresponsive to hypoxia. Russell and colleagues (33) found that there was an enhancement of moderate hypoxic vasoconstriction by small doses of almitrine bismesylate, continued enhancement of moderate hypoxia by a medium dose with simultaneous attenuation of responses to severe hypoxia, and after the largest dose (a bolus of 200 µg), attenuation of responses to all levels of hypoxia. However, a study performed in 30 patients with ARDS (25) showed that almitrine administered at a rate of 4 and 16 /kg/min had the same effect on oxygenation. The adjunction of NO did not show any difference between these two different doses. However, the decrease of PO₂ observed in the present study when norepinephrine was combined with inhaled NO and almitrine bismesylate as compared with the PO₂ measured when only inhaled NO and almitrine bismesylate were associated, suggests that the diffuse pulmonary vasoconstrictive effects of norepinephrine attenuated the specific effects produced by almitrine bismesylate on hypoxic lung areas.

One published study suggests that the use of inhaled NO does not modify the prognosis of patients developing ARDS (34). Even if the methodology of such a study is difficult to establish, it could be appreciable to reinforce the action of inhaled NO on oxygenation. This could be achieved by using a vasoconstrictor agent or by using prone positioning (35). Indeed, with improved oxygenation, patients may be ventilated with lower inspired oxygen concentrations and lower peak, mean, and PEEP airway pressures, thereby decreasing ventilator-associated lung injury.