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ABSTRACT |
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METHODS
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Inhaled nitric oxide (iNO), a selective pulmonary vasodilator and intravenously administered almitrine, a selective pulmonary vasoconstrictor, have been shown to increase PaO2 in patients with acute
respiratory distress syndrome (ARDS). This prospective study was undertaken to assess the cardiopulmonary effects of combining both drugs. In 48 consecutive patients with early ARDS, cardiorespiratory parameters were measured at control, after iNO 5 ppm, after almitrine 4 µg · kg
1 · min1, and
after the combination of both drugs. In 30 patients, dose response to 2, 4, and 16 µg · kg1 · min1 of
almitrine with and without NO was determined. Almitrine and lactate plasma concentrations were
measured in 17 patients. Using pure O2, PaO2 increased by 75 ± 8 mm Hg after iNO, by 101 ± 12 mm
Hg after almitrine 4 µg · kg1 · min1, and by 175 ± 18 mm Hg after almitrine combined with iNO
(p < 0.001). In 63% of the patients, PaO2 increased by more than 100% with the combination of both
drugs. Mean pulmonary artery pressure (
) increased by 1.4 ± 0.2 mm Hg with almitrine 4 µg/kg/
min (p < 0.001) and decreased by 3.4 ± 0.4 mm Hg with iNO and by 1.5 ± 0.3 mm Hg with the combination (p < 0.001). The maximum increase in PaO2 was obtained at almitrine concentrations 
4 µg · kg1 · min1, whereas almitrine increased dose-dependently. Almitrine plasma concentrations
also increased dose-dependently and returned to values close to zero after 12 h. In many patients
with early ARDS, the combination of iNO 5 ppm and almitrine 4 µg · kg1 · min1 dramatically increases
PaO2 without apparent deleterious effect allowing a rapid reduction in inspired fraction of O2. The
long-term consequences of this immediate beneficial effect remain to be determined.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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In acute respiratory distress syndrome (ARDS), the classic therapeutic approach for reversing hypoxemia is to apply a positive end-expiratory pressure (PEEP) during mechanical ventilation to recruit nonventilated alveolar territories that remain perfused. Because of the major reduction in aerated lung volume, high peak airway pressure and lung volutrauma may result from mechanical ventilation if minute ventilation is not substantially reduced (1, 2). Recently, a ventilatory strategy aimed at "keeping the lung open" with a concomitant reduction of tidal volume has been recommended to treat patients with ARDS (3). It results in "permissive hypercapnia," which carries its own risks (4).
Another therapeutic option is to redistribute pulmonary
blood flow towards aerated lung areas through selective vasoconstriction of pulmonary vessels perfusing non-aerated lung
areas or selective vasodilation of pulmonary vessels perfusing
aerated lung areas. In the late eighties, intravenously administered almitrine, a selective pulmonary vasoconstrictor, was
shown to increase arterial oxygenation via a redistribution of
pulmonary blood flow from shunt areas to lung units with normal ventilation perfusion ratio (5). In the early nineties, similar beneficial effects were obtained by administering inhaled
nitric oxide (iNO), a selective pulmonary vasodilator, in patients with ARDS (4, 6). Recently, 5 to 10 parts per million
of iNO combined with 16 µg · kg1 · min1 of almitrine administered intravenously were shown to have additive effects on
arterial oxygenation in patients with ARDS (9).
The aims of this prospective study performed in patients with early ARDS and impaired oxygenation were (1) to quantify the respective effects on arterial oxygenation of iNO, almitrine and the combination of almitrine and iNO, (2) to determine the dose response and assess short-term toxicity of almitrine combined with iNO.
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INTRODUCTION
METHODS
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Patients
The study was approved by the Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale of our institution. After obtaining written informed consent from the patient's next of kin, 48 consecutive and unselected patients with an ARDS dating from less than 72 h were included according to the following criteria: (1) extensive bilateral infiltrates on chest radiograph and computerized tomographic (CT) scan, (2) PaO2 < 150 mm Hg at an FIO2 of 1 without PEEP. Patients with left ventricular dysfunction (pulmonary capillary wedge pressure [Ppcw] > 18 mm Hg and left ventricular ejection fraction < 50% as assessed by transesophageal echocardiography) were excluded. Septic shock was defined as sepsis with systolic blood pressure < 90 mm Hg along with the presence of perfusion abnormalities such as lactic acidosis and oliguria (12).
All patients were anesthetized and artificially ventilated in a volume-controlled mode and had in place arterial and thermistor Swan-Ganz catheters for cardiovascular monitoring. As previously described (13), all patients had a high resolution thoracic CT scan in order to assess the extension of nonaerated lung areas after PEEP administration.
Measurements
Arterial pressure, EKG, and cardiac filling pressures were continuously recorded on a Gould ES 1000 recorder (Gould Ltd, Ilford, UK)
and measured at end-expiration. Cardiac output was measured using
the thermodilution technique with simultaneous withdrawing of systemic and pulmonary arterial blood samples within 1 min. PaO2, PvO2,
PaCO2 and pH were measured using a conventional analyzer (ILBGE;
Instrumentation Laboratories, Paris, France), whereas hemoglobin
and methemoglobin concentrations and arterial and mixed venous oxygen saturations were measured using an OSM3 hemoximeter (Radiometer Copenhagen, Neuilly-Plaisance, France). Arterial and mixed
venous blood samples that showed hemoglobin concentrations differing by more than 0.1 g/100 ml were considered diluted and the highest
hemoglobin concentration was used to calculate oxygen contents.
Standard formulas were used to calculate cardiac index (CI), systemic
vascular resistance index (SVRI), pulmonary vascular resistance index (PVRI), pulmonary shunt (
S/T), oxygen delivery (DO2), and
oxygen consumption (
O2). Expired CO2 was continuously recorded
and measured using an infrared capnometer, and the ratio of alveolar
deadspace to tidal volume (VDA/VT), was calculated as previoulsy described (11, 13). Respiratory pressure-volume (P-V) curves on inflation were obtained in each patient using the supersyringe method in
order to determine opening pressure (Pop) and respiratory compliance (Crs) (14).
NO was sequentially administered from a cylinder containing NO 900 ppm in nitrogen (Air Liquide, Meudon, France) into the proximal inspiratory limb of the ventilator using a sequential device delivering stable and reproducible inspiratory NO concentrations (15). Inspiratory tracheal concentrations of NO and NO2 were continuously measured using a fast-response chemiluminescence apparatus (NOX 4000 Sérès; NOX, Aix-en-provence, France) (11).
Almitrine plasma concentrations were determined by high performance liquid chromatography with detection by ultraviolet (HPLC-UV), developed by Servier (Courbevoie, France) and validated and
performed by Biotec Centre (Orléans, France). The method is linear
from 1 to 500 ng/ml. The mean accuracy is 
7% and 14%, respectively for the repeatability (intraday assays) and reproducibility (interday assays). The coefficient of variation was, respectively, 19 and 17%. Catecholamine and lactic acid blood concentrations were determined at control (PEEP) and after the end of 1 h of almitrine infusion. As previously described (4), catecholamine plasma concentrations were determined using a radioenzymatic assay based on the enzymatic methylation of norepinephrine and epinephrine by catechol-O-methyltransferase in the presence of tritiated S-adenosyl-L-methionine (radiolabeled SAMe3H; Amersham, Buckinghamshire, UK). Normal values were 200 to 300 pg/ml for norepinephrine (intra-assay variability,
4.2%, and interassay variability, 7.5%) and 25 to 55 pg/ml for epinephrine (intra-assay variability, 3.6%, and interassay variability, 10%). Lactic acid plasma concentrations were measured with Dimension (DuPont
de Nemours, Les Ulis, France). The technique used is a modification of
the Marbach and Weil method (16), which employs the oxidation of
lactate to piruvate. Reference interval was 0.4 to 2 mmol/L. Coefficient of variation was between 4 and 8%. Quality control was supported by an independent laboratory (Bio-Rad, Paris, France).
Study Protocol
On the day of inclusion, the CT scan was performed and ventilatory
settings were optimized. A PEEP of 10 cm H2O, which was equal to or
greater than the Pop that could be identified on the P-V curve of 25 patients, was applied to each patient. Tidal volume and respiratory
rate were adjusted to maintain PaCO2 between 40 and 50 mm Hg while
maintaining peak airway pressure below 35 cm H2O (3). On the second day of the study, hemodynamic and respiratory parameters were
recorded: (1) at control, (2) after administration of iNO 5 ppm for 15 min, (3) after administration of almitrine 4 µg · kg1 · min1 for 1 h,
and (4) after administration of almitrine 4 µg · kg1 · min1 and iNO
5 ppm for 15 min. After this first part of the study was completed, almitrine and NO were stopped and the patients were ventilated until
the next morning using PEEP and an FIO2 required for maintaining an
arterial oxygen saturation 
90%. On the third day of the study, dose
response to almitrine was studied in 30 patients. Cardiorespiratory parameters were measured after three doses of almitrine were administered for 1 h with and without iNO 5 ppm. Because of the long duration of action of almitrine, the three doses were administered in the
same order: 2, 4, and 16 µg · kg1 · min1. For a given dose of almitrine, cardiorespiratory parameters were measured either without
iNO or after 15 min of administration of iNO 5 ppm, the order of administration being randomized. Plasma concentrations of almitrine
and lactate were measured at the end of each infusion period (n = 17)
and 15 min, 1 h, 2 h, and 12 h after cessation of the 16 µg · kg1 · min1
infusion (n = 6). At control and after administration of almitrine 16 µg · kg1 · min1 for 1 h, catecholamine plasma concentrations were
measured in eight patients.
At the end of the study, patients who had responded to both almitrine and iNO were continued on both therapies for a mean period of
4 ± 3 d; patients who had responded to iNO alone were treated with
iNO 5 ppm; patients who had responded to almitrine alone were
treated with 2 or 4 µg · kg1 · min1, according to their dose response
to almitrine, for a mean duration of 3 ± 3 d. Patients who had not responded to any of the therapies did not subsequently received iNO or
almitrine. Periodically, almitrine and iNO were interrupted in order
to assess their effect on arterial oxygenation. They were definitively
stopped when an arterial oxygen saturation could be maintained
above 90% solely with a PEEP of 10 cm H2O and an FIO2 0.4.
Statistical Analysis
Hemodynamic and respiratory parameters at control and after administration of iNO, almitrine 4 µg·kg1·min1, and the combination of
both drugs were compared by a two-way analysis of variance for two
within-factors, factor iNO and factor almitrine. The presence or the
lack of a significant interaction between the two factors allowed us to
test whether NO and almitrine act synergistically or additively.
Univariate and multivariate analysis were performed to identify factors predicting the response to almitrine and iNO. The following parameters were tested : control values of PaO2, PaCO2, , PVRI, S/
T, VDA/VT, Crs, extension of lung hyperdensities, morphologic aspects of the thoracic CT scan (nondependent diffuse patchy hyperdensities versus bilateral consolidation of lower lobe), and presence or
absence of septic shock. Dose response to almitrine was tested by a
one-way analysis of variance for repeated measures (2, 4, and 16 µg · kg1 · min1). The influence of septic shock and iNO 5 ppm on dose
response to almitrine was analyzed by a three-way analysis of variance for one grouping factor, factor shock and two within-factors, factor
"dose of almitrine" and factor "iNO". All statistics were performed
using Statview 4.0.2 and SuperANOVA softwares (Abacus Concepts
Inc. Berkeley, CA). All data are presented as mean ± SEM, and a
p value < 0.05 was considered as significant.
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RESULTS |
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DISCUSSION
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Forty-two male and six female patients (56 ± 2 yr of age) were
included in the study. ARDS complicated major surgical procedures (n = 32), multiple trauma (n = 14), and medical diseases (n = 2) and was caused by acute bronchopneumonia
(n = 30), septic shock (n = 8), aspiration of gastric content
(n = 4), pulmonary contusion (n = 4), and cardiopulmonary
bypass (n = 2). Lung injury severity score (17) was 2.9 ± 0.1. Using pure O2 and a PEEP of 10 cm H2O, patients had a PaO2
of 141 ± 10 mm Hg, a VDA/VT of 35 ± 1%, a of 26 ± 1 mm
Hg, a Crs of 51 ± 4 ml/cm H2O and a percentage of nonaerated
lung areas assessed with a high resolution CT scan of 45 ± 2%.
Twenty-two patients had septic shock and were treated with
norepinephrine. Twenty-five of the 48 patients included died (52%).
As shown in Table 1, almitrine 4 µg · kg1 · min1 and iNO
increased PaO2 and S
O2 and decreased S/T, PaCO2, and
VDA/VT significantly. When iNO and almitrine were combined, additive effects were observed. When defining a positive response as an increase in PaO2 of at least 20% from the
control value, 69% of the patients responded to iNO and almitrine, 15% to iNO, but not to almitrine, 12% to almitrine but
not to iNO, and 4% did not respond to either drug (Figure 1).
As represented in Figure 2, almitrine was superior to NO
alone for inducing increases in PaO2 > 40% of the control values. Increases 100% were observed in 63% of the patients receiving the combination, in 45% of the patients receiving
almitrine alone, and in only 25% of the patients receiving iNO
alone (p < 0.001). In the 33 patients who responded to almitrine and iNO, both drugs were continued after the cessation
of the study allowing to reduce FIO2 below 0.6 in each of them.
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Inhalation of NO resulted in a significant decrease in
and PVRI, whereas almitrine slightly but significantly increased both parameters. The combination of iNO and almitrine resulted in a slight but significant decrease in and
PVRI (p < 0.001). All other hemodynamic and respiratory parameters remained unchanged. None of the parameters tested
as factors predicting the response to almitrine appeared statistically significant using the univariate analysis. In contrast,
iNO-induced increase in PaO2 correlated well with the control
values of (p = 0.002) and PVRI (p = 0.002).
As shown in Figure 3, the maximum increase in PaO2/FIO2
and decrease in S/T were observed at almitrine concentrations of 2 µg · kg1 · min1 in patients with septic shock and at
concentrations of 4 µg · kg1 · min1 in patients without septic
shock (p < 0.001). Dose response on and PVRI were similar in patients with and without septic shock. In both groups,
and PVRI increased dose-dependently. The addition of
iNO induced an additional increase in PaO2 and decrease in
QS/QT, limited almitrine-induced increase in and PVRI
but did not modify the dose response to almitrine. Almitrine 16 µg · kg1 · min1 had no effect on plasma concentrations of
norepinephrine (660 ± 306 versus 501 ± 151 pg/ml, n = 8),
epinephrine (84 ± 29 versus 143 ± 73 pg/ml, n = 8) and lactate (Figure 4). As shown in Figure 5, almitrine plasma concentrations increased dose-dependently, were not different in
patients with and without septic shock, and returned to values
close to zero within 12 h after the cessation of almitrine infusion.
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DISCUSSION |
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DISCUSSION
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When combining iNO, a selective pulmonary vasodilator of
ventilated lung areas, with intravenous almitrine, a selective
pulmonary vasoconstrictor of nonventilated lung areas, an increase in arterial oxygenation was observed in patients with
ARDS and persisting impaired arterial oxygenation despite
optimization of ventilatory settings. The increase in PaO2 was
of a far greater magnitude than the one resulting from the administration of iNO or almitrine alone. Almitrine 4 µg · kg1 · min1 was superior to iNO 5 ppm for inducing an increase in
PaO2 > 40% of control values and the combination of both
drugs more than doubled the PaO2 in 63% of the patients. As a
consequence, the inspired fraction of oxygen could be rapidly
lowered below 0.6 in most of the patients, thereby limiting the
risk of oxygen toxicity. The design of the present study did not
allow us to assess whether this beneficial effect was sustained
over time. These immediate beneficial effects were obtained
with iNO concentrations and almitrine doses much lower than
those previously recommended.
In the first study demonstrating the beneficial effects of
almitrine on arterial oxygenation in patients with ARDS (5), the group of Rodriguez-Roisin used 16 µg · kg1 · min1, a
concentration that, subsequently served as a reference for many investigators (9, 10, 18). In the present study, the maximal effect on arterial oxygenation was obtained for almitrine concentrations fourfold lower in patients without septic
shock and eightfold lower in patients with septic shock. Similarly, in the first study reporting the beneficial effect of iNO
on arterial oxygenation and pulmonary shunt in patients with
ARDS (6), the group of Falke used concentrations of 18 and
36 ppm, referring to dose-response studies performed in experimental animals (21, 22). Further studies performed in patients with ARDS demonstrated that the maximal effect was
observed at concentrations around 5 ppm (7, 11, 23, 24) and
that the dose-response was not modified by the concomitant
administration of almitrine (11).
Acute toxicity of iNO appears more related to the formation of nitrogen dioxide (NO2) (23, 25, 26) than to methemoglobin accumulation in the blood (27). The concentration of 5 ppm
that was used in the present study was shown to be associated
with NO2 concentrations inferior to the toxic threshold of 0.5 ppm (7, 11). One of the acute deleterious effect of almitrine 16 µg · kg1 · min1 consists of an increase in pulmonary arterial
pressure (5, 9, 11), which may generate additional leak of
plasma towards the alveolar space in patients with ARDS. By
using almitrine concentration 4 µg · kg1 · min1 in combination with iNO, slightly but significantly decreased, thereby suppressing the risk of increasing pulmonary edema
formation. Experimental studies have suggested that almitrine
may inhibit oxidative phosphorylation and induce tissular hypoxemia (28). In the present study, plasma lactates remained
unchanged after almitrine 16 µg · kg1 · min1, even in patients
with septic shock and increased basal concentration of lactates, suggesting that almitrine does not worsen tissular hypoxia. Administration of almitrine over several months can be associated with the occurrence of peripheral neuropathy (29). Measurement of plasma concentrations of almitrine in patients with chronic obstructive pulmonary disease suffering
from almitrine-induced peripheral neuropathy demonstrated
plasma levels 400 ng/ml (30). In the present study, almitrine
plasma concentrations 400 ng/ml were observed in all patients receiving 16 µg · kg1 · min1 and in only one patient
receiving 4 µg · kg1 · min1. Although the significance of almitrine plasma concentrations might be different in acute
or prolonged administration, these pharmacokinetic results
strongly suggest that a dose of 4 µg · kg1 · min1 is safe in
terms of acute toxicity.
By dilating constricted pulmonary veins and, to a lesser degree, constricted pulmonary arteries perfusing ventilated lung areas, iNO decreases pulmonary shunt by diverting pulmonary blood flow away from nonventilated regions and reduces
the alveolar dead space to tidal volume ratio by increasing the
perfusion of ventilated lung areas (4, 7, 11, 13, 15, 24, 31). In
addition, it could also reduce the pulmonary transvascular albumin flux by decreasing capillary microvascular pressure
(32). The present study confirms that at the early phase of
ARDS, the response to iNO is related to the basal increase in
and pulmonary vascular resistance (13, 23, 33). Several recent studies have shown that the beneficial effect of iNO on
arterial oxygenation is not prolonged over time, lasting less
than 72 h (31, 34, 35). In addition, the reduction of the FIO2 resulting from the improvement in arterial oxygenation is of
small clinical relevance (35). As a consequence, the interest
for inhaled NO could decline in the future because of the lack
of long-lasting effect on arterial oxygenation.
The beneficial effect of almitrine alone is related to a selective pulmonary vasoconstriction of precapillary pulmonary arteries perfusing lung areas exposed to a hypoxic challenge (36,
37). At doses < 4 µg · kg1 · min1, almitrine reinforces hypoxic pulmonary vasoconstriction, whereas at doses 4 µg · kg1 · min1, it constricts the entire pulmonary vascular bed
and may even partly impair hypoxic pulmonary vasoconstriction (18). These dose effects may explain the inconstancy of
the beneficial effect of almitrine reported in humans (9, 20)
and in experimental animals (19). The basal status of hypoxic
pulmonary vasoconstriction appears as a factor influencing
the response to almitrine: the more deficient the hypoxic pulmonary vasoconstriction, the greater the almitrine-induced
constrictor effect in lung areas exposed to hypoxia (38). In patients with ARDS and sepsis, hypoxic pulmonary vasoconstriction may be impaired by vasodilating substances released from the activated pulmonary endothelium such as prostaglandin E1, prostacyclin, or endogenous NO (39). In such situations, pulmonary vessels exposed to hypoxia may become
particularly sensitive to almitrine, explaining that maximal effects on arterial oxygenation and pulmonary shunt were obtained in patients with septic shock at lower almitrine concentrations than in patients without septic shock. By decreasing
the perfusion of nonventilated lung areas, almitrine decreases
pulmonary shunt and indirectly reduces alveolar dead space to
tidal volume ratio by increasing the perfusion of ventilated
lung areas (5). Almitrine may also induce slight but significant
increases in heart rate and cardiac output in experimental animals (37). In the present study, both parameters and circulating
catecholamines remained unchanged after almitrine administration, suggesting the lack of any systemic effects. Although it
was easy to identify factors influencing the effects of iNO, we
were unable to determine factors predicting the response to almitrine. An important limitation for using almitrine is the fact that the drug is commercially available in a limited number of European countries. In North America, it has not been
approved for treating patients with COPD or ARDS. As a
consequence, it still has to be considered as an experimental
treatment and cannot be routinely used in the treatment of
ARDS until controlled randomized studies demonstrate a long-lasting effect of almitrine alone or in combination with iNO on
arterial oxygenation and a beneficial influence on the outcome
of ARDS.
The resulting effects of combining almitrine and iNO are likely related to the respective vascular effect of each drug on aerated and nonaerated lung compartments and explain why additive and not synergistic respiratory effects were observed. It has recently been shown that an impaired hypoxic pulmonary vasoconstriction in nonaerated lung areas decreases the cardiopulmonary response to iNO (40). The present study confirms that when reinforcing hypoxic pulmonary vasoconstriction by small doses of almitrine, the NO-induced increase in arterial oxygenation can be markedly enhanced.
In conclusion, in 63% of patients with early ARDS and impaired oxygenation, the combination of iNO and almitrine more than doubled PaO2. This beneficial effect was obtained without any apparent detrimental effect, suggesting that such a pharmacologic approach may be a safe therapeutic option to rapidly reduce FIO2 below the toxic threshold of 0.6. Further controlled randomized studies are required to assess whether this immediate and spectacular improvement in arterial oxygenation continues over time and has any impact on the evolution of ARDS.
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Footnotes |
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Supported by a grant from DGICYT (Miniserio de Educaccion y Ciencia, Spain).
Presented in part at the Annual Congress of the European Society of Anaesthesiology, London, June 1-5, 1996.
Correspondence and requests for reprints should be addressed to Pr. Jean-Jacques Rouby, M.D., Ph.D., Département d'Anesthésie, Unité de Réanimation Chirurgicale, Hôpital de la Pitié, 83 boulevard de l'Hôpital, 75013 Paris, France.
(Received in original form April 9, 1998 and in revised form July 27, 1998).
The following members of the NO Almitrine Study group participated in this study: L. Abdennour, J. D. Law-Koune, Réanimation neurochirurgicale, Département d'Anesthésie de la Pitié, Paris; P. Malassiné, Service d'Obstétrique, Département d'Anesthésie de la Pitié, Paris; E. Mourgeon, S. Roche, C. Vézinet, Réanimation chirurgicale, Département d'Anesthésie de la Pitié, Paris; M. Arthaud, C. Devilliers, J. J. Guillosson, Laboratoire Central des Urgences, Hôpital de la Pitié, Paris; C. Landault, L. Cornet, Laboratoire de Biologie Médicale, Université Paris VI, P. F. Penelaud, C. Chezaubernard, Institut de Recherches Internationales Servier, Courbevoie, France; M. Puig, Servei d'Anesthesiologia, Hospital Universitari del Mar, Barcelona, Spain.| |
References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1. Rouby, J. J., T. Lherm, E. Martin de Lassale, P. Poète, L. Bodin, J. F. Finet, P. Callard, and P. Viars. 1993. Histologic aspects of pulmonary barotrauma in critically ill patients with acute respiratory failure. Intensive Care Med. 20: 187-192 .
2. Dreyfuss, D., P. Soler, and G. Saumon. 1995. Mechanical ventilation- induced pulmonary edema: interaction with previous lung alterations. Am. J. Respir. Crit. Care Med. 151: 1568-1575 [Abstract].
3.
Amato, M. B. P.,
C. S. Barbas,
D. M. Medeiros,
R. B. Magaldi,
G. P. Schettino,
G. Lorenzi-Filho,
R. A. Kairalla,
D. Deheinzelin,
C. Munoz,
R. Oliveira,
T. Y. Takagaki, and
C. R. R. Carvalho.
1998.
Effect
of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome.
N. Engl. J. Med.
338:
347-354
4. Puybasset, L., T. E. Stewart, J. J. Rouby, P. Cluzel, E. Mourgeon, M. F. Belin, M. Arthaud, C. Landault, and P. Viars. 1994. Inhaled nitric oxide reverses the increase in pulmonary vascular resistance induced by permissive hypercapnia in patients with ARDS. Anesthesiology 80: 1254-1267 [Medline].
5. Reyes, A., J. Roca, R. Rodriguez-Roisin, A. Torres, P. Ussetti, and P. D. Wagner. 1988. Effect of almitrine on ventilation-perfusion distribution in adult respiratory distress syndrome. Am. Rev. Respir. Dis. 137: 1062-1067 [Medline].
6.
Rossaint, R.,
K. J. Falke,
F. Lopez,
K. Slama,
U. Pison, and
W. M. Zapol.
1993.
Inhaled nitric oxide for the adult respiratory distress syndrome.
N. Engl. J. Med.
328:
399-405
7. Puybasset, L., J. J. Rouby, E. Mourgeon, T. E. Stewart, M. F. Belin, P. Grenier, M. Arthaud, P. Poète, L. Bodin, A. M. Korinek, and P. Viars. 1994. Inhaled nitric oxide in acute respiratory failure: dose-response curves. Intensive Care Med. 20: 319-327 [Medline].
8.
Young, J. D.,
W. J. Brampton,
J. D. Knighton, and
S. R. Finfer.
1994.
Inhaled nitric oxide in acute respiratory failure in adults.
Br. J. Anaesth
73:
499-502
9. Wysocki, M., C. Delcaux, E. Roupie, O. Langeron, N. Liu, B. Herman, F. Lemaire, and L. Brochard. 1994. Additive effect on gas exchange of inhaled nitric oxide and intravenous almitrine bismesylate in the adult respiratory distress syndrome. Intensive Care Med. 20: 254-259 [Medline].
10. Payen, D., C. Gatecel, and P. Plaisance. 1993. Almitrine effect on nitric oxide inhalation in adult respiratory distress syndrome [letter]. Lancet. 341: 1664 [Medline].
11. Lu, Q., E. Mourgeon, J. D. Law-Koune, S. Roche, C. Vezinet, L. Abdennour, E. Vicaut, L. Puybasset, M. Diaby, P. Coriat, and J. J. Rouby. 1995. Dose-response of inhaled NO with and without intravenous almitrine in adult respiratory distress syndrome. Anesthesiology 83: 929-943 [Medline].
12. American College of Chest Physicians Society of Critical Care Medicine Consensus Conference. 1992. Definition for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit. Care Med 20: 864-874 [Medline].
13. Puybasset, L., J. J. Rouby, E. Mourgeon, P. Cluzel, Z. Souhil, J. D. Law-Koune, T. Stewart, C. Devilliers, Q. Lu, S. Roche, P. Kalfon, E. Vicaut, and P. Viars. 1995. Factors influencing cardiopulmonary effects of inhaled nitric oxide in acute respiratory failure. Am. J. Respir. Crit. Care Med. 152: 318-328 [Abstract].
14.
Matamis, D.,
F. Lemaire,
A. Harf,
C. Brun-Buisson,
J. C. Ansquer, and
G. Atlan.
1984.
Total respiratory pressure-volume curves in the adult
respiratory distress syndrome.
Chest
86:
58-66
15. Mourgeon, E., L. Gallart, G. S. Umamaheswara, Rao, Q. Lu, J. D. Law-Koune, L. Puybasset, P. Coriat, and J. J. Rouby. 1997. Distribution of inhaled nitric oxide during sequential and continuous administration into the inspiratory limb of the ventilator. Intensive Care Med. 23: 849-858 [Medline].
16. Marbach, E. P., and M. H. Weil. 1967. Rapid enzymatic measurement of blood lactate and pyruvate. Clin. Chem 13: 314-325 [Abstract].
17. Murray, J., M. Matthay, J. Luce, and N. R. Flicke. 1988. An expanded definition of the adult respiratory distress syndrome. Am. Rev. Respir. Dis. 138: 720-723 [Medline].
18. Chen, L., F. L. Miller, G. Malmkvist, F. Clergue, C. Marshall, and B. E. Marshall. 1987. High-dose almitrine bismesylate inhibits hypoxic pulmonary vasoconstriction in closed chest dogs. Anesthesiology 67: 534-542 [Medline].
19. Leeman, M., M. Delcroix, J. L. Vachiery, C. Mélot, and R. Naeije. 1992. Almitrine and doxapram in experimental lung injury. Am. Rev. Respir. Dis 145: 1042-1046 [Medline].
20. Dreyfuss, D., K. Djedaini, J. J. Lanore, L. Mier, R. Froidevaux, and F. Coste. 1992. A comparative study of the effects of almitrine bismesylate and lateral position during unilateral bacterial pneumonia with severe hypoxemia. Am. Rev. Respir. Dis. 146: 295-299 [Medline].
21. Frostell, C., M. D. Fratacci, J. C. Wain, R. Jones, and W. M. Zapol. 1991. Inhaled nitric oxide: a selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 83: 2038-2047 [Medline].
22.
Dyar, O.,
J. D. Young,
L. Xiong,
S. Howell, and
S. John.
1993.
Dose-
response relationship for inhaled nitric oxide in experimental pulmonary hypertension in sheep.
Br. J. Anaesth.
71:
702-708
23. Lowson, S. M., G. F. Rich, P. A. McArdle, J. Jaidev, and G. N. Morris. 1996. The response to varying concentrations of inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesth. Analg. 82: 574-581 [Abstract].
24. Mourgeon, E., L. Puybasset, J. D. Law-Koune, Q. Lu, L. Abdennour, L. Gallart, P. Malassine, G. S. Umamaheswara, Rao, P. Cluzel, A. Bennani, P. Coriat, and J. J. Rouby. 1997. Inhaled nitric oxide in acute respiratory distress syndrome with and without septic shock requiring norepinephrine administration: a dose-response study. Crit. Care 1: 25-39 [Medline].
25. Bauer, M. A., M. J. Utell, P. E. Morrow, D. M. Speers, and F. R. Gibb. 1986. Inhalation of 0.30 ppm nitrogen dioxide potentiates exercise- induced bronchospasm in asthmatics. Am. Rev. Respir. Dis. 134: 1203-1208 [Medline].
26. Sandström, T., N. Stjernberg, A. Eklund, M. C. Ledin, L. Bjermer, B. Kolmodin-Hedman, K. Lindström, L. Rosenhall, and T. Angström. 1991. Inflammatory cell response in bronchoalveolar lavage fluid after nitrogen dioxide exposure of healthy subjects: a dose-response study. Eur. Respir. J. 3: 332-339 .
27. Young, J. D., O. Dyar, L. Xiong, and S. Howell. 1994. Methemoglobin production in normal adults inhaling low concentrations of nitric oxide. Intensive Care Med. 20: 581-584 [Medline].
28. Gottshal, E. B., S. Fernyak, G. Wuertemberger, and N. F. Voelkel. 1992. Almitrine mimics hypoxic vasoconstriction in isolated rat lungs. Am. J. Physiol. 263: 383-391 .
29. Gherardi, R., F. Louarn, C. Benvenuti, M. Perrier, J. L. Lejonc, A. Schaeffer, and J. D. Degos. 1985. Peripheral neuropathy in patients treated with almitrine bismesylate. Lancet 1: 1247-1250 [Medline].
30. Watanabe, S., R. E. Kanner, A. G. Cutillo, R. L. Menlove, R. T. Bachand, M. B. Szalkowski, and A. D. Renzetti. 1989. Long-term effect of almitrine bismesylate in patients with hypoxemic chronic obstructive pulmonary disease. Am. Rev. Respir. Dis. 140: 1269-1273 [Medline].
31.
Troncy, E.,
J. P. Collet,
S. Shapiro,
J. G. Guimmond,
L. Blair,
T. Ducruet,
M. Francoeur,
M. Charbonneau, and
G. Blaise.
1998.
Inhaled
nitric oxide in acute respiratory distress syndrome: a pilot randomized
study.
Am. J. Respir. Crit. Care Med.
157:
1483-1488
32. Benzing, A., P. Bräutigam, K. Geiger, T. Loop, U. Beyer, and E. Moser. 1995. Inhaled nitric oxide reduces pulmonary transvascular albumin flux in patients with acute lung injury. Anesthesiology 83: 1153-1161 [Medline].
33. Benzing, A., T. Loop, G. Mols, and K. Geiger. 1996. Effect of inhaled nitric oxide on venous admixture depends on cardiac output in patients with acute lung injury and acute respiratory distress syndrome. Acta Anaesthesiol. Scand. 40: 466-474 [Medline].
34. Dellinger, R. P., J. L. Zimmerman, R. W. Taylor, R. C. Straube, D. L. Hauser, G. J. Criner, K. Davis, T. M. Hyers, and P. Papadakos. 1998. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Crit. Care Med. 26: 15-23 [Medline].
35.
Michael, J. R.,
G. Richard,
J. R. Saffle,
M. Mone,
B. A. Markewitz,
K. Hillier,
M. R. Elstad,
E. J. Campbell,
B. E. Troyer,
R. E. Whatley,
T. G. Liou,
W. M. Samuelson,
H. J. Carveth,
D. M. Hinson,
S. E. Morris,
B. L. Davis, and
R. W. Day.
1998.
Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS.
Am. J. Respir.
Crit. Care Med.
157:
1372-1380
36. Romaldini, H., R. Rodriguez-Roisin, P. D. Wagner, and J. B. West. 1983. Enhancement of hypoxic pulmonary vasoconstriction by almitrine in the dog. Am. Rev. Respir. Dis. 128: 288-293 [Medline].
37.
Chen, L.,
F. L. Miller,
W. R. Clarke,
F. X. Clergue,
C. Marshall, and
B. E. Marshall.
1990.
Low-dose almitrine bismesylate enhances hypoxic pulmonary vasoconstriction in close-chest dogs.
Anesth. Analg.
71:
475-483
38. Naeije, R., P. Lejeune, J. L Vachiery, M. Leeman, C. Mélot, R. Hallemens, M. Delcroix, and S. Brimouille. 1990. Restored hypoxic pulmonary vasoconstriction by peripheral chemoreceptor agonists in dogs. Am. Rev. Respir. Dis. 142: 789-795 [Medline].
39. Marshall, B. E., C. W. Hanson, F. Frasch, and C. Marshall. 1994. Role of hypoxic pulmonary vasoconstriction in pulmonary gas exchange and blood flow distribution: 2. Pathophysiology. Intensive Care Med 20: 379-389 [Medline].
40. Benzing, A., G. Mols, T. Brieschal, and K. Geiger. 1997. Hypoxic pulmonary vasoconstriction in non-ventilated lung areas contributes to differences in hemodynamic and gas exchange responses to inhalation of nitric oxide. Anesthesiology 86: 1254-1261 [Medline].
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