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The Effects of Inhaled Nitric Oxide and Its Combination with Intravenous Almitrine on PaO2 During One-Lung Ventilation in Patients Undergoing Thoracoscopic Procedures

Moutafis, Marc MD; Liu, Ngai MD; Dalibon, Nicolas MD; Kuhlman, Guy MD; Ducros, Laurent MD; Castelain, Marie-Helene MD; Fischler, Marc MD

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Abstract

Hypoxemia during one-lung ventilation (OLV) can be prevented or attenuated by using a high inspired oxygen concentration (FiO2); if this does not suffice, continuous positive airway pressure to the nonventilated nondependent lung may be applied [1]. During thoracoscopic procedures, continuous positive airway pressure cannot be applied because inflation of the operative lung interferes with exposure for surgery, which is, of course, essential. A nonventilatory technique to prevent hypoxemia during OLV would thus be useful. Contradictory results have been reported using nitric oxide (NO) inhalation in the ventilated lung [2-5]. Since Payen et al. [6] suggested that the capability of NO to improve oxygenation could be potentiated if combined with infused pulmonary vasoconstrictor, NO inhalation and intravenous (IV) almitrine in combination have been used for the treatment of patients with severe adult respiratory distress syndrome (ARDS) [7,8].

The purpose of the present study was to compare gas exchange during OLV in two consecutive studies involving patients ventilated with pure oxygen or with a mixture of O2/NO and patients ventilated with pure oxygen or with a mixture of O2/NO while receiving IV almitrine.

Methods

After institutional approval and written, informed consent, 40 consecutive adult patients who met the requirements of the protocol were included in a randomized, open, two-part study. In Part I, 20 patients were divided into two groups: one group received O2 (Group 1) and the other received O2/NO (Group 2). In Part II, 20 patients were also divided into two groups: one group received O2 (Group 3) and the other received O2/NO/almitrine (Group 4).

Inclusion criteria were thoracoscopic procedures requiring OLV and blood flow to the operated lung ranging between 45% and 55% of total perfusion (radioisotope regional perfusion test performed a few days before surgery). Patients with echocardiographic evidence of pulmonary artery hypertension, even to a moderate degree, and those receiving any vasoactive drug were excluded.

Arterial blood gas analysis without oxygen administration and routine spirometric evaluation were performed preoperatively.

All patients were premedicated with 5 mg intramuscular midazolam. Arterial and peripheral venous cannulae were placed under local anesthesia on arrival in the operating room. Usual monitoring was used. Arterial blood pressure was measured using Baxter Uniflow 43260 transducers (Irvine, CA) and displayed using a 7010 monitoring system (Marquette, Milwaukee, WI). Evaluation of the hemodynamic consequences of NO inhalation and especially of IV almitrine administration, i.e. increase in pulmonary vascular resistance, was not possible in our study because it is contrary to the policy in our department to insert pulmonary artery catheters in patients undergoing standard surgical procedures of the lungs.

Anesthesia was induced with propofol (2 mg/kg), fentanyl (3 micro g [center dot] kg-1), and vecuronium (0.1 mg/kg) IV and maintained with the same drugs. After induction of general anesthesia, a left-sided double-lumen endobronchial tube was placed in all patients. The correct positioning of the double-lumen endobronchial tube was checked in both the supine and lateral decubitus positions. Complete lung separation was confirmed by the absence of leak from the nondependent lung using the bubble technique [9] and, finally, by the surgeon after the beginning of the procedure.

Ventilatory settings (Evita ventilator; Drager, Lubeck, Germany) were identical in all groups during two-lung ventilation (2LV) or OLV: 10 mL/kg tidal volume, 12 min ventilatory frequency, inspiratory to expiratory ratio of 1:2. In Groups 1 and 3, the lungs were ventilated with 100% oxygen. In Groups 2 and 4, NO was administered during the entire period of OLV. NO was supplied by a nitrogen tank delivering a mixture of 450 ppm NO and 7 ppm nitrogen dioxide (NO2). NO (20 ppm) was injected into the inspiratory limb of the breathing circuit before the Y piece via an injection prototype device connected to the nebulizer of the ventilator (Compagnie Francaise des Produits Oxygenes, Paris, France), which is synchronized with the inspiratory cycle. The amount of the additional flow coming from the nebulizer was 1 L/min of oxygen and 20-40 mL per respiratory cycle of nitrogen. Ventilator tidal volume was adjusted to keep minute expiratory volume constant throughout the study in Groups 2 and 4. Tracheal concentrations of NO and NO2 were measured at the end of the period of observation using an electrochemical apparatus, which allowed the determination of a mean airway concentration (Polytrons NO and NO2; Drager, Strasbourg, France) [10].

In Group 4 patients, almitrine was continuously infused via a separate venous catheter at a rate of 16 micro g [center dot] kg-1 [center dot] min-1 throughout the NO inhalation period.

If SpO2 decreased to less than 90% during the study, 2LV was restored. Arterial blood gas tensions were measured in all patients during 2LV 10 min after intubation with patients in the supine position (2LV-sup), 5 min after positioning in the lateral decubitus position (2LV-lat), and then every 5 min during OLV for a 30-min period (OLV-5, OLV-10, OLV-15, OLV-20, OLV-25, OLV-30). Surgery began after OLV-30. All arterial gas samples were analyzed immediately with standard blood-gas electrodes and the 288 Ciba-Corning blood gas system (Medfield, MA). At the same time (2LV-sup, 2LV-lat, OLV-5, OLV-10, OLV-15, OLV-20, OLV-25, and OLV-30), mean arterial pressure and heart rate were recorded.

The following ventilatory variables were recorded four times (2LV-sup, 2LV-lat, OLV-5, and OLV-30) by a ventilator module: expiratory tidal volume (in milliliters), peak airway pressure (Pawpk; in centimeters of water), mean airway pressure (Pawmean; in centimeters of water), and end-inspiratory plateau pressure (Paw (pl); in centimeters of water).

Data are expressed as mean +/- sem. Preoperative data were compared using the Mann-Whitney U-test. Measurements taken during 2LV-(and) 2LV-lat were compared with an unpaired Wilcoxon test (intergroup comparison) and a paired Wilcoxon test (intragroup comparison). From the initiation of 2LV-lat until the end of the observation period (OLV-30), consecutive measurements were compared using the repeated-measures analysis of variance. Post hoc analyses were performed with a Wilcoxon test (intragroup comparison) and Mann-Whitney U-test (intergroup comparison). Fisher's exact test was used to compare the number of patients who had a PaO2 of less than 100 mm Hg during OLV between groups. Probability values that were less than 0.05 were considered sufficient to reject a null hypothesis.

Results

The 40 patients were ASA physical status II or III.

Part I

The main result was that there was no significant difference in the mean PaO2 values during OLV regardless of whether NO was used.

Groups did not differ with respect to age (54 +/- 4.7 yr in Group 1 and 50 +/- 4.6 yr in Group 2) and weight (71.5 +/- 3.6 kg in Group 1 and 70.2 +/- 4.7 kg in Group 2). Preoperative arterial blood gas tensions and preoperative forced expiratory volume in 1 s (FEV1) were similar: PaO2 was 91.1 +/- 4.6 mm Hg in Group 1 and 85.3 +/- 5.7 mm Hg in Group 2, PaCO2 was 38.6 +/- 0.8 mm Hg in Group 1 and 36.7 +/- 0.7 mm Hg in Group 2, and FEV1 was 2.69 +/- 0.31 L/s in Group 1 and 2.23 +/- 0.21 L/s in Group 2.

SpO2 was more than 90% throughout the study in all patients.

Gas exchange and respiratory and hemodynamic variables are summarized Table 1.

Table 1
Table 1:
Gas Exchange and Respiratory and Hemodynamic Variables in Groups 1 and 2

All of these variables were similar during 2LV-(and) 2LV-lat.

Arterial blood gases measured from 2LV-lat to OLV-30 were identical, except for PaO2. Compared with the level found during 2LV-lat, PaO2 decreased (P value of the analysis of variance <0.0001). Differences were found in intragroup but not in intergroup comparisons. Mean PaO2 was 132 +/- 14 mm Hg 30 min after the beginning of OLV in Group 1 and 149 +/- 27 mm Hg in Group 2 (not significant [NS]). Four patients in Group 1 and five patients in Group 2 had a PaO2 of less than 100 mm Hg during OLV (NS).

Expiratory tidal volume was identical throughout the study.

Compared with the level measured during 2LV-lat, Pawpk, Pawpl, and Pawmean values increased in both groups at OLV-5 and at OLV-30 with no differences in the groups.

Mean arterial pressure and heart rate did not change throughout the study.

Mean NO tracheal concentrations, measured at OLV-30, were between 18 and 22 ppm. NO2 was less than 0.5 ppm in all cases.

Part 2

The main result was that there was a significant difference in PaO2 evolution during OLV regardless of whether the NO/almitrine combination was used.

Groups did not differ with respect to age (54 +/- 4.7 yr in Group 3 and 52 +/- 5.4 yr in Group 4) and weight (67.7 +/- 3.2 kg in Group 3 and 63.6 +/- 4.5 kg in Group 4). Preoperative arterial blood gases analysis and preoperative FEV1 were similar: PaO2 was 93.1 +/- 3.1 mm Hg in Group 3 and 87.7 +/- 2.5 mm Hg in Group 4, PaCO2 was 40.1 +/- 1.4 mm Hg in Group 3 and 36.4 +/- 1.5 mm Hg in Group 4, and FEV1 was 2.43 +/- 0.3 L/s in Group 3 and 2.25 +/- 0.1 L/s in Group 4.

SpO2 was more than 90% throughout the study in all patients.

Gas exchange and respiratory and hemodynamic variables are summarized Table 2.

Table 2
Table 2:
Gas Exchange and Respiratory and Hemodynamic Variables in Groups 3 and 4

All of these variables were similar during 2LV-(and) 2LV-lat.

Compared with its level during 2LV-lat, PaO2 decreased (P value of the analysis of variance <0.005). Differences were found in intragroup and in intergroup comparisons. PaO2 decreased in both groups from OLV-10 to OLV-30 in Group 3 (P < 0.01) and from OLV-5 to OLV-30 in Group 4 (P < 0.05). PaO2 values were statistically different between groups from OLV-15 to OLV-30 (P < 0.05 for comparison at OLV-15 and OLV-20, P < 0.001 for comparison at OLV-25 and OLV-30). Mean PaO2 was 146 +/- 16 mm Hg 30 min after the beginning of OLV in Group 3 and 408 +/- 33 mm Hg in Group 4 (P < 0.001). Four patients in Group 3 but no patient in Group 4 had a PaO2 of less than 100 mm Hg during OLV (NS).

Compared with the level found during 2LV-lat, PaCO2 decreased (P value of the analysis of variance <0.05). Differences were found in intragroup and in intergroup comparisons. PaCO2 decreased in Group 4 patients from OLV-20 to OLV-30 (P < 0.05). PaCO2 values were statistically different between Group 3 and 4 patients from OLV-25 to OLV-30 (P < 0.05).

Expiratory tidal volume was identical throughout the study.

Compared with the level measured during 2LV-lat, Pawpk and Pawmean values increased in both groups at OLV-5 and at OLV-30, and Pawpl values increased at OLV-30, with no differences in the groups.

Mean arterial pressure and heart rate did not change throughout the study.

Mean NO tracheal concentrations, measured at OLV-30, were between 18 and 22 ppm. NO2 was less than 0.5 ppm in all cases.

Discussion

The results of this study are that NO inhalation did not prevent a decrease in PaO2 during OLV, but its combination with IV almitrine did have a protective effect.

In our control groups (Groups 1 and 3), most patients with a PaO2 of less than 100 mm Hg during OLV could have been due to one of our inclusion criteria, which was a very similar initial lung perfusion ratio between the operated nonventilated lung and the contralateral lung. Hurford et al. [11] have reported that the proportion of patients with a PaO2 of less than 75 mm Hg during OLV increased proportionally with perfusion of the operated lung. In this study, 0 of 6 patients showed a PaO (2) below 75 mm Hg when blood flow to the operated lung was less than 35% of total flow, 1 of 6 showed a PaO2 below 75 mm Hg for blood flow ranging from 36% to 45%, 5 of 16 showed a PaO2 below 75 mm Hg for blood flow ranging between 46% and 55%, and 2 of 2 showed a PaO2 below 75 mm Hg when the operated lung received more than 55% of total flow. Furthermore, we assumed that the degree of hypoxic pulmonary vasoconstriction, which interferes with the level of PaO2, was quite similar among the patients. This was based on the following facts: same preoperative pulmonary functional status, absence of treatment with any vasomotor drug, and same level of PaCO2 during ventilation [1]. Total IV anesthesia was chosen because IV anesthetics do not interfere with hypoxic pulmonary vasoconstriction [1].

A recent experimental study has demonstrated that endogenously produced or inhaled NO plays an important role in the regulation of pulmonary blood flow. Freden et al. [12] studied various combinations of inhaled NO and IV administration of an NO synthase inhibitor in a left lobar lung hypoxia pig model. When 40 ppm NO was administered to the hyperoxic lung regions while the left lobar lung was still hypoxic, no effect on pulmonary blood flow and arterial blood gases was observed. When NO was administered to the hyperoxic lung regions after NO synthase inhibitor administration (30 mg/kg NG-nitro-L-arginine-methyl-esther infusion), the blood flow to the hypoxic lobe decreased to 2.5% +/- 1.6% of baseline and PaO2 increased dramatically from 244 +/- 17 mm Hg to 435 +/- 17 mm Hg.

In our study, the introduction of 20 ppm NO as soon as OLV began did not influence PaO2 evolution. Contradictory results have been reported using NO inhalation alone [2-5]. When 50 ppm NO was added [2], the perfusion of the oxygen-ventilated lung increased significantly from 54% to 71% of cardiac output in patients in the supine position. In the lateral position, introduction of 40 ppm NO after 10 to 15 minutes of OLV significantly improves arterial oxygenation [3] or has no effect on lung vascular resistance or on oxygenation [4]. Finally, the most complete study demonstrated that the introduction of 20 ppm NO during OLV did not change PaO2 and venous admixture in patients with coronary artery disease, with or without moderately increased pulmonary artery pressure [5]. All of these studies differ from ours, because we introduced NO at the onset of OLV. Furthermore, patients in one study [4] received isoflurane, and in another study, patients probably received antianginal and antihypertensive drugs [5]. In both situations, hypoxic pulmonary vasoconstriction could be reduced [1]. This could explain the reported particularly low mean values of PaO2 (86 +/- 8 mm Hg under FiO2 0.8, mean +/- sem) and high venous admixture (34% +/- 2%) in their control group [5]. Given that the beneficial effect of NO could be caused by the dilatation of the vascular bed of the ventilated lung, and because inhaled NO does not vasodilate nonconstricted pulmonary vessels [13-15] and has a greater effect when pulmonary vascular resistances increase [16], one could anticipate little or no effect of NO inhalation during OLV.

In Part II of the present study, PaO2 decreased less during OLV in patients receiving NO inhalation and IV almitrine infusion. Low-dose almitrine, a peripheral chemoreceptor agonist, increases hypoxic pulmonary vasoconstriction in isolated lungs [17-19]. The dose-effect curve of almitrine has been studied in a canine model with normal lungs ventilated with an hyperoxic gas on one side and a hypoxic mixture on the other [20]. A significant effect of almitrine, the amplification of physiologic hypoxic pulmonary vasoconstriction (i.e., decrease in hypoxic lung flow, increase in PaO2) occurred for doses equal to or larger than 3 micro g [center dot] kg-1 [center dot] min-1[20]. The clinical indications for almitrine are still being debated for acute situations. The effects of 10 cm H2 O positive end-expiratory pressure and of almitrine (0.25 mg/kg in 30 minutes) are identical in patients suffering from ARDS; both treatments increased PaO2 and decreased the ratio of venous admixture to total blood flow [21]. Almitrine and NO inhalation have been combined with additive effects on gas exchange [7,8]. Wysocki et al. [7] studied 17 patients with severe hypoxemia and increased mean pulmonary artery pressure because of ARDS. The PaO2/FiO2 ratio did not change with inhalation of 5 to 10 ppm NO alone, but it increased from 92 +/- 25 mm Hg to 130 +/- 56 mm Hg with the same dose of NO combined with 0.5 mg/kg almitrine; mean pulmonary artery pressure did not change significantly with almitrine alone or decrease with NO alone or NO/almitrine [7]. In six early ARDS patients who were highly responsive to inhaled NO, Lu et al. [8] demonstrated a dose-dependent increase in PaO2 for inspiratory NO concentrations ranging between 0.15 and 1.5 ppm; no change of this dose-response curve was noticed when 16 micro g [center dot] kg-1 [center dot] min-1 almitrine was administered.

Another result of our study was a slight, but significant, decrease in PaCO2 observed in the NO/almitrinetreated patients. This effect, previously described in ARDS patients receiving NO, was attributed to a decrease in the ventilatory dead space because of the reperfusion of ventilated lung areas [22].

There are several limitations in our study design. First, we did not use a nitrogen tank without NO in Groups 1 and 3, and consequently, the study was not blinded. However, the low amount of nitrogen delivered in Groups 2 and 4 could not significantly affect PaO2 evolution. The second limitation, which is a major one, is the absence of an almitrine-treated group. This can be explained by the potential limitation of its use, which is the risk of increased pulmonary vascular resistance [23]. Because pulmonary artery pressure monitoring could not be used in our study population, we used the combination of NO and almitrine, which is known to prevent pulmonary artery hypertension [7]. Additional studies are required to evaluate whether IV almitrine alone has the same beneficial effect as the NO/almitrine combination on PaO2 during OLV and its hemodynamic consequence. Finally, our study was designed with large doses of NO and almitrine, and the dose-effect relationship of each drug must be established.

In conclusion, we have demonstrated a preventive effect of NO/almitrine on PaO2 decrease during OLV, but we have not demonstrated that this combination could be used to treat hypoxemia when other methods have failed.

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