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Departments of *Anaesthesiology and Intensive Care Medicine and Internal Medicine, Justus-Liebig University, Giessen, Germany
Address correspondence and reprint requests to Stefan Scholz, MD, Department of Anaesthesiology and Intensive Care Medicine, Justus-Liebig-University, Rudolf-Buchheim-Strasse 7, D-35385 Giessen, Germany. Address e-mail to resp36{at}aol.com
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Abstract |
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PaO2, 42 ± 35 mm Hg versus 22 ± 20 mm Hg, 13 ± 18 mm Hg, and 15 ± 16 mm Hg; P < 0.05). NO at 4 ppm reduced intrapulmonary shunt flow, whereas a larger concentration exhibited no statistically significant effect. The authors conclude that NO improves arterial oxygenation more effectively at smaller doses than at larger doses. This dose-dependent effect remains to be confirmed in acute hypoxemia during OLV. IMPLICATIONS: Inhaled nitric oxide at 4 ppm improves arterial oxygenation during one-lung ventilation to a greater extent than larger doses, and this effect is caused by a reduction in intrapulmonary shunt.
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Introduction |
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Inhaled nitric oxide (NO) has the capability to improve oxygenation both in adults (2) and children (3) with acute respiratory distress syndrome (ARDS). Therefore, NO may improve oxygenation during OLV. However, several studies using NO at doses of 20 ppm (4–6) or 40 ppm (7) failed to demonstrate an improvement of oxygenation during OLV.
On the basis of investigations during different settings (3,8–10), the optimum dose of NO regarding arterial oxygenation is <10 ppm. Furthermore, large NO concentrations in patients with obstructive pulmonary disease can make pulmonary oxygenation worse by deteriorating ventilation-perfusion (
A/
) matching in the lung (11).
Perhaps the failure of previous studies to improve oxygenation during OLV was due to the administration of too-large doses of NO. The main objective of our experimental study was to test the hypothesis that doses <10 ppm of NO improve arterial oxygenation during OLV.
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Methods |
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Anesthesia was maintained by a continuous infusion of ketamine 8–10 mg · kg-1 · h-1 and midazolam 0.3 mg · kg-1 · h-1; pancuronium 0.3 mg · kg-1 · h-1 was used for muscle relaxation. IV injections of fentanyl 0.15–0.2 mg were given 5 min before surgical interventions. Throughout the experiment, Ringer’s solution 5 mg · kg-1 · h-1 and glucose 5% 2.5 mg · kg-1 · h-1 were infused.
An arterial catheter was surgically placed through the left carotid artery, and a continuous intravascular blood gas system, consisting of fluorescent PO2, pH and PCO2 sensors, and a thermocouple (Paratrend 7+; Diametrics, Highwycombe Bucks, UK), was inserted after in vitro calibration via the carotid artery catheter. A 5F pulmonary artery catheter was inserted via the right external jugular vein. The tip of the pulmonary artery catheter was placed just beyond the pulmonary valve. After the surgical preparation, the animals were left to rest for 45 min before the experiment was started.
The lungs were initially ventilated at a rate of 14 breaths/min with a Siemens Servo Ventilator 300 in the pressure-regulated, volume-controlled mode. Tidal volume was adjusted to achieve an arterial carbon dioxide tension (PaCO2) of 37–43 mm Hg. The FIO2 was set to 0.8 and maintained throughout the experiment. After 30 min, the tracheal tube was positioned distal to the upper right lobe ostium, which enters the trachea directly, under fiberoptic control. To establish OLV, the right mainstem bronchus was blocked by inflating the balloon of a pulmonary artery catheter at end-expiration. The respiratory rate was increased to 16 breaths/min, and tidal volume was adjusted to obtain a PaCO2 between 37 and 43 mm Hg. Animals were then turned to the left lateral decubitus position, and a right thoracotomy was performed. The right lung was exposed by placing a chest retractor between the third and fourth ribs. OLV was continuously monitored by inspecting the movements of the right lung.
NO was administered with a proportional gas injection system (Pulmonox-Mini; Messer-Griesheim, Krefeld, Germany), which uses an external orifice-type flowmeter to measure inspiratory flow. The nitrogen/NO gas mixture was injected 80 cm proximal to the Y-connector. NO concentrations were measured before the Y-piece of the breathing circuit.
Cardiac output (CO) determinations were performed in triplicate by injecting 5-mL ice-cold boluses of 5% dextrose randomly through the respiratory cycle. All pressures were recorded with reference to atmospheric pressure at midthoracic level and at end-expiration. Arterial and mixed venous blood samples were analyzed for PO2, PCO2, and pH, and oxygen saturation was determined by spectrophotometry.
A/ distributions were analyzed on six animals by using the multiple inert gas elimination technique (MIGET). The technique has been described before in detail (12,13). An isotonic saline solution equilibrated with six inert gases (sulfur hexafluoride, ethane, cyclopropane, halothane, ether, and acetone) was infused 30 min before the first blood sampling at a constant rate of 4 mL/min. The infusion rate was then reduced to 2.5 mL/min for the remainder of the experiment. Arterial and mixed venous blood samples were collected together with an expired gas sample from a heated mixing box and analyzed by gas chromatography. Separation and quantification of ethane, cyclopropane, halothane, diethyl ether, and acetone were performed with a gas chromatograph equipped with a flame ionization. Sulfur hexafluoride was measured by a gas chromatograph fitted with an electron capture detector (Fractovap; Carlo Erba, Milan, Italy). The distribution of ventilation and pulmonary blood flow was estimated through the retention and excretion values of the six inert gases. Shunt flow was defined as the fraction of blood perfusing unventilated regions of the lung and those with A/ ratios of <0.005; low A/ regions were those with a A/ ratio between 0.005 and 0.1. Regions with A/ ratios between 1 and 10 were defined as being normal, and those with A/ ratios between 10 and 100 were regarded as high A/ regions. Dead space was the percentage of ventilation to anatomic dead space and lung units with A/ ratios >100. The residual sum of squares was used to test the compatibility of the inert gas data to the derived A/ distribution by the least-squares method. An indication of acceptable quality of the A/ distributions was a residual sum of squares of 5.348 or less in half of the experimental runs (50th percentile) or 10.645 or less in 9% of the experimental runs (90th percentile) (14).
The experimental part of the study was started when the PaO2 reached a plateau after the institution of OLV. When the PaO2 remained constant for 30 min inside the ±5% boundary of its initial plateau value, NO doses of 4, 8, 16, and 32 ppm were randomly administered for 30 min. The stability of the PaO2 was assessed by continuous blood gas monitoring. Between two NO inhalations, a NO-free interval of at least 30 min was kept, and the animals were ventilated with the same gas mixture but without NO. Before and after each NO inhalation period, blood gas analysis and hemodynamic measurements were performed. Gas and blood samples for A/ distribution analysis were collected when a stable PaO2 had been reached and after each NO inhalation period.
All values are expressed as mean ± SD. Statistical analyses were performed with statistical software (SPSS 9.01 for Windows; SPSS, Inc., Chicago, IL).
The data before and after inhalation of each NO concentration were compared by means of the paired Student’s t-test with Bonferroni correction for 4 groups (4, 8, 16, and 32 ppm of NO). Before the paired Student’s t-test was applied, data were analyzed for deviations from the Gaussian distribution by the Kolmogorov-Smirnov test. To compute the P value for the test of normality, the Dallall and Wilkinson (15) approximation to Lilliefors’ method was used.
To compare the changes after inhalation of different concentrations of NO, a repeated-measures analysis of variance was performed. When significance was achieved, post hoc comparisons were made by the Tukey-Kramer multiple comparisons test.
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Results |
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PaO2 increased with NO in concentrations of 4, 8, 16, and 32 ppm and returned to baseline when the administration of NO was stopped. Inhaled NO at 4 ppm improved the PaO2 by 42%, which was significantly higher than the increases at 8, 16, and 32 ppm (P < 0.01; Fig. 1). PaCO2 and pH were not altered by inhaled NO at any level, and hemodynamic variables remained unchanged throughout the study. Neither CO nor mean pulmonary artery pressure changed significantly with the application of NO (Table 1).
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A/) was higher than normal but revealed no changes due to NO administration. The dispersion of perfusion (log SDQ) was in the range between 0.96 and 1.21, reflecting an increased heterogeneity in pulmonary perfusion during OLV. Pulmonary perfusion shifted toward areas of low A/ ratio, whereas ventilation shifted toward areas of high A/ ratio, indicating an impaired A/ matching (Fig. 2).
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Discussion |
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1 ppm. When NO doses exceeded 10 ppm, arterial oxygenation declined. A dose-dependent effect in the range from 0.15 to 1.5 ppm was also found by Lu et al. (8). However, in contrast to the findings of Gerlach et al. (16), oxygenation reached a plateau at 1.5 ppm and did not worsen with larger concentrations. A similar effect was observed by Okamoto et al. (3) in seven children with ARDS. The optimum dose of NO in their study was 4 ppm, and improvements in arterial oxygenation were also observed with NO concentrations of 0.13 ppm.
Perhaps inhaled NO exerts the largest benefit to gas exchange in the lung in which the pathophysiology is governed by an increased intrapulmonary shunt, e.g., ARDS, rather than by A/ mismatching, which is the predominant feature in chronic obstructive lung disease (COPD) (17). However, a dose-dependent effect of NO on arterial oxygenation may also be important in patients with COPD. Germann et al. (10) demonstrated in patients with COPD an improvement in oxygenation with NO doses of 5 ppm. A ceiling effect occurred when NO was increased to doses of 10 and 20 ppm. The improvement in arterial oxygenation is in contrast to the results of a study by Barbera et al. (11). This group found that NO at 40 ppm worsened PaO2; moreover, a deteriorated A/ matching with an increased perfusion to poorly ventilated lung regions was demonstrated by the multiple inert gas elimination technique.
Whether A/ mismatching due to COPD was a contributing factor in those OLV studies, which failed to improve oxygenation by large doses of NO, remains speculative. Fradj et al. (6) excluded patients with severe COPD, indicated by a forced expiratory volume of <50% of the predicted value within one second, and Moutafis et al. (5) gave no details regarding preexisting COPD. The failure of NO to improve arterial oxygenation in patients with A/ inequality as the major gas exchange abnormality was explained in an experimental study by Hopkins et al. (18): A/ inequality was created by the partial obstruction of one lobar bronchus. In five of eight dogs, pulmonary gas exchanged worsened. In these animals, inhaled NO resulted in a reduction in the pulmonary vascular resistance with an increase in blood flow to both the normal and low A/ regions. However, when the pulmonary vascular resistance decreased only in the normal areas of the lung, the blood flow to the regions of low A/ ratio was reduced and shifted toward areas of normal A/ ratio. This resulted in a reduction in A/ mismatching and improved pulmonary oxygenation. These findings support the hypotheses of a competition between local hypoxic pulmonary vasoconstriction (HPV) and vasodilation, resulting from delivery of different amounts of NO to regions of low and normal A/ ratio. The authors hypothesized that the minimum dose of NO required to vasodilate normal regions of the lung would be the most likely to improve arterial oxygenation, because the distribution of the gas to poorly ventilated regions would be proportionally less.
When the underlying gas exchange problem is one of intrapulmonary shunting, NO reduces the pulmonary vascular resistance of the normal, ventilated areas of the lung, resulting in an increased blood supply to well ventilated areas of the lung and an improvement in PaO2 (18). Consequently, NO should improve arterial oxygenation in a dose-dependent manner. In contrast to theory, we found that larger NO concentrations improved PaO2 to a lesser extent than NO at 4 ppm, and the only significant difference that was found with the multiple inert gas elimination technique was a reduction in shunt flow by 4 ppm NO. Because NO was applied when arterial PO2 during OLV had reached a plateau, a maximum HPV response in the nonventilated lung can be assumed. Thus, the finding that NO affected only intrapulmonary shunt flow is compatible with our experimental settings. However, the inverse relationship between NO dose and PaO2 remains to be elucidated. One possible explanation is that NO at larger doses spilled over into the systemic circulation (19). It has been demonstrated that S-nitrosylation of hemoglobin (SNO-Hb) preferably occurs in regions with high oxygen tension (e.g., the ventilated lung) and that the release of NO from the resultant SNO-Hb occurs at low oxygen tension (e.g., the nonventilated lung) (20). If such a spillover occurred in our study animals, perhaps NO at larger doses attenuated HPV of the upper lung. An increased blood flow into nonventilated areas of the upper lung, as detected by an increase in shunt flow during the inhalation of 16 and 32 ppm of NO, would again increase A/ inequalities and decrease PaO2.
Although the underlying mechanisms require further investigation, we have shown that NO at a small dose improves arterial oxygenation during OLV to a greater extent than larger doses. Before transferring our results into clinical practice, it must be clarified whether small doses of NO are as effective in acute hypoxemia as in stable OLV. We assessed dose-dependent effects of NO when PaO2 reached a plateau of approximately 220 mm Hg, which is very different from the clinical setting. Furthermore, NO in doses between 0.1 and 4 ppm, which are effective in patients with ARDS, should be tested during OLV. A possible dose-dependent interaction of NO with volatile anesthetic should be clarified in further investigations. We used propofol because it has been demonstrated that propofol does not inhibit HPV (21) and that its use results in improved oxygenation during OLV (22). Although NO seems not to be directly responsible for the inhibition of HPV by volatile anesthetics (23), interference with the vasodilator effects of NO have been shown (24). Finally, NO was tested in normal lungs, and it cannot be excluded that the effects differ from those in diseased lungs during OLV. However, it has been demonstrated in patients with severe COPD that smaller doses of NO improve PaO2 (10).
In summary, we demonstrated a dose-dependent effect of inhaled NO on arterial oxygenation during OLV. NO at 4 ppm improved PaO2 to a greater extent than at doses of 8, 16, and 32 ppm. The increase in PaO2 was due to a reduction in intrapulmonary shunt flow. The dose-dependent effects remain to be confirmed under the setting of acute hypoxemia during OLV.
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