INDEX COMPARISON OF NITROGEN DIOXIDE PRODUCTION DURING INHALED NITRIC OXIDE THERAPY WITH HIGH FREQUENCY OSCILLATORY VENTILATION AND INTERMITTENT MANDATORY VENTILATION
Nobuyuki Yamaguchi1, Satoshi Suzuki2 and Hajime Togari1 1 Department of Pediatrics, Nagoya City University Medical School 2 Department of Pediatrics, Nagoya City Johoku Hospital
Address requests for reprint to: Nobuyuki Yamaguchi, MD
Department of Pediatrics, Nagoya City University Medical School
1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467, Japan.
Phone: 052-853-8246, FAX: 052-842-3449
E-mail: yamaguti@med.nagoya-cu.ac.jp
SUMMARY
We compared the production of nitrogen dioxide (NO2) in the ventilatory circuit when high frequency oscillatory ventilation (HFOV) is used as the mode of mechanical ventilation versus intermittent mandatory ventilation (IMV). This study was performed using Humming V ventilator with a neonatal circuit and a 50 ml silicone test lung. Nitric oxide (NO) gas was administrated into the inspiratory limb at a distance of 80 cm from the Y piece, which was connected to the adapter of the endotracheal tube. The tubes used for the NO administration line were two sizes 6 mm / 4 mm (ID-4) and 4 mm / 2 mm (ID-2) in the outer / inner diameter. When the NO concentrations measured at the Y piece were 1, 2, 5, 10, 20, 30 and 40 ppm, the NO2 concentrations at the same place were simultaneously measured. The NO2 concentrations in the combination of the HFOV/ID-4 were significantly higher than those in the combinations of the IMV/ID-4, the IMV/ID-2 and the HFOV/ID-2 in all of the NO concentrations except 30 ppm and 40 ppm. This occurs because the back and forth movements of the gas generated by the oscillation had an influence on the mixing of the NO and oxygen gases in the NO administration line.
INTRODUCTION
Nitric oxide (NO) is an endogenous vasodilator, produced by the endothelium in response to both chemical and physical stimuli [1,2]. Inhaled NO is a selective pulmonary vasodilator that does not change systemic vascular resistance, because binding to the hemoglobin in blood inactivates it almost immediately [3-6]. The pulmonary vasodilatory effect of inhaled NO has been well established in animals and patients with pulmonary hypertension. The optimal dose and adverse effects of this new treatment remain uncertain. Of great importance, is the fact it reacts with oxygen to form nitrogen dioxide (NO2) which is known to damage pulmonary epithelium and cause pulmonary edema in animals [7]. High frequency oscillatory ventilation (HFOV) is more effective to treat infants with severe respiratory failure than conventional mechanical ventilation, because it permits a recruit atelectatic lung and sustained lung volume. Therefore, inhaled NO with HFOV is actually used to rescue neonatal respiratory failure that has experienced difficulty with a conventional treatment. The possibility remains that the oscillation generated in the ventilatory circuit during HFOV easily induces the mixing of NO and oxygen during intermittent mandatory ventilation (IMV), thus resulting in the increase of the NO2 production. However, there are very few reports about NO2 production in the ventilatory circuit during HFOV [8].
The aim of this study was to compare the NO2 production in the ventilatory circuit when HFOV was used as the mode of the mechanical ventilation versus that when IMV was used.
METHODS
NO gas was obtained as a mixture of 1004 ppm NO in a balance of nitrogen (Daido Hoxan, Tokyo, Japan). Nitrogen dioxide (NO2) was present at a concentration of less than 1 ppm in this stock tank. The NO2 concentration in the tank was certificated by the gas company with an infrared analyzer. The study was performed using Humming V ventilator (Daido Hoxan) equipped with a neonatal circuit, a servocontrolled humidifier (Model MR 320, Fisher and Paykel, Auckland) and a 50 ml silicone test lung. The ventilator was capable of both the HFOV mode delivered through a piston oscillator and the pressure-limited, time-cycled IMV mode. NO gas was administrated into the inspiratory limb at a distance of 80 cm from the Y piece, which was connected to the adapter of the endotracheal tube (Figure 1). The flow in the NO administration line was regulated by a precision flowmeter with a needle valve (Model RK1202M, KOJIMA, Tokyo, Japan). The tubes used for the NO administration line were made from Teflon in two sizes 6 mm / 4 mm (ID-4) and 4 mm / 2 mm (ID-2) in outer / inner diameter and 200 cm in length. NO and NO2 concentrations were measured every 10 sec by a chemiluminescence analyzer (Model 42, Thermoenvironmental Instruments, Massachusetts) at the Y piece. The chemiluminescense analyzer actually measures only NO concentrations, but does not measure NO2 concentrations. The reaction of NO with ozones produces a characteristic luminescence with an intensity proportional to the concentration of NO. To measure the NOx (NO + NO2) concentration, NO2 must be transformed to NO in a converter box heated to approximately 325ūC. The converted NO molecules along with the original NO molecules react with ozone. The resulting signal represents the NOx concentration. The NO2 concentration is determined by subtracting the signal obtained in the NO mode from the signal obtained the NOx mode. The sampling flow at the Y piece was kept at 0.25 L/min constantly throughout this study. The tube used for the sampling line was made from Teflon and its size was 6 mm / 4 mm in outer / inner diameter and 10 cm in length. The exhaust gases from the expiratory limb were passed through an absorber to scavenge NO and NO2. The ventilatory settings were as follows; FiO2 :1.0, peak inspiratory pressure (PIP) :20 cmH2O, positive end-expiratory pressure (PEEP) :3 cmH20, ventilatory rate :30 breaths/min, inspiratory time :0.6 sec and ventilatory flow :8 L/min in IMV mode and FiO2 :1.0, mean air pressure :10 cmH2O, stroke volume :10 ml and ventilatory flow :8 L/min (the flow in the ventilatory circuit was fixed at 8 L/min constantly in the HFOV mode of the Humming V ventilator) in HFOV mode. When the NO concentrations measured at the Y piece were 1, 2, 5, 10, 20, 30 and 40 ppm by regulating the flow at 0.01 to 0.4 L/min in the NO administration line, the NO2 concentrations at the same place were simultaneously measured. And the NO2 concentrations were compared when IMV or HFOV was used as the mode of mechanical ventilation and when the tubes used for the NO administration line were the ID-4 or the ID-2. Measurement of the NO2 concentration was repeated 5 times and the overall values were expressed as a mean ± SD. All results were analyzed using the Fisher's Protected Least Significant Difference and a p < 0.05 was considered statistically significant. RESULTS
Figure 2 shows the NO2 concentrations at the Y piece for each of the NO concentrations (1, 2, 5, 10, 20, 30 and 40 ppm) at the same place during IMV or HFOV when the tubes used for the NO administration line were the ID-4 or the ID-2. The NO2 concentrations in the combinations of the IMV/ID-4, the IMV/ID-2 and the HFOV/ID-2 were almost 0 ppm in the NO concentrations of 1 ppm and 2 ppm and were significantly increased as the NO concentrations were increased 5 to 40 ppm (p<0.01 or p<0.05). However, the NO2 concentrations in combination with the HFOV/ID-4 were significantly decreased as the NO concentrations were increased 1 to 5 ppm (p<0.01 or p<0.05), and were significantly increased as the NO concentrations were increased 10 to 40 ppm (p<0.01 or p<0.05). And the NO2 concentrations in the combination of the HFOV/ID-4 were significantly higher than those in the combination of the other three patterns in all of the NO concentrations except 30 ppm and 40 ppm (p<0.001 to the HFO/ID-4 ver the IMV/ID-4, the IMV/ID-2 and the HFO/ID-2 in the NO concentrations of 1-10 ppm, p<0.05 to the HFO ID-4 ver the IMV/ID-2 and the HFO/ID-2 in the NO concentration of 20 ppm).
DISCUSSION
Inhaled NO therapy has been singled out as a last means of rescue in the neonatal field, because presently NO gas is not a licensed medical gas in Japan. There are some problems found with this means of therapy, such as metheamoglobinemia formed by the reaction between oxyhaemoglobin and the NO2 produced by the contact of the inhaled NO with oxygen. The magnitude and speed of the NO2 formation are dependent on the concentrations of each the oxygen and NO at the contact time of both gases [9-12]. In the treatment of infants with persistent pulmonary hypertension of the newborn, inhaled NO can be easily oxidized to NO2 in the presence of high concentrations of oxygen which are required by refractory hypoxemia.
The use of HFOV is more effective to treat infants with severe respiratory failure than conventional mechanical ventilation, because it permits a recruit atelectatic lung and sustained lung volume [13-15]. Therefore, inhaled NO with HFOV is actually used to rescue neonatal respiratory failure that has experienced difficulty with a conventional treatment. It was reported that inhaled NO with HFOV was a very useful method to improve oxygenation in infants who had severe persistent pulmonary hypertension of the newborn complicated by diffuse parenchymal lung disease with collapsed alveoli [16-18]. This was because it allowed a steady recruitment of collapsed alveoli and thus the NO gas was readily able to reach the alveoli. However, there are very few reports about the production of NO2 in the ventilatory circuit during HFOV [8]. We performed this study to assess the safety of inhaled NO with HFOV therapy.
It was assumed that the production of the NO2 in the ventilatory circuit was increased during HFOV because of the back and forth movements of the gas generated by the oscillation enhanced during the mixing of the NO and oxygen gases. In this study, however, we found that the NO2 concentrations at the Y piece during HFOV were not increased as compared with ones during IMV when the tube used for the NO administration line was the ID-2, which had 2 mm in the inner diameter. And when the tube used for the NO administration line was the ID-4, which had 4 mm in the inner diameter, the NO2 productions in the ventilatory circuit during HFOV were higher than those during IMV at 1, 2, 5 and 10 ppm NO at the Y piece. We previously reported in a study of the same design that the inspiratory pressure in the ventilatory circuit during IMV generated a back flow in the NO administration line [19]. There is a possibility that the back and forth movement in the ventilatory circuit during HFOV has an influence on the gas in the NO administration line. When the oscillation under 100 % oxygen gas in the ventilatory circuit transmits to the 1004 ppm NO gas in the NO administration line, the gas mixing accelerates the NO2 production in the NO administration line as compared with during IMV. The lower the NO concentrations at the Y piece and the wider the inner diameter of the NO administration line, the slower the flow in the NO administration line and the period of the contact between the NO and oxygen gases are longer. For the reasons mentioned above, we conclude that the NO administration line with a wide inner diameter during the NO inhalation therapy with HFOV should not be used for prevention of the large amount of the NO2 productions. It seems that there is no difference in the NO2 production generated by the mixing of the NO and oxygen gases in the ventilatory circuit between the NO administration site and the Y piece during HFOV and IMV. This occurs because the flow of 8 L/min in the ventilatory circuit is extremely fast as compared to the flow 0.01 to 0.4 L/min in the NO administration line.
The system to deliver NO during mechanical ventilation is not yet commercially available in Japan. In the future development of the NO delivery system, the NO gas should be delivered into the inspiratory limb through a narrow tip of the NO administration line when especially the NO inhalation therapy with HFOV is used. As a result, the flow in the NO administration line will not be dependent on the back and forth movement of gases in the ventilatory circuit during HFO.
ACKNOWLEDGMENTS
This study was supported by Daido Hoxan Inc., Japan.
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LEGENDS
Fig.1. Schematic diagram of NO delivery system used in this study.
Fig.2. The NO2 concentrations (mean ± SD) at the Y piece for each of the NO concentrations (1 - 40 ppm) measured at the Y piece. Measurements of the NO2 concentration were repeated 5 times.
The NO2 concentrations marked with "a" and "b" are significantly higher (a:p<0.05, b:p<0.01) than the NO2 concentrations in the one step low NO concentrations, respectively. The NO2 concentrations marked with "c" and "d" are significantly lower (c:p<0.05, d:p<0.01) than the NO2 concentrations in one step low NO concentrations, respectively.