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A safe clinical system for nitric oxide inhalation therapy for pediatric patients

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A safe clinical system for nitric oxide inhalation therapy for pediatric patients
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  Pediatric Pulmonology 22:174-181 (1996) Diagnostic and Therapeutic Methods - A Safe Clinical System for Nitric Oxide Inhalation Therapy for Pediatric Patients Katsuyuki Miyasaka, MD, PhD, Hiroyuki Fujiwara, MD, Masao Takata, MD, Hirokazu Sakai, MD, Carla Liberatore, MD, Li Sun, MD, and Tran N. Phuc Summary. A safe clinical system for nitric oxide (NO) inhalation therapy was developed. The system consists of three parts: a NO controller, a NO monitor, and a patient circuit. NO gas flow and carrier gas flow are controlled by a special rust-proof hermal mass flowmeter. Standard gas quality NO gas (10,000 ppm, balance nitrogen) is used. The outlet of the NO gas tank is connected to the distal end of a heated humidifer that is very close (12 mL) to the patient, to decrease acidic water precipitation and decrease contact time between NO and oxygen 02). Fail-safe mechanisms to prevent he delivery zyxwvut f a hypoxic mixture or excessive NO concentration are incorporated. lnspiratory NO concentration s continuously monitored by a modified electro- chemical NO meter. The patient circuit consists of a breathing circuit and a ventilator with a scavenging unit. A modified Mapleson D type circuit s used. Fresh gas, humidified and mixed with NO, is introduced o the patient connection port. A mechanical ventilator, either of conventional or of high-frequency oscillation ype, is connected o the expiratory limb of the Mapleson D circuit. A coaxial scavenging unit including activated charcoal is placed in between the expiratory limb and the ventilator. The adjustment of inspiratory NO concentration (y) was accurate over a wide range (1-80 ppm) of concentrations (x) (y = 0.36 0.96x, R2 = 0,999, n = 45) and showed good agreement with the chemilurninescence method. lnspiratory nitrous oxide NO,) concentration was less than 0.3 ppm, and acidic water accumulation as measured by NO, and NO, was less than 5 ppm, even at an extremely high NO concentration of 80 ppm with an Fi02 of 1.0 and 10 Umin of fresh gas flow. Environmental NO and zyxwvu Op concentrations n the ICU remained below 0.005 and 0.05 ppm, respectively. This system was used clinically on 214 pediatric patients and proved to be accurate, safe, and useful. Pediatr Pulmonol. 1996; 22:174-181. zyx   996 Wiley-Liss, Inc. Key words: Nitric oxide, mass flowmeter, pulmonary hypertension, inhalation therapy. INTRODUCTION In recent years, a series of clinical research studies have shown nitric oxide (NO) to be a promising tool to treat intractable pulmonary hypertension.] NO inhala- tion therapy is in its infancy, bringing with it a multitude of unanswered questions concerning methodology, safety, and toxicity.ss6 zyxwvutsr   variety of NO delivery systems have been briefly described in the literature, but there is pres- ently no widely recognized system for clinical We developed a clinical NO administration system that is safe for patients and health care personnel. It consists of a NO controller with a specially designed mass flow- meter, a continuous NO monitor, and a patient circuit with a modified Mapleson D circuit (T-piece). o NO Administration System The system we developed is illustrated in Figure 1. It consists of three parts: 1 a NO controller, zyxwvut   a NO moni- tor, and 3 a patient circuit. zyxwvu   1996 Wiley-Liss, Inc. NO Gas Controller NO gas flow and carrier gas flow are controlled and monitored. NO gas [ 10,000 ppm in nitrogen (N,) in accor- dance with Japan Industrial Standards (JIS K 0001-1992) first class quality standard gas; Nippon Sanso, Japan] is contained in a cylinder and is connected to a specially From the Department of Anesthesia and ICU, Pathophysiology Re- search Laboratory, National Children's Hospital and Children's Medical Research Center, Setagaya, Tokyo, Japan. Received September 23, 1994; (revision) accepted for publication May 15, 1996. Part of this study was presented at the 1st International Congress on Pediatric Pulmonology held in Nice, France, June zy -5 1994. Address correspondence and reprint requests to Dr. Katsuyuki Miya- saka, Department of Anesthesia and ICU, National Children's Hospital, 3-35-31 Taishido, Setagaya, Tokyo, Japan 154.  NO Delivery System 175 Air-Oxygen blender. zyxwvuts ' Fig. 1. The system consists of three parts: a NO controller, a NO monitor, and a patient circuit. The outlet of NO gas is con- nected to the distal side of a heated humidifier, very close to the patient. Several fail-safe mechanisms are incorporated. In- spiratory NO concentration is continuously monitored by a mod- zyxwvu designed rust-proof mass flowmeter (Metran, Japan; 0.1 mL/min resolution; maximum flow of 100 ml/min) with a stainless steel pipe. NO gas pressure is reduced to zyxwv   kg/cmz by a pressure regulator before it enters the NO flowmeter. A soda lime chamber (50 g capacity) and a stainless steel mesh filter are attached proximal to the NO flowmeter to remove undesirable NOz and soda lime dust.12 NO gas leaves the flowmeter through the NO outlet of the NO controller. The outlet of NO gas is Abbreviations ANOVA Analysis of variance HFO High-frequency oscillation HPLC High-pressure liquid chrornotography N2 Nitrogen NO Nitric oxide N02- Nitrite NOz Nitrogen dioxide N03- Nitrate 02 Oxygen heck valves Flow rate set dials NO Controller -  / O selection switch Master switch IU rn, Mass Flow Controller NO shut off valve Mechanical restricture ,000 ppm N2 balanced) Coaxial scavenging Central vacuum Activated charcoa ified electrochemical NO meter. The patient circuit consists of a breathing circuit and a ventilator with a scavenging unit. A modified Mapleson D type circuit is used. A coaxial scavenging unit including activated charcoal is placed in between the expir- atory limb and the ventilator. then connected to the distal end (outlet) of the fresh gas delivery tube after the fresh gas comes out of the heated humidifier. This prevents excess acidic water accumula- tion in the humidifier chamber. The amount of time that NO and oxygen are in contact is thus kept to a minimum as NO gas is mixed with oxygen toward the end of the circuit just before the gas mixture is delivered to the patient. The NO mass flowmeter is electronically controlled by a digital switch that prevents NO flow only after the carrier gas has been turned on (NO fail-safe shut-off system). A specially designated NO selection switch must be pressed to start NO gas flow, but it can only be activated after carrier gas flow has begun. In addition to the elec- tronic safeguard mechanism, a fixed mechanical control- ler is incorporated into the NO mass flowmeter so that it cannot deliver more than 100 ml/min. Camer gas (a mixture of oxygen and air) concentration is adjusted by a pneumatic air-oxygen mixer. Its flow rate is electronically controlled by another mass flowmeter (10 mL/min resolution: minimum flow of zy   L/min and  176 zyxwvusrq iyasaka et al. maximum flow of 12 L/min). The outlet of the carrier gas tubing is then introduced to a heated humidifier. Hu- midified carrier gas will then be mixed with NO gas at the outlet side of the heated humidifier and introduced to a Mapleson D circuit by a short (50 cm in length, or 12 zyxwvutsrq L in volume) PVC bubble tuble (Argyle, United States) as fresh gas flow to the patient. Check valve mechanisms are incorporated downstream of both mass flowmeters to prevent reversed flow. A stainless steel mechanical pressure relief valve (see at 100 cmH,O) is placed in between the NO flowmeter and the outlet. Another stainless steel adjustable pressure relief safety valve (usually set at 80 cmHzO) is incorpo- rated at the carrier gas outlet. Since minimum carrier gas flow is set at zyxwvuts   L/min and maximum NO flow is restricted to 100 mWmin, the NO concentration with this system never exceeds 200 ppm and the F,02 never goes below 0.20. If necessary, however, an F,O, of 0.99 is readily possible with up to 100 ppm of NO. Flow rates of carrier gas and NO gas are monitored and displayed digitally. Delivered NO concentration is calculated from carrier gas flow and NO gas flow and then displayed (0.1 ppm resolutions). The whole system is backed up by battery power for 1 hour in case of accidental power failure. The mass flowmeters we use in this system utilize thermal mass flow sensor^.'^ The principle is outlined in Figure 2. A constant ratio of the flow of gas is diverted into the thermal mass flow sensor tube. The sensor tube is encircled by two heating elements that are heated by electric current. As the gas flows through the sensor, a temperature differential is produced between two points, and the change in resistance due to this differential is detected. The flow of the gas is calculated from the change in resistance of the elements and the specific heat of the gas. There are few mechanical parts and no direct contact of gas and heating elements. Stable flow control is thus possible over a wide range of gas flow rates, and the accuracy is claimed to be better than zyxwvuts 0.5 of set value. The effect of the F,Oz changes on the accuracy of the air- oxygen mass flowmeter is claimed to be less than -C 1.5% of set value. NO Gas Monitor An electrochemical NO meter (Pac I1 NO, Drager, Germany) is used. Fresh gas flow is sampled at the site of patient connection at a rate of 150 mL/min by using a specially designed rust-proof diaphragm vacuum pump. The sampled gas is then introduced to a NO meter using a specially made T-adapter. Polyethylene tubing and a water trap are used in the circuit. Sampled gas is not returned to the patient circuit to avoid pressurizing the NO sensor. The sampled gas is introduced to a scavenging unit, which is described later. An additional electrochemi- cal NOz meter (Pac I1 NOz, Drager, Germany) is also used for intermittent monitoring of fresh gas flow to the patient and environmental air. Patient Circuit This consists of two parts: a breathing circuit, and a ventilator and scavenging unit. zyx reathing circuit. A modified Mapleson D type cir- cuit made of polycarbonate (Mera, Tokyo) is used. Fresh gas, humidified and mixed with NO, is introduced to the patient connection port. An adapter is inserted here for continuous gas monitoring. The end of the expiratory limb (minimum 500 mL volume) is connected to a ventilator (Newport E-100A, NMI, United States) for mechanical ventilation. Thus the patient will inhale only fresh gas flow. The ventilator flow is used to deliver only fresh gas flow to the patient. The exhalation valve with a coaxial scavenging unit is placed between the expiratory limb and the ventilator. Exhalation valve and scavenging unit. Special hous- ing and tubing are used to collect excess gas from the exhalation valve of the ventilator. Gas scavenging is car- ried out by a coaxial suction unit with activated charcoal, which was srcinally designed for anesthetic gas scaveng- ing.” A central piping vacuum system (via a 5 L capacity in-line activated charcoal canister for NO adsorption; Yamatosanki, Japan) is used as a vacuum source. MATERIALS AND METHODS The NO delivery system we developed was both bench and clinically tested for accuracy and safety. Bench Study The NOx Analyzer M-42 (TENC, Japan) was used for the verification of NO and NO2 concentrations, but the LCD 700AL analyzer (ECO Physics Ag, Switzerland) was used when NO concentration was above 20 ppm. Analyzers were calibrated with a first-class quality stan- dard gas (NO 10 or 40 ppm, balance N2) prior to each experiment. Carrier gas flow was set to 10 L/min (with an Fi02 of 1 .O , and calculated inspiratory concentrations of NO (set concentration) were tested against chemilumi- nescence at the patient site. NO2 concentration was also measured at the patient site and just outside the coaxial scavenging unit. Environmental air (in the treatment area at 150 cm above the floor, before and during NO inhalation), central piped oxygen, air, and nitrogen, NO, and NO, concentra- tions were also measured by chemiluminescence. NO, production when using a less concentrated source of NO (1,000 ppm NO cylinder) was measured and com- pared with NOz production from our system, which uses a NO cylinder with a concentration of 10,000 ppm. A  A zyxwvu 177 * b Control Circuit Actual Flow Rate Digital Display Amplifier Thermal Wire Bridge Circuit Flow Sensor Flow Control Flow Divider Fig. 2 A constant ratio of the flow of the gas is diverted into the thermal mass flow sensor tube by the flow divider. The sensor tubeis encircled by two heating elements that are heated by electric current. As the gas flows through the sensor, a tem- perature differential is produced between two points, and the zyxwvu NO concentration of 20 ppm and a carrier gas flow of 10 L/min were used for this experiment. Nitrate (NO;) and nitrite (NO;) condensation in the heated humidifier (M-328, Fisher-Paykel, New Zealand) and breathing circuit were collected every zyxwvu   hours and measured by high-pressure liquid chromatography (HPLC) (LCM-1, Waters, United States) over 24 hours. A carrier gas flow of 10 Wmin (FiOz = 1.0) with 80 pprn NO concentration was used. Humidifier chamber water was refilled with each sampling. zyxwvut ata Analysis Data points are the averages of zyxwvuts   experiments con- ducted on separate occasions. All values are reported as means SD. The degree of correlation between set val- ues and measured (chemiluminescence) values was as- sessed by linear regression analysis. Agreement was eval- uated by calculating bias (mean difference between two measures) and precision SD of the mean difference) based on the method proposed by Bland and Altman.14 Data of two groups were compared by using two-way analysis of variance (ANOVA) for repeated measures. Significance values of P < 0.05 were considered statisti- cally significant. Valve change in resistance due to this differential is detected. The flow of the gas is calculated from the change in resistance of the elements and the specific heat of the gas. The flow signal thus measured controls the flow control valve. Clinical Trial The study protocol, which followed the z linical NO Application Guidelines set by a Pediatric Medical Re- search Fund study group on “Pathophysiology and Treat- ment of Severe Cardiorespiratory Failure of Infants and Children (H5-PR8)” sponsored by the Japanese Ministry of Health, was approved by the Institutional Ethical Com- mittee and was used clinically on 214 pediatric patients (age 0 days to 17 years) over a period of more than 10,000 hours. Informed consent was obtained from the parents before treatment of any patient. NO concentration admin- istered ranged from 2 to 80 ppm with a carrier gas flow of 5 or 10 L and an FiOz of 0.4-1.0. Nitrate and NO; ion concentration and the pH of the water that condensed in the circuit were sampled intermittently (every 6-24 hours) in the initial 30 patients, and a total of 185 samples was measured. RESULTS Bench Study Table 1 shows the programmed NO concentration and measured concentrations of NO and NOz (by chemilumi-  178 Miyasaka et at. zyxwvu  6 zyxwvut   Q Q zyx I I I 1 I I zy   10 20 30 40 50 60 70 80 Average of set values and chemilumi. values ppm) Fig. 3. Differences in set NO concentrations and measured inhalational NO concentrations by chemiluminescence method are plotted against the best estimate of true values the mean of two methods). The limits of agreement (-3.8 and 2.5) are small enough to conclude that this system has good accuracy. zyxwvutsr nescence) at the patient site and just outside the coaxial scavenging unit. Measured NO concentrations (y) corre- lated well with set concentrations (x) over a wide range (1-80 ppm) (y = 0.36 + 0.96~; 2 = 0.999; n = 45 nd showed good agreement with the chemiluminescence method (Fig. 3). The concentrations of NO measured electrochemically and by chemiluminescence agreed well over a wide range of NO concentrations (Fig. 4 . The concentration of NO in the cylinders (either 10,000 or 1,000 ppm) did not affect inhaled NOz concentration when identical FiOz and NO concentrations were set with the same carrier flows (Table 2). Inspiratory NOz concentration was 0.3 pprn at the pa- tient site at a delivered NO concentration of 80 pprn with an Fi02 of 1.0 and 10 Wmin of fresh gas flow. When inspired NO concentration was set to 20 ppm with an Fi02 f 1.0, NO2 concentration was less than 0.1 ppm. The concentrations of NO; and NO; in precipitated water over time remained less than zyxwvut   ppm. The pH of precipitated water remained 5.4 r above at all times. Clinical Trial The system was used on 214 pediatric patients aged 0 days (3.2 kg) to 17 years (52.4 kg). Carrier flows were usually set to 10 L/min. High-frequency oscillation at 15 Hz (Humming V, Metran, Japan) instead of conventional ventilation was used in 36 cases. Maximum concentration delivered with this system was 80 ppm for 12 hours. The longest continuous use of NO inhalation in this series was 21 days. Inspired NO concentrations were very reliable and sta- ble. Environmental NO or NO2 concentrations n the treat- ment area never exceeded 0.05 ppm, though we found NO and NO2 levels in our hospital environment to run around 0.005 and 0.04 ppm, respectively. Nitrate and NO; condensations n the breathing circuit samples never exceeded 5 ppm, and pH stayed above 5.4. Nitrate and NO; were not detected in the chamber water of the hu- midifier. DISCUSSION Little has been reported on the devices used in clinical applications of NO therapy. It is understandable that makeshift systems have been used in the majority of clinical studies reported to date. Mechanical flowmeters and gas regulating valves generally used in medical gas industries are not rust proof, nor have they back-pressure compensation and, therefore, are not suited for delicate gas flow c0ntrol.'~3~~ hile NO may be useful in therapy of selected pathological conditions, NO and its derivatives possess significant toxicity. For these reasons we devel- oped a system with patient and environmental safety in mind.
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