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Inhaled nitric oxide in neonatal and paediatric transport
Early Human Development 84 (2008) 725–729
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Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Best practice guideline
Inhaled nitric oxide in neonatal and paediatric transport Daniel Lutman, Andy Petros ⁎ Children's Acute Transport Service, 44B Bedford Row, London WC1R 4LL, UK
a r t i c l e Keywords: Flight Transport Paediatric Neonatal Inhaled nitric oxide
i n f o
a b s t r a c t Since the first reports of the use of inhaled nitric oxide in the early 1990s its applications have been refined to a number of specific conditions. Pre-term and term neonates benefit significantly in the improvement of oxygenation in conditions such as hypoxic respiratory failure and persistent pulmonary hypertension of the neonate and the reduction in referral rates to extra corporeal membrane oxygenation. Many neonatal units still do not have the ability to administer inhaled nitric oxide though an increasing number of neonatal units have acquired the capability to deliver inhaled nitric oxide in recent years with commercially available delivering devices. In either case if the neonate needs transfer for further management or extra corporeal membrane oxygenation the journey can be improved if inhaled nitric oxide is introduced during transport or could deteriorate if inhaled nitric oxide was discontinued during transport. Delivery of inhaled nitric oxide during transport can be technically challenging and the consequences of increased or interrupted delivery can be dangerous. The different modes of transport either by road or air can influence the method of delivery. We describe our method of delivering inhaled nitric oxide during the retrievals we undertake and how this changes depending upon the type of journey performed. We also suggest guidelines for its use during transport and outline the precautions we take to ensure safety of patient and carers during transport. © 2008 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How is nitric oxide presented? . . . . . . . . . . . . . . . . . . . . . . How is nitric oxide measured? . . . . . . . . . . . . . . . . . . . . . . How is nitric oxide delivered? . . . . . . . . . . . . . . . . . . . . . . 4.1. Continuous flow via a calibrated rotameter . . . . . . . . . . . . . 4.2. AeroNOx device (Pulmonox Medical Inc, Tofield, Alberta, Canada) . . 4.3. INOvent device (Datex-Ohmeda, Madison, WI) . . . . . . . . . . . 4.4. INOmax DS transport system (INO therapeutics 7601-B Murphy Drive, 5. Mode of transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Ambulance . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Fixed wing and helicopter . . . . . . . . . . . . . . . . . . . . . 6. Health and safety exposure limits . . . . . . . . . . . . . . . . . . . . . 7. Transport regulations . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. General regulations for road transport . . . . . . . . . . . . . . . 7.2. Regulations for civil fixed wing air transport . . . . . . . . . . . . 7.3. Regulations for civil helicopter air transport . . . . . . . . . . . . . 7.4. Regulations for military air transport . . . . . . . . . . . . . . . . 8. Guidelines for carrying gases on airplanes and ambulances . . . . . . . . . 9. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
⁎ Corresponding author. E-mail addresses: [email protected] (D. Lutman), [email protected] (A. Petros). 0378-3782/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2008.08.003
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . WI 53562) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction There are a number of specific indications for the use of inhaled nitric oxide in neonates and children. These include persistent pulmonary hypertension of the newborn (PPHN) where its use significantly reduces the need for extracorporeal membrane oxygenation (ECMO) [1]. It is also used in hypoxic respiratory failure despite lack of good evidence for its success [2] and conditions where pulmonary hypertension prevails [3]. Inhaled nitric oxide (iNO) is often started prior to transport as part of the initial resuscitation and stabilisation of a critically ill patient. Once initiated it is inadvisable to interrupt delivery as this could cause a serious deterioration during the transport [4,5]. Hence, systems have to be developed to deliver iNO during transport either land based or air borne [6,7]. At the Children's Acute Transport Service (CATS) we offer a retrieval service for the children in North Thames, London, UK. We retrieve about 1000 children per year and have done so since 2001. There are on average 100 occasions/yr when inhaled nitric oxide has to be used to help in the transport of critically ill neonates and children both on land and in the air. The different modes of transport require different techniques and safety precautions. 2. How is nitric oxide presented? In the UK ‘INO therapeutics UK’ (a subsidiary of BOC) hold the patent for the only formulation of nitric oxide licensed for human use under the non-generic name ‘INOmax’. The only formulation available to the authors within the UK is that of 400 ppm mol/mol nitric oxide in nitrogen and all further discussions will assume that this formulation is the source of the gas. A variety of other cylinder sizes and formulations are available in other countries and the reader is advised that some of the operational practices discussed here may not be appropriate for some cylinder sizes and formulations. The 400 ppm mol/mol formulation is available within the UK in two sizes of aluminium cylinder 2 l and 10 l. Both cylinder types are filled at a pressure of 155 bar absolute which for a 2 l cylinder at 1 bar and 15 °C brings 307 l of gas and for a 10 l cylinder at 1 bar absolute and 15 °C brings 1535 l of gas. The cylinders are used with a regulator which reduces the cylinder pressure for use either with a rotameter or with the ‘INOvent ’delivery system. The cylinders may be safely
Fig. 2. Delivery system used to deliver nitric oxide during transport.
operated to an altitude of 10,000 ft (personal communication, Peter Rothery, General Manager UK, INO therapeutics UK, correct as of 7th April 2008). Our current understanding of nitric oxide suggests that there are very few patients who will respond only to iNO levels greater than 20 ppm [1] and the same study did not identify a benefit to those individuals regardless of response. The risk of methaemaglobinaemia, nitrogen dioxide toxicity and the reduction of fractional inspired oxygen concentration by dilution with the carrier gas nitrogen are all increased above 20 ppm. Doses above 20 ppm are not used by the authors on transport. 3. How is nitric oxide measured? iNO is delivered and measured in parts per million. It is most accurately measured using a chemiluminescent technique. However, this is impractical on transport and small chemical sensors are used (Micro Medical Ltd, Kent, UK) (Fig. 1). Nitric oxide reacts with oxygen within the ventilator circuit to produce nitrogen dioxide. Nitrogen dioxide can cause lung damage at
Table 1 Flow rates for iNO (ml/min) to achieve approximate ppms (iNO monitor must be used) (our thanks to Lisa Martin, Respiratory Therapist, for this data)
Fig. 1. Commercially available Microgas iNO analyser used to measure nitric oxide delivered in ppm.
5 l/min 6 l/min 7 l/min 8 l/min 9 l/min 10 l/min 11 l/min 12 l/min 13 l/min 14 l/min
5 ppm
10 ppm
15 ppm
20 ppm
63 75 88 100 113 125 138 150 163 175
125 150 175 200 225 250 275 300 325 350
188 225 263 300 338 375 413 450 488 525
250 300 350 400 450 500 550 600 650 700
D. Lutman, A. Petros / Early Human Development 84 (2008) 725–729
Fig. 3. INOvent delivery system permanently installed in the CATS ambulance.
lower concentrations than nitric oxide and the concentration within breathing systems needs to be b0.5 ppm. Nitrogen dioxide should be continuously measured. High levels are frequently encountered when purging the delivery systems before use. The delivery systems should always be completely purged before patient connection.
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Nitric oxide gas consumption is easily set once the flow rate is established. For planning purposes Table 1 is used as an estimate. In common with all transport gases we recommend that even if a suitable quantity of gas can be carried in a single cylinder, at least two cylinders complete with regulators are carried. The 2 l size ‘INOmax’ cylinder will deliver 20 ppm nitric oxide for almost 10 h if the flow (ventilator or bagging circuit) is approximately 10 l per minute. Within our transport service, therefore, the calculation can usually be simplified to two cylinder-regulators. Clearly such a simple, inexpensive and lightweight system is robust enough to survive the most challenging transport environments. If a single component malfunctions it can be replaced. The delivery of nitric oxide does not depend on electrical power and the analysers require batteries infrequently. The rotameter can be used at altitude (see mode of transport). However there are many disadvantages to such a system as the primary nitric oxide delivery system. The main problem is that the flow of nitric oxide is continuous, whereas the gas flow from the ventilator may be intermittent. This will result in alternating high and low concentrations of nitric oxide in the gas as it travels down the inspiratory limb. The significance of this effect is unknown. The other main issue is that more monitoring and vigilance is required from the transport team; the rotameter valve can be delicate and difficult to adjust and more significantly that the flow can be changed inadvertently if the housing of the rotameter knob is not shielded from objects moving around it. 4.2. AeroNOx device (Pulmonox Medical Inc, Tofield, Alberta, Canada) This system is not available within the UK and has not been evaluated by the authors. Its low weight, portability and relative simplicity might make it particularly suited to the transport environment.
4. How is nitric oxide delivered? 4.3. INOvent device (Datex-Ohmeda, Madison, WI) iNO can be delivered using a number of different systems: 1) As a continuous flow via a calibrated rotameter 2) via the AeroNOx device (Pulmonox Medical Inc, Tofield, Alberta, Canada) 3) via the INOvent device (Datex-Ohmeda, Madison,WI) 4) via the INOmax DS transport system (INO therapeutics 7601-B Murphy Drive, WI 53562). 4.1. Continuous flow via a calibrated rotameter This is the simplest delivery system (Fig. 2) and can be used as either the primary or backup delivery system. Nitric oxide gas passes from the cylinder through the regulator and then to the rotameter. The assembly is first purged to clear nitrogen dioxide and an appropriate flow is selected (Table 1). Nitric oxide is added into the inspiratory limb of the breathing system. As ‘INOmax’ is a formulation containing nitric oxide and nitrogen, it is potentially asphyxiant and an oxygen meter should be used to monitor the fractional inspired oxygen concentration of the resultant blend of gas. The oxygen meter should be set so that an undesirable reduction of inspired fractional oxygen concentration will result in an audible and visible alarm. Nitric oxide concentration is measured at the patient end of the circuit. At CATS originally both nitric oxide and nitrogen dioxide were measured. After several years of experience with the system we chose to compromise on nitrogen dioxide measurement in favour of a simpler more robust nitric oxide analyser. In normal operations we had never registered a significant nitrogen dioxide level either within the circuit or environmentally. Again alarms are set which provide a visual and auditory indication of high or low iNO measurements. The circuit is run with a test lung for several minutes to allow fine tuning of the nitric oxide flow and stabilisation of the nitric oxide analyser. The nitric cylinder and rotameter are mounted on a carry handle to improve portability and to allow the system to be attached to the transport trolley regardless of the mode of transport.
The most sophisticated method of delivery is via the ‘INOvent’ delivery system. This computerised system blends nitric oxide automatically using a flow sensor and provides a continuous measurement of inspired oxygen concentration, nitrogen dioxide concentration and nitric oxide concentration. The main advantage of this system is the tight control of iNO concentration over a wide variety of continuous or intermittent gas flows. This is the only system that will deliver a constant iNO concentration during intermittent flow ventilation. The system can be moved easily between different types of ventilator (conventional or high frequency) without adjustment. Additional advantages include a variety of gas concentrations
Fig. 4. Environmental alarms used to detect nitric oxide.
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and cylinder pressure alarms. In the transport environment however the complexity of this system does lead to some disadvantages. A major computer or electrical system failure (that does not respond to a ‘reboot’) is unlikely to be resolvable on transport. Like all computerised systems it is vulnerable to extremes of temperature, humidity, electrical interference and vibration. The internal batteries allow for an interruption of electrical power supplies but because they are rarely used and frequently charged tend to exhibit ‘memory’. This can dramatically shorten the interval over which the unit can operate when disconnected from the mains. Additionally the cylinder pressures and consumption of nitric oxide gas is not displayed on the unit whilst in operation. This would be of less significance within a paediatric intensive care unit where two large (10 l) nitric oxide cylinders are employed for each ‘INOvent’ bringing a maximum total of 3070 l of gas. On transport, where portability and weight are important safety factors, the small (2 l) nitric oxide cylinders are used. Inevitably more attention must be paid to gas planning and gas consumption and appropriate safety margins drawn up. Nitric oxide consumption is often less when using the INOvent than when using the simple rotameter delivery system because it changes with flow. The main risk is to use a ventilator mode that utilises a greater flow than expected, which will use a correspondingly larger quantity of nitric oxide than expected. The ‘INOvent’ system is arguably best used in a permanent ambulance or trolley fitting with integral power and gas supplies (Fig. 3). It is our practice to pair it with a simple rotameter delivery system to provide operational redundancy. Spare ‘o’ rings should be carried for each regulator (these can be seen in the illustrations taped to the systems). 4.4. INOmax DS transport system (INO therapeutics 7601-B Murphy Drive, WI 53562) This system has been recently launched within the United States specifically for use in transport. The design is of low weight, high portability and has the ability to maintain iNO concentrations during intermittent flow ventilation. The unit has been validated for use with several transport ventilators. This unit has not been evaluated within the UK at present.
Many ambulances have transformers that can deliver power supplies suitable for electronic iNO delivery systems. The systems themselves can often be permanently mounted within the vehicle or on the patient stretcher. Nitric oxide gas supplies are more easily stored and piped within dedicated vehicles. A backup iNO delivery system is desirable and at CATS we use a backup rotameter system until the patient is loaded into our ambulance when the permanent ‘INOvent’ system takes over. This process ensures that the teams remain entirely familiar with both systems. 5.2. Fixed wing and helicopter CATS undertakes between 50 and 70 flight transports each year. These longer transports are often for specialist services such as for ECMO assessment and iNO is frequently employed. Although in principal it would be desirable to conduct all iNO delivery using an electronic system the current lack of dedicated air ambulances for inter facility transport within the UK makes this uneconomic. We currently favour the simplicity and low weight of the rotameter system for iNO delivery despite the disadvantages discussed above. The system and its spare cylinder are secured to the patient stretcher whilst the vehicle is in motion. Rotameters estimate volume by measuring a pressure differential, accuracy is therefore affected by changes in barometric pressure. The rotameters at CATS (series 1100 Mobrey Measurements Ltd, UK) have a relatively high pressure input so that the pin valve has to be placed before the rotameter tube. This means that the rotameter tube will be at ambient pressure. As the cabin altitude decreases the density of the gas in the rotameter falls causing the rotameter to under read. The effect is more noticeable at high gas flows and high cabin altitudes and will vary according to the individual rotameter (personal communication, Rob Broomhead, Flotech Solutions Ltd, Stockport UK). In practice the flows set at sea level can continue without adjustment [9]. iNO concentration should be carefully monitored using the analyser when changing the iNO concentration and if iNO therapy is initiated whilst at altitude. 6. Health and safety exposure limits
5. Mode of transport In all modes of transport spare regulator ‘o’ rings should be carried for each regulator. Partial or complete failure of the ‘o’ ring occurs very occasionally and whenever the regulators are changed this component should be examined for wear. An insidious leak may be the most difficult to spot in practice and in all modes of transport cylinder pressures should be checked intermittently and environmental monitoring for elevated nitric oxide levels should be considered (Fig. 4). Process guidelines need to be developed to cover normal operation of the delivery systems as well the actions to take in case of a leak or other failure (see Guidelines for carrying gases on airplanes and ambulances). Scavenging apparatus is available for iNO but in normal operation at CATS it is difficult to detect any environmental nitric oxide or nitrogen dioxide in any of our vehicles [8]. 5.1. Ambulance Most inter facility transports are by road and this is the most frequent mode of transport in which iNO is delivered. Although many transport services use flight transport for critically ill patients undergoing long journeys, a road journey of between 2 and 3 h is not uncommon. Many helicopter and fixed wing transports will include a road transport element. Accidents occur most frequently by road and it is important that the delivery system is properly secured within the vehicle. These factors tend to result in the use of electronic delivery systems.
There is a current review of the UK Workplace Exposure Limits of nitrogen monoxide (nitric oxide) and nitrogen dioxide and so there is
Table 2 CATS guidelines for carrying gases on airplanes and ambulances Normal flight operations—standard precautions ▪Ensure equipment is secured appropriately. ▪Ensure equipment is fully functional in the transport environment (not compromised by altitude or vibration). ▪Ensure alarms are both visual and auditory. ▪Ensure personnel are trained and competent to use the equipment. Normal flight operations—nitric oxide precautions ▪Ensure fractional inspired oxygen concentration is monitored and alarms set. ▪Ensure appropriate iNO monitoring is in place and alarms set. ▪Perform purging procedure to ensure minimum nitrogen dioxide exposure is followed. ▪Ensure appropriate environmental monitoring is considered. ▪Ensure patient responses to nitric oxide are documented. ▪Perform 15 fifteen min checks of iNO concentration, nitric oxide flow, and cylinder pressure. Abnormal flight operations—nitric oxide leak Inform team/pilots immediately. ▪Switch off cylinder—if possible depending on child's condition. ▪Increase FiO2—if possible and not already maximum. ▪Check that vehicle cabin air exchange is optimal. ▪Consider alternate intravenous pulmonary vasodilators e.g. iv adenosine (50 mcg/ kg/min) Consider en route diversion.
D. Lutman, A. Petros / Early Human Development 84 (2008) 725–729
no recommendation in the UK Health and Safety Executive (UK HSE) list of approved workplace exposure limits [10]. A Chemical Hazard Alert Notice (CHAN) had been issued by the UK Health and Safety Executive (UK HSE) recommending a Time Weighted Average (8 h TWA) exposure of 1 ppm for both after animal data suggested that the development of emphysema was a risk. However all CHANs have been suspended since December 2006. Since 1989 UK HSE has recommended Occupational Exposure Standards of 25 ppm (8 h TWA) with short term exposure of 35 ppm for nitric oxide and 3 ppm (8 h TWA) with short term exposure of 5 ppm for nitrogen dioxide.
729
cabin volume in use at CATS is the Augusta Westland 109E helicopter and the highest concentration of iNO available is 400 ppm. Assuming complete mixing and no exchange of air within this vehicle a complete discharge of a full 307 l INOmax cylinder would result in a concentration of 31 ppm iNO. Guidelines used by CATS for using iNO on airplanes and ambulances are shown in Table 2. One of the advantages of helicopters in this circumstance is that the airspeed can quickly be reduced to allow a window or door to be opened to facilitate ventilation, a procedure that should be established with the aircraft operator in advance. 9. Conclusion
7. Transport regulations 7.1. General regulations for road transport According to the United Nations Committee of Experts on the Transport of Dangerous Goods number: 1956, ‘INOmax’ is a dangerous goods class: 2.2. Proper shipping name is: Compressed gas, N.O.S. (Nitric oxide, Nitrogen). The UK Hazchem code is: 2T. Road ambulances should display a compressed gas sticker but are exempt from the Dangerous Goods regulations for INOmax when used for the medical treatment. [11] 7.2. Regulations for civil fixed wing air transport Nitric oxide is designated as UN number: 1956 and is considered as Dangerous goods, ICAO/IATA class: 2.2. Its correct shipping name designation is: Compressed gas, N.O.S. (Nitric oxide, Nitrogen). At present for UK registered aircraft or non-UK aircraft operating in UK airspace it is a legal requirement for the aircraft operator to comply with JAR-OPS 1 Subpart R [12]. From July 16th 2008 it will be a legal requirement for the aircraft operator to comply with OPS 1 (EU OPS 1). The European Aviation Safety Agency (EASA) (granted regulatory ability 8/04/2008) will take over regulation by 2012 but the requirements have yet to be agreed. Under JAR-OPS 1 Subpart R 1.1160 INOmax is exempt from the Technical Instructions for the Safe Transport of Dangerous Goods by Air [ICAO Doc 9284-AN/905] ‘with the approval of the operator to provide, during flight, medical aid to a patient’ provided that the cylinder is specially constructed for the purpose. This exemption covers a positioning flight as well. 7.3. Regulations for civil helicopter air transport At present for UK registered aircraft or non-UK aircraft operating in UK airspace it is a legal requirement for the aircraft operator to comply with JAR-OPS 3 Subpart R. The European Aviation Safety Agency (EASA) (granted regulatory ability 8/04/2008) will take over regulation by 2012 but the requirements have yet to be agreed. The exemption for fixed wing air ambulances applies to helicopters [JAROPS 3.1160]. 7.4. Regulations for military air transport Military air transport of nitric oxide is regulated by the Air Navigation Order but under article 95 they may operate under Military Aviation Policy Regulations and Directives (Joint Service Publications 550–556 and others) [13]. The requirements for air ambulance purposes can be expected to match those of civilian operations. 8. Guidelines for carrying gases on airplanes and ambulances Kinsella et al. have explored many of the safety aspects of delivering iNO within the confines of various vehicles [14]. The article examines the likely staff exposure to iNO assuming a complete cylinder discharge during a transport in various vehicles. The smallest
▪ iNO can be safely delivered on transport in a variety of ways. ▪ The method employed depends on many factors including, patient group, modes of transport and local regulations. ▪ Training and practical experience are invaluable regardless of the system employed. ▪ Very few patients will respond only to iNO levels greater than 20 ppm. ▪ The 2 l size ‘INOmax’ cylinder will deliver 20 ppm nitric oxide for almost 10 h at approximately 10 l per minute. ▪ Alarms should provide visual and auditory indications of high or low iNO measurements. ▪ Process guidelines need to be developed to cover normal operation of the delivery systems as well the actions to take in case of a leak or other failure. References [1] The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med 1997;336:597–604. [2] Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2006 Oct;18(4) CD000399. [3] Bizzarro M, Gross I. Inhaled nitric oxide for the postoperative management of pulmonary hypertension in infants and children with congenital heart disease. Cochrane Database Syst Rev 2005 Oct;19(4) CD005055. [4] Lowe CG, Trautwein JG. Inhaled nitric oxide therapy during the transport of neonates with persistent pulmonary hypertension or severe hypoxic respiratory failure. Eur J Pediatr 2007;166:1025–31. [5] Westrope C, Roberts N, Nichani S, Hunt C, Peek GJ, Firmin R. Experience with mobile inhaled nitric oxide during transport of neonates and children with respiratory insufficiency to an extracorporeal membrane oxygenation center. Pediatr Crit Care Med 2004;5:542–6. [6] Jesse NM, Drury L, Weiss MD. Transporting neonates with nitric oxide: the 5-year ShandsCair experience. Air Med J 2004;23:17–9. [7] Kinsella JP, Schmidt JM, Griebel J, Abman SH. Inhaled nitric oxide treatment for stabilization and emergency medical transport of critically ill newborns and infants. Pediatrics 1995;95:773–6. [8] Dhillon JS, Kronick JB, Singh NC, Johnson CC. A portable nitric oxide scavenging system designed for use on neonatal transport. Crit Care Med 1996;24:1068–71. [9] James MF, White JF. Anesthetic considerations at moderate altitude. Anesth Analg 1984;63:1097–105. [10] UK Health and Safety Executive (UK HSE) Table 1 List of approved workplace exposure limits. http://www.hse.gov.uk/coshh/table1.pdf (accessed 13/05/2008). [11] INOmax Material safety data sheet, INO Therapeutics, 1060 Allendale Dr. Port Allen, LA 70767, United States of America. [12] Joint Aviation Requirements, Amendment 11, Joint Aviation Authorities Committee, Global Engineering Documents, 15 Inverness Way, Englewood, Colorado 80112, United States of America. [13] Statutory Instrument 2005.No. 1970 The Air Navigation Order 2005, ISBN 0110732537, Crown Copyright July 2005. [14] Kinsella JP, Griebel J, Schmidt JM, Abman SH. Use of inhaled nitric oxide during interhospital transport of newborns with hypoxemic respiratory failure. Pediatrics 2002;109:158–61.
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Best practice guideline
Inhaled nitric oxide in neonatal and paediatric transport Daniel Lutman, Andy Petros ⁎ Children's Acute Transport Service, 44B Bedford Row, London WC1R 4LL, UK
a r t i c l e Keywords: Flight Transport Paediatric Neonatal Inhaled nitric oxide
i n f o
a b s t r a c t Since the first reports of the use of inhaled nitric oxide in the early 1990s its applications have been refined to a number of specific conditions. Pre-term and term neonates benefit significantly in the improvement of oxygenation in conditions such as hypoxic respiratory failure and persistent pulmonary hypertension of the neonate and the reduction in referral rates to extra corporeal membrane oxygenation. Many neonatal units still do not have the ability to administer inhaled nitric oxide though an increasing number of neonatal units have acquired the capability to deliver inhaled nitric oxide in recent years with commercially available delivering devices. In either case if the neonate needs transfer for further management or extra corporeal membrane oxygenation the journey can be improved if inhaled nitric oxide is introduced during transport or could deteriorate if inhaled nitric oxide was discontinued during transport. Delivery of inhaled nitric oxide during transport can be technically challenging and the consequences of increased or interrupted delivery can be dangerous. The different modes of transport either by road or air can influence the method of delivery. We describe our method of delivering inhaled nitric oxide during the retrievals we undertake and how this changes depending upon the type of journey performed. We also suggest guidelines for its use during transport and outline the precautions we take to ensure safety of patient and carers during transport. © 2008 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How is nitric oxide presented? . . . . . . . . . . . . . . . . . . . . . . How is nitric oxide measured? . . . . . . . . . . . . . . . . . . . . . . How is nitric oxide delivered? . . . . . . . . . . . . . . . . . . . . . . 4.1. Continuous flow via a calibrated rotameter . . . . . . . . . . . . . 4.2. AeroNOx device (Pulmonox Medical Inc, Tofield, Alberta, Canada) . . 4.3. INOvent device (Datex-Ohmeda, Madison, WI) . . . . . . . . . . . 4.4. INOmax DS transport system (INO therapeutics 7601-B Murphy Drive, 5. Mode of transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Ambulance . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Fixed wing and helicopter . . . . . . . . . . . . . . . . . . . . . 6. Health and safety exposure limits . . . . . . . . . . . . . . . . . . . . . 7. Transport regulations . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. General regulations for road transport . . . . . . . . . . . . . . . 7.2. Regulations for civil fixed wing air transport . . . . . . . . . . . . 7.3. Regulations for civil helicopter air transport . . . . . . . . . . . . . 7.4. Regulations for military air transport . . . . . . . . . . . . . . . . 8. Guidelines for carrying gases on airplanes and ambulances . . . . . . . . . 9. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
⁎ Corresponding author. E-mail addresses: [email protected] (D. Lutman), [email protected] (A. Petros). 0378-3782/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2008.08.003
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1. Introduction There are a number of specific indications for the use of inhaled nitric oxide in neonates and children. These include persistent pulmonary hypertension of the newborn (PPHN) where its use significantly reduces the need for extracorporeal membrane oxygenation (ECMO) [1]. It is also used in hypoxic respiratory failure despite lack of good evidence for its success [2] and conditions where pulmonary hypertension prevails [3]. Inhaled nitric oxide (iNO) is often started prior to transport as part of the initial resuscitation and stabilisation of a critically ill patient. Once initiated it is inadvisable to interrupt delivery as this could cause a serious deterioration during the transport [4,5]. Hence, systems have to be developed to deliver iNO during transport either land based or air borne [6,7]. At the Children's Acute Transport Service (CATS) we offer a retrieval service for the children in North Thames, London, UK. We retrieve about 1000 children per year and have done so since 2001. There are on average 100 occasions/yr when inhaled nitric oxide has to be used to help in the transport of critically ill neonates and children both on land and in the air. The different modes of transport require different techniques and safety precautions. 2. How is nitric oxide presented? In the UK ‘INO therapeutics UK’ (a subsidiary of BOC) hold the patent for the only formulation of nitric oxide licensed for human use under the non-generic name ‘INOmax’. The only formulation available to the authors within the UK is that of 400 ppm mol/mol nitric oxide in nitrogen and all further discussions will assume that this formulation is the source of the gas. A variety of other cylinder sizes and formulations are available in other countries and the reader is advised that some of the operational practices discussed here may not be appropriate for some cylinder sizes and formulations. The 400 ppm mol/mol formulation is available within the UK in two sizes of aluminium cylinder 2 l and 10 l. Both cylinder types are filled at a pressure of 155 bar absolute which for a 2 l cylinder at 1 bar and 15 °C brings 307 l of gas and for a 10 l cylinder at 1 bar absolute and 15 °C brings 1535 l of gas. The cylinders are used with a regulator which reduces the cylinder pressure for use either with a rotameter or with the ‘INOvent ’delivery system. The cylinders may be safely
Fig. 2. Delivery system used to deliver nitric oxide during transport.
operated to an altitude of 10,000 ft (personal communication, Peter Rothery, General Manager UK, INO therapeutics UK, correct as of 7th April 2008). Our current understanding of nitric oxide suggests that there are very few patients who will respond only to iNO levels greater than 20 ppm [1] and the same study did not identify a benefit to those individuals regardless of response. The risk of methaemaglobinaemia, nitrogen dioxide toxicity and the reduction of fractional inspired oxygen concentration by dilution with the carrier gas nitrogen are all increased above 20 ppm. Doses above 20 ppm are not used by the authors on transport. 3. How is nitric oxide measured? iNO is delivered and measured in parts per million. It is most accurately measured using a chemiluminescent technique. However, this is impractical on transport and small chemical sensors are used (Micro Medical Ltd, Kent, UK) (Fig. 1). Nitric oxide reacts with oxygen within the ventilator circuit to produce nitrogen dioxide. Nitrogen dioxide can cause lung damage at
Table 1 Flow rates for iNO (ml/min) to achieve approximate ppms (iNO monitor must be used) (our thanks to Lisa Martin, Respiratory Therapist, for this data)
Fig. 1. Commercially available Microgas iNO analyser used to measure nitric oxide delivered in ppm.
5 l/min 6 l/min 7 l/min 8 l/min 9 l/min 10 l/min 11 l/min 12 l/min 13 l/min 14 l/min
5 ppm
10 ppm
15 ppm
20 ppm
63 75 88 100 113 125 138 150 163 175
125 150 175 200 225 250 275 300 325 350
188 225 263 300 338 375 413 450 488 525
250 300 350 400 450 500 550 600 650 700
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Fig. 3. INOvent delivery system permanently installed in the CATS ambulance.
lower concentrations than nitric oxide and the concentration within breathing systems needs to be b0.5 ppm. Nitrogen dioxide should be continuously measured. High levels are frequently encountered when purging the delivery systems before use. The delivery systems should always be completely purged before patient connection.
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Nitric oxide gas consumption is easily set once the flow rate is established. For planning purposes Table 1 is used as an estimate. In common with all transport gases we recommend that even if a suitable quantity of gas can be carried in a single cylinder, at least two cylinders complete with regulators are carried. The 2 l size ‘INOmax’ cylinder will deliver 20 ppm nitric oxide for almost 10 h if the flow (ventilator or bagging circuit) is approximately 10 l per minute. Within our transport service, therefore, the calculation can usually be simplified to two cylinder-regulators. Clearly such a simple, inexpensive and lightweight system is robust enough to survive the most challenging transport environments. If a single component malfunctions it can be replaced. The delivery of nitric oxide does not depend on electrical power and the analysers require batteries infrequently. The rotameter can be used at altitude (see mode of transport). However there are many disadvantages to such a system as the primary nitric oxide delivery system. The main problem is that the flow of nitric oxide is continuous, whereas the gas flow from the ventilator may be intermittent. This will result in alternating high and low concentrations of nitric oxide in the gas as it travels down the inspiratory limb. The significance of this effect is unknown. The other main issue is that more monitoring and vigilance is required from the transport team; the rotameter valve can be delicate and difficult to adjust and more significantly that the flow can be changed inadvertently if the housing of the rotameter knob is not shielded from objects moving around it. 4.2. AeroNOx device (Pulmonox Medical Inc, Tofield, Alberta, Canada) This system is not available within the UK and has not been evaluated by the authors. Its low weight, portability and relative simplicity might make it particularly suited to the transport environment.
4. How is nitric oxide delivered? 4.3. INOvent device (Datex-Ohmeda, Madison, WI) iNO can be delivered using a number of different systems: 1) As a continuous flow via a calibrated rotameter 2) via the AeroNOx device (Pulmonox Medical Inc, Tofield, Alberta, Canada) 3) via the INOvent device (Datex-Ohmeda, Madison,WI) 4) via the INOmax DS transport system (INO therapeutics 7601-B Murphy Drive, WI 53562). 4.1. Continuous flow via a calibrated rotameter This is the simplest delivery system (Fig. 2) and can be used as either the primary or backup delivery system. Nitric oxide gas passes from the cylinder through the regulator and then to the rotameter. The assembly is first purged to clear nitrogen dioxide and an appropriate flow is selected (Table 1). Nitric oxide is added into the inspiratory limb of the breathing system. As ‘INOmax’ is a formulation containing nitric oxide and nitrogen, it is potentially asphyxiant and an oxygen meter should be used to monitor the fractional inspired oxygen concentration of the resultant blend of gas. The oxygen meter should be set so that an undesirable reduction of inspired fractional oxygen concentration will result in an audible and visible alarm. Nitric oxide concentration is measured at the patient end of the circuit. At CATS originally both nitric oxide and nitrogen dioxide were measured. After several years of experience with the system we chose to compromise on nitrogen dioxide measurement in favour of a simpler more robust nitric oxide analyser. In normal operations we had never registered a significant nitrogen dioxide level either within the circuit or environmentally. Again alarms are set which provide a visual and auditory indication of high or low iNO measurements. The circuit is run with a test lung for several minutes to allow fine tuning of the nitric oxide flow and stabilisation of the nitric oxide analyser. The nitric cylinder and rotameter are mounted on a carry handle to improve portability and to allow the system to be attached to the transport trolley regardless of the mode of transport.
The most sophisticated method of delivery is via the ‘INOvent’ delivery system. This computerised system blends nitric oxide automatically using a flow sensor and provides a continuous measurement of inspired oxygen concentration, nitrogen dioxide concentration and nitric oxide concentration. The main advantage of this system is the tight control of iNO concentration over a wide variety of continuous or intermittent gas flows. This is the only system that will deliver a constant iNO concentration during intermittent flow ventilation. The system can be moved easily between different types of ventilator (conventional or high frequency) without adjustment. Additional advantages include a variety of gas concentrations
Fig. 4. Environmental alarms used to detect nitric oxide.
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and cylinder pressure alarms. In the transport environment however the complexity of this system does lead to some disadvantages. A major computer or electrical system failure (that does not respond to a ‘reboot’) is unlikely to be resolvable on transport. Like all computerised systems it is vulnerable to extremes of temperature, humidity, electrical interference and vibration. The internal batteries allow for an interruption of electrical power supplies but because they are rarely used and frequently charged tend to exhibit ‘memory’. This can dramatically shorten the interval over which the unit can operate when disconnected from the mains. Additionally the cylinder pressures and consumption of nitric oxide gas is not displayed on the unit whilst in operation. This would be of less significance within a paediatric intensive care unit where two large (10 l) nitric oxide cylinders are employed for each ‘INOvent’ bringing a maximum total of 3070 l of gas. On transport, where portability and weight are important safety factors, the small (2 l) nitric oxide cylinders are used. Inevitably more attention must be paid to gas planning and gas consumption and appropriate safety margins drawn up. Nitric oxide consumption is often less when using the INOvent than when using the simple rotameter delivery system because it changes with flow. The main risk is to use a ventilator mode that utilises a greater flow than expected, which will use a correspondingly larger quantity of nitric oxide than expected. The ‘INOvent’ system is arguably best used in a permanent ambulance or trolley fitting with integral power and gas supplies (Fig. 3). It is our practice to pair it with a simple rotameter delivery system to provide operational redundancy. Spare ‘o’ rings should be carried for each regulator (these can be seen in the illustrations taped to the systems). 4.4. INOmax DS transport system (INO therapeutics 7601-B Murphy Drive, WI 53562) This system has been recently launched within the United States specifically for use in transport. The design is of low weight, high portability and has the ability to maintain iNO concentrations during intermittent flow ventilation. The unit has been validated for use with several transport ventilators. This unit has not been evaluated within the UK at present.
Many ambulances have transformers that can deliver power supplies suitable for electronic iNO delivery systems. The systems themselves can often be permanently mounted within the vehicle or on the patient stretcher. Nitric oxide gas supplies are more easily stored and piped within dedicated vehicles. A backup iNO delivery system is desirable and at CATS we use a backup rotameter system until the patient is loaded into our ambulance when the permanent ‘INOvent’ system takes over. This process ensures that the teams remain entirely familiar with both systems. 5.2. Fixed wing and helicopter CATS undertakes between 50 and 70 flight transports each year. These longer transports are often for specialist services such as for ECMO assessment and iNO is frequently employed. Although in principal it would be desirable to conduct all iNO delivery using an electronic system the current lack of dedicated air ambulances for inter facility transport within the UK makes this uneconomic. We currently favour the simplicity and low weight of the rotameter system for iNO delivery despite the disadvantages discussed above. The system and its spare cylinder are secured to the patient stretcher whilst the vehicle is in motion. Rotameters estimate volume by measuring a pressure differential, accuracy is therefore affected by changes in barometric pressure. The rotameters at CATS (series 1100 Mobrey Measurements Ltd, UK) have a relatively high pressure input so that the pin valve has to be placed before the rotameter tube. This means that the rotameter tube will be at ambient pressure. As the cabin altitude decreases the density of the gas in the rotameter falls causing the rotameter to under read. The effect is more noticeable at high gas flows and high cabin altitudes and will vary according to the individual rotameter (personal communication, Rob Broomhead, Flotech Solutions Ltd, Stockport UK). In practice the flows set at sea level can continue without adjustment [9]. iNO concentration should be carefully monitored using the analyser when changing the iNO concentration and if iNO therapy is initiated whilst at altitude. 6. Health and safety exposure limits
5. Mode of transport In all modes of transport spare regulator ‘o’ rings should be carried for each regulator. Partial or complete failure of the ‘o’ ring occurs very occasionally and whenever the regulators are changed this component should be examined for wear. An insidious leak may be the most difficult to spot in practice and in all modes of transport cylinder pressures should be checked intermittently and environmental monitoring for elevated nitric oxide levels should be considered (Fig. 4). Process guidelines need to be developed to cover normal operation of the delivery systems as well the actions to take in case of a leak or other failure (see Guidelines for carrying gases on airplanes and ambulances). Scavenging apparatus is available for iNO but in normal operation at CATS it is difficult to detect any environmental nitric oxide or nitrogen dioxide in any of our vehicles [8]. 5.1. Ambulance Most inter facility transports are by road and this is the most frequent mode of transport in which iNO is delivered. Although many transport services use flight transport for critically ill patients undergoing long journeys, a road journey of between 2 and 3 h is not uncommon. Many helicopter and fixed wing transports will include a road transport element. Accidents occur most frequently by road and it is important that the delivery system is properly secured within the vehicle. These factors tend to result in the use of electronic delivery systems.
There is a current review of the UK Workplace Exposure Limits of nitrogen monoxide (nitric oxide) and nitrogen dioxide and so there is
Table 2 CATS guidelines for carrying gases on airplanes and ambulances Normal flight operations—standard precautions ▪Ensure equipment is secured appropriately. ▪Ensure equipment is fully functional in the transport environment (not compromised by altitude or vibration). ▪Ensure alarms are both visual and auditory. ▪Ensure personnel are trained and competent to use the equipment. Normal flight operations—nitric oxide precautions ▪Ensure fractional inspired oxygen concentration is monitored and alarms set. ▪Ensure appropriate iNO monitoring is in place and alarms set. ▪Perform purging procedure to ensure minimum nitrogen dioxide exposure is followed. ▪Ensure appropriate environmental monitoring is considered. ▪Ensure patient responses to nitric oxide are documented. ▪Perform 15 fifteen min checks of iNO concentration, nitric oxide flow, and cylinder pressure. Abnormal flight operations—nitric oxide leak Inform team/pilots immediately. ▪Switch off cylinder—if possible depending on child's condition. ▪Increase FiO2—if possible and not already maximum. ▪Check that vehicle cabin air exchange is optimal. ▪Consider alternate intravenous pulmonary vasodilators e.g. iv adenosine (50 mcg/ kg/min) Consider en route diversion.
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no recommendation in the UK Health and Safety Executive (UK HSE) list of approved workplace exposure limits [10]. A Chemical Hazard Alert Notice (CHAN) had been issued by the UK Health and Safety Executive (UK HSE) recommending a Time Weighted Average (8 h TWA) exposure of 1 ppm for both after animal data suggested that the development of emphysema was a risk. However all CHANs have been suspended since December 2006. Since 1989 UK HSE has recommended Occupational Exposure Standards of 25 ppm (8 h TWA) with short term exposure of 35 ppm for nitric oxide and 3 ppm (8 h TWA) with short term exposure of 5 ppm for nitrogen dioxide.
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cabin volume in use at CATS is the Augusta Westland 109E helicopter and the highest concentration of iNO available is 400 ppm. Assuming complete mixing and no exchange of air within this vehicle a complete discharge of a full 307 l INOmax cylinder would result in a concentration of 31 ppm iNO. Guidelines used by CATS for using iNO on airplanes and ambulances are shown in Table 2. One of the advantages of helicopters in this circumstance is that the airspeed can quickly be reduced to allow a window or door to be opened to facilitate ventilation, a procedure that should be established with the aircraft operator in advance. 9. Conclusion
7. Transport regulations 7.1. General regulations for road transport According to the United Nations Committee of Experts on the Transport of Dangerous Goods number: 1956, ‘INOmax’ is a dangerous goods class: 2.2. Proper shipping name is: Compressed gas, N.O.S. (Nitric oxide, Nitrogen). The UK Hazchem code is: 2T. Road ambulances should display a compressed gas sticker but are exempt from the Dangerous Goods regulations for INOmax when used for the medical treatment. [11] 7.2. Regulations for civil fixed wing air transport Nitric oxide is designated as UN number: 1956 and is considered as Dangerous goods, ICAO/IATA class: 2.2. Its correct shipping name designation is: Compressed gas, N.O.S. (Nitric oxide, Nitrogen). At present for UK registered aircraft or non-UK aircraft operating in UK airspace it is a legal requirement for the aircraft operator to comply with JAR-OPS 1 Subpart R [12]. From July 16th 2008 it will be a legal requirement for the aircraft operator to comply with OPS 1 (EU OPS 1). The European Aviation Safety Agency (EASA) (granted regulatory ability 8/04/2008) will take over regulation by 2012 but the requirements have yet to be agreed. Under JAR-OPS 1 Subpart R 1.1160 INOmax is exempt from the Technical Instructions for the Safe Transport of Dangerous Goods by Air [ICAO Doc 9284-AN/905] ‘with the approval of the operator to provide, during flight, medical aid to a patient’ provided that the cylinder is specially constructed for the purpose. This exemption covers a positioning flight as well. 7.3. Regulations for civil helicopter air transport At present for UK registered aircraft or non-UK aircraft operating in UK airspace it is a legal requirement for the aircraft operator to comply with JAR-OPS 3 Subpart R. The European Aviation Safety Agency (EASA) (granted regulatory ability 8/04/2008) will take over regulation by 2012 but the requirements have yet to be agreed. The exemption for fixed wing air ambulances applies to helicopters [JAROPS 3.1160]. 7.4. Regulations for military air transport Military air transport of nitric oxide is regulated by the Air Navigation Order but under article 95 they may operate under Military Aviation Policy Regulations and Directives (Joint Service Publications 550–556 and others) [13]. The requirements for air ambulance purposes can be expected to match those of civilian operations. 8. Guidelines for carrying gases on airplanes and ambulances Kinsella et al. have explored many of the safety aspects of delivering iNO within the confines of various vehicles [14]. The article examines the likely staff exposure to iNO assuming a complete cylinder discharge during a transport in various vehicles. The smallest
▪ iNO can be safely delivered on transport in a variety of ways. ▪ The method employed depends on many factors including, patient group, modes of transport and local regulations. ▪ Training and practical experience are invaluable regardless of the system employed. ▪ Very few patients will respond only to iNO levels greater than 20 ppm. ▪ The 2 l size ‘INOmax’ cylinder will deliver 20 ppm nitric oxide for almost 10 h at approximately 10 l per minute. ▪ Alarms should provide visual and auditory indications of high or low iNO measurements. ▪ Process guidelines need to be developed to cover normal operation of the delivery systems as well the actions to take in case of a leak or other failure. References [1] The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med 1997;336:597–604. [2] Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2006 Oct;18(4) CD000399. [3] Bizzarro M, Gross I. Inhaled nitric oxide for the postoperative management of pulmonary hypertension in infants and children with congenital heart disease. Cochrane Database Syst Rev 2005 Oct;19(4) CD005055. [4] Lowe CG, Trautwein JG. Inhaled nitric oxide therapy during the transport of neonates with persistent pulmonary hypertension or severe hypoxic respiratory failure. Eur J Pediatr 2007;166:1025–31. [5] Westrope C, Roberts N, Nichani S, Hunt C, Peek GJ, Firmin R. Experience with mobile inhaled nitric oxide during transport of neonates and children with respiratory insufficiency to an extracorporeal membrane oxygenation center. Pediatr Crit Care Med 2004;5:542–6. [6] Jesse NM, Drury L, Weiss MD. Transporting neonates with nitric oxide: the 5-year ShandsCair experience. Air Med J 2004;23:17–9. [7] Kinsella JP, Schmidt JM, Griebel J, Abman SH. Inhaled nitric oxide treatment for stabilization and emergency medical transport of critically ill newborns and infants. Pediatrics 1995;95:773–6. [8] Dhillon JS, Kronick JB, Singh NC, Johnson CC. A portable nitric oxide scavenging system designed for use on neonatal transport. Crit Care Med 1996;24:1068–71. [9] James MF, White JF. Anesthetic considerations at moderate altitude. Anesth Analg 1984;63:1097–105. [10] UK Health and Safety Executive (UK HSE) Table 1 List of approved workplace exposure limits. http://www.hse.gov.uk/coshh/table1.pdf (accessed 13/05/2008). [11] INOmax Material safety data sheet, INO Therapeutics, 1060 Allendale Dr. Port Allen, LA 70767, United States of America. [12] Joint Aviation Requirements, Amendment 11, Joint Aviation Authorities Committee, Global Engineering Documents, 15 Inverness Way, Englewood, Colorado 80112, United States of America. [13] Statutory Instrument 2005.No. 1970 The Air Navigation Order 2005, ISBN 0110732537, Crown Copyright July 2005. [14] Kinsella JP, Griebel J, Schmidt JM, Abman SH. Use of inhaled nitric oxide during interhospital transport of newborns with hypoxemic respiratory failure. Pediatrics 2002;109:158–61.