Nitric Oxide Therapy Part A 1. Nitric Oxide Overview -Nitric Oxide Chemistry -Nitric Oxide and the Lung (Endogenous) -Nitric Oxide (Exogenous) -Metabolism of Nitric Oxide in the Lung -Dosing and Weaning of Nitric Oxide -References for Section 1

2. Nitric Oxide Delivery (brief theory of operation and features) 3. Device Overview -Titration Delivery System -Calculations for NO delivery -Sampling -Sensors -Analysis -Safety Shut Off -Front Panel -Gas Connections -Battery -Calibration -Follow “flush procedure”

4. Nitric Oxide delivery and set up -Before you leave -When you arrive

5. What disease processes do best or worst with Nitric Oxide 6. Clinical things to look for and things you need to be aware of during flight in regards to that particular device or therapy 7. Why is this device so useful on transport and how has using this device changed things for your transport team 8. Discuss how the device can be mounted or positioned during transport (configurations) 9. Clinical tips regarding use of this device 10. Special considerations when integrating this device into your transport program

Nitric Oxide and Transport 1. Nitric Oxide Overview Nitric Oxide Chemistry Nitric oxide (NO) has a short half life and is considered a free radical which makes it highly volatile and reactive. NO reacts readily with metals and salts (e.g. iron, copper). This simple molecule is composed of 1 atom of oxygen and 1 atom of nitrogen. When nitric oxide combines with oxygen, nitrogen dioxide (NO2) is created.

2NO + O2 = NO2 This reaction depends on the NO and O2 concentration as well as contact time (dwell time). NO2 is thought to be a toxic gas that can cause damage to the respiratory system. This damage depends on the concentration inhaled and the exposure time. During inhaled NO therapy, it is important to keep NO2 levels as low as possible. Most clinicians try to keep the NO2 level at less than 2 ppm. The OSHA standard for inhaled NO is 25 ppm, and for NO2, 5 ppm personal exposure limit (PEL) for an 8-hour time-weighted average (TWA).

Nitric Oxide and the Lung (Endogenous) Our bodies produce nitric oxide endogenously. In the lung, NO controls the vessels that surround the alveoli. When nitric oxide is increased, the vessels dilate. When vasodilation occurs, the inside of a vessel gets larger and more blood flows through the vessel. The body is selfregulating; it will try to keep the ventilation and the blood flow (perfusion) equal in the lung. This is ventilation / perfusion matching.

Nitric Oxide (Exogenous) In low concentrations, nitric oxide is given via inhalation (exogenously). A positive response may be indicated by an improvement in clinical markers such as SPO2, PaO2, or by a reduction in pulmonary vascular resistance (PVR). When inhaled nitric oxide is delivered to the patient, the nitric oxide travels down the airways and goes only to the areas of the lung where ventilation or gas exchange is taking place. It diffuses rapidly into the smooth muscle of the blood vessel where it causes vasodilation. After the NO passes into the capillary blood stream it is bound by hemoglobin in red blood cells. Once it is bound by hemoglobin, creating methemoglobin, it can no longer exert its vasodilator properties. At clinically therapeutic applied NO levels, the blood that leaves the lungs cannot exert its vasodilator effects on the rest of the vessels in the body. Inhaled nitric oxide thus has minimal systemic effects and is highly selective. The great thing about nitric oxide is that it goes only to the areas of the lung that are being ventilated and causes changes in the local pulmonary blood flow. This makes nitric oxide unique as a specific pulmonary vascular agent. It exerts its desired action, binds to the hemoglobin in the vessels of the lung, and does not exert its vasodilator effects on the systemic circulation.

Metabolism of Nitric Oxide in the Lung Nitric oxide is rapidly metabolized. When NO combines with hemoglobin, NO can no longer exert its vasodilator effects and methemoglobin is created. O2 carrying capacity can be decreased with high levels of methemoglobin. When higher concentrations of nitric oxide are used, more methemoglobin is created. When administering NO to patients the methemoglobin levels must be measured.

Dosing and Weaning of Nitric Oxide Both the NO and the NO2 levels that are being delivered to the patient must be continuously analyzed. High concentrations of NO may be toxic to the tissues. NO2 can possibly cause pulmonary edema, acid pneumonitis, and death. A majority of clinicians appear to be using lowdose nitric oxide. When the NO is mixed in the patient’s breathing circuit, the FiO2 (fraction of inspired oxygen) delivered to the patient will be lower. It is important to also monitor inspired oxygen levels at a point distal to the point of NO delivery. Clinical monitoring must also be performed to evaluate the patient’s progress on nitric oxide therapy. Most clinicians wean nitric oxide slowly and have a set protocol for weaning. The rate and step-size of weaning that can be accomplished varies from patient to patient. Ability to wean nitric oxide is usually evaluated by reviewing a patient’s oxygen saturation, FiO2, pulmonary artery pressures (PAP), and PEEP levels. Some patients may exhibit a significant increase in pulmonary artery pressure following a sudden discontinuance or a large decrease of nitric oxide. It is important to monitor the patient closely while weaning the concentration of NO.

References for Section 1 (above)

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Roberts JD Jr, Fineman JR, Morin RC 3 , Shaul PW, Rimar S, Schreiber MD, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med 1997;336(9):605-610. Davidson D, Barefield ED, Kattwinkel J, Dudell G, Damask M, Straube R, et al. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, doublemasked, placebo-controlled dose-response, multi-center study. The I-NO/PPHN Study Group. Pediatrics 1998:101(3 Pt 1): 325-334. Kinsella JP, Truog WE, Walsh WF, Goldberg RN, Bancalari E, Mayock DE, et al. Randomized, multicenter trial of inhaled nitric oxide and high-frequency ventilation in severe, persistent pulmonary hypertension of the newborn. J Pediatr 1997;131 (1 Pt 1:55-62. Rossaint R, Gerlach H, Schmidt-Ruhnke H, Pappert D, Lewandowski K, Steudel W, Falke K. Efficacy of inhaled nitric oxide in patients with severe ARDS. Chest 1995; 107(4):1107-1115. Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled nitric oxide in ARDS Study Group. Crit Care Med 1998; 26(1):15-23. Micheal JR, Barton RG, Saffle JR, Mone M, Markewitz BA, Hillier K, et al. Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS. Am J. Respir Crit Care Med 1998;157(5 Pt 1):1372-1380. Troncy E, Collet JP, Shapiro S. Guimond JG, Blair L, Ducruet T, et al. Inhaled nitric oxide in acute respiratory distress syndrome: a pilot randomized controlled study. Am J Respir Crit Care Med 1998;157(5 Pt 1):1483-1488. Lundin S, Mang, H, Smithies M, Stenquist O, Frostell C, for the European Study Group of Inhaled Nitric Oxide. Inhalation of nitric oxide in acute lung injury : Preliminary results of a European multi-center study (abstract). Int Care Med 1997;23 (Suppl 1):S2. NIOSH recommendations for occupational safety and health standards 1988. MMWR Morb Mort Wkly Rep 1988;37 (Suppl 7):1-29.

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Inhaled nitric oxide: delivery systems and

Hess DR. Adverse effects of toxicity of inhaled nitric oxide. Resp Care 1999;44:315-329. Bigatello LM. Strategies to enhance the efficacy of nitric oxide therapy. Resp Care 1999;44:331-337. Bigatello LM, Hurford WE, Kacmerek RM, Roberts JD, Zapol WM. Prolonged inhalation of low concentrations of nitric oxide in patients with severe adult respiratory distress syndrome. Anesthesiology 1994;80(4):761-770. Miller Ol, Pang SF, Keech A, Celemajer DS. Rebound pulmonary hypertension on withdrawal from inhaled nitric oxide. Lancet 1994:346(8966):51-52. Buga GM, Griscavage JM, Rogers NE, Ignarro LJ. Negative feedback regulation of endothelial cell function by nitric oxide. Circ Res 1993;73: 808-812. Gerlach H, Pappert D, Lewandowski K, Rossaint R, Falke KJ. Long term inhalation with evaluated low doses of nitric oxide for selective improvement of oxygenation in patients with adult respiratory distress syndrome. Inten Care Med 1993; 19(8):443-449. Aranda M, Pearl R. The biology of nitric oxide. Resp Care 1999;44:156-166. Roberts J. Inhaled nitric oxide for hypoxemic respiratory failure of the newborn. Resp Care 1999;44;169-173. Gerlach M, Keh D, Gerlach H. Inhaled nitric oxide for acute respiratory distress. syndrome. Resp Care 1999;44:184-192. Bacha E. Perioperative use of inhaled nitric oxide for heart and lung transplantation. Resp Care 1999;44;205-209

2. Nitric Oxide Delivery (brief theory of operation and features) -The self-contained Nitric Oxide delivery system contains an NO, NO2 and O2 analyzer. -The Nitric Oxide Delivery Device allows you to provide uninterrupted delivery of therapeutic Inhaled Nitric Oxide at a variety of settings ( 0-80 ppm). Most Clinicians choose to start at a dose of 20 ppm or lower. -Once a patient is started on Nitric Oxide Therapy they cannot be discontinued abruptly. You must wean patients slowly, therefore you must have an NO device that allows you to transport patients. -The Nitric Oxide Delivery Device weighs around 10 pounds and has been tested in air and ground transport. -Battery life is 5 hours

3. Device Overview -nitric oxide delivery system and NO, NO2, and O2 analyzer -used during transport -Nitric Oxide Delivery Device weighs ~10 lb. -dimensions 10 x 12 x 5 in. (H x W x D)

Titration Delivery System -regulated to 50 psig by a CGA 626 NO regulator -delivered via SS high pressure quick connect hose -precision metering valve (controlled via front panel) regulates NO flow to patient circuit -NO gas flow is measured before delivery via a mass flow meter -mass flow meter range 0-2 Lpm in 10ml/min increments -use NO flow estimation formula to estimate where to set NO flow for desired NO concentration -a delivery line is used to delivery the NO into the patient circuit

Calculations for NO delivery -initial NO flow = vent flow (L/min) X desired [NO] ppm (L/min) source tank [NO] ppm

Sampling -continuous sampling at ~150 ml/min from breathing circuit -analysis occurs four times per second and updates screen every second -if sample line should become occluded, the sample line occlusion LED will illuminate, and the pump will shut off -place sample line 6-12 inches from the patient wye connection -the sample tubing removes water vapor only (via patented electrically charged membrane) -dry gas sample is then drawn through a 5 micron particulate filter into sensor housing where analysis takes place

Sensors -trouble free use for ~12 months -lifetime depends on concentrations being analyzed -normal lifetime ~1000 hours of continuous use when exposed to 100 ppm NO and 10 ppm NO2 -must have bias voltage all the time (battery must be charged) -unbiased sensors need up to 48 hours to fully bias (new sensors)

Analysis -measurement in ppm -NO and NO2 molecules diffuse across cell membrane -molecules react with electrolyte solution causing an electrical current between the anode and the cathode -current produced is proportional to NO or NO2 concentration

Alarms -adjustable alarm limits for NO and NO2 -audible and visual (1minute silence)

Safety Shut Off -system is activated and terminates NO flow when the NO dose analyzed is 5 ppm above that which has been set as the high NO alarm and 1 ppm above that set for the high NO2 alarm -The system will restore NO flow when the NO being measured drops below 5ppm above the high alarm and/or the NO2 being measured drops below 1ppm above the high alarm. -the flow of NO gas is also shut off when the NO value reaches 100 ppm and/or the NO2 value reaches 12 ppm. This is nonadjustable.

Front Panel -back-lit digital liquid crystal display -zero NO and NO2 (will read DONE when zero is complete) -power ON/OFF -HI/LOW alarm settings -alarm silence (one minute) -NO/NO2 calibration pots -oxygen analyzer -O2 calibration pot -NO flow meter (mass flow meter 0-2 LPM in 10 ml/min increments -NO flow control (precision metering valve) -check sample line LED

Gas Connections -quick connect gas inlet -sample gas inlet -delivery gas outlet

Battery -rechargeable 6 volt sealed lead acid battery mounted inside analyzer -a fully charged battery will last ~5 hours -expected battery life 1 year -amount of charge is indicated by the letter “B” -there are six levels of charge indicated by how much of the “B” is filled in -“LOW BATTERY” battery no longer carries enough charge to reliably operate the electronics (message will remain on screen for a few minutes). If unit is not connected to the power supply the messages “CONNECT CHARGER” , “DATA INVALID” and “NITRIC OFF” will appear until the display fades out due to lack of power. Nitric oxide is no longer being delivered. -12 volt universal power supply allows internal charging circuit to recharge the internal battery (~24 hours) (self regulating) -a fully discharged battery requires ~ 24 hours to fully recharge -plug in whenever possible

Calibration -zero NO and NO2 sensors daily and calibrate weekly -should only take two to four minutes

Nitric Oxide Delivery Device “flush procedure” -always follow the flush procedure before delivery of NO to the patient -never turn on the NO delivery gas without first turning on the ventilator flow -hook up the ventilator to a test lung (patient should be manually ventilated during this procedure and the ventilator parameters should be set to the patients pre-NO gas settings)

4. Nitric Oxide Delivery Device set up (before you leave / when you arrive) Before you leave -make sure you have enough NO gas for the trip (tank duration) -make sure your NO tanks are secured to the incubator -check to be sure that the unit has been plugged in and if the battery is fully charged -check to make sure that the device has been calibrated recently -perform a zero calibration -always take the battery charger with you -always take extra “NO Worries” and circuits -turn the device on before you leave and make sure it is functioning within its specifications -you should always take a “back-up” NO system in case your primary system fails

When you arrive -attach regulator to NO tank -attach braided stainless steel hose to regulator -purge system 5 times -attach other end of braided stainless steel hose to Unit -attach circuit to ventilator -attach delivery line to unit and to ventilator circuit

-attach sampling line to unit and to ventilator circuit -turn on ventilator to intended settings (use a cork or test lung) -perform flush procedure -perform calculation for NO delivery -set NO flow meter to desired flow (based on calculation) -be sure that the NO and NO2 readings are accurate and acceptable -set the NO and NO2 alarms -place patient on the ventilator Note: Changes to the ventilator flow will also change the nitric oxide concentrations. Be sure to be aware of your alarm setting before making changes to the ventilator flow or the NO concentration (safety systems may be activated).

5. What disease processes do best or worst with Nitric Oxide -used for primary or secondary pulmonary hypertension related to diseases such as CDH, MAS, Sepsis, or Extremely low birth weight infants

6. Clinical details to look for and be aware of during flight in regards to that particular device or therapy -battery life. -trouble shooting once you has received a low battery alarm you have 4 minutes until the device stops functioning. You should have an extra charger or should institute the INO Stat Bagger: (see below) -you should also have a system for bagging the patient include diagram on how to set-up an anesthesia bag for bagging with Nitric. -you should have back-up circuits and delivery/sample lines -equipment should be transport ready calibrated and charged. -weekly calibrations are your first indicator that cells need to be changed or maintenance is required, set up a program with documentation (proof) of calibration -if machine is left unplugged the electrochemical cells pull voltage from the batter until the battery goes dead -once the battery is dead the cells de-bias and take 24-48 hours to re-bias -make sure you have enough NO gas, NO can not be discontinued abruptly

7. Why is this device so useful on transport and how has using this device changed things for your transport team -portability, weighs approximately 10 lbs and easily secures to a transport incubator and can be used in the ground, rotor wing and fixed wing environment. Securing equipment is a must with safety regulations and CAMTS requirements -battery Life, fully charged will run 5 hours -allows you to easily deliver NO and monitor for NO2 and NO2 -has been tested with continuous flow ventilators only -more facilities are using Nitric Oxide in their units but do not have the capability to transfer to a higher level of care, really brings this proven life saving gas to the patient.

8. Discuss how the device can be mounted or positioned during transport (configurations)

9. Clinical tips regarding use of this device -always have it plugged in and charging -circuits are pre-made and in a bag for easy set-up -tanks are kept in the transport dept -charging is done by our RT department -must have a primary person responsible for calibration.

10. Special considerations when integrating this device into your transport program Concerns -potential regulator failure and sudden leakage of a small NO transport cylinder inside an enclosed space. -if small transport cylinder leaks what nitric oxide concentration will the patient, care givers, and flight crew be exposed to

Assumptions -pressurized aircraft (air only) have poor air exchange, therefore there is little fresh air to dilute the potentially toxic gas if a cylinder should leak.

Things to be aware of on transport -may need to be approved by your local FAA -have studies on hand that have proven that with a catastrophic tank failure it is still safe to carry the gas, thus is why we do not worry about environmental Nitric Oxide.

Special Considerations -review of studies for use in ambulance, and air.