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The use of nitric oxide therapy in the transport of newborns with persistent pulmonary hypertension
Pediatric Perspective
Benjamin J. Tung, RN, CEN, EMT-P
The Use of Nitric Oxide Therapy in the Transport of Newborns with Persistent Pulmonary Hypertension Persistent pulmonary hypertension of the newborn (PPHN), sometimes known as persistence of the fetal circulation, originally was reported in 1969 by Gersony,1 who described infants with persistent characteristics of fetal circulation in the absence of recognizable cardiac, pulmonary, hematologic, or central nervous system disease. In newborns with PPHN, the normal cardiorespiratory changes at birth do not occur. This lapse, in turn, leads to suprasystemic pulmonary artery pressures, resulting in a right to left shunting of blood through the patent ductus arteriosus, the foramen ovale, or both. Hypoxemia in the term newborn, out of proportion to the amount of physical lung injury, should be evaluated for PPHN. Diagnosis can be made using several methods, including echocardiography, pre- and postductal PaO2 measurements, and cardiac catheterization.1 Echocardiography can provide very specific information regarding the structural condition of the heart and shunting of blood flow. With color flow doppler imaging, the level and direction of shunting can be determined. Pre- and postductal PaO2 measurements can determine the degree of right to left shunting. Oxygenation levels are observed from preductal sites (right radial or right temporal arteries) and postductal sites (umbilical artery or posterior tibial artery). These samples must be drawn simultaneously. A preductal PaO2 of ≥ 20 mm Hg compared with the postductal PaO2 is considered significant.2 Cardiac catheterization is reserved for those infants for whom PPHN cannot be ruled out after other, less invasive diagnostic methods. Cardiac catheterization also is useful in the diagnosis of other congenital cardiac anomalies. After the diagnosis is made, the treatment of PPHN can be managed on several fronts. Ventilation therapy, metabolic alkalization, the use of vasodilators, nitric oxide (NO) therapy, and extracorporeal membrane oxygenation (ECMO) are the most common forms of treatment. The purpose of this article is to discuss the use of inhaled NO therapy in the transport of infants with PPHN. Two recent national trials have shown that NO is an effective treatment. From these trials, the Food and Drug Administration has approved the use of inhaled NO for hypoxic respiratory failure in the term or near term newborn. NO is a colorless, highly diffusible gas with a density similar to air. It elicits smooth muscle relaxation and, when inhaled into the lungs, reduces the vasoconstriction that causes pulmonary hypertension. NO is administered through the ventila10
tor circuit and blended with inhaled oxygen. When NO is diffused in the lungs, its combination with hemoglobin rapidly inactivates it, limiting its effect on pulmonary vasculature.1 Once an infant has been diagnosed with PPHN, ventilator therapy should be optimized to maintain proper lung inflation, which improves NO distribution, delivery, and response. NO therapy often is begun at rates of 20 parts per million (ppm) and weaned to patient response. Doses may range as high as 80 ppm, although this rarely is necessary. The use of NO therapy will cause a corresponding dose-dependent drop in FiO2 delivery. Complications from inhaled NO therapy include the potential toxicity of NO and its oxidized byproduct, nitrogen dioxide (NO2). Animal and human studies have shown that the low concentrations of NO used to treat PPHN (6 to 20 ppm) show no evidence of acute pulmonary injury, and the concentration of formed NO2 (< 4 ppm) is well below toxic levels. Another potential source of patient toxicity is the formation of methemoglobin leading to methemoglobinemia. Again, the range of NO used to treat PPHN is usually too low to create significant levels of methemoglobin. Transport of critically ill newborns and infants has become an important part of regionalized neonatal care. Newborns with PPHN frequently require transport to a neonatal center capable of providing advanced ventilatory care. Because the use of high frequency jet and oscillatory ventilation are not yet practical during transport, the use of NO during transport is becoming more popular. Patients already on high frequency ventilation may require the addition of NO therapy to tolerate a conventional ventilator during transport. The response to NO therapy is usually rapid and can aid in the diagnosis of PPHN before transport. PPHN does not always respond to NO therapy, and advanced care (ie, ECMO) still may be necessary. Realizing that an infant will require more intensive care can allow the receiving tertiary center to gather appropriate resources before the patient’s arrival. One transport concern involved in NO use has been the safety of crew members exposed to NO that has been exhaled into the atmosphere. Schmidt and Griebel3 have extensively studied the question of safety during the transport of infants receiving NO therapy. By using various aircraft and electrochemical cells to measure NO, various exposure levels were studied. During one 30-minute test flight, NO was bled directly into the test aircraft at 40 ppm using continuous oxygen flow at 20 L/min. The environmental levels never climbed above 0.1 ppm during bench testing. The conclusion was that the level of exposure to Air Medical Journal 20:5
Figure 1. Transport Inovent Delivery System
Figure 2. Injector Module
NO by crew members is insignificant; even in the event of a catastrophic NO tank rupture, the level of NO still would be well below toxic levels. The Department of Transportation classifies INOmax (INO Therapeutics, Inc., Clinton, N.J.) as a division 2.2 nonflammable gas—the same category as oxygen. The Federal Aviation Administration has no specific regulation on the use of INOmax during transport, although they suggest carrying the material’s safety data sheet (MSDS) while carrying the drug on board an aircraft. The MSDS also identifies NO as a class 2.2 nonflammable gas.4 The University of Michigan neonatal transport team is using the Transport Inovent Delivery System (Datex-Ohmeda, Madison, Wis.), shown in Figure 1, to provide NO therapy to infants with PPHN. The unit uses the “D” size INOmax therapy cylinders mounted to the transport isolette. The Inovent delivery system measures 8.5 inches high by 13.8 inches wide by 15.8 inches deep and weighs 46.2 pounds. Because transport isolettes can vary from program to program, the Transport Inovent Delivery System needs to be considered carefully as extra weight can become an issue. The relatively compact set mounts the Inovent system above the gas tanks. The other important system component is the injector module, shown in Figure 2, which measures gas flow and delivers a consistent level of NO despite changes in ventilator settings. The injector module also constantly measures levels of NO, NO2, and oxygen. NO is a useful adjunct in the treatment of PPHN in term newborns and has reduced the number of infants requiring ECMO therapy. The ability to use NO during the transport of these infants has improved the quality of their care in many ways. It allows transport teams to begin this very effective therapy at referring hospitals, providing for safer patient transport. It also allows transport teams to better anticipate those newborns who will require more advanced care, resulting in effective use and implementation of health care resources.
3. Griebel JL, Schmidt JM. Technical aspects of transporting critically ill infants using inhaled nitric oxide [abstract]. Presented at the 1999 Snowbird High Frequency Conference. 4. United States Department of Transportation, Research and Special Programs Administration. Hazardous materials regulations title 49 CFR, parts 100-185.
Benjamin J. Tung, RN, CEN, EMT-P, is a flight nurse specialist with University of Michigan Health Systems’ Survival Flight in Ann Arbor, Mich. Reprint orders: Mosby, Inc., 11830 Westline Industrial Dr., St. Louis, MO 63146-3318; phone (314) 453-4350; reprint no. 74/1/118334 doi:10.1067/mmj.2001.118334
References 1. Goldsmith JP, Karotkin EH. Assisted ventilation of the neonate. 3rd ed. Philadelphia: W.B. Saunders; 1996. 2. Donn SM. The Michigan manual: a guide to neonatal intensive care. 2nd ed. Armonk (NY): Futura Publishing; 1997. p. 347.
September-October 2001
11
Benjamin J. Tung, RN, CEN, EMT-P
The Use of Nitric Oxide Therapy in the Transport of Newborns with Persistent Pulmonary Hypertension Persistent pulmonary hypertension of the newborn (PPHN), sometimes known as persistence of the fetal circulation, originally was reported in 1969 by Gersony,1 who described infants with persistent characteristics of fetal circulation in the absence of recognizable cardiac, pulmonary, hematologic, or central nervous system disease. In newborns with PPHN, the normal cardiorespiratory changes at birth do not occur. This lapse, in turn, leads to suprasystemic pulmonary artery pressures, resulting in a right to left shunting of blood through the patent ductus arteriosus, the foramen ovale, or both. Hypoxemia in the term newborn, out of proportion to the amount of physical lung injury, should be evaluated for PPHN. Diagnosis can be made using several methods, including echocardiography, pre- and postductal PaO2 measurements, and cardiac catheterization.1 Echocardiography can provide very specific information regarding the structural condition of the heart and shunting of blood flow. With color flow doppler imaging, the level and direction of shunting can be determined. Pre- and postductal PaO2 measurements can determine the degree of right to left shunting. Oxygenation levels are observed from preductal sites (right radial or right temporal arteries) and postductal sites (umbilical artery or posterior tibial artery). These samples must be drawn simultaneously. A preductal PaO2 of ≥ 20 mm Hg compared with the postductal PaO2 is considered significant.2 Cardiac catheterization is reserved for those infants for whom PPHN cannot be ruled out after other, less invasive diagnostic methods. Cardiac catheterization also is useful in the diagnosis of other congenital cardiac anomalies. After the diagnosis is made, the treatment of PPHN can be managed on several fronts. Ventilation therapy, metabolic alkalization, the use of vasodilators, nitric oxide (NO) therapy, and extracorporeal membrane oxygenation (ECMO) are the most common forms of treatment. The purpose of this article is to discuss the use of inhaled NO therapy in the transport of infants with PPHN. Two recent national trials have shown that NO is an effective treatment. From these trials, the Food and Drug Administration has approved the use of inhaled NO for hypoxic respiratory failure in the term or near term newborn. NO is a colorless, highly diffusible gas with a density similar to air. It elicits smooth muscle relaxation and, when inhaled into the lungs, reduces the vasoconstriction that causes pulmonary hypertension. NO is administered through the ventila10
tor circuit and blended with inhaled oxygen. When NO is diffused in the lungs, its combination with hemoglobin rapidly inactivates it, limiting its effect on pulmonary vasculature.1 Once an infant has been diagnosed with PPHN, ventilator therapy should be optimized to maintain proper lung inflation, which improves NO distribution, delivery, and response. NO therapy often is begun at rates of 20 parts per million (ppm) and weaned to patient response. Doses may range as high as 80 ppm, although this rarely is necessary. The use of NO therapy will cause a corresponding dose-dependent drop in FiO2 delivery. Complications from inhaled NO therapy include the potential toxicity of NO and its oxidized byproduct, nitrogen dioxide (NO2). Animal and human studies have shown that the low concentrations of NO used to treat PPHN (6 to 20 ppm) show no evidence of acute pulmonary injury, and the concentration of formed NO2 (< 4 ppm) is well below toxic levels. Another potential source of patient toxicity is the formation of methemoglobin leading to methemoglobinemia. Again, the range of NO used to treat PPHN is usually too low to create significant levels of methemoglobin. Transport of critically ill newborns and infants has become an important part of regionalized neonatal care. Newborns with PPHN frequently require transport to a neonatal center capable of providing advanced ventilatory care. Because the use of high frequency jet and oscillatory ventilation are not yet practical during transport, the use of NO during transport is becoming more popular. Patients already on high frequency ventilation may require the addition of NO therapy to tolerate a conventional ventilator during transport. The response to NO therapy is usually rapid and can aid in the diagnosis of PPHN before transport. PPHN does not always respond to NO therapy, and advanced care (ie, ECMO) still may be necessary. Realizing that an infant will require more intensive care can allow the receiving tertiary center to gather appropriate resources before the patient’s arrival. One transport concern involved in NO use has been the safety of crew members exposed to NO that has been exhaled into the atmosphere. Schmidt and Griebel3 have extensively studied the question of safety during the transport of infants receiving NO therapy. By using various aircraft and electrochemical cells to measure NO, various exposure levels were studied. During one 30-minute test flight, NO was bled directly into the test aircraft at 40 ppm using continuous oxygen flow at 20 L/min. The environmental levels never climbed above 0.1 ppm during bench testing. The conclusion was that the level of exposure to Air Medical Journal 20:5
Figure 1. Transport Inovent Delivery System
Figure 2. Injector Module
NO by crew members is insignificant; even in the event of a catastrophic NO tank rupture, the level of NO still would be well below toxic levels. The Department of Transportation classifies INOmax (INO Therapeutics, Inc., Clinton, N.J.) as a division 2.2 nonflammable gas—the same category as oxygen. The Federal Aviation Administration has no specific regulation on the use of INOmax during transport, although they suggest carrying the material’s safety data sheet (MSDS) while carrying the drug on board an aircraft. The MSDS also identifies NO as a class 2.2 nonflammable gas.4 The University of Michigan neonatal transport team is using the Transport Inovent Delivery System (Datex-Ohmeda, Madison, Wis.), shown in Figure 1, to provide NO therapy to infants with PPHN. The unit uses the “D” size INOmax therapy cylinders mounted to the transport isolette. The Inovent delivery system measures 8.5 inches high by 13.8 inches wide by 15.8 inches deep and weighs 46.2 pounds. Because transport isolettes can vary from program to program, the Transport Inovent Delivery System needs to be considered carefully as extra weight can become an issue. The relatively compact set mounts the Inovent system above the gas tanks. The other important system component is the injector module, shown in Figure 2, which measures gas flow and delivers a consistent level of NO despite changes in ventilator settings. The injector module also constantly measures levels of NO, NO2, and oxygen. NO is a useful adjunct in the treatment of PPHN in term newborns and has reduced the number of infants requiring ECMO therapy. The ability to use NO during the transport of these infants has improved the quality of their care in many ways. It allows transport teams to begin this very effective therapy at referring hospitals, providing for safer patient transport. It also allows transport teams to better anticipate those newborns who will require more advanced care, resulting in effective use and implementation of health care resources.
3. Griebel JL, Schmidt JM. Technical aspects of transporting critically ill infants using inhaled nitric oxide [abstract]. Presented at the 1999 Snowbird High Frequency Conference. 4. United States Department of Transportation, Research and Special Programs Administration. Hazardous materials regulations title 49 CFR, parts 100-185.
Benjamin J. Tung, RN, CEN, EMT-P, is a flight nurse specialist with University of Michigan Health Systems’ Survival Flight in Ann Arbor, Mich. Reprint orders: Mosby, Inc., 11830 Westline Industrial Dr., St. Louis, MO 63146-3318; phone (314) 453-4350; reprint no. 74/1/118334 doi:10.1067/mmj.2001.118334
References 1. Goldsmith JP, Karotkin EH. Assisted ventilation of the neonate. 3rd ed. Philadelphia: W.B. Saunders; 1996. 2. Donn SM. The Michigan manual: a guide to neonatal intensive care. 2nd ed. Armonk (NY): Futura Publishing; 1997. p. 347.
September-October 2001
11