0899–5885/02 $15.00 + .00
`
`Pharmacology
`
`Inhaled Nitric Oxide
`in Infants and Children
`
`Linda E. Ware, MSN, RN
`
`Endogenous nitric oxide (NO)4, 8, 17, 23, 24, 29
`has been identified as affecting endothelium-
`derived relaxing factor, which produces
`pulmonary vasodilation. Neonates,
`infants,
`and children may develop pulmonary hyper-
`tension that does not respond to endogenous
`NO; therefore, exogenous NO can be used to
`induce pulmonary vasodilation.
`
`Causes of
`Pulmonary Hypertension
`
`All infants are born with pulmonary hyper-
`tension. While in utero, the fetus receives
`oxygen from the mother via the placenta,
`with most blood being shunted away from
`the lungs by the foramen ovale and duc-
`tus arteriosus. Fetal systemic pressure is low
`and pulmonary pressure is high. When the
`newborn takes a first breath and the umbil-
`ical cord is cut, these formations begin to
`close. Normally during this process, high pul-
`monary pressures begin to decrease, while
`systemic pressures begin to increase. Persis-
`tent pulmonary hypertension of the newborn
`(PPHN) or persistent fetal circulation (PFC),
`
`From the Le Bonheur Children’s Medical Center, Mem-
`phis, Tennessee
`
`a life-threatening condition, can result when
`this process does not take place.
`Conditions associated with pulmonary hy-
`pertension in the newborn include meco-
`nium aspiration, respiratory distress synd-
`rome, pneumonia, sepsis, pneumothorax,
`prematurity, and congenital diaphragmatic
`hernia. In some cases, the cause of pulm-
`onary hypertension cannot be determined.24
`Anatomic differences in the lungs, such as
`hypertrophy or hyperplasia of the pulmonary
`smooth muscle, can also cause pulmonary
`hypertension. Patients with congenital di-
`aphragmatic hernias may have hypoplasia of
`the lungs as well as problems with the system
`tone.24
`that
`regulates pulmonary vascular
`Preoperative or postoperative pulmonary
`hypertension seen in patients with congenital
`heart disease is linked to significant morbidity
`and mortality.18, 25, 28
`Hageman et al14 classified PPHN as ei-
`ther primary or secondary. Primary PPHN is
`caused by hypoxemia or acidemia, which
`alters the pulmonary vessels’ ability to va-
`sodilate. Secondary PPHN is defined as any
`condition that places the infant at risk for
`pulmonary vasoconstriction, such as meco-
`nium aspiration, pneumonia, sepsis, and
`congenital anomalies of the lung and airway.
`Death in the primary PPHN results from the
`inability to maintain adequate oxygenation.
`The outcome for
`infants with secondary
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`CRITICAL CARE NURSING CLINICS OF NORTH AMERICA / Volume 14 / Number 1 / March2002
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`
`PPHN depends on whether the severity of
`the underlying disease causes respiratory
`failure.
`
`sents a risk of intracranial hemorrhage or
`bleeding disorders.24 ECMO is costly and
`requires specially trained staff and special
`equipment.
`
`Treatments for Pulmonary
`Hypertension Before
`Nitric Oxide
`
`PPHN can be treated using a variety of ther-
`apies aimed at decreasing the pulmonary
`hypertension and increasing oxygenation. In-
`tubation and assisted ventilation are used to
`increase oxygenation to facilitate the end re-
`sult of pulmonary artery vasodilation. Neu-
`roblockade and sedation can be used to max-
`imize ventilation. Patients on a mechanical
`ventilator can be hyperventilated to produce
`alkalosis. Sodium bicarbonate also can be in-
`fused to increase alkalization. This medica-
`tion must be closely monitored, however, to
`prevent hypernatremia and increase serum
`osmolarity.24, 26
`Dobutamine, tolazoline, and prostacycline
`are used to increase systemic pressure, while
`magnesium sulfate can dilate the vessels.
`Note that these vasodilators dilate the sys-
`temic vessels as well as the pulmonary arter-
`ies, which can cause systemic hypotension.24
`In 1984, Hageman et al14 reviewed charts
`of neonates in three neonatal intensive care
`units (NICUs) who had discharge diagnoses
`of PPHN. The most common treatments for
`PPHN during 1980 and 1981 were hyperven-
`tilation (HV) alone, or HV and tolazoline.
`Treatment with HV achieved a statistically sig-
`nificant survival rate.
`Extracorporeal membrane oxygenation
`(ECMO) is a newer treatment modality that
`can be used after other treatments have
`been unsuccessful. Each institution that uses
`ECMO has specific criteria that must be met
`for an infant or child to be considered a
`candidate for the treatment.
`ECMO is based on the principles of car-
`diopulmonary bypass (CPB), where blood is
`removed by a cannula and filtered through
`a machine that
`removes carbon dioxide
`and oxygenates the blood. The blood is
`returned to the patient
`through another
`cannula. ECMO requires
`surgical place-
`ment of the cannulae. The patient must be
`heparinized to prevent clotting, which pre-
`
`Use of Nitric Oxide
`
`NO is a gas that has been found to be an ef-
`fective pulmonary vasodilator without caus-
`ing systemic vasodilation. Administered by
`inhalation, NO is short-acting (between 2 and
`10 seconds) because it binds to hemoglobin,
`which inactivates it.12, 26 NO is easy to admin-
`ister and its cost is relatively low.17
`NO is used in neonates, infants, and chil-
`dren with pulmonary hypertension who have
`not responded to conventional
`treatment.
`CPB may raise the pulmonary vascular re-
`sistance in children who have undergone
`open-heart surgery. Wessel et al28 studied en-
`dothelial function following CPB and found
`that pulmonary endothelial dysfunction and
`pulmonary hypertension may be caused by
`CPB. Inhaled NO (INO) was used as a selec-
`tive pulmonary vasodilator with pulmonary
`hypertension after CPB.
`Adatia et al1 described a diagnostic use for
`INO for neonates after cardiac surgery. After
`CPB, impairment of endothelium-dependent
`vascular relaxation can complicate the post-
`operative course by causing transient pulmo-
`nary hypertension.28 To determine whether
`this is the result of an anatomic pulmonary
`blood flow obstruction or pulmonary vaso-
`constriction, Adatia studied 15 patients who
`developed postoperative pulmonary hyper-
`tension or excessive cyanosis by adminis-
`tering INO.1 Nine of the neonates showed
`decreased pulmonary artery pressure and
`pulmonary vascular resistance. The remain-
`ing 6 did not respond to INO and had an
`anatomic obstruction to pulmonary blood
`flow. Therefore, postoperative patients who
`do not respond to INO should receive addi-
`tional diagnostic tests, which may indicate the
`need for further surgery.
`Jesse Roberts et al23 studied the use of
`inhaled, low concentration of NO and oxygen
`in children with congenital heart defects un-
`dergoing cardiac catheterization. The patients
`were given 80 ppm NO and fraction of in-
`spired oxygen (FIO2) 0.21 to 0.30, or FIO2 0.9.
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`INHALED NITRIC OXIDE IN INFANTS AND CHILDREN
`
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`
`Within 1 to 3 minutes, pulmonary vascular re-
`sistance and pulmonary artery pressure were
`decreased. When INO was stopped, pul-
`monary vascular resistance and pulmonary
`artery pressure returned to baseline readings.
`When FIO2 0.9 was administered without NO,
`pulmonary vascular resistance did not de-
`crease below the baseline measurements.
`Use of INO during cardiac catheterization
`allows the physician to determine which
`children are unable to reduce pulmonary hy-
`pertension because of a restricted pulmonary
`vascular bed.
`
`Concentration of
`Nitric Oxide
`
`Varying NO concentrations have been stud-
`ied to determine which best produces pul-
`monary vasodilation while minimizing toxic
`effects. Clark et al4 gave neonates 10 ppm of
`NO for a maximum of 24 hours and 5 ppm
`for no more than 96 hours. ECMO was used
`on 64% of the control group and 38% of
`the NO group (P = 0.001). The 30-day mor-
`tality rate was similar for the control group
`(8%) and for the NO group (7%). There was
`less chronic lung disease in the NO group
`(7%) compared to 20% in the control group
`(P = 0.02).
`Davidson et al6 studied NO 5 ppm, 10 ppm,
`or 80 ppm. Most patients demonstrated im-
`provement in oxygenation with NO. Only
`patients with 80 ppm NO demonstrated ele-
`vated methemoglobinemia and nitrogen
`dioxide (NO2) levels. None of the patients
`had prolonged bleeding times.
`The Franco-Belgium Collaborative NO
`Trial Group11 studied preterm and near-term
`neonates with respiratory failure. The need
`for mechanical ventilation and length of stay
`in the intensive care unit was shortened,
`while oxygenation was improved, on low-
`dose (10 ppm) NO for near-term neonates.
`NO did not prove beneficial
`for preterm
`neonates.
`The Neonatal Inhaled Nitric Oxide Study
`Group20 studied INO and respiratory failure
`in infants with congenital diaphragmatic her-
`nia (CDH). INO was not found to be effec-
`tive in improving oxygenation of infants with
`CDH.
`
`Miller et al18 used very low-dose INO (2 to
`20 ppm) to treat pulmonary hypertension
`following congenital heart repair surgery.
`Pulmonary vasodilation was effective in
`patients with high pulmonary vascular re-
`sistance, especially if the pulmonary artery
`pressure/systemic arterial pressure ratio was
`high. Low-dose NO may decrease the toxic
`effects of NO.
`Curran et al5 studied postoperative repair
`of congenital heart patients utilizing INO for
`postoperative pulmonary hypertension. Five
`patients had complete atrioventricular canal.
`These patients were treated with conven-
`tional measures—hyperventilation, FIO2 0.80,
`and inotropic agents. When INO was added,
`there was no statistical difference between
`conventional treatment and NO.
`An additional 15 postoperative congenital
`heart defect patients with a variety of de-
`fects were studied.5 These patients had re-
`fractory pulmonary hypertension and were
`given INO. Eleven patients had good results
`when INO was given at low concentrations
`(10 to 20 ppm). Curran5 stated that if low con-
`centrations (20 ppm or 40 ppm) did not pro-
`duce pulmonary vasodilation, higher concen-
`trations were ineffective.
`Davidson et al6 also demonstrated that
`80 ppm NO showed no advantage over NO at
`5 ppm and 20 ppm.
`
`Toxic Effects of Nitric Oxide
`and Treatments
`
`When NO binds with hemoglobin, it forms
`methemoglobin, which can effect the ability
`of oxygen to bind to hemoglobin and thereby
`decrease oxygenation.26 Methemoglobin lev-
`els should be kept lower than 5%.19, 20 Low-
`ering the amount of NO administered in 20%
`decrements,6 or lowering NO by 50%,5 de-
`creases the amount of methemoglobin in the
`blood. If methemoglobin does not correct to
`a satisfactory level with decreasing NO, NO
`can be stopped and methylene blue can be
`given intravenously, 1 to 2 mg/kg3, 26 over
`5 minutes, repeated in 1 hour if needed. (If
`methylene blue is used, urine and feces will
`have a blue-green color.3) Wessel et al29 de-
`creased methemoglobin by giving 500 mg vi-
`tamin C injections and a blood transfusion.
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`WARE
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`Methemoglobin is metabolized by methe-
`moglobin reductase.29 Members of some eth-
`nic groups and low-birth weight neonates
`may have a deficiency of methemoglobin re-
`ductase. INO byproducts are removed within
`48 hours by urine, feces, and salivary glands.
`NO is oxidized to form nitric dioxide,
`which can damage the lungs,5, 10, 17, 24 and
`may cause pneumonitis, pulmonary edema,
`emphysema, or death. Studies have shown
`that formation of nitric dioxide can be min-
`imized when NO has a short
`interaction
`with oxygen, which can be accomplished by
`delivering NO proximally or distally to the
`inspiratory limb.17 Besides a short interaction
`time between oxygen and NO, levels of NO
`and oxygen should be kept at the lowest
`effective levels.10 Levels of NO and nitric
`dioxide must be monitored at, or distal to, the
`patient to detect toxic levels.17 NO should be
`decreased if nitric dioxide exceeds 7 ppm.20
`Nonventilator patients can receive NO by
`using a non-rebreather mask,17 with NO
`delivered through a one-way valve.29 The
`above recommendations of short interaction
`of oxygen and NO and monitoring of the
`NO/NO2 should also be followed with NO by
`mask.
`Nitric oxide also is associated with affect-
`ing platelet function, which could increase
`
`SUMMARY
`
`bleeding. The exact mechanism has not been
`determined.19
`
`Weaning Nitric Oxide
`
`Davidson et al7 investigated successful wean-
`ing from INO. After treatment was deter-
`mined to be a success or failure, the treatment
`gas was decreased by 20% in five steps. Oxy-
`genation was monitored and remained sta-
`ble during the initial weaning of 0, 5, 20, and
`80 ppm of treatment gas. However, when the
`treatment gas was stopped, three NO groups
`showed a decrease in oxygenation. The de-
`crease was statistically significant as well as
`clinically noted in the 4 ppm and 16 ppm
`groups but not the 1 ppm group. There were
`no adverse effects from the withdrawal of
`the INO. Careful monitoring and weaning
`is necessary to prevent rebound pulmonary
`hypertension.
`This study suggested that FIO2 should be in-
`creased by 20% with the cessation of the INO
`to prevent decreased oxygenation.7 Infants
`who are treatment failures should be kept on
`INO while being placed on ECMO or trans-
`ferred to an ECMO center. Stopping INO may
`cause rapid deterioration and life-threatening
`hypoxemia.
`
`NO has been used successfully to treat PPHN, reducing the need for ECMO. NO
`has also been used in the cardiac catheterization laboratory to determine if pul-
`monary hypertension will decrease with NO. Patients who do not respond to
`NO are at higher risk after open-heart surgery, because their pulmonary hyper-
`tension will be difficult to treat. Postoperatively, NO can be used to determine if
`pulmonary hypertension is caused by vasoconstriction or by an obstruction.
`Inhaled Nitric Oxide at a Glance
`• Action: Selective pulmonary vasodilation without systemic vasodilation.
`• Use: Treatment of pulmonary hypertension.
`• Concentration and route: Lowest concentration that will produce pulmonary
`vasodilation and improved oxygenation.
`Concentration should be kept < 80 ppm.
`• Contraindication: Neonate that is ductal-dependent.
`• Toxic effects: Keep methemoglobin level < 5%.
`Keep nitric dioxide, which can cause lung damage, < 7 ppm.
`Risk of bleeding.
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`INHALED NITRIC OXIDE IN INFANTS AND CHILDREN
`
`5
`
`• Monitor: Levels of NO/NO2.
`Platelets.
`Arterial blood gas (ABG).
`Methemoglobin.
`• Weaning: Decrease NO by 20%, monitoring ABG at 3- to 4-hour intervals.
`If there is a decrease in oxygenation, increase NO.
`Increase FIO2 20% when NO is discontinued.
`Unsuccessful treatment with NO—keep on NO until ECMO is available.
`
`REFERENCES
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`26. Thompson S, Vyas J: Is NO news good news? Up-
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`
`Address reprint requests to
`Linda E. Ware, MSN, RN
`Le Bonheur Children’s Medical Center
`50 North Dunlap
`Memphis, TN 38103
`
`e-mail: warel@lebonheur.org
`
`006
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