Pilbeam: Mechanical Ventilation, 4th Edition
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`Special Techniques in Mechanical Ventilation
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`SECTION IV: Nitric Oxide
`
`OUTLINE
`
`PROPERTIES OF NO
`SELECTIVE PULMONARY VASODILATION
`TOXIC EFFECTS AND COMPLICATIONS OF INHALED NO
`
`Direct Inhalation of High Concentrations
`
`Nitrogen Dioxide
`
`Methemoglobin
`
`Peroxynitrite
`
`Platelet Inhibition
`
`NO in Patients with Severe Left Ventricular Dysfunction
`CLINICAL APPLICATION
`PPHN
`NO Use in Other Neonatal Disorders
`ARDS
`Lung Transplantation
`SYSTEMS FOR DELIVERING INHALED NO
`I-NOvent Delivery System
`Continuous-Flow Ventilator System
`Premixed NO System
`NO Injection System
`Scavenging NO from Delivery Systems
`WITHDRAWAL OF INHALED NO
`
`LEARNING OBJECTIVES
`
`Upon completion of this section the reader will be able to do the following:
`
`
`1. Describe physical characteristics of nitric oxide.
`2. List the normal concentration range for ambient nitric oxide, inhaled nitric oxide
`levels in smokers, and therapeutic levels of inhaled nitric oxide.
`3. Explain the cellular process in which endogenous nitric oxide is produced.
`4. Discuss the effects of inhaled nitric oxide on the pulmonary circulation,
`ventilation/perfusion matching, and pulmonary shunt.
`5. Identify side effects and complications of inhaled nitric oxide.
`6. Name the medication used in treating methemoglobinemia.
`7. Compare the use of inhaled nitric oxide in patients with persistent pulmonary
`hypertension of the newborn and those with acute respiratory distress syndrome.
`8. Describe the advantages and disadvantages of the four nitric oxide delivery
`systems presented.
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`In certain pulmonary disorders such as persistent pulmonary hypertension of the newborn
`(PPHN) and acute respiratory distress syndrome (ARDS), pulmonary vasoconstriction
`and pulmonary hypertension contribute to shunting and hypoxemia. In an effort to find a
`way to reverse these difficulties, a simple, common gas molecule called nitric oxide (NO)
`has been studied and used as a potential treatment to improve oxygenation and reduce
`shunting. This section reviews the use of NO as a therapeutic inhaled gas.
`
`PROPERTIES OF NO
`
`NO is a highly reactive gaseous radical commonly found in the environment. Between 10
`and 100 ppb are present in the atmosphere. Smokers may inhale as much as 400 to 1000
`ppm when they inhale tobacco smoke.1 Although NO is normally present in our
`environment, it is still considered an air pollutant.2 In fact, NO is even present in the
`compressor gas supplies of hospitals, and breathing these gases may affect patients.3
`NO is endogenous to and produced by a variety of body cells. It is also an important
`messenger molecule. For example, NO is accountable for the activity of the endothelium-
`derived relaxing factor, an agent that relaxes smooth muscles and augments blood flow in
`veins. The effectiveness of certain medications, such as sodium nitroprusside and
`nitroglycerin, is in fact attributed to their release of NO.
`The formation of NO in cells is dependent on the presence of L-arginine, an amino
`acid. NO is produced in the presence of NO-synthase, an enzyme. The resulting NO
`typically diffuses to a neighboring cell where it binds with and activates guanylate
`cyclase. In the presence of guanosine triphosphate, activated guanylate cyclase increases
`production of cyclic guanosine 3′,5′-monophosphate, which produces certain biological
`effects within cells, such as smooth muscle relaxation (Figure 1).4
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`Fig. IV-1
`Biological pathway for the endogenous production of NO. bNOS, Neuronal-type
`constitutive NO synthase; cGMP, cyclic guanosine 3′5′-monophosphate; cNOS,
`constitutive NO synthase; eNOS, endothelial NO synthase; GTP, guanosine triphosphate;
`iNOS, inducible NO synthase; L-NAME, L-NG, arginine methyl ester; L-NMMA, L-NG-
`monomethyl arginine; NOS, NO synthase. (From Hess D: Heliox and inhaled nitric
`oxide. In MacIntyre NR, Branson RD: Mechanical ventilation, Philadelphia, 2001,
`Saunders.)
`
`
`NO has been measured in exhaled gases and within the nasopharynx and the
`paranasal sinuses in human beings.5,6 The NO in the nasopharynx is actually inhaled and
`absorbed. NO present in the paranasal sinuses may have a bacteriostatic effect within the
`sinuses.6 In inflammatory conditions such as asthma and bronchiectasis, the amount of
`exhaled NO increases above the normal amount. This may be a result of increasing NO
`synthesis from neutrophils and macrophages.7
`
`SELECTIVE PULMONARY VASODILATION
`
`
`NO is important to pulmonary medicine because it can be inhaled through the lungs and
`cause selective pulmonary vasodilation. When very low concentrations of NO (0.25 to 20
`ppm by volume) are inhaled in the lungs and delivered to ventilated alveoli, vasodilation
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`of adjacent pulmonary vessels occurs, resulting in improvement in ventilation/perfusion
`) matching, reduction of shunting, and increase of PaO2.8,9 This occurs without
`(
`/
`dilating systemic vessels because the inhaled NO rapidly combines with hemoglobin
`once it diffuses into the blood stream and is inactivated. NO is not in itself a selective
`pulmonary vasodilator, but it becomes one when administered as an inhaled gas.4 Other
`intravenous vasodilators such as nitroglycerin and sodium nitroprusside are not selective.
`These vasoactive agents result in lower systemic and pulmonary blood pressure. In
`addition, they increase blood flow to both ventilated and nonventilated alveoli, which
`increases intrapulmonary shunting and reduces arterial oxygenation.10
`
`TOXIC EFFECTS AND COMPLICATIONS OF INHALED NO
`
`Inhaled NO, although beneficial as a selective vasodilator, has undesirable side effects.
`Most of these effects are minimal when NO is administered in appropriate amounts by
`experienced practitioners. However, clinicians using the gas should be familiar with the
`potential complications.
`
`Direct Inhalation of High Concentrations
`
`Direct inhalation of extremely high concentrations of the NO gas either by accidental
`iatrogenic administration or in farmers exposed to the gas when filling silos (silo filler’s
`disease) can result in shortness of breath, hypoxemia, pulmonary edema, and even
`death.11,12 Although actual amounts of NO inhaled are not addressed in this section, one
`can only imagine the quantity of NO sufficient to cause death if cigarette smoke can
`contain as much as 1000 ppm. Table 1 illustrates some of the responses detected at
`various concentrations of NO administered to human beings.4
`
`Table 1
`Response in Human Subjects Exposed to Various Concentrations of
`Inhaled NO
`Exposure Amount of NO
`1 ppm
`
`Response
`Small decrease in specific airway conductance in healthy
`volunteers
`A decrease in PaO2 and an increase in airway resistance
`in normal subjects after 15 min
`Decreased airway conductance in patients with chronic
`obstructive pulmonary disease
`
`15-20 ppm
`
`80 ppm
`
`
`
`Nitrogen Dioxide
`
`NO rapidly combines with oxygen to form the toxic irritant nitrogen dioxide (NO2).
`Exposure to NO2 has been shown to result in lung injury, loss of cilia, hypertrophy, and
`focal epithelial hyperplasia of the terminal bronchioles in rats.13 In the presence of water,
`NO2 forms nitric acid. The precise effects of these substances on human lungs are being
`investigated.
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`Methemoglobin
`
`After exposure to high levels of NO gas (80 ppm), the level of methemoglobin (metHb)
`in the blood increases.4 (Note: Therapeutic inhalation of 20 ppm NO or less does not
`typically produce methemoglobinemia.) MetHb is a form of hemoglobin in which the
`iron molecule in the heme portion has been converted from the normal ferrous state
`(Fe+2) to the oxidized ferric state (Fe+3). MetHb is commonly present in concentrations
`less than 2%. This normal amount may actually exist because of the metabolism of
`endogenous NO.
`When NO reacts with oxyhemoglobin it forms inorganic nitrate and methemoglobin.
`Inorganic nitrate is unstable and reacts with hemoglobin to form methemoglobin and NO.
`The NO reacts with oxyhemoglobin, and so on.
`MetHb blood levels of less than 5% do not require treatment. However, higher
`percentages of metHb do require treatment because metHb interferes with the oxygen-
`carrying capacity of the blood. MetHb cannot bind to oxygen, and its presence actually
`interferes with the ability of normal hemoglobin to carry oxygen (leftward shift of the
`oxyhemoglobin dissociation curve). Methylene blue infusion is the common treatment for
`high metHb levels. Methylene blue increases reduced nicotinamide adenine dinucleotide
`metHb reductase. Ascorbic acid (vitamin C) can also be used for treatment.4
`
`Peroxynitrite
`
`Peroxynitrite (ONOO–) is a toxic substance produced when endogenous NO reacts with
`– yields ONOO–. This can occur in biological systems
`–): NO + O2
`an oxide radical (O2
`and may have toxic effects on these systems.14 Whether inhaled NO produces a reaction
`is not currently known.4
`
`Platelet Inhibition
`
`NO may inhibit platelet adhesion, aggregation, and agglutination. The importance of this
`clinical side effect has yet to be determined.15
`
`NO in Patients with Severe Left Ventricular Dysfunction
`
`In some patients with severe left heart failure, high levels of inhaled nitric oxide (40 to 80
`ppm) have been shown to reduce pulmonary vascular resistance and increase pulmonary
`artery occlusion pressure.16 With a drop in pulmonary vascular resistance and therefore a
`decrease in afterload to the right heart, improvement in right heart output increases
`venous return to the left ventricle. If the left ventricle is functioning poorly, the resulting
`increased left ventricular filling may worsen pulmonary edema. This response may be
`dose related. In patients with elevated pulmonary artery occlusion pressure (25 mm Hg or
`greater) and severe left ventricular dysfunction, inhaled NO therapy should be avoided.4
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`CLINICAL APPLICATION
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`Because of its properties, inhaled NO is being used to manage patients with PPHN,
`ARDS, and congenital heart disease.17,18 The response to NO inhalation varies between
`the type of pulmonary problem and individuals. Some patients have significant decreases
`in pulmonary vascular resistance and improvements in oxygenation, and others do not
`respond at all.19
`
`PPHN
`
`Box 1 describes the condition known as PPHN.20 Treatment of PPHN is generally
`directed at the known cause—for example, oxygen therapy for hypoxemia, surfactant for
`respiratory distress syndrome, glucose for hypoglycemia, and inotropic agents for low
`cardiac output and systemic hypotension.20 If hypoxemia persists in spite of therapy,
`intubation and mechanical ventilation are typically required. Alternative treatments
`include high-frequency ventilation and inhaled NO. (See Chapter 22 for information on
`high-frequency ventilation.) Rescue therapy might include high-frequency ventilation or
`exogenous surfactant along with NO. When all of these treatments fail, extracorporeal
`life support (also known as extracorporeal membrane oxygenation [ECMO]) may be
`instituted. (See section on extracorporeal gas exchange techniques on this Web site.)
`
`Box 1 PPHN
`Under normal conditions after birth, as the lungs become aerated, pulmonary vascular
`resistance decreases as the pulmonary veins become well oxygenated. At the same time,
`systemic vascular resistance increases as the placenta is removed from circulation. PPHN
`is a complex syndrome that presents after birth when the normal transformation of fetal
`circulation to extrauterine circulation does not take place.
`
`Three functional types of PPHN exist:
`1. Vascular spasm triggered by many different conditions (e.g., hypoxemia,
`hypoglycemia, hypotension, pain)
`2. Increased muscle wall thickness, a chronic condition that develops in utero in
`response to several factors (e.g., chronic fetal hypoxia, increased pulmonary blood
`flow, pulmonary venous obstruction)
`3. Decreased cross-sectional area of pulmonary vessels
`
`PPHN is suspected if the infant has rapidly changing oxygen saturations without any
`change in FIO2. It is also suspected if hypoxemia is out of proportion to the pulmonary
`disease identified with chest radiography or PaCO2 values. In infants with suspected
`PPHN who have a significant right-to-left shunt through the ductus arteriosus, a large
`difference between SpO2 values measured on the right arm and on a leg is usually
`present.
`
`
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`
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`In patients with moderate PPHN, treatment with NO improves oxygenation
`(PaO2) and reduces the amount of ventilatory support required. Thus inhaled NO used in
`moderate PPHN may prevent progression to severe PPHN.21 The use of NO therapy may
`reduce the requirement for ECMO in infants with severe PPHN (e.g., P[A-a]O2 greater
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`than 600 mm Hg).21,22 However, NO may not be beneficial in patients with a high degree
`of structural pulmonary abnormalities (hypoplasia or alveolar capillary dysplasia) that
`interfere with the action of the gas. In patients with PPHN and congenital diaphragmatic
`hernia, NO remains an unproven treatment and ECMO should not be postponed in those
`fulfilling ECMO criteria.23
`
`
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`NO Use in Other Neonatal Disorders
`
`In addition to PPHN, a number of other clinical conditions can result in hypoxemic
`respiratory failure in the newborn, including meconium aspiration, pneumonia, and
`respiratory distress syndrome. When inhaled NO is used in conjunction with conventional
`treatment strategies, such as mechanical ventilation, surfactant therapy, and high-
`frequency ventilation, infants treated with NO have a lower mortality rate and less need
`for extracorporeal life support.24
`
`ARDS
`
`ARDS is an inflammatory process in the lungs that results in pulmonary edema, severe
`hypoxemia (PaO2/FIO2 less than 200), reduced lung compliance, and increased shunt.
`(See Chapter 14 for additional information on ARDS and its management.)
`The use of NO in patients with ARDS was first reported by Rossaint et al,9 who
`
`reported a reduction in pulmonary artery pressures, an increase in PaO2, and a decrease in
`shunt. Similar findings were reported by others.18 In patients with ARDS, the most
`appropriate dose of NO appears to be low (5 ppm).4
`Meade and Herridge8 evaluated the results of four large studies using inhaled NO in
`patients with acute lung injury and ARDS. Their results concluded that none of the
`studies found an important survival benefit, and that although inhaled NO therapy could
`produce dramatic improvements in oxygenation in some patients, no evidence that it
`improved outcome was found. They recommended that NO therapy be limited to salvage
`therapy in patients in respiratory extremis only.
`
`Lung Transplantation
`
`In a study of 14 patients receiving lung transplantation for end-stage lung disease and
`pulmonary hypertension, NO demonstrated no harmful side effects, did not lengthen the
`time on mechanical ventilation, and may have reduced the incidence of acute graft
`rejection.25
`
`SYSTEMS FOR DELIVERING INHALED NO
`
`When the decision is made to used NO for therapy, the procedure for its administration
`must include a few key factors (Box 2).4 The four basic types of systems for NO delivery
`are a commercially available system (I-NOvent Delivery System, Datex Ohmeda,
`Madison, Wis.), one used with a continuous-flow ventilator such as those used with
`pediatric ventilation, a premixed NO system, and an NO injection system.
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`Box 2 Important Considerations when Designing an In-house System for
`Delivering NO to Ventilated Patients
`The delivery system must be simple to operate and dependable.
`The dose of NO should be stable and precise.
`Levels of NO and NO2 need to be monitored.
`The level of NO2 inhaled must be kept as low as possible.
`The delivery system should not interfere with ventilator function.
`FIO2 is monitored after the connection where NO is titrated into the system because NO
`decreases FIO2.
`
`I-NOvent Delivery System
`
`The I-NOvent Delivery System is designed to be used with any type of ventilator,
`including a high-frequency oscillator (Figure 2).26 The system is typically mounted on a
`transport cart with two NO gas cylinders. An injection module from the unit is positioned
`on the inspiratory side of the patient ventilator circuit near the port where the gas flow
`comes from the ventilator and goes to the patient. The injection module contains a flow
`sensor and gas injection tube. The flow sensor precisely monitors the flow coming from
`the ventilator. NO is injected in proportion to the flow measured and the set NO dose
`selected (range, 0 to 80 ppm by an 800-ppm cylinder). The device uses either a high- or a
`low-flow controller, which ensures that the I-NOvent is able to deliver an accurate
`concentration of desired NO over a wide range of flows (neonatal to adult patients). The
`sensors measure O2, NO, and NO2 from gases sampled near the ventilator Y-connector.
`The top-mounted display console (see Figure 2) provides a digital readout of parameters.
`Available alarms are listed in Box 3.
`
`
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`Fig. IV-2
`The I-NOvent Delivery System. (Courtesy Pamela West, RRT, Medical Center of Central
`Georgia, Macon, Ga.)
`
`
`
`
`
`Box 3 Available Alarms on the I-NOvent Delivery System
`High and low NO
`High NO2
`High and low O2
`Calibration required
`Electrochemical (gas monitoring) sensor failure or weakening
`Monitoring failure
`Loss of gas pressure
`Delivery system failure
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`Continuous-Flow Ventilator System
`
`In pediatric ventilators that use continuous flow for patient ventilation, a system has been
`described for titrating NO into the inspiratory line of the ventilator.27 The schematic
`drawing of a NO delivery system shown in Figure 3 has been used in continuous-flow
`pediatric ventilators.
`
`
`Fig. IV-3
`Schematic drawing of a delivery system for inhaled NO using a continuous-flow pediatric
`ventilator. (From Hess D: Heliox and inhaled nitric oxide. In MacIntyre NR, Branson
`RD: Mechanical ventilation, Philadelphia, 2001, Saunders.)
`
`
`
`
`The design works as follows. NO from a cylinder source is infused into the
`inspiratory limb of the ventilator near the ventilator. The analyzer is mounted at least 30
`cm (12 inches) from this connection to ensure adequate gas mixing and avoid dosing
`errors.4 Because the residual time of NO in the system is short, the generation of NO2
`should be low. The expected NO dose is calculated as follows4:
`
`
`NO dose = (NO flow × Source [NO] concentration)/(NO flow + Ventilator flow)
`
`
`
`High-frequency oscillation (HFO) is another technique used in the management of
`severe hypoxemia in infants. HFO incorporates a continuous bias flow of gas. Studies
`have shown that NO can be injected in several sites into the circuit at a continuous
`titration rate and that NO mixing is adequate. Injection upstream from the humidifier
`(prehumidifier) during HFO is preferable because it produces the smallest amount of
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`fluctuation in NO gas concentration.26 (For information on HFO, see Chapters 22 and
`23.)
`
`Premixed NO System
`
`Figure 4 illustrates a system of premixing of NO before delivery of the gas into a
`ventilator circuit. A gas blender is used to accurately control mixing of a controlled
`amount of NO (e.g., 800 ppm), which is connected to the O2 inlet of the blender while
`either nitrogen (N2) or air is connected to the air inlet of the blender. These mixed gases
`are added to the gas inlet of the ventilator. N2 should be used instead of air with high
`doses of NO (more than 20 ppm), high FIO2 delivery (more than 0.9), or low minute
`volume settings.28 NO dose and FIO2 delivery should be confirmed by gas analysis (see
`Figure 4).
`
`
`
`Fig. IV-4
`Schematic drawing of a premixing NO delivery system. NO (800 ppm) is mixed with N2
`or air and introduced into the air inlet of a ventilator. The settings on the external blender
`and ventilator FIO2 control determine the delivered NO concentration. (From Hess D,
`Bigatello L, Kacmarek RM, et al: Respir Care 41:437, 1996.)
`
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`NO Injection System
`
`NO injection systems use a continuous flow of NO added to the inspiratory limb of a
`ventilator to administer NO. The mean NO dose delivered to the patient is estimated by
`the following equation4:
`
`
`NO desired = NO flow × source (NO)/
`
`E
`
`
`This type of NO delivery is not recommended for conventional ventilation for several
`reasons. First, the inspiratory circuit fills with NO during expiration when the patient
`circuit is sealed. Thus, during the next mandatory breath delivery, a high dose of NO is
`administered with the breath.29 This produces large fluctuations of NO that go undetected
`if a rapid-response NO analyzer is not used.30 If mandatory breaths are mixed with
`spontaneous breaths, as with synchronized intermittent mechanical ventilation, NO
`delivery is even more inconsistent from breath to breath. Second, the added flow into the
`circuit may make it difficult for the ventilator to sense a patient’s inspiratory breath and
`may fail to trigger a breath. Third, the patient may receive an oxygen-deficient breath.
`During low tidal volume delivery, the volume of NO in any single breath may represent a
`sufficient part of the breath, thus reducing the available oxygen to the patient.4 Fourth,
`the concentration of NO delivery by this method is affected by flow waveform selected,
`changes in flow,
`E setting, and the site where the NO is injected.
`
`Scavenging NO from Delivery Systems
`
`The Occupational Safety and Health Administration sets limits on the exposure time of
`health care providers to NO and NO2 (time-weighed average of 25 ppm over an 8-hour
`period).4 This is higher than the typical amount of NO present during inhaled NO dose
`(20 ppm or less). The amount of ambient NO present when inhaled NO is being used
`therapeutically has been measured in very low amounts (less than 0.25 ppm) whether
`efforts were made to scavenge the NO from the system or not.4,31 Even using scavenger
`systems to uptake a ventilator’s vented gases is not completely efficient because
`ventilator circuits typically have small leaks. With a scavenger system in use, the system
`should not impede the outflow of exhaled gas or alter ventilator function. One possible
`option for cleaning vented gases is to allow a ventilator’s exhaled gas to pass through a
`canister of potassium permanganate and charcoal to remove NO and NO2.4
`
`WITHDRAWAL OF INHALED NO
`
`During daily attempts at withdrawal of inhaled NO in some patients, rebound hypoxemia
`and pulmonary hypertension may occur.9,32 The reason for this rebound effect is not
`known. To help avoid this potential problem associated with NO withdrawal, the
`following steps are recommended4:
`
`
`1. Use the lowest effective dose of NO during therapy (5 ppm or less).
`2. Maintain NO therapy until the patient's clinical status is improved (i.e., positive
`end-expiratory pressure of 5 cm H2O, FIO2 0.4 or less).
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`3. Prepare to maintain the hemodynamic status of the patient if necessary.
`4. Increase the FIO2 to 0.6 to 0.7 before withdrawing the inhaled NO.
`
`
`
`Inhaled NO may be cost effective and appropriate for rescue therapy of selected infants
`with PPHN.33 Although NO may transiently improve oxygenation in adults and children
`with acute hypoxic respiratory failure, lack of sufficient data prevents determination of
`the effectiveness of inhaled NO in reducing mortality rate.8,34 The use of alternative
`treatments, such as HFO and surfactant, may be as effective with or without the
`administration of NO. A recent alternative to inhaled NO in adult patients may be
`nebulized Flolan, which may be as effective and less costly than inhaled NO. This
`alternative medication warrants study.
`
`REVIEW QUESTIONS
`
`1. Which of the following is true regarding the characteristics of NO?
`I. NO occurs endogenously in cells
`II. NO is normally present in ambient air
`III. Normal ambient concentration of NO is 400 ppm
`IV. NO is formed in cells by using L-arginine
`a. I only
`b. III only
`c. II and IV
`d. I, II, and IV
`2. Which of the following are benefits of using NO inhalation in some patients?
`I.
`Reduces systemic blood pressure
`II. Produces selective vasodilatation of pulmonary vessels
`III.
`Increases diffusion of O2 across the alveolar-capillary membrane
`IV.
`Improves
`/
` matching
`a. III only
`b. II and IV
`c. I and III
`d. I, II, and IV
`3. Toxic effects of and complications from inhaled NO include which of the following?
`I. Direct inhalation of high concentrations results in shortness of breath,
`hypoxemia, pulmonary edema, and even death.
`II. Combining NO and O2 produces NO2, a toxic irritant.
`III. MetHb can be produced when high levels of NO are inhaled.
`IV. NO may inhibit platelet adhesion.
`a. II only
`b. III only
`c. I and IV
`d. I, II, III, and IV
`4. Inhaled NO has been used clinically in all except in which of the following disorders?
`a. Severe left ventricular failure
`b. PPHN
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`c. ARDS
`d. Lung transplant
`5. Which of the following delivery systems may result in uneven delivery of inhaled NO
`and difficulty for the patient in triggering the ventilator?
`a. Commercially available system (I-NOvent Delivery System)
`b. NO injection system
`c. Continuous-flow pediatric ventilator
`d. Premixed NO system
`
`
`ANSWERS TO REVIEW QUESTIONS
`
`
`1. d
`2. b
`3. d
`4. a
`5. b
`
`
`REFERENCES
`
`
`1. Dupuy PM, Lancom JP, Francois M, et al: Inhaled cigarette smoke selectively
`reverses human hypoxic vasoconstriction, Intensive Care Med 21:941, 1995.
`2. The National Institute of Occupational Safety and Health Administration (OSHA)
`recommendations for occupational safety and health standards, 1988, MMWR
`37:1, 1988.
`3. Pinsky MR, Genc F, Lee KH, et al: Contamination of hospital compressed air
`with nitric oxide: unwitting replacement therapy, Chest 111:1759, 1997.
`4. Hess D: Heliox and inhaled nitric oxide. In MacIntyre NR, Branson RD:
`Mechanical ventilation, Philadelphia, 2001, Saunders.
`5. Lundberg JO, Weitzberg E, Lundberg JM, et al: Nitric oxide in exhaled air, Eur
`Respir J 9:2671, 1996.
`6. Lundberg JO, Farkas-Szallasi T, Weitzberg E, et al: High nitric oxide production
`in human paranasal sinuses, Nat Med 1:370, 1995.
`7. Kharitonov SA, Chung KF, Evans D, et al: Increased exhaled nitric oxide in
`asthma is mainly derived from the lower respiratory tract. Am J Respir Crit Care
`Med 153:1773, 1996.
`8. Meade MO, Herridge MS: An evidence-based approach to acute respiratory
`distress syndrome, Respir Care 46:1368, 2001.
`9. Rossaint R, Falke KJ, Loper F, et al: Inhaled nitric oxide for the adult respiratory
`distress syndrome, N Engl J Med 328:399, 1993.
`10. Wood G: Effect of antihypertensive agents on the arterial partial pressure of
`oxygen and venous admixture after cardiac surgery, Crit Care Med 25:1807,
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