447
`
`Inhaled Nitric Oxide in Congenital
`Heart Disease
`
`Jesse D. Roberts Jr., MD; Peter Lang, MD; Luca M. Bigatello, MD;
`Gus J. Vlahakes, MD; and Warren M. Zapol, MD
`
`Background. Congenital heart lesions may be complicated by pulmonary arterial smooth muscle
`hyperplasia, hypertrophy, and hypertension. We assessed whether inhaling low levels of nitric oxide (NO),
`an endothelium-derived relaxing factor, would produce selective pulmonary vasodilation in pediatric
`patients with congenital heart disease and pulmonary hypertension. We also compared the pulmonary
`vasodilator potencies of inhaled NO and oxygen in these patients.
`Methods and Results. In 10 sequentially presenting, spontaneously breathing patients, we determined
`whether inhaling 20-80 ppm by volume of NO at inspired oxygen concentrations (FIO2) of 0.21-0.3 and
`0.9 would reduce the pulmonary vascular resistance index (Rp). We then compared breathing oxygen with
`inhaling NO. Inhaling 80 ppm NO at lIO2 0.21-0.3 reduced mean pulmonary artery pressure from 48± 19
`to 40+14 mm Hg and Rp from 658±421 to 491±417 dyne * sec * cm' * m-2 (mean±SD, both p<0.05).
`Increasing the nlO2 to 0.9 without adding NO did not reduce mean pulmonary artery pressure but reduced
`Rp and increased the ratio of pulmonary to systemic blood flow (Qp/Q5), primarily by increasing Qp
`(p<0.05). Breathing 80 ppm NO at FIO2 0.9 reduced mean pulmonary artery pressure and Rp to the lowest
`levels and increased Qp and Qp/Q, (all p<0.05). While breathing at FIo2 0.9, inhalation of 40 ppm NO
`reduced Rp (p<0.05); the maximum reduction of Rp occurred while breathing 80 ppm NO. Inhaling 80
`ppm NO at FiO2 0.21-0.9 did not alter mean aortic pressure or systemic vascular resistance. Methemo-
`globin levels were unchanged by breathing up to 80 ppm NO for 30 minutes.
`Conclusions. Inhaled NO is a potent and selective pulmonary vasodilator in pediatric patients with
`congenital heart disease complicated by pulmonary artery hypertension. Inhaling low levels of NO may
`provide an important and safe means for evaluating the pulmonary vasodilatory capacity of patients with
`congenital heart disease without producing systemic vasodilation. (Circulation 1993;87:447-453)
`KEY WORDs * hypertension, pulmonary artery a
`congenital heart disease * endothelium-derived
`relaxing factor *
`nitric oxide
`
`C ongenital heart lesions that increase pulmonary
`blood flow1 or cause pulmonary venous ob-
`struction2 may produce pulmonary artery
`smooth muscle hypertrophy and hyperplasia3 and pul-
`monary vasoconstriction. Current drug therapies for
`pulmonary artery hypertension are nonselective and
`dilate systemic blood vessels. Unless surgical correction
`of the underlying congenital heart lesion occurs early in
`life, pulmonary vasoconstriction may persist, progress to
`vascular obliteration, and produce a high morbidity.4
`Nitric oxide (NO), which has identical activity as
`endothelium-derived relaxing factor,5.6 is produced
`from L-arginine7 by endothelial NO synthase.8 NO
`diffuses into subjacent vascular smooth muscle and
`mediates vasodilation by stimulating soluble guanylate
`cyclase to produce cyclic GMP (cGMP).910 Inhaling low
`levels of NO reverses hypoxic pulmonary vasoconstric-
`
`From the Departments of Anesthesia (J.D.R.Jr., L.M.B.,
`W.M.Z.), Pediatrics (J.D.R.Jr., P.L.), and Surgery (G.J.V.), Har-
`vard Medical School at Massachusetts General Hospital, Boston,
`Mass.
`Supported by the Foundation for Anesthesia Education and
`Research and US Public Health Service grant HL-42397.
`Address for reprints: Jesse Roberts Jr., MD, Department of
`Anesthesia, Massachusetts General Hospital, Boston, MA 02114.
`Received May 20, 1992; revision accepted October 19, 1992.
`
`tion in lambs weighing 25-35 kg11 and adult volunteers12
`and reduces pulmonary vascular resistance in adults
`with primary pulmonary hypertension13 and the adult
`respiratory distress syndrome.14 We have reported that
`inhaling 80 ppm NO for 30 minutes increases preductal
`and postductal oxygenation in infants with persistent
`pulmonary hypertension of the newborn.15 NO diffuses
`into the intravascular space, where it rapidly binds to
`hemoglobin, becoming inactivated and thereby prohib-
`iting systemic vasodilation. This reaction leads to the
`formation of methemoglobin.16
`In the present study, we demonstrate that inhaling
`NO for brief periods selectively reduces pulmonary
`vasoconstriction in pediatric patients with congenital
`heart disease complicated by pulmonary artery hyper-
`tension. We also compare the pulmonary vasodilatory
`effectiveness of low concentrations of inhaled NO with
`oxygen breathing in pediatric patients with congenital
`heart disease undergoing cardiac catheterization.
`Methods
`These investigations were performed with approval
`by the subcommittees for human studies of the Massa-
`chusetts General Hospital and an IND approval by the
`US Food and Drug Administration. Informed consent
`was obtained from the parents of our patients.
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`448
`
`Circulation
`
`Vol 87, No 2
`
`February 1993
`
`TABLE 1.
`
`Patient Characteristics-Baseline Conditions
`
`Patient
`1
`
`2
`3
`4
`5
`
`6
`7
`8
`
`9
`10
`
`Age
`3 Months
`
`3 Months
`5 Months
`7 Months
`10 Months
`
`14 Months
`4.5 Years
`6.5 Years
`
`3.5 Years
`5.5 Years
`
`Lesion
`VSD
`
`VSD, ASD
`AVC
`AVC
`VSD
`
`VSD
`PV stenosis
`Small VSD,
`no shunt
`Mitral stenosis
`AVG-repaired
`MR severe
`
`Medications
`Digoxin, diuretics
`
`Digoxin
`Digoxin, diuretics
`Digoxin, diuretics
`
`Digoxin
`Digoxin, diuretics
`
`Other
`conditions
`Holt-Oram
`syndrome
`Trisomy 21
`Trisomy 21
`Trisomy 21
`Situs inversus
`totalis
`Trisomy 21
`
`Digoxin, diuretics
`
`Trisomy 21
`
`FiO2
`0.21
`
`0.21
`0.21
`0.21
`0.21
`
`0.21
`0.21
`0.21
`
`0.21
`0.30
`
`pHa
`7.42
`
`7.38
`7.37
`7.35
`7.37
`
`7.29
`7.36
`7.35
`
`7.35
`7.40
`
`Paco2
`41
`
`Pao2
`57
`
`41
`53
`35
`32
`
`54
`45
`41
`
`45
`59
`
`62
`56
`49
`97
`
`48
`75
`137
`
`73
`60
`
`Mean+SD
`VSD, ventricular septal defect; ASD, atrial septal defect; AVC,
`regurgitation.
`
`71±27
`45+9
`7.36+0.03
`complete atrioventricular canal; PV, pulmonary vein; MR, mitral
`
`Nitric Oxide Delivery System
`NO gas (800-1,000 ppm in N2, Airco, Riverton, N.J.)
`was mixed with N2 using a standard low-flow blender
`(Bird Blender, Palm Springs, Calif.). The NO and N2
`gas mixture was then mixed with varying quantities of
`air and oxygen shortly before introduction into the 1-1
`reservoir of a pediatric nonrebreathing mask (Baxter
`Healthcare Corp., Valencia, Calif.) worn by the patient.
`This system allowed separate regulation of the inspired
`concentrations of NO as quantified by chemilumines-
`cence17 (model 14A, ThermoEnvironmental Instru-
`ments Inc., Franklin, Mass.) and oxygen (Hudson Oxy-
`gen Meter 5590, Temecula, Calif.). The total gas flow
`rate was maintained above 8 1 min-', which reduced
`the NO residence time within the breathing circuit and
`hence the time for oxidation of NO to NO2. The stock
`NO gas contained up to 1% of the nitrogen oxides as
`NO2 (e.g., 800 ppm NO stock gas contained less than 8
`ppm NO2); the inspired NO2 concentration did not
`exceed 5% of the NO level. Exhaled gases, as well as
`those discharging from the chemiluminescence instru-
`ment, were scavenged.
`Patient Studies
`During diagnostic cardiac catheterization, we investi-
`gated separately the hemodynamic effects of inhaling
`low levels (20-80 ppm) of NO and a high FIo2 by 10
`successively studied, spontaneously breathing pediatric
`patients with congenital heart disease complicated by
`pulmonary hypertension. After sedation and placement
`of vascular catheters under local anesthesia, the specific
`cardiac lesions were defined with standard hemody-
`namic measurements and angiographic techniques. Pul-
`monary and femoral arterial blood pressures were de-
`termined with indwelling catheters and fluid-filled
`transducers (model 1280C, Hewlett-Packard, Palo Alto,
`Calif.). In patients with intracardiac shunting (patients
`1-6; Tables 1 and 2), pulmonary and systemic blood
`flows were determined by measuring oxygen consump-
`tion (MRM-2, Waters Instruments, Rochester, Minn.),18
`calculating pulmonary artery and pulmonary vein oxygen
`content from Pao2 and hemoglobin oxygen saturation
`
`(Radiometer, Copenhagen), and using the Fick principle.
`In patients without an angiocardiographically demon-
`strated intracardiac shunt, cardiac output was deter-
`mined in triplicate utilizing the thermodilution technique
`of injecting 3-ml aliquots of 0°C normal saline (COM-2,
`Baxter, Irvine, Calif.). Vascular resistance and central
`shunt were determined with standard formulae, and
`resistance was indexed to body surface area.'9
`In the 10 successive patients with pulmonary artery
`hypertension defined by an initial peak pulmonary
`artery pressure of more than half the systolic arterial
`pressure, the hemodynamic response to 10-minute pe-
`riods of breathing at FiO2 0.9 with or without inhaling
`low levels of NO was determined. In the first seven
`patients treated (excluding patients 2, 3, and 6), the
`response of the pulmonary circulation to 10-minute
`periods of sequentially inhaling 0, 20, 40, and 80 ppm
`NO at FiO2 0.9 was determined. In the last eight patients
`studied, the hemodynamic effects of inhaling 80 ppm
`NO at FiO2 0.21 were determined. In the six patients
`with an intracardiac shunt (patients 1-6), pulmonary
`and systemic blood flows were determined while breath-
`ing at FiO2 0.21 and at FiO2 0.9 with and without 80 ppm
`NO. Arterial blood was obtained for optical determina-
`tion of methemoglobin levels20 before and at the com-
`pletion of the study.
`All values are presented as mean+ SD. ANOVA with
`repeated measures was utilized; a posteriori testing was
`performed using a Fisher's protected least significant
`difference test.2' In comparing the patients with Tri-
`somy 21 with others, a one-tailed Student's t test was
`used.21 Significance is judged at a 5% level.
`Results
`A total of 10 patients (age range, 3 months to 6.5
`years) were studied (Table 1). Six patients (patients
`1-6) had increased pulmonary blood flow due to a
`ventricular septal defect (VSD) or complete atrioven-
`tricular canal (AVC), and two patients had pulmonary
`venous hypertension. One patient had pulmonary hy-
`pertension after repair of a VSD and pulmonary vein
`stenosis, and one had pulmonary hypertension associ-
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`
`ated with a hemodynamically insignificant VSD. Of the
`five patients with Trisomy 21, three had a complete
`AVC (one of which was corrected), and two had a VSD.
`All 10 patients had pulmonary hypertension with a
`baseline mean pulmonary artery pressure of 48±19
`mm Hg and pulmonary vascular resistance index (Rp)
`of 658±421 dyne * sec * cm` * m-2 (Table 2). The mean
`pulmonary artery pressure of the five patients with
`Trisomy 21 was 60±19 mm Hg and higher than that of
`the other five patients whom we studied (p<0.05). In
`the six patients with an intracardiac shunt, the pulmo-
`nary-to-systemic blood flow ratio was 2.0±0.8. Except
`for patient 10, who chronically breathed at FIo2 0.30,
`nine patients were breathing room air. The baseline
`pHa and Paco2 values were within the normal range
`(Table 1) and did not change during the study
`(p>0.05). Breathing at FiO2 0.9 increased Pao2 to
`292±83 mm Hg; breathing 80 ppm NO at FiO2 0.9
`produced a Pao2 of 287±119 mm Hg (p>0.05). Approx-
`imately two thirds of the patients were chronically
`treated with digoxin; daily diuretic therapy was given to
`half of the patients. The baseline hematocrit was
`37±5%.
`The dose-response of pulmonary hemodynamics to
`0-80 ppm inhaled NO at FiO2 0.9 was determined in
`seven patients. Adding NO to the hyperoxic gas mixture
`decreased Rp in a dose-dependent manner (Figure 1).
`Breathing 40 ppm NO at FiO2 0.9 significantly decreased
`Rp below both baseline and hyperoxic levels (pO0.05).
`The maximum reduction of Rp was achieved by inhaling
`80 ppm NO at FiO2 0.9. We therefore used 80 ppm NO
`to determine the hemodynamic effects of inhaled NO at
`FiO2 0.21-0.3 or 0.9.
`Inhaling 80 ppm NO at FiO2 0.21-0.3 or 0.9 rapidly
`reduced mean pulmonary artery pressure and Rp below
`the baseline level (pcO.05). However, pulmonary ar-
`tery hypertension returned within minutes of cessation
`of NO inhalation. In patients with an intracardiac shunt
`(patients 1-6), inhaling 80 ppm NO at FiO2 0.21 mod-
`estly elevated pulmonary blood flow from 8.8±5.2 to
`13.4±8.7 0.91 min* m-2 (p>0.05). Breathing 80 ppm
`NO at FiO2 0.9 significantly elevated pulmonary blood
`flow to 15.7±7.8 1l min-* m-2 and pulmonary-to-sys-
`temic blood flow ratio from 2.0±0.8 to 4.7±2.5 (both
`p<O.OS) (Figure 2). Although the greatest reduction in
`Rp occurred while inhaling 80 ppm NO at FiO2 0.21-
`0.30 in patients with high baseline levels of Rp, when
`breathing NO at FiO2 0.90, eight of 10 patients exhibited
`a reduction in Rp (Table 2 and Figure 3). Each of the
`patients with Trisomy 21 had reduced mean pulmonary
`artery pressure and Rp values when measured during
`NO inhalation at FiO2 0.21-0.90.
`In contrast to inhaling NO, breathing at FiO2 0.9
`without added NO did not reduce mean pulmonary
`artery pressure but did reduce Rp to 535±379
`dyne * sec * cm-5 m2 (p<0.05). In patients with an
`intracardiac shunt, breathing at FiO2 0.9 without added
`NO increased pulmonary blood flow from 8.8±5.2 to
`15±7.8 1. min`1 m2 (pcO.05, Figure 2). For patients
`without an intracardiac shunt, breathing at FiO2 0.9
`without added NO only modestly elevated pulmonary
`blood flow (Table 2).
`Although inhaled NO was a potent pulmonary vaso-
`dilator in eight of 10 pediatric patients with pulmonary
`hypertension. inhaling 80 ppm NO at both FiO2O.21 and
`
`Roberts et al
`
`Inhaled Nitric Oxide in CHD
`
`449
`
`0.9 did not produce systemic vasodilation and did not
`alter mean aortic pressure, systemic blood flow, or
`systemic vascular resistance index (Rs). Inhaling up to
`80 ppm NO for 30 minutes did not change the circulat-
`ing methemoglobin levels (0.7±0.7% before NO,
`0.7±0.4% after NO; n=7,p=0.53).
`Discussion
`In our studies of 10 pediatric patients with congenital
`heart disease and pulmonary artery hypertension, in-
`haling 80 ppm NO at either the baseline FiO2 (0.21-
`0.30) or at FIo2 0.9 reduced pulmonary vascular resis-
`tance and pulmonary artery pressure within 1-3
`minutes without decreasing systemic arterial pressure or
`resistance (Table 2). In each of our patients, within
`minutes after cessation of NO inhalation, pulmonary
`vascular resistance and pulmonary artery pressure re-
`turned to baseline levels. We found that inhaling 80
`ppm NO at FiO2 0.9 produced the maximum reduction
`of Rp in eight of our 10 patients and increased pulmo-
`nary blood flow in all six patients with an intracardiac
`shunt (Figures 2 and 3). In contrast, breathing at FiO2
`0.9 without NO did not reduce mean pulmonary artery
`pressure below baseline values and produced only a
`modest decrease of Rp compared with baseline mea-
`surements (Figure 3). Thus, inhaling NO can dilate
`pulmonary vasoconstriction that is not caused by hy-
`poxia in congenital heart disease.
`The patients in our study with the greatest level of
`pulmonary hypertension or pulmonary vascular resis-
`tance had the most consistent reduction of mean pul-
`monary artery pressure and Rp with NO inhalation.
`Many of these patients also had Trisomy 21. Other
`investigators have reported that patients with Trisomy
`21 and congenital heart disease exhibit the highest
`levels of pulmonary hypertension22,23 and that 90% of
`patients with Trisomy 21 presenting for diagnostic car-
`diac catheterization will have significant pulmonary
`hypertension.22 Although only 5% of pediatric patients
`with congenital heart disease who undergo cardiac
`catheterization have Trisomy 21,23 approximately half of
`the pediatric patients with congenital heart disease and
`pulmonary artery hypertension have Trisomy 21.22,24
`Congenital heart lesions can produce pulmonary ar-
`tery hypertension with vascular smooth muscle hyperpla-
`sia and hypertrophy.3 After corrective cardiac surgery,
`the pulmonary vascular bed in some patients with con-
`genital heart diseases may not regress sufficiently to
`accommodate the postoperative hemodynamic changes.
`It often is desirable to determine the vasodilatory capac-
`ity of the pulmonary circulation during preoperative
`cardiac catheterization to attempt to predict the postop-
`erative pulmonary vascular resistance. Hyperoxic breath-
`ing has been used to determine the vasodilatory capacity
`of the lung. Currently used vasodilator agents such as
`prostacyclin (PGI2),25 tolazoline,26 prostaglandin E1,27
`and sodium nitroprusside27 may reduce the pulmonary
`vascular resistance. However, these intravenous agents
`are nonselective and dilate the systemic circula-
`tion.25,27-29 Thus, we chose to compare the pulmonary
`vasodilator potency of inhaled NO with oxygen as it is the
`only other pulmonary vasodilator in widespread use that
`does not cause systemic vasodilation. This study demon-
`strates that inhaled NO is a selective pulmonary vasodi-
`lator that exhibits a far greater vasodilatory effect than
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`
`450
`
`Circulation
`
`Vol 87, No 2
`
`February 1993
`
`TABLE 2.
`
`Pao2
`
`P PAR
`
`PjV
`
`P AO
`
`Physiological Responses to Inhaling NO Without and With High Oxygen Concentrations
`0 ppm NO
`RP
`
`R,
`
`PS
`
`Patient
`FIo2 0.21-0.30
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`Mean±SD
`FiO2 0.90
`391
`1
`45
`6
`243
`67
`4.4
`12.8
`1,183
`2
`225
`347
`68
`7
`60
`2.5
`12.2
`1,838
`311
`3
`55
`215
`70
`7
`2.1
`17.8
`2,437
`148
`4
`72
`55
`3
`1,286
`236
`4.1
`17.6
`357
`5
`70
`25
`2
`28.6
`1,206
`64
`4.5
`90
`0
`89
`184
`6
`1,822
`1,229
`4.0
`5.2
`346
`7
`2
`24
`80
`2.4
`3,324
`732
`2.4
`35
`315
`8
`854
`78
`4
`2,069
`2.9
`2.9
`9
`18
`82
`67
`376
`1,350
`870
`4.5
`4.5
`266
`10
`16
`33
`2,181
`2.4
`566
`75
`2.4
`536±376t
`48±19
`Mean±SD
`1,870±675
`292±83
`75±7
`7±6
`10.6±8.8
`3.4±1.0
`PFA, mean pulmonary artery pressure; Ppv, mean pulmonary venous pressure; PAO, mean aortic pressure; Rp,
`pulmonary vascular resistance index; R,, systemic vascular resistance index; Qp, pulmonary blood flow; Q5, systemic
`blood flow. The hemodynamic effects of inhaling 80 ppm NO at FiO2 0.21-0.9 by pediatric patients with congenital heart
`disease. Pressure units (P) are mm Hg, and resistance units (R) are dyne sec. cm`S m-2; Op and Os are in
`1 min-1 m
`*p<0.05 value differs from FiO2 0.21-0.3 without inhaled NO.
`tp<0.05 value differs from FiO2 0.9 without inhaled NO.
`
`57
`62
`56
`49
`97
`48
`75
`137
`73
`60
`71±27
`
`47
`52
`66
`70
`31
`80
`25
`37
`35
`32
`48±19
`
`5
`7
`3
`5
`4
`2
`2
`4
`15
`15
`6±5
`
`55
`70
`68
`72
`72
`80
`70
`82
`55
`70
`69±9
`
`419
`782
`883
`321
`151
`1,558
`707
`1,014
`410
`485
`673+411
`
`767
`1,830
`1,558
`975
`1,135
`1,358
`2,117
`2,429
`1,079
`1,758
`1,501±534
`
`8.0
`4.6
`5.7
`16.2
`14.3
`4.0
`2.6
`2.6
`3.9
`2.8
`6.5±4.9
`
`5.2
`2.8
`3.3
`5.5
`4.8
`4.6
`2.6
`2.6
`3.9
`2.8
`3.8±1.1
`
`hyperoxic breathing. A much larger study correlating the
`effects of preoperative inhaled NO with postoperative
`hemodynamic course should be performed in the future.
`Our study demonstrates that inhaled NO is a potent
`pulmonary vasodilator. There are two recent reports
`comparing the pulmonary vasodilatory effects of intrave-
`nous prostacyclin with inhaled NO in two adult patient
`populations: adults with primary pulmonary hyperten-
`sion13 and adult respiratory distress syndrome.14 Despite
`the differences in etiology of the pulmonary vascular
`hypertension in these two syndromes, inhaled NO pro-
`duced more consistent pulmonary vasodilation than
`PGI2, without causing systemic vasodilation.
`The pulmonary and systemic vasodilation produced
`by intravenous prostacyclin has been extensively studied
`in congenital heart disease. Bush et a125 evaluated the
`pulmonary vasodilatory potency of intravenous PGI2 in
`20 pediatric patients with congenital heart disease and a
`Rp (p=0.65, unpaired t test) and mean pulmonary
`artery pressure (p=0.98) similar to those of the patients
`whom we studied. Bush and coworkers reported that
`intravenous infusions of 20 ng . kg` - min` PGI2 re-
`duced Rp by 186 dyne. sec * cm`5 m-2 when the pa-
`tients breathed at FiO2 0.21, and PGI2 reduced Rp by
`136 dyne. sec. cm`5 * m2 when the patients breathed at
`FiO2 1.0. In comparison with this study of intravenous
`
`prostacyclin, we found 24% and 70% greater reduction
`of Rp when 80 ppm NO was breathed at FiO2 0.21-0.3
`and 0.9, respectively, in contrast to PGI2. This indirect
`comparison suggests that inhaled NO may produce
`more potent and selective pulmonary vasodilation than
`PGI2 in pediatric patients with congenital heart disease.
`Studies of patients with pulmonary hypertension fol-
`lowing congenital heart surgery reported a reduction of
`mean pulmonary artery pressure during treatment with
`intravenous nitroprusside, a NO donor compound.29
`Inhaled NO diffuses directly into pulmonary vascular
`smooth muscle cells and activates guanylate cyclase9.10
`to produce vasodilation. NO that diffuses into the
`pulmonary circulation is rapidly inactivated by combi-
`nation with hemoglobin, thereby preventing systemic
`vasodilation. Our laboratory has reported selective pul-
`monary vasodilation by NO inhalation in sheep weigh-
`ing 25-35 kg with pulmonary vasoconstriction produced
`by hypoxia or infusion of a stable thromboxane analogue
`(U46619)11; NO vasodilation was not altered by indo-
`methacin treatment, suggesting prostacyclin production
`was not involved.30 Recently, we reported that inhaled
`NO is a pulmonary vasodilator that rapidly and com-
`pletely reverses hypoxic pulmonary vasoconstriction
`without producing systemic hypotension in the newborn
`lamb with a transitional circulation.31,32 We also re-
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`Roberts et al
`
`Inhaled Nitric Oxide in CHD
`
`451
`
`TABLE 2.
`
`Continued
`
`Patient
`FIo2 0.21-0.30
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`Mean±SD
`FiO2 0.90
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`Mean±SD
`
`Pao2
`
`PPA
`
`PRY
`
`PA;
`
`80 ppm NO
`RP
`
`69
`76
`53
`59
`76
`58
`73
`127
`
`30
`42
`47
`50
`25
`65
`22
`40
`
`7
`7
`6
`2
`1
`0
`2
`4
`
`65
`58
`63
`72
`65
`75
`72
`78
`
`67
`411
`372
`195
`153
`1,018
`571
`1,199
`
`RS
`
`1,199
`1,838
`1,606
`1,462
`1,422
`1,175
`2,269
`2,533
`
`(P
`
`27.6
`6.8
`8.8
`19.7
`12.5
`5.1
`2.8
`2.4
`
`QS
`
`4.2
`2.4
`2.9
`3.8
`3.6
`5.1
`2.8
`2.4
`
`74±23
`
`40±14*t
`
`4±3
`
`69±7
`
`498±412*
`
`1,688±494
`
`10.7±8.9
`
`3.4±1.0
`
`457
`409
`298
`113
`358
`177
`279
`337
`327
`111
`287±119
`
`32
`45
`42
`55
`27
`52
`18
`37
`30
`35
`37±11*t
`
`10
`8
`7
`7
`2
`0
`2
`4
`18
`25
`8±8
`
`75
`68
`63
`70
`72
`85
`72
`72
`85
`85
`75±8
`
`91
`137
`148
`192
`60
`561
`492
`879
`240
`285
`308±260*
`
`1,694
`2,597
`2,213
`927
`1,334
`1,047
`2,741
`1,838
`1,702
`2,045
`1,814±607
`
`19.4
`21.6
`18.9
`20.1
`33.3
`7.4
`2.6
`3.0
`4.0
`2.8
`13.3±10.7*
`
`3.4
`2.0
`2.1
`5.5
`4.2
`6.5
`2.6
`3.0
`4.0
`2.8
`3.6±1.5
`
`ported that inhaled NO improved systemic oxygenation
`in many critically ill infants with persistent pulmonary
`hypertension of the newborn.15 Inhaled NO (10-80
`ppm) reverses hypoxic pulmonary vasoconstriction in
`normal human volunteers12 and patients with adult
`respiratory distress syndrome for periods up to 53
`days.14 Pepke-Zaba et al13 reported that Rp decreased
`in eight adult patients with chronic PA hypertension
`breathing 80 ppm NO but did not report PA pressure or
`cardiac output. NO inhalation has recently been re-
`ported to be a bronchodilator of the methacholine-
`constricted guinea pig.33
`
`RpNap m
`
`It is likely that there is no toxicity associated with
`breathing 20-80 ppm NO for the brief period of a
`cardiac catheterization. No pulmonary injury, which is
`more likely to be associated with NO2 inhalation, was
`apparent in our patients. Recently, seven patients with
`severe adult respiratory distress syndrome were treated
`by inhaling 20 ppm NO for 11-53 days with a consis-
`
`6p
`30
`1.min1.lm 2 251
`
`_t
`
`.14
`
`go
`
`40
`
`NO(ppm) |
`20
`0
`l0b
`0.21 - 0.AD0@
`FIGURE 1. Bar graph of effect on pulmonary vascular
`resistance index (Rp) ofbreathing 20-80ppm NO at FIo2 0.9
`by seven pediatric patients with congenital heart disease.
`tp<0.OS value differsfrom both baseline and FIO2 0.9 without
`inhaled NO. Increasing the FIO2 from baseline (0.21-0.3) to
`0.9 did not change Rp. Adding 40ppm NO reduced Rp below
`both baseline and Fio2 0.9 levels; the maximal pulmonary
`vasodilatory effect was obtained by breathing 80 ppm NO in
`oxygen.
`
`FIGURE 2. Bar graphs ofhemodynamic effects ofbreathing
`at FRo2 0.9 and 80 ppm NO by six pediatric patients with
`congenital heart disease and an intracardiac shunt. Units for
`bloodflow (Q) are 1 min' * m 2. tp<0.05 value differsfrom
`Fio2 0.21 without NO. *p<0.05 value differs from FIO2 0.21
`with 80 ppm NO. Breathing 80ppm NO at FRo2 0.9 increased
`pulmonary blood flow (Qp). Inhaling 80 ppm NO at FIo2
`0.21-0.3 and 0.9 did not alter systemic blood flow (Q).
`Breathing at FRO2 0.9 with or without 80 ppm NO increased
`QpIQs. Maximum elevation of QplQ. occurred while inhaling
`80 ppm NO at Fio2 0.9.
`
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`
`452
`
`Circulation
`
`Vol 87, No 2
`
`February 1993
`
`F102 0.21-0.30 and 80 ppm NO
`
`1401-
`g ~
`12@06
`10/ /
`I~
`fa-
`1i
`/0
`s09n
`
`,/
`
`@O
`
`~~~/
`
`/
`
`*
`
`*Tri0omy 21
`O Othus
`-Lh~ of medhy
`
`0
`
`400
`
`000
`Basene Rp
`Fl02 0.90 and 80 ppm NO
`Irn,1
`
`120
`
`F102 0.90 and no Inhald NO
`14m
`
`/
`
`/1
`
`/0
`
`0
`
`Bi
`T O
`
`0
`
`1/0 0
`/
`
`,
`
`0
`
`&rn
`
`/irn
`cc 4m
`
`/
`
`0
`
`/
`
`0.
`
`1400
`'E1260
`h-
`1
`.4n
`n
`1.
`t 1
`
`1-
`
`1-
`
`1-
`
`a-r
`
`'00 000
`A0 400 rn
`
`O
`
`e
`
`ir
`
`'/0
`0
`
`rn
`
`1200
`
`1rn
`
`rn
`RP
`Baseline Rp
`Scatterplots ofhemodynamic effects ofbreathing
`FIGURE 3.
`at Fio2 0.90 and 80 ppm NO by 10 pediatric patients with
`congenital heart disease and pulmonary artery hypertension.
`The units of pulmonary vascular resistance index (Rp) are
`dyne sec cm-'. m-2. The baseline Rp was measured while
`breathing at Fio2 0.21-0.30 without addition ofNO gas. The
`Rp with treatment was during breathing at Fio2 0.21-0.90
`with or without 80 ppm NO. *, Values from patients with
`Trisomy 21; o, values from patients without Trisomy 21. The
`stippled line is where the treatment would not change pulmo-
`nary pressure from baseline values. Inhaling NO at Fio2
`0.21-0.90 reduced Rp in the many patients; those with a
`higher baseline pulmonary hypertension had greater pulmo-
`nary vasodilation. In all patients with Trisomy 21 (a),
`inhaling 80 ppm NO at Ff02 0.21-0.90 reduced Rp. Breathing
`at Fio2 0.90 without NO did not consistently reduce Rp.
`
`tently reduced pulmonary artery pressure and an in-
`creased Pao2.14 Six of these patients survived, and there
`was no clinical evidence of additional lung injury due to
`NO inhalation. Methemoglobin levels can be increased
`by inhalation of NO but did not increase in either the
`patients with adult respiratory distress syndrome14 or
`our patients with congenital heart disease.
`This study demonstrates that 40-80 ppm inhaled NO
`is a selective pulmonary vasodilator of pediatric patients
`suffering from congenital heart lesions complicated by
`pulmonary artery hypertension that does not dilate the
`systemic circulation. It is probable that inhaling NO at
`cardiac catheterization can assess pulmonary vasodila-
`tory capacity in pulmonary hypertension and may safely
`allow the preoperative identification of children with a
`critically limited and restricted pulmonary vascular bed.
`Acknowledgments
`The authors are indebted to E. Marsha Elixson, RN, MS,
`the staff of the Knight Cardiac Catheterization Suite, Dr.
`Robert Kacmarek, and the staff of the Respiratory Care
`Department. We would also like to thank Drs. Edward Low-
`enstein, David Wessel, and Kenneth D. Bloch for helpful
`comments on the manuscript.
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