PATHOBIOLOGY
`
`EDITED BY
`
`LOUIS J. IGNARRO
`
`@
`
` PRAXAIR 1024
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`001
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`

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`002
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`
`Nitric Oxide
`Biology and Pathobiology
`
`Edited by
`
`Louis J. Ignarro
`
`Department of Molecular and Medical Pharmacology
`UCLA School of Medicine
`Los Angeles, California
`
`ACADEMIC PRESS
`
`San Diego
`
`A Harcourt Science and Technology Company
`San Francisco New York
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`This book is printed on acid-free paper. (§)
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`Copyright © 2000 by ACADEMIC PRESS
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`International Standard Book Number: 0-12-370420-0
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`PRINTED IN THE UNITED STATES OF AMERICA
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`930
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`SECTION III Principles of Pathobiology
`
`Abnormal endothelium-dependent vascular relaxation in patients with
`essential hypertension. N. Engl. 1. Med. 323• 22- 27 ·
`. .
`.
`Petros, A., Bennett, D., and Vallance: P. (1991). Effect ofmtnc ox!~~~.~~
`thase inhibitors on hypotension In patients with septic shock.
`
`Pet\!~8~15~::~5~.· Leone, A., Moncada, S. , Bennett, D., and Vallance, P.
`
`({994.l. Effec;s of a nitric oxide synthase inhibitor in humans With septiC
`shock. Cardiovasc. Res. 28, 34-39.
`.
`Riezebos, J., Watts, I. S., and Vallance, P. (1994). Endothehn recept~rs
`mediating functional responses in human small artenes and vems. Bl. J.
`. Pharma~ol.S111,1609J-6;5. Loh E. Loscalzo, J., Francis, S, A., and
`Sim~~~a~~r. ·M. t:~ (e;;NS). Effect' of ~itric oxide synthase inhibition on
`
`bleeding time in humans. J. Cardiovasc. Pharmacol. 26, 339-342.
`Stamler, J. S., Loh, E., Roddy, M. A., Currie, K. E., and Creage~a~~~;
`(1994). Nitric oxide regulates basal systemic and pulmonary
`resistance in healthy humans. Crrculatwn 89, 2035-2040.
`Steinberg, H. 0., Brechtel, G., Johnson, A., Fmebe~g, .N., ~nd .Baron, A.
`(1994). Insulin-mediated skeletal muscle vasodilat~on IS mtnc oxide
`dependent. A novel action of insulin to increase mtnc oxide release.
`J. Clin. Invest. 94, 1172-1179.
`.
`Taddei, S., Virdis, A., Mattei: P., Ghiado~i, L., Sudano, I., an~nS"a~~e:~:~e~~
`(1996). Defective L-argmme-mtnc oxide pathway m offsp
`"
`tial hypertensive patients. Circulation94, 1298-1303.
`.
`Vallance, P., and Charles, I. ( 1998). Nitric oxide m sepsis: Of nuce and men.
`Sepsis 1, 93-100.
`
`Vallance, P., Collier, J., and Moncada, S. (1989a). Effects of endothelium
`derived nitric oxide on peripheral arteriolar tone Lll man. Lancet 2,
`
`Vall~~:~.1g~~ollier, J., and Moncada, S. (1989b). Nitric ~xide synthesized
`
`from L-arginine mediates endothelium dependent dilatiOn In human
`
`veins in vivo. Cardiovasc. Res. 23,.1053- 1057.a The effect of endo-
`Vallance, P., Benjanun, N., and Collier, J. (1992 ).
`"
`.
`thelium-derived nitric oxide on ex vivo whole blood platelet aggre,atiOn
`199~b)
`in man. Euro. J. Clin. Plwrmacol. 42, 37-41.
`Vallance, P., Leone, A., Calver,-A., Collier, J., and Moncada, S. (
`.~ ..
`Accumulation of an endogenous inhibitor of mtnc oxide synthesis m
`chronic renal failure. Lancet 339, 572-575.
`.
`Vallance, P., Patton, S., Bhagat, K., MacAllister, R., Radoms~I, .~··
`Moncada, S., and Malinski, T. (1995). Direct measurement of mtuc
`oxide in human beings. Lancet 346, 153-' ~54. H S ( 1998) Nitric oxide
`Wh 't R p Deane C. Vallance, P., and Mar us,
`.
`.
`.
`~;~th~s~ inhibi;ion' in humans reduces cerebral blood flow but not the
`hyperemic response to hypercapnia. Stroke 29, 467-472). N'
`'d
`.
`Williams, D. J' Moosavi, A. H., and Imms, F. J. (1995 .
`Jtnc OXI e
`contributes to local heat induced vasodilation Ill man. J. Physwl. 483,
`A . J.
`d !nuns F J
`A
`.
`126-127.
`1
`Williams, D. J., Vallance, P., Neild, G. H., Spence!,
`., an
`.
`(1997). Nitric oxide-mediated vasodilatiOn In human pregnancy.
`Physiol. 272, H748-H752.
`
`Ill .
`
`.
`
`- - - - - -
`
`CHAPTER 56
`
`Clinical Therapy with Inhaled
`Nitric Oxide in Respiratory Diseases
`
`William E. Hurford, Wolfgang Steudel, and Warren M. Zapol
`Department of Anesthesia and Critical Care
`Massachusetts General Hospital
`Harvard Medical School
`Boston, Massachusetts
`
`MANY INSIGHTS INTO THE MECHANISMS OF ACTION OF NITRIC OXIDE (NO) HAVE BEEN RAP(cid:173)
`IDLY APPLIED TO TREAT PATIENTS. SINCE THE REPORTED APPLICATIONS OF INHALED NO IN
`THE LABORATORY (FROSTELL et al., 1991) AND IN ADULT PATIENTS WITH PRIMARY PUL(cid:173)
`MONARY HYPERTENSION (PEPKE-ZABA eta/., 1991), HUNDREDS OF STUDIES HAVE BEEN CON(cid:173)
`DUCTED TO DETERMINE THE CLINICAL APPLICABILITY OF INHALED NO. IN SELECTED GROUPS
`OF SEVERELY ILL AND HYPOXIC CHILDREN AND ADULTS, INHALED NO IMPROVES ARTERIAL
`OXYGENATION AND SELECTIVELY REDUCES PULMONARY ARTERIAL HYPERTENSION (PAH). NO
`INHALATION THERAPY, IN COMBINATION WITH CONVENTIONAL (NEONATAL INHALED NITRIC
`OXIDE STUDY GROUP, 1997A; ROBERTS et al., 1997) OR HIGH-FREQUENCY OSCILLATORY
`VENTILATION (KINSELLA et al., 1997), CAN SIGNIFICANTLY IMPROVE ARTERIAL OXYGENATION
`AND REDUCE THE NEED FOR EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO), AN
`EXPENSIVE AND INVASIVE SUPPORT PROCEDURE IN NEWBORN PATIENTS WITH HYPOXIC RESPI(cid:173)
`RATORY FAILURE. HOWEVER, IT REMAINS UNCERTAIN WHETHER NO INHALATION IMPROVES
`SURVIVAL RATES IN ADULTS WITH SEVERE ACUTE LUNG INJURY.
`
`NEW APPLICATIONS FOR NO INHALATION HAVE BEEN DISCOVERED. STUDIES INDICATE
`THAT INHALED NOMA Y DECREASE ISCHEMIA-REPERFUSION INJURY (BACHA eta/., 1996) AND
`MAY BE USEFUL TO TREAT THROMBOTIC DISORDERS (ADRIE et al., 1996; NONG et al., 1997).
`By INCREASING THE 0,~ AFFINITY OF SICKLE CELL HEMOGLOBIN, INHALED NO MAY PREVENT
`OR TREAT SICKLE CELL CRISIS. THIS CHAPTER WILL REVIEW THESE DIVERSE CLINICAL APPLI(cid:173)
`CATIONS FOR INHALED NO THERAPY
`
`Background
`
`monary vasodilator, in a variety of both animal models and
`clinical conditions.
`The d_ ~nistrnJii 11 of 'nhOJ<I ,
`ft -IJ in1 pro es sys-
`t•Cillli o; yg ·rmt~ l'l tlur· -g :.·um• lung injru-)'. omm nly used
`nc>l.Liyadmioi.o;t~tl' 'l' s
`· lo . dirft.re '}'ro e asehy(cid:173)
`Ultr-a
`lung: nd can
`pu ··c pu]m ary 11 , OOOJJslricli wjlhi1 ll1
`worsen oxygenation. Inhaled nitric oxide, by being delivered
`to areas of the lungs that are best ventilated and then
`by being rapidly bound to hemoglobin and inactivated in
`
`931
`
`Copyright © 2000 by Academic Press.
`All rights of reproductjon jn any form reserved
`
`005
`
`

`
`932
`
`SECTION III Principles of Pathobiology
`
`the circulation, can selectively vasodilate ventilated lung
`regions. Regions of the lungs that are not ventilated are not
`exposed to inhaled NO. Oxygenation improves via a reduc(cid:173)
`tion in relative blood flow to nonventilated regions.
`Borland and co-workers administered inhaled NO to pa(cid:173)
`tients and volunteers to determine the diffusing capacity of
`the lung (Borland and Higenbottam, 1989). They found that
`a single breath of nitric oxide could be administered safely.
`Because NO is also an atmospheric pollutant (Alberts,
`1994), human toxicity studies (von Nieding et al., 1975) and
`exposure recommendations (Centers for Disease Control,
`1988) had been previously reported and provided the foun(cid:173)
`dation for initial clinical studies. Today, substantiated indi(cid:173)
`cations for inhaled nitric oxide (Table I) include hypoxic
`respiratory failure of the newborn (Clark, 1999; Hoffman et
`al., 1997; Kinsella et al., 1997; Neonatal Inhaled Nitric
`Oxide Study Group, 1997a; Roberts et al., 1997) and the
`assessment of pulmonary vascular reactivity in patients with
`pulmonary hypertension (Fishman et al., 1998). Inhaled NO
`has also been used in the treatment of acute respiratory dis(cid:173)
`tress syndrome (ARDS), lung and cardiac transplants, con(cid:173)
`genital and acquired heart disease, and chronic pulmonary
`hypertension, and it has been used to produce desirable di(cid:173)
`rect effects on blood elements, specifically for the treatment
`of acute chest syndrome in sickle cell disease.
`
`Neonatal Respiratory Failure
`
`Persistent pulmonary hypertension ofthe newborn (PPHN)
`is a clinical syndrome characterized by sustained pulmonary
`hype11ension and severe hypoxemia, resulting in cyanosis
`that is unresponsive to oxygen therapy. Persistent pulmo(cid:173)
`nary hypertension of the newborn may be due to a variety
`of etiologies (Roberts, 1993). Diagnostic confirmation of
`PPHN includes echocardiographic observation of a right-to(cid:173)
`left shunt through the ductus arteriosus or foramen ovale,
`due to increased pulmonary vascular resistance (PVR), in
`the absence of congenital heart disease. Conventional treat(cid:173)
`ment strategies include breathing high inspired 0 2 concen-
`
`Table I Clinical Indications for Inhaled Nitric Oxide
`
`Substantiated
`Hypoxic respiratory failure and persistent pulmonary hypertension of
`the newborn (PPHN)
`Assessment of pulmonary vascular reactivity in patients with pulmonary
`hypertension
`
`Investigational
`Acute respiratory distress syndrome (ARDS)
`Lung and cardiac transplantation
`Congenital and acquired heart disease
`Chronic pulmonary hypertension
`Ischemia-repetfusion injury
`Anti platelet effects
`Acute chest syndrome in sickle cell disease
`Bronchodilation
`
`CHAPTER 56 Clinical Therapy with Inhaled NO in R~!ipi
`
`Diseases
`
`200
`
`1 0 Control
`•
`Nitric oxide
`
`933
`
`bs!'lflliall.l.d in nltllll-
`
`C»
`:r:
`E
`.§
`~N
`a..
`
`A
`
`Base Line
`
`After Treatment
`
`)(
`(J)
`"C
`E
`c
`0
`-~
`c
`(J)
`Cl > )(
`0
`
`After Treatment
`Base Line
`Figure 1 Short-term effects of inhaled NO on systemic oxygenation in
`mfants w!lh severe hypoxemia and persistent pulmonary hypertension of
`~he newbo~. Treatment With mtnc oxide inhalation (80 ppm at FiO, 0.9 for
`0~ ~:n~n - 30), but not w!lh place.bo inhalation (control, mtrogen at FiO,
`28), after randomized assignment Significantly (p < 0.001) im-
`,
`proved postductal PaO, (A) and oxygenation index (B) compared with bas(cid:173)
`~~:~~-9~;~ues are means ± SO Reprinted with permission from Roberts et
`
`Acute Respiratory Distress Syndrome
`
`Pulmonary Vascular Resistance
`Rossaint ~tal. (1993) demonstrated that inhaled NO pro(cid:173)
`duced selectiVe pulmonary vasodilation in patients with se(cid:173)
`vere ARDS (Fig. 2). This was later confirmed by larger
`studies (~ellinger et al., 1998; Manktelow et al., 1997). In
`so~e patl~nts, NO-induced pulmonary vasodilation was suf(cid:173)
`fiClent to Improve right ventricular performance (Rossaint et
`al., 1995a). In children with ARDS, inhaled NO (20 ppm)
`decr~ased mean pulmonary artery pressure (MPAP) by 25%
`and mcreased cardiac i~dex by 14% (Abman et al., 1994).
`Inh~led NO ~lso effectively relieved the pulmonary hyper(cid:173)
`ten~wn as~ociated with the use of permissive hypercapnia in
`patients with ARDS (Puybasset et al., 1994).
`Inhaled NO_ ( 40 ppm) decreased pulmonary capillary
`pressure (Benzmg and Geiger, 1994) and pulmonary trans-
`
`006
`
`

`
`940
`
`100
`
`c::
`
`60 -
`
`E.Z
`Q) <1l
`
`~~ 80
`ii 40
`£~ 20
`0
`
`0
`
`40
`80
`60
`10
`40
`P02 (mmHg)
`NO (ppm)
`Figure 6 Effects of NO on oxygen affinity of red blood cells. Exposure to NO (80 ppm for 15 min) shifted to the left the
`oxygen dissociation curve of hemoglobin S erythrocytes (left). The effect of NO exposure on P50 of hemoglobin S erythro(cid:173)
`cytes was dose dependent (right). Values are means ± SE. Reprinted with permission from Head eta/. (1997).
`
`Nitrotyrosine residues were detected in the airway speci(cid:173)
`mens of two infants requiring prolonged ventilation with NO
`in this study. The relative contribution of NO inhalation and
`endogenous NO formation to nitrotyrosine formation in the
`lung is unclear, however, because nitrotyrosine formation
`has been demonstrated in acutely injured lungs without the
`exogenous administration of NO (Haddad et al., 1994; Kooy
`et al., 1995). Studies of survivors of ARDS treated with
`inhaled NO reported no obvious differences in pulmonary
`function compared with ARDS patients not treated with NO
`(Luhr et al., 1998). The doses of NO in current clinical use
`are less than that received with cigarette exposure and are
`nearly within the range encountered while breathing the air
`of many urban centers (Lee et al., 1997).
`
`Methemoglobinemia
`
`Blood methemoglobin concentrations have been regu(cid:173)
`larly monitored in clinical trials of inhaled NO in adults and
`neonates (Dellinger et al., 1998; Kinsella et al., 1997; Neo(cid:173)
`natal Inhaled Nitric Oxide Study Group, 1997a,b; Roberts et
`al., 1997). The incidence of methemoglobinemia has been
`low. Its occurrence is more common in neonates and with
`high inhaled doses, but it is usually well tolerated. There
`have been no reports of sequelae to methemoglobinemia in
`randomized studies. Methemoglobinemia is easily treated by
`reducing the dose of NO. Single reported cases of more se(cid:173)
`vere methemoglobinemia during NO therapy have occurred
`in the setting of high doses (Hess et al., 1997). Chemical
`therapies, such as methylene blue and ascorbic acid, are
`available, but they should not be necessary if methemoglo(cid:173)
`bin levels are monitored.
`
`Inhibition of Platelet Function
`
`Inhaled NO inhibits platelet function. Increased bleeding
`times and decreased platelet aggregation have been reported
`in experimental animals and patients (George et al., 1998;
`Hogman et al., 1993b, 1994; Samama et al., 1995). In ran(cid:173)
`domized studies of adults and term and nearly full-term in(cid:173)
`fants, however, an increased incidence of clinical bleeding
`
`has not been substantiated (Dellinger et al., 1998; Kinsella
`et al., 1997; Neonatal Inhaled Nitric Oxide Study Group,
`1997a,b; Roberts et al., 1997). Indeed, platelet inhibition
`could be therapeutic, rather than detrimental. Nevertheless,
`a cautious approach to the possibility of worsened bleeding
`during inhaled NO therapy remains prudent, especially in
`premature infants who have a high incidence of intracranial
`hemorrhages (Meurs et al., 1997).
`
`Adverse Hemodynamic Effects
`
`Inhaled NO may also have adverse hemodynamic effects.
`Inhalation of NO may vasodilate the pulmonary circulation
`and increase blood flow entering the left ventricle. In patients
`with preexisting severe left ventricular dysfunction, an in(cid:173)
`creased left ventricular end-diastolic pressure (Hayward et
`al., 1996; Loh et al., 1994; Semigran et al., 1994) and pul(cid:173)
`monary edema (Bocchi et al., 1994) during NO breathing
`have been reported. This increase may be due to small in(cid:173)
`creases in left ventricular volume associated with improved
`right ventricular function that, in tum, produced exaggerated
`increases in pulmonary capillary wedge pressure when the
`left ventricle is poorly compliant. Monitoring of left ventric(cid:173)
`ular function may be indicated when inhaled NO is admin(cid:173)
`istered to patients with severe left ventricular dysfunction.
`Rebound hypoxemia and pulmonary hypertension may
`occur after the sudden discontinuation of NO (Bigatello et
`al., 1994; Lavoie et al., 1996; Rossaint et al., 1993). It has
`been suggested that the downregulation of endogenous NO
`synthesis by NO inhalation is responsible for rebound PAH
`(Ma et al., 1996; Rengasamy and Johns, 1993). Data ob(cid:173)
`tained in rats with hypoxic pulmonary hypertension, ho':(cid:173)
`ever, suggest that inhibition of endogenous NO synthesis
`play a minor role in rebound PAH: no changes of lung en(cid:173)
`dothelial nitric oxide synthase (NOS) protein levels, NOS
`diYily,
`·m.lolhdium-tlependcnl :uuJ
`-i dependent
`"'"'
`'l"''rtcd :.flcr 3 week inhalin 20 ptlm 0 ·
`dillll10il were
`rJ
`LLmg guan)'llll cy- ·k~ ct~'\'tl was Lrun '~,:
`tiC rea.
`lr Ler I w e - rNO ~nha]atiun, butgund)'n I cyclt!b.e a llvllY
`luf "« ran
`lllHll!li.d afler J wa:h or NO jn
`·a
`;:( tiJ..
`1998).
`
`SECTION III Principles of Pathobiology
`
`CHAPTER 56 Clinical bt!rnl)}' with Inhaled NO in ~Sillr<llul) Diseases
`
`941
`
`__ •... •-·-
`
`,e'
`
`P50 =,26 ~:
`'":
`:
`...
`
`P50 = 32.5
`
`oAir
`• .80 ppm NO
`1n a1r
`
`20
`
`100
`
`120
`
`36
`
`35
`34
`Ol 33
`I
`E 32
`~
`31
`30
`29 •
`28
`
`a..
`
`80
`
`~~bound hypoxemia and pulmonary hypertension can be
`anticipated, and attenuated by increasing the Fi0
`, and, per(cid:173)
`h~~s, through the administration of phosphodiesterase in(cid:173)
`hibitors (He~s et al., 1997). The administration of a type
`V phosphodiesterase inhibitor, dipyridamole, has been re(cid:173)
`~orted to prevent rebound PAH following discontinuation of
`mhaled NO (al-Alaiyan et al., 1996; Ivy et al., 1998; Ziegler
`et al., 1998).
`
`2
`
`Summary
`
`Inhaled NO offers a novel therapy for the treatment of
`~ulmonary hypertensive diseases and the symptomatic re(cid:173)
`hef of hypoxemia. The use of inhaled NO reduces the nec(cid:173)
`essity for ECMO in newborns and infants with acute
`h~po~emic respiratory failure. Proper indications, contrain(cid:173)
`dicatwns, dosing criteria, and implications of the toxic ac(cid:173)
`tions of NO remain to be fully delineated. Randomized
`clinical. studies of patients with carefully defined specific
`a~ute disease states characterized by pulmonary hyperten(cid:173)
`swn or hypoxemia (e.g., pulmonary embolism, severe PAH,
`pos~pneumonectomy pulmonary edema, acute rejection fol(cid:173)
`lowmg lung transplantation) and of premature newborns
`with respiratory failure remain to be completed. If such trials
`~re carefully designed and conducted, we may define addi(cid:173)
`twnal group~ of patients that may benefit from, or may be
`harmed by, mhaled NO. Chronic ambulatory inhaled NO
`therapy may someday prove valuable for patients with pul(cid:173)
`monary hypertension. The use of inhaled NO continues to
`?e a ~nique and fascinating approach to studying and treat(cid:173)
`mg diseas~s as diverse as acute rejection of the transplanted
`lung and sickle cell crisis.
`
`Acknowledgments
`
`This work was supported by U.S. Public Health Service Grant HL-
`42397 (Dr. Zapol). The Massachusetts General Hospital has licensed a
`patent covering the use of nitric oxide inhalation and has a right to receive
`royalties.
`
`References
`
`Abman, S. H., Kinsella, J.P., Schaffer, M.S., and Wilkening, R. B. (1993).
`Inhaled nitric oxide in the management of a premature newborn with
`~~~~~;;~piratory distress and pulmonary hypertension. Pediatrics 92,
`
`Abman, S. H., Griebel, J. L., Parker, D. K., Schmidt, J. M., Swanton, D.,
`and Krnsella, J.P. (1994). Acute effects of inhaled nitric oxide in chil(cid:173)
`dren with severe hypoxemic respiratory failure. J. Pediat1: 124
`881-888.
`'
`Adatia, I., Lillehei, C., Arnold, J. H., Thompson, J. E., Palazzo, R., Fackler,
`1. C., and Wessel, D. L. (1994). Inhaled nitric oxide in the treatment of
`postoperative graft dysfunction after lung transplantation. Ann. Thome.
`Surg. 57,1311-1318.
`Adatia, I., Perry, S., Landzberg, M., Moore, P., Thompson, J. E., and Wes(cid:173)
`sel, D. L. (1995). Inhaled nitric oxide and hemodynamic evaluation of
`patients with pulmonary hypertension before transplantation. J. Am.
`Colt. Cardia/. 25, 1656-1664.
`
`Adrie, C., Bloch, K. D., Moreno, P. R., Hurford, W. E., Guerrero, J. L.,
`~olt, R.,_Zapol, W. M., Gold, H. K., and Semigran, M. J. (1996). Inhaled
`~111~;,~i:,~~:. I1~;;~~~;2~~ronary artery patency after thrombolysis. Cir-
`al-Alaiyan, S., al-Omran, A., and Dyer, D. (1996). The use of phosphodies(cid:173)
`t~rase inhibitor (dipyridamole) to wean from inhaled nitric oxide.lnten(cid:173)
`stve Care Med. 22, 1093-1095.
`Alberts, W. M .. (1994). Indoor air pollution: NO, NO,, CO, and CO,.
`1. Allergy Cluz. lmmwzo/. 94, 524-526.
`Allman, K., Young, J., Carapiet, D., Stevens, J., Ostman-Smith, I., and
`Archer, L. (1996). Effects of oxygen and nitric oxide in oxygen on
`pulmonary arterzal pressures of children with congenital cardiac defects
`Pediat1: Cardia/. 17, 246-250.
`.
`Am~to, M. B. P., Barbas, C. S. V., Medeiros, D. M., Magaldi, R. B., Schet(cid:173)
`trno, G. ~·· Lorenzi-Filho, G., Kairalla, R. A., Deheinzelin, D., Munoz,
`C., Ohvezra.' R., Ta~agaki, T. Y., and Carvalho, C. R. R. (1998). Effect
`of a protective-ventzlatton strategy on mortality in the acute respiratory
`distress syndrome. N. Engl. J. Med. 338, 347-354.
`Ande~son III, H., Steimle, C., Shapiro, M., Delius, R., Chapman, R.,
`Hmchl, R:, and Bartlett, R. (1993). Extracorporeallife support for adult
`cardwrespuatory failure. Surgery 114, 161-173.
`Argenzi_ano, M., Choudhri, A. F., Moazami, N., Rose, E. A., Smith, c. R.,
`Levm, H: R., ~merling, A. 1., and Oz, M. C. (1998). Randomized,
`double-bhnd trzal of inhaled nitric oxide in LVAD recipients with pul(cid:173)
`monary hypertension. Ann Thome. Surg. 65, 340-345.
`Auler, J. 0., Jr, Carmona, M., Bocchi, E., Bacal, F., Fiorelli, A., Stolf, N.,
`and Jatene, A. (1996). Low doses of inhaled nitric oxide in heart trans(cid:173)
`pLml rLX:Iricrli•.J. 1-l't'Urt
`''ill '1"rolnsp/ant. IS, 443-450.
`Bad D. A, Uu'l'('. P. ht
`l..mi,' , C.1 pcJs'llr, A., Mazmanian, G.-M.,
`~tu1~l1'1'1e Ilk. V d. Dttnnl. H., 11~11, J.-M .. and Darteville, P. (1996).
`1111 b..>n r.q I iHii I J 1111-tcrm I lo
`nitric oxide on graft func(cid:173)
`.
`twn after lung transplantation. Paris-Sud University Lung Transplanta(cid:173)
`twn Group. 1. Thome. Cardiovasc. Stag. 112, 590-598.
`Barabra, J. A., Roger, N., Roc a, J., Rovira, I., Higenbottam, T. w., and
`Rodngu~z-Ro_Isrn: R. (1~96). Worsening of pulmonary gas exchange
`With mtnc oxide rnhalatwn in chronic obstructive pulmonary disease.
`Lancet 347,436-440.
`Benzing, A., and Geiger, K. (1994). Inhaled nitric oxide lowers pulmonary
`capillary pressure and c~anges longitudinal distribution of pulmonary
`vascular resistance m patients with acute lung injury. Acta Anaesthesia/.
`Scand. 38, 640-645.
`Benzing, A., Brautigam, P., Geiger, K., Loop, T., Beyer, U., and Moser, E.
`~:~.;
`(1995). Inhaled nitric oxide reduce flll.lm lll.lry 1
`JLib!unin
`, 1'1.53-1 J 1
`flux m patients with a.: I l11 (tn,iury.AunJ, 1/rl/ttJU'
`Berner, M., Berghetti, M., p:ll•r..S..imrrer, ~..
`. •rhn11 b,l ., 1111tl moil B.
`I.)' uf ~ lll(cid:173)
`1& I" IQ'jt ilii: Vt!o>lilil rliH'.IlJ'I
`(1996). Inhaled nitric
`mo~ary vascular bed in children with long-standing pulmonary hyper(cid:173)
`tenswn and congenital heart disease. Am. J. Cardia/. 77, 532-535.
`Bigatello, L. M, Hurford, W. E., Kacmarek, R. M., Roberts, J. D., Jr., and
`Zapol, W. M. (1994). Prolonged inhalation of low concentrations of
`nitric oxide in patients with severe adult respiratory distress syndrome.
`
`:~~e;~~ ~~j0ulmonary hemodynamics and oxygenation. Anesthesiology
`Bocchi, ~- A.,_ Bacal, F., Auler Junior, J. 0., Carmone, M. J., Bellotti, G.,
`and Piiegg1, F. (1994). Inhaled nitric oxide leading to pulmonary edema
`In stable severe heart failure. Am. J. Cardia/. 74, 70-72.
`Borland, C. D., and Higenbottam, T. W. (1989). A simultaneous single
`breath measurement of pulmonary diffusing capacity with nitric oxide
`and carbon monoxide. Eur. Respir. J. 2, 56-63.
`Centers for Disease Control (1988). Recommendations for occupational
`safety and health standard. MM WR 37, 21.
`Chan nick, R. N. (1999). Chronic use of inhaled nitric oxide for pulmonary
`hypertension. k. pir. CQ#i'~,:!l:~-221.
`, J, W .• ..i'nbnson, F. W., Williams, P. J., Auger,
`Channick, R. N., Nc
`W. R., F~d~lh .P. fl. utd MJ~. K. M. (1996). Pulsed delivery of
`mhaled mtrzc oud 111 p;! lil: l\ ~J,jdJ primary pulmonary hypertension:
`An ambulatory delivery system and initial clinical tests. Chest 109
`1545-1549.
`,
`
`007
`
`

`
`CHAPTER 58
`
`Nitric Oxide and
`Persistent Pulmonary
`Hypertension in the Newborn
`
`·teinhorn .. . and Ja
`'obJ H.
`Ru
`I!Wl Wl'.! P('£11 i.111/1 ~·r.rllr
`/Jt<t'«l'liJILilf lJ t\"!/intr'l'(''i,
`C/11 "'l,qo, fllillu1~·
`~f)l"/l<trlmrl n tl} fllr11sinf"KJ' am! l'<:Ji.llrir.:.'!.. SrmC! Urli't·rTl ''1 N!!w trml; at Rn/Jtll(•
`Buffit'f), .r'w)IJr,l;
`
`Ut
`
`'fHE TRANSITION OF TilE PULMONARY CIRCULATION FROM A IDGH RESISTANCE-LOW FLOW
`CIRCULATION IN TilE FETUS TO A LOW RESISTANCE-IDGH FLOW CIRCULATION IN 1HE NEW(cid:173)
`BORN IS A COMPLEX PROCESS THAT INVOLVES 1HE SIMULTANEOUS DOWNREGULATION OF
`VASOCONSTRICTOR MEDIATORS AND UPREGULATION OF VASODILATOR¥ MEDIATORS SUCH
`AS NITRIC OXIDE (NO). IN TilE VAST MAJORITY OF INFANTS, TillS PROCESS OCCURS SPON(cid:173)
`TANEOUSLY AND QllCKLY AND DOES NOT REQillRE ANY INTERVENTION. OCCASIONALLY,
`HOWEVER, TilE TRANSffiON MAY BE DIFFICULT OR ABNORMAL, AND REQillRE PROMPT
`AND EFFECTNE RESUSCITATION TO ENSURE A SUCCESSFUL ADAPTATION TO TilE EXTRA(cid:173)
`UTERINE ENVIRONMENT.
`
`l.lllRir-t{'l 'lliAN~Ulil l!ii I'I.J!.sl!i'Th..,TI-1 1.1\1 •
`ONE DISEASE THAT LEADS TO COMPLICATI ,
`llU& PPfiNI ~Ill II IS
`!\!All\' IJ\'PF.Il
`'
`tJF
`IC.I\(T(.l!IZI:,I) 11\1 p, II..I.JR
`I'; 01· lliF.
`'
`!P R~ 1'1'1 Dj_. "Rh
`. AJFTEJ( llllffll, R~' L'ITIIo"G 1.!
`.IlK\' \'MC'II'-"r.t R 1ST. Nt:
`1HF tltl I
`II I'IO:r(IJ\ lt.Nil Sf!VI'-IQ OIS'IIil:!. .. ~. U:o.mH ST,\ IJ:L"!Il Tilt; I'H\'~Hli.J ....
`I' lfll> " ll,O.t
`'•\R\
`CIRCULATION DURING TilE TRANSITION FROM FETUS TO NEWBORN HAS HELPED NEONATOLO(cid:173)
`GISTS DEVELOP NEW TECHNIQUES FOR TilE ~TAJ'o','\0 !M
`CIATED WITH IDGH MllRTA H''l
`'r> r.J'UHiliDI
`,
`PPHN EXHIBIT RED nm NO -:v 1
`IN 1lJ 'SE NI!.(WA1R .. 0n1Eit MI?'I'HUJlSTt)
`PULMONARY BLOOD FLOW AND CORRECT HYIH.iU
`INCREASE cGMP, SUCH AS INffiBffiON OF ('(]MP '>1-'l, Il-l
`FORM (PDE5), EITHER ALONE OR IN COMIII'
`\ l'fll 0
`k.IUN'tJ IN\' •
`(l Thb S
`1C
`liON
`NOVEL TiffiRAPEUTIC MODALITIES FOR TREATING TillS CONDffiON. IT IS ANTICIPATED THAT
`TillS COMBINATION TIIERAPY WILL DECREASE 1HE CONCEN'IRATION OF NO REQillRED FOR A
`TIIERAPEUTIC EFFECT; THUS ATTENUATING POTENTIALLY DELETERIOUS EFFECTS RESULTING
`FROM TilE FREE RADICAL ACTIONS OF NO.
`Tms CHAPTER WILL STRESS 1HE ROLE OF NO IN (1) TilE NORMAL FETAL CIRCULATION,
`(2) 1HE TRANSITION OF 1HE CIRCULATION AT BIRTH, AND (3) TilE ETIOLOGY AND TREATMENT
`OF PPHN IN NEWBORNS. IT IS IMPORTANT TO NOTE THAT ALTHOUGH THEY WILL BE DISCUSSED
`ONLY BRIEFLY, MULTIPLE FACTORS IN ADDffiON TO NO CONTRIBUTE TO BOTH THE NORMAL
`TRANSffiON AND THE PATHOPHYSIOLOGY OF PPHN.
`
`Nitric Oxide
`
`963
`
`Copyright © 2000 by Academic Press.
`All rights of reproduction in any form reserved.
`
`008
`
`

`
`970
`
`Events that Initiate Transition
`
`The stimuli that seem to be most important in decreasing
`PVR at birth are the rhythmic ventilation of the lungs with a
`gas and the increase in oxygen tension in the lungs. Each of
`these stimuli by itself will decrease PVR and increase pul(cid:173)
`monary blood flow, but the largest effects are seen when the
`two events occur simultaneously (Teitel et al., 1990). Study(cid:173)
`ing the role of oxygenation independent of ventilation dur(cid:173)
`ing transition is technically challenging. Chronically instru(cid:173)
`mented near-term fetal lambs have been studied while the
`ewe breathes oxygen in a hyperbaric chamber at three at(cid:173)
`mospheres. During hyperbaric oxygenation, fetal pulmonary
`vascular resistance decreases and pulmonary blood flow in(cid:173)
`creases to levels comparable to after birth (Fig. 4).
`Pulmonary endothelial cells play a central role in the
`pulmonary vascular transition through the production and
`release of numerous mediators that act on the subjacent
`smooth muscle cell layer. A complete discussion of their
`products is outside the scope of this chapter. However, the
`main endothelial products currently believed to be respon(cid:173)
`sible for the pulmonary vasodilation at transition include
`arachidonic acid metabolites and nitric oxide. Prostacyclin
`(PGI
`) is the arachidonic acid metabolite most studied in the
`2
`transition of the pulmonary circulation at birth. Prostacyclin
`may be important in pulmonary vasodilation following
`rhythmic distention of the lung, but does not appear to me(cid:173)
`diate the pulmonary vascular response to oxygenation in the
`fetus (Morin et al., 1988). Despite a large body of research,
`the importance of prostacyclin in the transition at birth re-
`mains unclear.
`
`Changes in NO-cGMP Signaling at Birth
`
`The decrease in PVR is further augmented by a rapid
`increase in the oxygen-mediated availability of NO through
`
`SECTION III Principles of Pathobiology
`
`CHAPTER 58 NO and Persistent Pu I
`.
`110ll il~ Hypertenswn in the Newborn
`
`971
`
`a variety of mechanisms. Inhibition of nitric oxide synthase
`blocks the pulmonary vascular response of the near-term fe(cid:173)
`tal lamb to hyperbaric oxygenation (Fig. 4). Oxygen directly
`increases basal and acetylcholine-stimulated cGMP produc(cid:173)
`tion in the pulmonary vasculature (Shaul et al., 1992). Acute
`changes in oxygen tension do not produce similar changes
`in mesenteric arteries, suggesting that this dramatic effect of
`oxygen is due to a direct and specific effect on NO produc(cid:173)
`tion by fetal pulmonary arteries (Shaul and Wells, 1994).
`The acute oxygen modulation of pulmonary endothelial NO
`production does not appear to be a result of production of a
`local receptor agonist, or changes in availability of oxygen
`or L-arginine as substrates for NOS. Oxygen may, however,
`directly effect NOS by altering pulmonary endothelial cell
`calcium homeostasis.
`Oxygen also causes a rapid increase in red blood cell
`adenosine triphosphate (ATP). ATP or its metabolite adeno(cid:173)
`sine cause pulmonary vasodilation in the fetus, a response
`that is blocked by inhibition of NOS (Konduri et al., 1992;
`Steinhorn et al., 1994b). ATP may stimulate endothelial NO
`production either by binding to purinergic receptors or di(cid:173)
`rectly to NOS. Plasma ATP levels increase in the pulmonary
`arteries of fetal lambs during ventilation with oxygen, and
`the decrease in PVR that accompanies ventilation with oxy(cid:173)
`gen is abolished by blockade of adenosine and ATP receptors
`(Konduri et al., 1993). Thus, increased synthesis and release
`of ATP may cause pulmonary vasodilation in response to
`birth-related stimuli in the ovine fetus.
`The peptide bradykinin stimulates endothelial NO pro(cid:173)
`duction, and is a potent pulmonary vasodilator in the fetus.
`Ventilating fetal lambs with oxygen, or exposing the fetus to
`hyperbaric oxygen, increases the blood concentrations of
`bradykinin (Heymann et al., 1969). However, blockade of
`bradykinin receptors does not block the pulmonary vasodi(cid:173)
`lation to oxygen (Banerjee et al., 1994), and it is unknown
`whether a direct interaction between bradykinin and NO
`plays a role in the development of the response to oxygen.
`Closure of the ductus arteriosus at birth and the decrease
`in PVR lead to a large increase in pulmonary blood flow.
`This increase in pulmonary blood flow increases shear stress
`in the pulmonary vasculature and activates signaling cas(cid:173)
`cades in endothelial cells which produce and/or potentiate
`pulmonary vasodilation via increased synthesis and release
`of NO. An increase in shear stress increases eNOS mRNA
`and protein expression in lung tissue (Black et a/., 1997).
`Therefore, whenever a stimulus initiates an increase in pul-
`111 Jlu.!L)' bl• M..l now l1u.ring tnmsition, it increases shear stress
`• m.l ·ru01L : :1 pu iti c feedback loop in which increased NO
`:->}l lllhe ·i~> inc ill> s [JUlmru.m. ry blood flow still further. At
`l!!a...,l •
`rtion tlr lh.:: f!u hnonary vasodilation that results
`from shear stress may be attributed to NO-mediated activa(cid:173)
`tion of K+ -channels (Kv) in smooth muscle cells (Ston11e et
`al., 1999).
`The pattern of expression of wlublc gun ~yl nt~: c)1:h1«= I
`similar to eNOS, with the tughcs l level ur expr' Sltlll nnd
`activity noted in the first day t~Uowin • binh. FlliiPI.:nnLl
`'
`within 1 hour following birth, PDE5 ru:ti •il •. pro~dn. und
`in newborn la.mb :.~n l 111111 I!
`mRNA dramatically decreas
`
`Ca++
`Figure 7 Diagram of the factors that fa
`-
`tance at birth_ The size and density of letters::~ ;~w pulmonary :ascular resis(cid:173)
`ttons and activity.
`nes Ieflect relative concentra-
`
`lungs (Hanson eta!. 1998b) Th
`following birth wo~ld b
`.
`e low level ofPDE5 activity
`NO on
`I
`e expected to enhance the effect of
`cGMP l~u ~~nary vascular smooth muscle by increasing
`crease in ;~~ m a! ~anner t~~tt correlates well with the de-