3 Inhaled nitric oxide

3 Inhaled nitric oxide G E O R G E F. R I C H

There is rapidly growing evidence that inhaled nitric oxide (NO) decreases pulmonary vascular resistance (PVR) without affecting systemic vascular resistance (SVR). Furthermore, there is evidence that inhaled NO improves oxygenation by enhancing matching of ventilation to perfusion and decreasing pulmonary shunting. This is encouraging because no selective or even preferential pulmonary vasodilator has previously been identified. The effectiveness of current vasodilators such as nitroglycerin, sodmm nitroprusside, or prostaglandlns, is limited because of simultaneous vasodilation of the systemic circulation. The resulting systemic hypotension may decrease coronary perfusion pressure in adults or increase right to left shunting through the ductus arteriosus in infants. Furthermore, intravenous vasodilators may also increase pulmonary shunt and decrease oxygenation Anaesthetists and intensive care physicians may be particularly interested in administering inhaled NO to decrease PVR and/or improve oxygenation in several situations. 1. 2. 3.

Newborns with persistent pulmonary hypertension (PPHN) who are hypoxaemlc because of decreased pulmonary blood flow. Adults or children with pulmonary hypertension and right ventricular dysfunction who cannot be separated from cardiopulmonary bypass. Patients with adult respiratory distress syndrome (ARDS) who are hypoxaemic and have elevated PVR.

E N D O G E N O U S NITRIC OXIDE

The use of inhaled NO as a selective pulmonary vasodilator has developed from the understanding that NO is a potent endogenous vasodilator. NO is now known to be the same as the potent endogenous vasodIlator, endothehum-derived relaxing factor (EDRF) (Ignarro et al, 1987b) Synthesized from L-arginine by the enzyme EDRF/NO synthase(s), NO is a cell messenger now implicated in wide-ranging physiological and pathophysiological actions in the cardiovascular, immune, and nervous systems (Moncada et al, 1991). In blood vessels, EDRF/NO is produced by endothelium and causes vasodilation through basal release and in response to a wide Badhere's Chmcal Anaestheszology-Vol 9, No 1, March 1995 ISBN 0-7020-1849--X

37 Copyright © 1995, by Ballh~rc Tmdall All rights of reproduction in any form reserved

38

G.F. RICH

range of vasodilator agents (Furchgott, 1984). It is a potent vasodilator which also inhibits platelet aggregation and adhesion and may play a major role in diseases such as atherosclerosis and hypertension, cerebral and coronary vasospasm, and ischaemia-reperfusion injury (Moncada et al, 1991). The common nitro-vasodilators, nitroglycerin and sodium mtroprusside act by releasing NO (Kruszyna et al, 1987). EDRF/NO appears to activate soluble guanylyl cyclase to increase guanoslne 3',5'-cyclic monophosphate (cGMP) content in several tissues including vascular smooth muscle and brain (Rapoport and Murad, 1983). Cyclic GMP causes relaxation in vascular smooth muscle by several proposed mechanisms including the activation of a cyclic GMP-dependent protein kinase which leads to the phosphorylation and activation of Ca 2÷ATPase and the subsequent extrusion of Ca 2 + from the cell or enhancement of Ca 2+ uptake into the sarcoplasmlc reticulum. EDRF/NO plays a major role in the pulmonary vasculature by regulating resting pulmonary vascular tone and producing endothelium-dependent pulmonary vasodilation. Studies have demonstrated both a continuous basal release of EDRF/NO and a vasodIlator-mediated release associated with production of cyclic GMP (Ignarro et al, 1987b; Hasunuma et al, 1991). Most investigations have demonstrated that EDRF/NO has a significant role in maintaining the normal low resting pulmonary vascular tone (Adnot et al, 1991; Nishiwaki et al, 1992). Flow or shear stress induced vasodilation in the pulmonary circulation may also be mediated by NO release (Cornfield et al, 1992). Several agents including acetylcholine and bradykinin cause release of EDRF/NO from the pulmonary endothelium and are endothehumdependent vasodilators. When the endothelium is absent or damaged these agents produce vasoconstriction (Chand and Altura, 1981). EDRFdependent vasodilation of the pulmonary vasculature has been shown to be markedly inhibited or abolished in patients with chronic hypoxic cor pulmonale resulting from end-stage chronic obstructive lung disease (DinhXuan et al, 1991). In these pulmonary disease states where endothelial and EDRF/NO function is impaired, several endogenous agents which are normally vasodllators may cause vasoconstriction and contribute to increased PVR, The administration of inhaled NO may in effect serve as replacement therapy in these circumstances.

SELECTIVE PULMONARY VASODILATION IN ANIMAL STUDIES Inhaled NO theoretically produces pulmonary vasodilatlon by the same mechanism as endogenous NO after diffusing from the alveoli Into the pulmonary vascular smooth muscle. However, NO binds rapidly to haemoglobin and is inactivated as it is exposed to the pulmonary circulation (Gibson and Roughton, 1957; Rich et al, 1993b). Therefore, inhaled NO does not dilate the systemic circulation. In 1991, Frostell et al demonstrated that inhaled NO is a selective pul-

I N H A L E D NITRIC O X I D E

39

monary vasodilator which reverses hypoxlc pulmonary vasoconstriction (HPV) and pulmonary hypertension induced by the thromboxane analogue U46619 in sheep (Frostell et al, 1991). Inhaled NO in concentrations of 5-80 parts per million (ppm) produced a rapid dose-dependent reduction of the pulmonary hypertension caused by U46619 infusion. Onset and offset of the effects of inhaled NO occurred within 3-6 minutes. Low concentrations of inhaled NO (5ppm) significantly reduced the pulmonary artery pressure (PAP) whereas almost complete attenuation of the vasoconstriction occurred with inhalation of 40 and 80 ppm Inhalation of NO (80 ppm) for 1 hour during U46619 infusion produced sustained pulmonary vasodllation to a normal PAP and PVR. Inhaled NO did not decrease systemic arterial pressure or SVR in either U46619 or hypoxlc experiments. Fratacci et al (1991) demonstrated that inhaled NO was also a selective pulmonary vasodilator of heparin-protamine vasoconstriction produced in sheep. Breathing NO (40-180 ppm) reduced the PAP without causing systemic vasodilation. Pulmonary vasodilation has been demonstrated to be dose-dependent with an EDs0 of 39 ppm in a sheep endotoxin model (Dyar et al, 1993). Rich et al (1993b) used isolated rat lungs to determine the dose-response relationship and the role of blood in modulating pulmonary and systemic vasodilation secondary to inhaled NO. Inhaled NO has direct dosedependent (13-1000 ppm) vasodilatlng effects on the pulmonary vasculature as cardiac output, left atrial pressure, and ventilation were held constant. Low concentrations of NO significantly attenuated the increase in PAP secondary to hypoxla and angiotensin II by approximately 15-30%. These results agree with Rimar and Glllas (1992) who demonstrated that inhaled NO (120ppm) decreased PAP by approximately 25% in isolated rabbit lungs constricted with the thromboxane analogue U46619. Rimar and Glllas also demonstrated the endothelium-independent effects of inhaled NO because the amount of pulmonary vasodilation was the same before and after free radical injury of the pulmonary endothelium. Free NO is measurable in samples taken from isolated rat lungs perfused with physiological buffer but not blood, which demonstrates that NO crosses from the alveoli into the pulmonary circulation but is bound to haemoglobin (Rich et al, 1993b). Complete binding occurs even when NO is inhaled m concentrations as high as 1000ppm. The presence of haemoglobin also appears to prevent a significant amount of potential pulmonary vasodilation. This was demonstrated by the greater effects of inhaled NO in attenuating the increase in PAP secondary to angiotensin II in physiological buffer compared to whole blood perfused isolated rat lungs. Roos et al (1994) determined the sites of vasodilatlon of inhaled NO in comparison to sodium nitroprusside m isolated rat lungs. The sites were determined by analysing the arterial, venous, and double occlusion data with a two resistor (small arteries and veins) and three capacitor (large arteries, large veins, and capillaries) model of the pulmonary orculatlon. Inhaled NO and sodium mtroprusside dilated small resistance arteries and veins, whereas sodium nitroprusside but not inhaled NO dilated larger capaotance arteries and veins This is because inhaled NO is inactivated by

40

G.F.

RICH

blood prior to reaching the pulmonary veins. The larger pulmonary arteries are not dilated by inhaled NO because they are upstream from the alveoli.

POTENTIAL TOXICITY

Nitric oxide is an oxide of nitrogen formed during high temperature combustion processes and is a common air pollutant. The US Occupational Safety and Health Administration has set the time-weighted average NO value at 25 ppm. Exposure of rats to inhaled NO (43 ppm) for 6 days or 1500 ppm for 15 minutes does not cause pulmonary pathological effects according to light and electron microscopy (Hugod, 1979; Stavert and Lehnert, 1990). Nitric oxide reacts with oxygen and superoxide to form potentially toxic and reactive products such as nitrogen dioxide (NO2), dinitrogen trioxide, dinitrogen tetraoxide, and peroxynitrate. The rate of oxidation of NO to NO2 is dependent on the initial concentration of NO and the inspired oxygen concentration. A 10 ppm NO mixture undergoes 50% conversion to NO2 in about 7 hours (Rabson et al, 1960). Low concentrations of NO2 (2 ppm), in contrast to NO, are extremely toxic and cause changes in lung histopathology (Evans et al, 1972). The reaction of NO with superoxide to form peroxynitrate may be particularly disconcerting because superoxide formation is increased in acute inflamatory disease. Peroxynitrate is a potentially cytotoxic radical and can form the more reactive hydroxyl radical (Kippenol, 1992). Other aspects of NO including possible mutagenic effects and specific effects on cell function independent of structural changes are more difficult to assess and have not been well evaluated. The ability of NO to affect adenosine diphosphate (ADP) ribosylation in several cellular systems and to inactivate or alter the funcnon of a number of iron and haem-based proteins makes such concerns significant (Brune and Lapetina, 1989). Nitric oxide combines with haemoglobin forming nitrosyl haemoglobin with an affinity 1500 times higher than that measured for carbon monoxide (Gibson and Roughton, 1957). Nitrosyl haemoglobin is oxidized to methaemoglobin when oxygen is present by a poorly understood method. Methaemoglobin, in turn, is metabolized to nitrites and nitrates by reductase enzymes and excreted by the kidneys or absorbed by the gastrointestinal system (Oda et al, 1975; Yoshida and Kasama, 1987).

ADMINISTRATION OF INHALED NO

Nitric oxide is a gas obtained as a premixed concentration (1-1000 ppm) in nitrogen. Inhaled NO is passed through a soda lime canister which absorbs NO2 and can be admimstered to either the inspiratory limb of the breathing circuit or to the low pressure gas inlet of most ventilators. Measurement of the concentration of inhaled NO can be determined by chemiluminescence, raman spectroscopy, or electrochemical methods.

INHALED NITRIC OXIDE

41

SELECTIVE PULMONARY VASODILATION PULMONARY HYPERTENSION

IN HUMANS

WITH

Frostell et al (1993) demonstrated that low concentrations of inhaled NO attenuate the increase in PAP resulting from hypoxic pulmonary vasoconstriction (HPV) m normal human volunteers. Pulmonary vasodflaUon was not accompanied by a decrease in systemic arterial pressure or SVR These results m human volunteers confirm what has previously been demonstrated in expenmental ammals. There have been several invesngations utilizing inhaled NO in paUents with pulmonary hypertension. Pepke-Zaba et al (1991) demonstrated that inhaled NO causes selective pulmonary vasodilation in patients with chronic pulmonary hypertension. The effects of inhaled NO (40 ppm) and prostacyclin (PGI2 24~g/h) were investigated in these patients. There was a dose-dependent pulmonary vasodilatlon to PGI2, however, SVR also declined. In contrast, inhaled NO decreased PVR by 5-68% from basehne but was not associated with a decrease in systemic arterial pressure or SVR. The onset and offset times of the vasodilatory effects of inhaled NO were less than 3 minutes. Rich et al (1993b) studied the effects of inhaled NO (20ppm) m 20 patients undergoing cardiac surgery for mltral valve disease and five patients 800

600

• 0 O

8

0

0

0

400

0.L \ o n

200

O Control

NO

~

0 Control

Figure 1. The pulmonary vascular resistance (dynes cm sec 5) before, during, and after mhalanon of NO for each patient prior to cardmpulmonary bypass Inhaled NO ~lgmficantly ( P < 0 01) decreased PVR

42

G.F. alCH

requiring ventricular assist devices (VADs) to support their circulation. Inhaled NO decreased PVR before and after cardiopulmonary bypass and in patients supported with a VAD (Figure 1). All other haemodynamic variables remained unchanged. Pulmonary vasodilation resulting from inhaled NO was proportional to the basehne PVR. There was no difference between the effects of inhaled NO before and after cardiopulmonary bypass despite the administration of intravenous nitrates and the possible damage to the endothelium post-cardiopulmonary bypass. Two other groups have also demonstrated that inhaled NO selectively decreases PVR in patients with mitral valve disease (Girard et al, 1992; Snow et al, 1994). Roberts et al (1993b) investigated the effects of inhaled NO in 10 paediatric patients (age 3 months to 6.5 years) with congenital heart disease undergoing cardiac catheterization. Inhaled NO selectively decreased the PVR, with the largest decreases occurring in the patients with the highest baseline PVR. Furthermore, inhaled NO decreased PVR beyond reduction by an fraction of inspired oxygen (FIO2) of 0.9. In infants and children, inhaled NO has also been reported to aid in separation from cardiopulmonary bypass (CPB) (Sellden et al, 1993; Tibballs, 1993), T R E A T M E N T FOR PERSISTENT P U L M O N A R Y H Y P E R T E N S I O N OF THE N E W B O R N

In the hypoxic newborn lamb, inhaled NO rapidly reduced PAP and increased pulmonary blood flow without reducing SVR or dilating the ductus arteriosus (Roberts et al, 1993b). Furthermore, the haemodynamic effects of inhaled NO in ovine transitional pulmonary circulation appear to cause sustained pulmonary vasodilation (Kinsella et al, 1992a). Zayek et al (1993) studied a model of PPHN in which the ductus arteriosus of the lamb was hgated 13 days prior to delivery. In this model inhaled NO increased survival rate without increasing the incidence of acute lung injury. Roberts et al (1992) examined whether inhaled NO could improve preductal and postductal oxygen saturation m newborns with a patent ductus arteriosus and PPHN. Inhaled NO (80 ppm) rapidly increased the preductal oxygen saturation from 88 to 97% while breathing 90% oxygen. Likewise, inhaled NO raised the postductal oxygen saturation from 82 to 90%. Inhalation of NO (80 ppm) for 10 minutes raised the postductal oxygen tension (PaO2) in all but two of the six patients whereas inhaling less than 80ppm NO did not produce significant improvement. In none of the newborns did inhaled NO cause systemic hypotension or elevation in methaemoglobin levels. Hypoxaemia returned within 5 minutes upon discontinuation of NO in five newborns whereas systemic oxygenation continued to improve in one patient. Kinsella et al (1992b) reported the effects of inhaled NO for 24 hours in 6 newborns with severe PPHN who were candidates for extracorporeal membrane oxygenation. Arterial oxygenation improved progressively with inhaled NO 20ppm over the first 4 hours. Despite decreasing the inhaled NO concentration to 6 ppm, the improvement in oxygenation was sustained.

43

I N H A L E D NITRIC O X I D E

Table 1. Inhaled NO m infants with persistent pulmonary hypertension Study period Basehne 1 h (20 p p m NO) 4 h (20 p p m NO) 24 h (6 p p m NO)

P(a-A)O2 0 0 0 0

08 18 25 30

+ + + +

0 01 0.03* 0 03* 0 04*

OI 68 29 18 13

+ 16 + 6* + 3* + 3*

Arterial/alveolar oxygen rano (P[a-A]O2) and oxygenation index (OI = mean airway pressure × FIO2 × 100/ PaOzcmH20/mmHg) Basehne measurements and response to NO inhalation at 24h (mean+s E M n = 15) * P< 0 01 compared to basehne measurement

Kinsella et al have since increased their total experience to 15 infants (Kinsella et al, 1993). Thirteen of the 15 infants with P P H N showed a significant increase in arterial/alveolar 02 ratio and oxygen index and subsequently did not require extracorporeal m e m b r a n e oxygenation (Table 1). In contrast to adults, acute inhalatlonal N O therapy to reduce P V R may be sufficient to resolve P P H N . Finer et al (1994) studied the effects of mulnple concentrations of inhaled N O in 23 infants with P P H N . Thirteen infants had a significant i m p r o v e m e n t in oxygenation. There was no significant difference in the response to inhaled N O between concentrations of 5 and 8 0 p p m . This is important because it indicates that the most appropriate concentration of inhaled N O may be less than 5 ppm.

BRONCHODILATION In a guinea-pig model where bronchoconstriction was produced by methacholine infusion, inhaled N O caused a rapid, dose-dependent, and reversible decrease in lung resistance and an increase in dynamic lung compliance (Dupuy et al, 1992). Inhaled N O produced significant bronchodilatton at low inhaled concentrations ( 5 p p m ) although a greater and more rapid decrease in airway resistance occurred at 100 and 300ppm. Tolerance to inhaled N O did not develop during a steady-state methacholine infusion for 1 hour. Administration of either terbutallne or N O produced an additive reduction in lung resistance independent of the sequence of administration. Decreased airway resistance and increased lung compliance have also been observed in a rabbit model ( H o g m a n et al, 1993a). In normal human volunteers and in patients with chronic obstructive pulmonary disease, inhaled NO (80 ppm) had no effect on airway conductance measured by body plethysmography ( H o g m a n et al, 1993b). Inhaled N O mildly modulated the effects of methacholine-induced bronchoconstrictlon m volunteers In patients with bronchial asthma, airway conductance increased significantly but less than with beta-agomsts.

44

o.F. RICH

T R E A T M E N T OF H Y P O X A E M I A AND THE ADULT RESPIRATORY DISTRESS S Y N D R O M E (ARDS)

Intravenous pulmonary vasodilators inhibit HPV and decrease PVR in all areas of the lungs. The net effect is a decrease in oxygenanon secondary to increased venous admixture and/or pulmonary shunt. In contrast, inhaled NO should predominantly vasodilate ventilated areas of the lung and have httle or no effect on non-ventilated areas. Therefore, inhaled NO should improve arterial oxygenanon by reducing intrapulmonary shunting and improving the matching of vennlation to perfusion. The effects of inhaled NO on intrapulmonary shunting have been studied in an ovme lavage ARDS model (Rovira et al, 1994). Inhaling NO (60 ppm) at the same FIO2 for 10 minutes increased oxygenation and decreased venous admixture most hkely by cGMP-mediated vasoddation of ventilated lung regions. These effects did not appear to be related to the decrease in PVR. Inhaled NO has also been demonstrated to improve oxygenation and selectively decrease PVR in a porcine endotoxin shock model (Weitzberg et al, 1993) Rossaint et al (1993) determined the effects of inhaled NO m patients with ARDS having lung injury scores of 3.2-4.0. During brief inhalation of NO (18 and 36 ppm) the PAP decreased and the PaO2/FIO2 increased (Figure 2). The shunt fraction was decreased by 3 + 1% and the fraction of blood flowing to the lungs with normal ventilation to perfuslon ratios increased 5 +_ 1%. Inert gas analysis revealed that the beneficial effects of inhaled NO were secondary to a redistribution of pulmonary blood flow away from nonventllated regions of the lung and towards ventilated regions, thereby ~mprowng the matching of ventilation to perfus~on. In the same study NO (5-20 ppm) was inhaled by seven panents for 3-53 days without tolerance or elevations in methaemoglobin levels. During brief dally discontmuations of inhaled NO treatment the PAP consistently increased and the PaO2/FI02 decreased. Gerlach et al (1993a,b) also demonstrated that inhaled NO selecnvely decreased PVR while improving oxygenation in patients with ARDS. These effects were dose-dependent with an EDs0 of 100 parts per billion (ppb) for improvement in oxygenation and an EDs0 of 2-3 ppm for reduction in PAP (Figure 3). The peak effect in oxygenation occurred at 10ppm while the peak decrease in PVR occurred at 100 ppm. Concentranons above 10 ppm appeared to worsen oxygenation and improvements m oxygenation were not associated with reductions in PVR. This study is important in that it demonstrate that very low concentrations of NO (i.e. ppb), which is a dose similar to atmospheric concentranons, may be effective m improving oxygenation. The decrease in PVR and venous admixture secondary to inhaled NO has also been demonstrated to be proportional to their baseline values (B~gatello et al, 1994). The improvements in PVR and oxygenation have also been documented in patients with chronic obstructive pulmonary disease (Adnot et al, 1993). In these patients PVR changes were similar in response to inhaled NO or acetylcholine, but acetylcholine also decreased SVR and worsened oxyge-

INHALED NITRIC OXIDE

45

nation. In contrast, inhaled NO selectively decreased PVR and improved gas exchange. In cardiac surgical patients undergoing one-lung ventilation, inhaled NO did not alter oxygenation, as would be expected with intravenous vasodllators (Rich et al, 1994). Inhaled NO has also been demonstrated to maintain rather than improve oxygenation while reversing HPV in 6o! E E

50

~

40

i

Q.

g_

*

$

riB"

~ 30

t' ...... ~. il ........

I

I

Base line

.,t~ ii

I

I

Nitric oxide 18 ppm 36 ppm

Base line

350 300 ~> 250 E E 200

6

150

i . v

I' I

6 loo

z i

'"

o

i i

V

50 I

I

Base hne

I

I

N~tnc oxide 18 ppm 36 ppm

Base line

60 50 40 •

* • ~..

ao 20

"'" " t ""

; ....

,

.[

• "'"', ,,. -.; -o. .

.,•

.....

~

10 I

Base hne

",,.

.............. ,

~ ' : ...... :': ~ . . . . . ~:l

G

I

I

"

Nitric oxide 18ppm

36ppm

I

Base line

Figure 2. Mean pulmonary artery pressure (PAP, mmHg), arterial oxygenauon efficiency (PaOz/FIO2 mmHg) and lntrapulmonary shunting (Qs/Qt, %) m nine patients with ARDS during inhalation of nitric oxide Solid symbols represent patients treated with extracorporeal membrane oxygenation

46

G

100

[

L%I

I

..~---'~

v. R~CH

1

80 60

PaOa

40

o "' - 2 0 -40

,

PAP

.

.

-60

-80 -100

I 0

I 001

EDso PaO2

I 0 10

I 10

EDso PAP

I 100

100

NO dose (ppm)

Figure 3.

Dose response of PaO2 and PAP to respiratory NO doses Values are expressed as percentage compared to the mmal value (0% effect) and the highest registered alteration (100% effect) The estimated EDs0 of N O of Improvement of arterial oxygenation is different from the reduction m PAP.

sheep (Pison et al, 1993). It is possible that inhaled NO may improve oxygenation in diseased lungs which have significant mismatching of ventilation to perfuslon but maintain oxygenation in normal lungs. It remains to be determined if inhaled NO will improve oxygenation m thoracotomy patients with lung disease who are receiving one-lung ventilation. SUMMARY AND FUTURE CONSIDERATIONS FOR INHALED NO

Inhaled NO has received tremendous attention in recent years. It is a new approach to the treatment of pulmonary hypertension and its associated diseases. Animal and human studies have been tremendously successful in demonstrating that inhaled NO is a reversible, dose-dependent, and selective pulmonary vasodilator. Inhaled NO significantly decreases PVR in patients with primary pulmonary hypertension and in patients who have pulmonary hypertension secondary to mitral valve disease. A decrease in PVR and the resulting increase in pulmonary blood flow improves oxygenation in infants with PPHN. These results are particularly exciting because there is currently no selective pulmonary vasodilator available. The method of delivery and the site of action of inhaled NO make ~t possible to improve oxygenation in patients who are hypoxaemic secondary to lung disease. Inhaled NO increases oxygenation by decreasing venous admixture and pulmonary shunting in patients with ARDS and chronic destructive pulmonary disease

INHALED NITRIC OXIDE

47

Although the initial results with inhaled NO are promising, the majority of studies have only examined the effects of inhaled NO for short periods Further research is needed to demonstrate whether inhaled NO has longterm beneficial effects. This may include long-term therapy for right ventrlcular failure secondary to pulmonary hypertension, and the ability of inhaled NO to reverse and prevent pathological changes associated with pulmonary hypertension. Although inhaled NO decreases PVR, it has yet to be determined if inhaled NO improves the ability to separate patients with pulmonary hypertension from cardiopulmonary bypass. There are also no randomized, blinded clinical trials which have demonstrated that inhaled NO reduces mortality from ARDS or decreases the need for extracorporeal membrane oxygenation in infants with PPHN. Finally, before long-term therapy can become commonly used, more laboratory and controlled clinical trial research needs to be done to determine if there are long-term toxic effects of inhaled NO in paediatric and adult populations.

REFERENCES Adnot S, Raffestin B, Eddahlbl Set al (1991) Loss of endothehum-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia Journal of Cllmcal Ini,est~gatlon 87:155-162 Adnot S, Kouyoumdjlan C, DeFoullloy C et al (1993) Hemodynamlc and gas exchange responses to infusion of acetylchohne and inhalation of nitric oxide in patients with chronic obstructive lung disease and pulmonary hypertension Amerwan Review of Respiratory Disease 148:310-316 Blgatello LM, Hurford WE, Kacmarek RM et al (1994) Prolonged inhalation of low concentrations of nitric oxide in patients with severe adult respiratory distress syndrome Anesthesiology 80:761-770 Brune B & Lapetlna EG (1989) Activation of a cytosolic ADP-rlbosyltrangenase by nitric oxide-generating agents Journal of Biological Chemistry 264:8455-8458 Chand N & Altura BM (1981) Acetylchollne and bradykinin relax intrapulmonary arteries by acting on ECs role in lung vascular disease Science 213:1376-1379 Cornfield DN, Chatfield BA, McQueston JA et al (1992) Effects of birth-related stimuli on L-arglnine-dependentpulmonaryvasodllatloninovlne fetus AmertcanJournalofPhyslology 262 (Heart and Circulation Physiology 31) H1474-H1478 Dlnh-Xuan AT, Hlgenbottam TW, Clelland CA et al (1991) Impairment of endothehumdependent pulmonary-artery relaxation in chronic obstructive lung disease New England Journal of Medwme 324:1539-1547 Dupuy PM, Shore SA, Drazen JM'et al (1992) Bronchodilator action of inhaled nitric oxide in guinea pigs Journal of Chntcal Investigation 90:421-428 Dyar O, Young JD, Xiong Let al (1993) Dose-response relationship for inhaled nitric oxide in experimental pulmonary hypertension in sheep. Brtttsh Journal of Anae~the~m 71: 7027O8 Evans MJ, Stephens RJ, Cabral LJ & Freeman G (1972) Cell renewal in the lungs of rats exposed to low levels of NO2 Archives Environmental Health 24:180-188 Finer NN, Etches PC, Kamstra B e t al (1994) Inhaled nitric oxide in infants referred for extracorporeal membrane oxygenation Dose response Journal of Pedmtrtcs 124: 3023O8 Fratacci M-D, Frostell CG, Chen T-Y et al (1991) Inhaled nitric oxide A selective pulmonary vasodzlator of heparln-protamlne vasoconstriction in sheep Anesthesiology 75:990-999 Frostell C, Frataccl M-D, Wain JC et al (1991) Inhaled nitric oxide a selective pulmonary vasodilator reversing hypoxlc pulmonary vasoconstriction Circulation 83:2038-2047

48

G . F . RICH

Frostell CG, Blomqvlst H, Hedenstlerna Get al (1993) Inhaled mtrxc oxide selectively reverses human hypoxlc pulmonary vasoconstriction without causing systemic vasodllatlon Anesthesiology 78:427-435 Furchgott RF (1984) The role of endothehum in the responses of vascular smooth muscle to drugs Annual Review of Pharmacology and Tomcology 24:175-197 Gerlach H, Pappert D, Lewandowskl K & Falke KJ (1993a) Long-term inhalation with evaluated low doses of nitric oxide for selective improvement of oxygenation In patients with adult respiratory distress syndrome Intensive Care Medtcme 19:443-449 Gerlach H, Rossamt R. Pappert D & Falke KJ (1993b) Time-course and dose-response of nitric oxide inhalation for systemic oxygenation and pulmonary hypertension In patients with adult respiratory distress syndrome European Journal of Chntcal Investigation 23: 499502 Gibson QH & Roughton FJW (1957) The kinetics of equilibria of the reactions of mtrlc oxide with sheep hemoglobin Journal of Physiology (London) 136: 507-526. Girard C, Lehot JJ, Clerc J e t al (1992) Inhaled nitric oxide after mltral valve replacement In patients with chronic pulmonary artery hypertension. Anesthesiology 77:880-883 Hasunuma K, Yamaguchl T, Rodman DM et al (1991) Effects of lnhibitors of EDRF and EDHF on vasoreactivlty of perfused rat lungs American Journal of Physzology 260 (Cellular and Molecular Physiology 4): L97-L104 Hogman M, Frostell C. Arnberg H et al (1993a) Inhalation of mtrlc oxide modulates methachohne-induced bronchoconstnctlon in the rabbit European Respiratory Journal 6: 177-180 Hogman M, Frostell CG, Hedenstrom H et al (1993b) Inhalation of nitric oxide modulates adult human bronchial tone Amertcan Revtew ofResptratory Dtsease 148:1474-1478 Hugod C (1979) Effect of exposure to 43 ppm nitric oxide and 3 6ppm nitrogen dioxide on rabbit lung A light and electron microscopic study InternattonalArchtves of Oceupattonal Enwronmental Health 42:159-167 Ignarro LJ, Byrns RE & Woods KS (1987a) Endothehum-dependent modulation of cGMP levels and intrinsic smooth muscle tone in ~solated bovine intrapulmonary artery and vein. Ctrculatton Research 60:82-92 Ignarro LJ, Buga GM, Wood KS et al (1987b) Endothehum-derlved factor produced and released from artery and vein is nitric oxide Proceedings of the Nattonal Academy of Scwnces USA 84:9265-9269 Klnsella JP, McQueston JA, Rosenberg A A et al (1992a) Hemodynamlc effects of exogenous nitric oxide in ovlne transitional pulmonary circulation Amertcan Journal of Phystology 263 (Heart Circulatory Phystology 32) H875-H880 Klnsella JP, Nelsh SR, Shaffer E & Abman SH (1992b) Low-dose lnhalatlonal mtrac oxide in persistent pulmonary hypertension of the newborn The Lancet 340" 819-820 Kmsella JP, Nelsh SR, Ivy DD et al (1933) Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide Journal of Pedzatncs 123:103-108 Koppenol WH, Moreno J J, Pryor WA et al (1992) ChemicalResearch In Toxicology 5:834-842 Kruszyna H, Kruszyna R, Smith RP & Wilcox DE (1987) Red blood cells generate nitric oxide from directly acting, nitrogenous vasodllators Toxtcology and Apphed Pharmacology 91: 429--438 Moncada S, Palmer RMJ & Hlggs EA (1991) Nitric oxide Physiology, pathophyslology, and pharmacology Pharmacology Review 43:109-142 Nlshawakl K, Nyhan DP, Rock P et al (1992) NW-mtro-L-argmIne and pulmonary vascular pressure-flow relationship m conscious dogs Amerwan Journal of Physiology 262 (Heart and Ctrculutzon Physiology 31): H1331-H1337 Oda H, Kusumoto S & Nakallma T (1975) Nltrosyl-hemoglobln formation in the blood of animals exposed to nitric oxide Archives of Environmental Health 30:453~,55 Pepke-Zaba J, Hlgenbottam TW, Dlnh-Xuan AT et al (1991) Inhaled nitric oxide as a cause of selective pulmonary vasoddatlon in pulmonary hypertension Lancet 338: 1173-1174. Pison U, Lopez FA, Heldelmeyer CF et al (1993) Inhaled nitric oxide reverses hypoxlc pulmonary vasoconstriction without impairing gas exchange Journal of Apphed Physiology 74:128%1292 Rabson SR, Qullham JH & Goldblatt E (1960) The elimination of nitrous fumes from blasting gases Journal of South Afrwan Institute of Mineral Metallurgy 61:152-199

INHALED NITRIC OXIDE

49

Rapoport R & Murad F (1983) Endothehum dependent and mtrovasodllator induced relaxatlon of vascular smooth muscle Role of cyclic GMP Journal of Cychc Nucleotzde and Protem Phosphorylanon Research 9:281-296 Rich GF, Murphy GD, Johns RA & Roos CM (1993a) Inhaled nitric oxide Selectwe pulmonary vasodllatlon in cardiac surgical patients Anesthesiology 78:1028-1035 Rich GF, Roos CM, Anderson SM et al (1993b) Inhaled nitric oxide. Dose response and the effects of blood in the isolated rat lung Journal of Apphed Physiology 75:1278-1284 Rich GF, Lowson SM, Johns RA et al (1994) Inhaled nitric oxide selectively decrcases pulmonary vascular resistance without lmpamng oxygenation during one-lung ventilation in patients undergoing cardiac surgery Anesthesiology 80:57-62 RImar S & Glllis CN (1992) Pulmonary vasodilatlon by inhaled nitric oxide after endothelial injury Journal of Apphed Physiology 73:2179-2183 Roberts JD, Polaner DM, Lang P & Zapol WM (1992) Inhaled nitric oxide m persistent pulmonary hypertension of the newborn The Lancet 340:818-819 Roberts JD, Lang P, Blgatello LM et al (1993a) Inhaled nitric oxide m congenital heart disease Circulation 87:447-453 Roberts JD, Chen TY, Kawai N et al (1993b) Inhaled nitric oxide reverses pulmonary vasoconstriction m the hypoxlc and acidotic newborn lamb Circulation Research 72: 246-254 Roos CM, Rich GF, Uncles D U e t al (1994) Sites of vasodllation by inhaled nitric oxide versus sodium nltroprusslde in endothehn constricted isolated rat lungs Journal of Applied Physiology 77:51-57 Rossamt R, Falke K J, Lopez F et al (1993) Inhaled nitric oxide for the adult respiratory distress syndrome New England Journal of Medtcme 328:399-405 Rovira I, Chen T-Y, Wmkler M e t al (1994) Effects of inhaled nitric oxide on pulmonary hemodynamics and gas exchange in an ovlne model of ARDS Journal of Apphed Physiology 76:345-355 Sellden H, Wlnberg P, Gustafsson LE et al (1993) Inhalation of nitric oxide reduced pulmonary hypertension after cardiac surgery in a 3 2-kg infant Anesthesiology 78: 577-580. Snow DJ, Gray SJ, Ghosh S e t al (1994) Inhaled nitric oxide in patients with normal and increased pulmonary vascular resistance after cardiac surgery British Journal of Anaesthesia 72:185-189 Stavert DM & Lehnert BE (1990) Nitric oxide and nitrogen dioxide as inducers of acute pulmonary injury when inhaled at relatively high concentrations for brief periods Inhalation Toxicology 2:53-67 Tibballs J (1993) Chmcal applications of gaseous nitric oxide Anaesthesia and lntemlve Care 21:866-871 Weltzberg E, Rudehlll A & Lundberg JM (1993) Nitric oxide inhalation attenuates pulmonary hypertension and improves gas exchange in endotoxln shock European Journal of Pharmacology 233:85-94 YoshIda K & Kasama K (1987) Biotransformation of nitric oxide Environmental Health Perspectives 73:201-206 Zayek M, Wild L, Roberts JD & Morln FC (1993) Effect of nitric oxide on the survival rate and incidence of lung injury in newborn lambs with persistent pulmonary hypertension Journal of Pediatrics 123:"947-952