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DOI 10.1378/chest.114.3.780 1998;114;780-786 Chest

Claes-Håkan Bergh and Sven-Erik Ricksten Åsa Haraldsson, Niels Kieler-Jensen, Ulla Nathorst-Westfelt,

ResistanceWith Elevated Pulmonary Vascular Evaluation of Heart Transplant CandidatesInhaled Aerosolized Prostacyclin in the Comparison of Inhaled Nitric Oxide and

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Comparison of Inhaled Nitric Oxide and InhaledAerosolized Prostacyclin in the Evaluation of HeartTransplant Candidates With Elevated PulmonaryVascular Resistance*Asa Haraldsson, MD; Niels Kieler-fensen, MD, PhD;Ulla Nathorst-Westfelt, MD, PhD; Claes-Hdkan Bergh, MD, PhD; andSven-Erik Ricksten, MD, PhD

Study objective: Elevated pulmonary vascular resistance is a risk factor in heart transplantationand reversibility of high pulmonary vascular resistance is evaluated preoperatively in potentialrecipients using IV vasodilators or inhaled nitric oxide. Prostacyclin is a potent vasodilator, whichwhen inhaled, has selective pulmonary vasodilatory properties. The aim of this study was to

compare the central hemodynamic effects of inhaled prostacyclin with those of inhaled nitricoxide in heart transplant candidates.Design: A pharmacodynamic comparative study.Setting: Cardiothoracic ICU or laboratory for diagnostic heart catheterization at a universityhospital.Patients: Ten heart transplant candidates with elevated pulmonary vascular resistance (>200 dynes .

s . cm-5 and/or a transpulmonary pressure gradient > 10 mm Hg) were included in the study.Interventions: Nitric oxide (40 ppm) and aerosolized prostacyclin (10 jxg/mL) were administered byinhalation in two subsequent 10-min periods. Hemodynamic measurements preceeded and followedinhalation of each agent.Measurements and results: Both inhaled nitric oxide and inhaled prostacyclin reduced mean

pulmonary artery pressure (.7% vs .7%), pulmonary vascular resistance (.43% vs .49%), and thetranspulmonary gradient (.44% vs .38%). With inhaled prostacyclin, an 11% increase in cardiacoutput was observed. Other hemodynamic variables, including the systemic BP, remained unaffectedby each of the agents.Conclusions: Inhaled prostacyclin induces a selective pulmonary vasodilation that is comparable tothe effect of inhaled nitric oxide. Major advantages with inhaled prostacyclin are its lack of toxicreactions and easy administration as compared with the potentially toxic nitric oxide requiring morecomplicated delivery systems. (CHEST 1998; 114:780-786)

Key words: aerosolized prostacyclin; heart transplantation; inhalation; nitric oxide; pulmonary hypertensionAbbreviations: CO=cardiac output; CVP=central venous pressure; HR=heart rate; LV=left ventricle; MAP=mean arterialBP; MPAP=mean pulmonary artery pressure; NO=mitric oxide; N02=nitrogen dioxide; PCWP=pulmonary7 capillary wedgepressure; PGI2=prostacyclin; PVR=pulmonary vascular resistance; Sa02.arterial oxygen saturation; SV=stroke volume;Sv02=mixed venous oxygen saturation; SSVR=systemic vascular resistance; TPG=transpulmonary pressure gradient

*From the Departments of Anesthesia and Intensive Care (Drs.Haraldsson, Kieler-Jensen, Nathorst-Westfelt, and Ricksten)and Cardiology (Dr. Bergh), Sahlgrenska University Hospital,Goteborg, Sweden.Supported by the Swedish Medical Research Council (No. 8682and 4341), The Medical Faculty of Goteborg (LUA), GoteborgMedical Association, and Sahlgrenska University Hospital Foun¬dations.Presented in part at the International Society for Heart andLung Transplantations 17th annual meeting and scientific ses¬

sions, April 2-5, 1997, London, England.Manuscript received November 19, 1997; revision acceptedMarch 2, 1998.Correspondence to: Sven-Erik Ricksten, MD, PhD, Departmentfor Anesthesia and Intensive Care, Sahlgrenska University Hos¬pital, S-413 45 Goteborg, Sweden

"C1 levated pulmonary vascular resistance (PVR) in-*-J heart transplant candidates increases the periop¬erative morbidity and mortality due to acute rightventricular failure of the graft after orthotopic hearttransplantation.13 Potential recipients are evaluatedby measurement of central hemodynamic variablesand calculation of the transpulmonary pressure gra¬dient (TPG) (mean pulmonary artery pressure[MPAP] minus pulmonary capillary wedge pressure[PCWP]) and PVR. The reversibility of an elevatedPVR is usually determined by IV administration ofvasodilators such as nitrates or prostaglandins.4 If thepulmonary hypertension is reversible, the patient can

780 Clinical Investigations



be considered as suitable for orthotopic heart trans¬

plantation and a vasodilator can be used periopera-tively to prevent and treat right ventricular failure ofthe transplanted heart.46 Due to the shortage ofdonor organs, it is even more important to determinereversibility and hence avoid transplantation of lungsresulting in an efficient utilization of available grafts.

However, neither nitrates nor prostaglandins exerta desirable selective pulmonary vasodilation whenused IV but may instead induce systemic vasodilationwith hypotension which, in turn, will jeopardize rightventricular perfusion.4'7-8 The biomediator nitric ox¬

ide (NO) has, when inhaled in concentrations of 5 to80 ppm, selective pulmonary vasodilatory propertieswithout effects on the systemic vasculature.9-11 Adisadvantage with NO is that it is a highly toxicmolecule and the production of methemoglobin andhigher oxides of nitrogen is a major concern requir¬ing specialized delivery systems and monitoring.1213

Prostacyclin (PGI2) is another biomediator synthe¬sized by the vascular endothelium. It is a potentvasodilator with no toxic effects and a half-life of 2 to3 min.14-16 Inhaled PGI2 has been shown to induce a

dose-dependent selective pulmonary vasodilation af¬ter heart surgery and heart transplantation17 and tohave beneficial effects on the pulmonary vasculatureand oxygenation in patients with ARDS as well as

other conditions associated with pulmonary hyper¬tension.18-22The aim of the present study was to compare the

pulmonary vasodilatory effects of inhaled PGI2 withthose of inhaled NO in heart transplant candidateswith elevated PVR.

Materials and Methods

The study was performed at Sahlgrenska University Hospital,Goteborg, Sweden, and approved by the Human Ethics Com¬mittee of the Medical Faculty, University of Goteborg. Tenpatients, 4 female and 6 male (24 to 59 years of age, mean 49years) with elevated PVR (PVR >200 dyne . s . cm"5 and/or TPG>10 mm Hg) were included after informed consent. The patientswere scheduled for diagnostic right heart catheterization. Thediagnoses were ischemic (n=5) or dilated (n=5) cardiomyopathy(Table 1).Measurements of central hemodynamics were performed us¬

ing a radial artery catheter and a pulmonary artery thermodilu¬tion catheter (Swan-Ganz model 131H-7F; Edwards Laboratory;Santa Ana, Calif) inserted via the right jugular vein. The followingvariables were measured or calculated: cardiac output (CO) was

measured in triplicate, heart rate (HR), stroke volume (SV),systolic, diastolic, and mean (MAP) arterial BPs, systolic, dia¬stolic, and mean (MPAP) pulmonary arterial pressures, centralvenous pressure (CVP), PCWP, systemic vascular resistance(SVR) and PVR, and the TPG (MPAP-PCWP). The PVR/SVRratio was also calculated for each drug. Arterial and mixed venous

oxygen saturation (Sa02 and Sv02) were measured as well as

PaO£. The intrapulmonary shunt fraction and whole body-oxygenextraction were calculated using standard formulas.

Table 1.Patient Characteristics Prior to Inclusion*

Patient/Age>yr/Sex Diagnosis

PVR,dyne . s . cm"

TPG,mm Hg LVEF

1/24/M2/50/M3/59/M4/52/M5/58/F6/59/F7/57/M8/59/M9/50/F

10/24/F

DCMIHDIHDIHDDCMDCMIHDDCMDCMDCM

479196351464281936

f

189769267

141123291339151125

0.20

0.200.300.300.300.150.200.180.20

*DCM=dilated cardiomyopathy; IHD=ischemic heart disease;LVEF=left ventricular ejection fraction.

f Missing value due to major tricuspid valve insufficiency.| Missing value.

Experimental Procedure

The study was divided into four subsequent 10-min periods,each followed by hemodynamic measurements and sampling forarterial and mixed venous oxygen content. The experimentalprocedure started with a control period of spontaneous breathingat an inspiratory fraction of oxygen of 30% via a tightfitting facemask in a nonrebreathing system. After baseline hemodynamicmeasurements, NO (40 ppm) was added to the system for 10 minfollowed by another 10-min control period. Aerosolized PGI2(Flolan; Wellcome Laboratories; Beckenham, Kent, UK) was

then administered for 10 min at a concentration of 10 ixg/mL byinhalation through a mouthpiece, using a high-efficiency nebu¬lizer (see below).

NO Administration and MonitoringThe delivery system for NO to the breathing gas8 consisted of

two mass-flow-regulators controlling the flow of NO mixed innitrogen (1,000 ppm; AGA Gas AB; Solna, Sweden) and an

oxygen/air mixture, respectively. A soda-lime-absorber placedclose to the patient on the inspiratory limb was used forscavenging of nitrogen dioxide (N02). N02 measurements withultraviolet technique (Binos NO; Leybold-Horaeus GmbH;Hanau, Germany) in breathing gas to the patient has shown NOsvalues well below 0.5 ppm at the NO and oxygen concentrationused in the present study (40 ppm and 30%, respectively). Thelevel of inhaled NO was monitored continuously using electro¬chemical fuel-cell-technique (City Technology; London, UK).

Prostacyclin Administration

The nebulizer used for inhalation of PGI2 (Maxin MA-2;Clinova Medical AB; Malmo, Sweden) (Fig 1) is a high-efficiencynebulizer; 68% of the particles have a mean mass diameter <4jxm. The delivery rate is low output 0.2 to 0.3 mL/min, and theflow of aerosol with a driving pressure of 5 bar is 4.5 L/min. Lungdeposition is 90% and lung retainment is 50% according to themanufacturer. PGI2 was prepared in a glycine buffer (0.188%glycine, 0.147% sodium chloride, pH 10.5) immediately beforeuse to a concentration of 10 ixg/mL. Each patient received 2 to 3mL of PGI2 solution (20 to 30 ixg).Statistical AnalysisData are presented as mean±SEM. Data were compared using

a two-way analysis of variance for repeated measurements. The

CHEST / 114 / 3 / SEPTEMBER, 1998 781



Figure 1. Nebulizer (Maxin MA-2).

differential effect of PGI2 as compared with NO were evaluatedusing the analysis of variance interaction analysis.23 A p value<0.05 was considered to indicate statistical significance.

Results

in

Patient characteristics prior to inclusion are shownTable 1. Mean values for central hemodynamic

variables during control and during PGI2 and NOinhalation are given in Table 2. No CO values were

obtained for patient 7 due to a severe tricuspid valveinsufficiency. Individual data on the effects of inha¬lation on MPAP, PCWP, TPG, and PVR are shownin Figure 2.

Effects of Inhaled NO 40 ppm on CentralHemodynamics (Table 2)During inhalation of NO, PCWP increased

(+21%) while MPAP decreased (-7%) as well asTPG (-42%), PVR (-43%), and PVR/SVR ratio

Table 2.Effects of Inhaled NO (40 ppm) and Inhaled PGI2 (10 pg/mL) on Central Hemodynamics*Control NO Control PGI, NO vs PGI9

HR, beats/minMAP, mm HgMPAP, mm HgPCWP, mm HgCVP, mm HgCO, L/minSV, mLPVR, dyne . s

SVR, dyne . s

P/STPG, mm HgPa02, kPaSa02, %Sv02, %02 extr, %IPSF, %

cm

cm-

87±880±343±424±210±23.7±0.350±10437±87

1,633 ±1270.27±0.0519±315±198±0.458±541±56.2±1.5

89±880±340±4f29±3f9±2

3.7+0.451±10250±67j

1,668±1820.15±0.04{ll±2j15±198±0.458±542±56.1±1

87±681±242±424±210±23.6±0.447±9431±91

1,650 ±1380.26±0.0518±313±197±0.756±542±69.0±2.1

87:78:39:29:9:

4.0:51d

221 d1,484:!0.16:!

10:!12 d95 d59d

14.2d

:6:4:4t:3f:2:0.4f:9:55|1560.04J¦M3156:3.0|

NSNSNSNSNS..¦§NSNSNSNSNSNSNSNSNS

*Mean±SEM. P/S=PVR/SVR ratio; 02 extr= whole body oxygen extraction; IPSF=intrapulmonary shunt fraction; NS= not significant.fp<0.05 control vs NO, control vs PGI2.}p<0.01 control vs NO, control vs PGI2.§p<0.05 NO vs PGI2.




MPAPmmHg 80

60

40

20

PCWPm m H g

40

-V-

30

20

10H v- . -v

NO PC! 2 NO PGI2

TPGmmHg 40

30

20-

NO

PVRdynes xs x cm-5

1000

750-

500

250-

C PGI2 C.!.NO C PGI2

Figure 2. Individual data on the effects of inhaled NO (40 ppm) and inhaled PGI9 (prostacyclin, 10|xg/mL) on MPAP, PCWP, TPG, and PVR.

(.44%). Inhaled NO caused no changes in HR,MAP, CVP, CO, SV, or SVR.

Effects of Inhaled PGI2 on Central Hemodynamics(Table 2)During inhalation of PGI2, PCWP increased

(+21%) while MPAP decreased (-7%) as well as

TPG (-44%), PVR (-49%), and PVR/SVR ratio(.38%), while there were no changes in HR, MAP,CVP, SV, or SVR. Inhaled PGI2 induced an increasein CO ( + 11%).

Oxygenation Parameters

During inhalation of PGI2 or NO, no changes inSa02, Sv02, oxygen extraction, or Pa02 were ob¬served. The intrapulmonary shunt was significantlyincreased during PGI2 inhalation.

Discussion

In the present study, we have compared theeffects of inhaled aerosolized PGI2 (concentration insolution 10 |ULg/mL) with those of inhaled NO (40ppm) on central hemodynamics in heart transplantcandidates with congestive heart failure and elevatedPVR. The main findings were that inhaled PGI2induced a pulmonary vasodilation, with a decrease inPVR, MPAP, and TPG, comparable to that inducedby inhaled NO. Furthermore, inhaled PGI2 causedno significant effect on SVR. It is not immediatelyobvious why inhaled PGI2, in contrast to inhaledNO, induced a slight (11%) but significant increasein CO. Previous in vitro studies have suggested thatPGI2 may exert a mild positive inotropic effect2425which, however, has not been confirmed in pa¬tients.26-27 One could speculate whether the ten¬dency of a PGI2-induced decrease in SVR reflected

CHEST/114/3/SEPTEMBER, 1998 783



a minor "spill-over" of PGI2 to the systemic circula¬tion, in turn unloading the failing left ventricle (LV).More patients are required to establish whether, infact, such a spill-over effect of inhaled PGI2 is real or

not.Evidence that inhalation of aerosolized PGI2 may

induce a selective pulmonary vasodilation was firstprovided by Welte et al28 in a canine model ofpulmonary hypertension. Inhaled PGI2 has also beenshown to reduce pulmonary arterial pressure andimprove oxygenation in both adults and infants withrespiratory distress syndrome.19'2229 We have re¬

cently described the effects of incremental concen¬

trations of inhaled PGI2 (2.5, 5, and 10 [xg/mL) inpatients with postoperatively elevated PVR afterheart surgery or heart transplantation.17 In thatstudy, inhaled PGI2 induced a selective dose-depen¬dent decrease in PVR and the TPG with no effectson systemic vasculature and with a maximal effectseen at an inhaled concentration of 10 ixg/mL. Theselective pulmonary vasodilatory effect of NO is welldescribed in both animal and human studies.9'3031Gradually increased doses of inhaled NO (5 to 80ppm) have been documented to decrease PVR inpatients with chronic pulmonary hypertension, incardiac surgical patients, after heart transplantation,and in patients supported with ventricular assistdevices after heart surgery.1011'32'33 In a recentstudy, we evaluated the effects of incremental dosesof inhaled NO (5, 10, 20, and 40 ppm) on PVR inheart transplant candidates with elevated PVR.8 Wefound that inhaled NO at a concentration of 20 ppmwas the lowest mean dose to cause a maximalreduction in PVR, even though a few patients re¬

quired 40 ppm.The use of NO for evaluation of heart transplant

candidates with pulmonary hypertension has beendescribed previously not only by us8 but also byothers.34-35 The decrease in PVR in those studies wasassociated with an increase in PCWP. The mecha¬nism behind this NO-induced increase in PCWP inpatients with left heart failure is unknown. It isprobably not caused by an NO-induced negativeinotropic effect as NO is most likely inactivated byhemoglobin before it reaches the LV and NO donorssuch as sodium nitroprusside or nitroglycerin do notexert a negative effect on myocardial contractility.We therefore hypothesized that inhaled NO causes a

redistribution of blood from precapillary to postcap-illary pulmonary capacitance vessels with a conse¬

quent increase in LV end-diastolic volume and fillingpressure.8 This would have caused an increase in LVstroke volume in a normal LV but not in our patientswith severely depressed LV function. A small in¬crease in the capacity of postcapillary capacitancevessels and LV end-diastolic volume, induced by

NO, might cause a large increase in PCWP due tothe increased stiffness of the failing LV. This hypoth¬esis is supported by the finding that NO induces a

greater vasodilation of postcapillary compared withprecapillary vessels in patients with ARDS and highPVR.36 This hypothesis was further supported by a

recent study of Hare et al,37 in which the effects ofinhaled NO on LV filling pressure were studied inpatients with LV failure receiving an LV assistdevice. When the pump delivered a fixed systemicflow, the selective reduction in PVR by NO in¬creased left atrial pressure, ie, inhaled NO increasesLV filling pressure by increasing pulmonary venous

volume. In the present study, an increase in LVfilling pressure was seen, both for inhaled PGI2 andinhaled NO, suggesting that the mechanism behindthe decrease in PVR and TPG is probably the same

for inhaled PGI2 as for inhaled NO. In other words,one could speculate that both inhaled NO andinhaled PGI2 act to a greater extent on the postcap¬illary compared with the precapillary portion of thepulmonary vascular bed.

In this study, both PGI2 and NO inhalation pro¬duced a selective pulmonary vasodilation as illus¬trated by the marked decrease in the PVR/SVR ratio.Pulmonary vasodilation by IV vasodilators is accom¬panied by a corresponding decrease in SVR, with no

decrease in the PVR/SVR ratio and a decrease inarterial pressure.8 This systemic hypotension limitsthe use of IV nonselective vasodilators in the evalu¬ation of heart failure patients with elevated PVR,especially in those with ischemic heart disease, andalso in the postoperative treatment of these patientsafter heart transplantation.8'33-38 In contrast, inhala¬tion of PGI2 and NO produces a rapid and reversiblepulmonary vasodilation without concomittant sys¬temic hypotension.817'33

In recent studies, the pulmonary hemodynamiceffects of inhaled NO have been compared withthose of inhaled aerosolized PGI2 in patients withARDS22 and severe pulmonary hypertension.39Walmrath et al22 demonstrated in 16 patients withARDS that inhaled NO and inhaled PGI2 reduceMPAP, PVR, and intrapulmonary shunt to the same

extent. In six patients with severe primary or second¬ary pulmonary hypertension, inhaled PGI2 was even

more effective than inhaled NO in the reduction ofMPAP or PVR as demonstrated by Olschewski.39One can thus conclude from the data of those reportsand the present study that the efficacy of inhaledPGI2 to improve pulmonary hemodynamics in pa¬tients with high PVR, irrespective of the underlyingdisease, is at least comparable to that seen withinhaled NO.

In the present study, it was observed that inhala¬tion of PGI2 induced a slight increased pulmonary




shunt that could be explained by an increase in lungwater in these patients with severe cardiac failure,because of the increase in PCWP, in combinationwith a prolonged period in the supine position.Indeed, some patients also developed clinical signsof pulmonary congestion during NO and PGI2 inha¬lation that was associated with the development ofpronounced V waves on the PCWP tracing.

Inhaled PGI2 has no toxic effects or toxic metab¬olites and requires only standard systems for nebu¬lizing therapy. Possible side effects of PGI2 are

profound hypotension and tachycardia induced by an

overdose of the agent. Systemic effects of PGI2inhalation have been reported only with inhaledconcentrations of PGI2 100 times greater than thosereported in the present study.40 Inhibition of plateletaggregation is another possible side effect of PGI2inhalation that may increase the risk of intraoperativeand postoperative bleeding. However, no effects on

platelet aggregation were demonstrated during pro¬longed (8 h) PGI2 inhalation in an animal setting,41but should be studied also in humans. A majorconcern has also been the effect of the highlyalkaline glycine buffer PGI2 solution on global bio¬chemical and cellular composition of the alveolarepithelial lining fluid. This was investigated in an

experimental lamb model in which inhaled PGI2 for8 h did not cause signs of acute pulmonary toxicity.41

In conclusion, a brief period of inhaled PGI2provides a simple, pulmonary selective test of thereversibility of an elevated PVR in heart transplantcandidates, which is comparable to the effects ofinhaled NO with respect to both pulmonary vascularand systemic effects. The advantages of inhaled PGI2in comparison to NO is its atoxicity and simpletechnology for its administration.

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DOI 10.1378/chest.114.3.780 1998;114;780-786 Chest

Bergh and Sven-Erik Ricksten Åsa Haraldsson, Niels Kieler-Jensen, Ulla Nathorst-Westfelt, Claes-Håkan

Elevated Pulmonary Vascular ResistanceProstacyclin in the Evaluation of Heart Transplant Candidates With

Comparison of Inhaled Nitric Oxide and Inhaled Aerosolized

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