Download Resistance With Elevated Pulmonary Vascular Evaluation of

Comparison of Inhaled Nitric Oxide and
Inhaled Aerosolized Prostacyclin in the
Evaluation of Heart Transplant Candidates
With Elevated Pulmonary Vascular
Resistance
Åsa Haraldsson, Niels Kieler-Jensen, Ulla Nathorst-Westfelt,
Claes-Håkan Bergh and Sven-Erik Ricksten
Chest 1998;114;780-786
DOI 10.1378/chest.114.3.780
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ISSN:0012-3692
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1998 by the American College of Chest Physicians
Comparison of Inhaled Nitric Oxide and Inhaled
Aerosolized Prostacyclin in the Evaluation of Heart
Transplant Candidates With Elevated Pulmonary
Vascular Resistance*
Haraldsson, MD; Niels Kieler-fensen, MD, PhD;
Ulla Nathorst-Westfelt, MD, PhD; Claes-Hdkan Bergh, MD, PhD; and
Sven-Erik Ricksten, MD, PhD
Asa
Study objective: Elevated pulmonary vascular resistance is a risk factor in heart transplantation
and reversibility of high pulmonary vascular resistance is evaluated preoperatively in potential
recipients using IV vasodilators or inhaled nitric oxide. Prostacyclin is a potent vasodilator, which
when 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 nitric
oxide in heart transplant candidates.
Design: A pharmacodynamic comparative study.
Setting: Cardiothoracic ICU or laboratory for diagnostic heart catheterization at a university
hospital.
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 by
inhalation in two subsequent 10-min periods. Hemodynamic measurements preceeded and followed
.
.
inhalation of each agent.
Measurements and results: Both inhaled nitric oxide and inhaled prostacyclin reduced mean
vascular resistance (.43% vs .49%), and the
pulmonary artery pressure (.7% vsvs .7%), pulmonary
inhaled
With
prostacyclin, an 11% increase in cardiac
transpulmonary gradient (.44% .38%).
output was observed. Other hemodynamic variables, including the systemic BP, remained unaffected
by each of the agents.
Conclusions: Inhaled prostacyclin induces a selective pulmonary vasodilation that is comparable to
the effect of inhaled nitric oxide. Major advantages with inhaled prostacyclin are its lack of toxic
reactions and easy administration as compared with the potentially toxic nitric oxide requiring more
complicated delivery systems.
(CHEST
1998; 114:780-786)
Key words: aerosolized prostacyclin; heart transplantation; inhalation; nitric oxide; pulmonary hypertension
Abbreviations: CO=cardiac output; CVP=central venous pressure; HR=heart rate; LV=left ventricle; MAP=mean arterial
BP; MPAP=mean pulmonary artery pressure; NO=mitric oxide; N02=nitrogen dioxide; PCWP=pulmonary7 capillary wedge
pressure; 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
Departments of Anesthesia and Intensive Care (Drs.
Haraldsson, Kieler-Jensen, Nathorst-Westfelt, and Ricksten)
and Cardiology (Dr. Bergh), Sahlgrenska University Hospital,
*From the
Goteborg, Sweden.
Supported by the Swedish Medical Research Council (No. 8682
and 4341), The Medical Faculty of Goteborg (LUA), Goteborg
Medical Association, and Sahlgrenska University Hospital Foun¬
dations.
Presented in part
at the International Society for Heart and
Lung Transplantations 17th annual meeting and scientific ses¬
sions, April 2-5, 1997, London, England.
received November 19, 1997; revision accepted
Manuscript
March 2, 1998.
Correspondence to: Sven-Erik Ricksten, MD, PhD, Department
for Anesthesia and Intensive Care, Sahlgrenska University Hos¬
pital,
780
S-413 45
Goteborg, Sweden
"C1 levated pulmonary vascular resistance (PVR)
in
-*-J heart
erative
transplant candidates increases the periop¬
morbidity and mortality due to acute right
ventricular failure of the graft after orthotopic heart
transplantation.13 Potential recipients are evaluated
by measurementofofthecentral hemodynamic variables
and calculation
transpulmonary pressure gra¬
dient (TPG) (mean pulmonary artery pressure
[MPAP] minus pulmonary capillary wedge pressure
[PCWP]) and PVR. The reversibility of an elevated
PVR is usually determined by IV administration of
vasodilators such as nitrates or prostaglandins.4 If the
pulmonary hypertension is reversible, the patient can
Clinical
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1998 by the American College of Chest Physicians
Investigations
be considered as suitable for orthotopic heart trans¬
and a vasodilator can be used perioperaplantation
to
tively prevent and treat right ventricular failure of
the transplanted heart.46 Due to the shortage of
donor organs, it is even more important to determine
and hence avoid transplantation of lungs
reversibility
in
an
efficient utilization of available grafts.
resulting
neither
nitrates nor prostaglandins exert
However,
a desirable selective pulmonary vasodilation when
used IV but may instead induce systemic vasodilation
with hypotension which, in turn, will jeopardize right
ventricular perfusion.4'7-8 The biomediator nitric ox¬
ide (NO) has, when inhaled in concentrations of 5 to
80 ppm, selective pulmonary vasodilatory properties
without effects on the systemic vasculature.9-11 A
NO is that it is a highly toxic
disadvantage with
molecule and the production of methemoglobin and
concern requir¬
higher oxides of nitrogen is a major
and
ing specialized delivery systems monitoring.1213
Prostacyclin (PGI2) is another biomediator synthe¬
sized by the vascular endothelium. It is a potent
vasodilator with no toxic effects and a half-life of 2 to
3 min.14-16 Inhaled PGI2 has been shown to induce a
dose-dependent selective pulmonary vasodilation af¬
ter heart surgery and heart transplantation17 and to
have beneficial effects on the pulmonary vasculature
and oxygenation in patients with ARDS as well as
other conditions associated with pulmonary hyper¬
tension.18-22
The aim of the present study was to compare the
effects of inhaled PGI2 with
pulmonary vasodilatory
those of inhaled NO in heart transplant candidates
PVR.
with
elevated
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. Ten
patients, 4 female and 6 male (24 to 59 years of age, mean 49
years) with elevated PVR (PVR >200 dyne s cm"5 and/or TPG
>10 mm Hg) were included after informed consent. The patients
were scheduled for diagnostic right heart catheterization. The
diagnoses 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 following
variables 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, central
.
.
pressure (CVP), PCWP, systemic vascular
(SVR) and PVR, and the TPG (MPAP-PCWP). The
venous
resistance
PVR/SVR
Table 1.Patient Characteristics Prior to Inclusion*
Patient/
Age>
PVR,
yr/Sex
Diagnosis
1/24/M
2/50/M
3/59/M
4/52/M
5/58/F
6/59/F
7/57/M
8/59/M
9/50/F
10/24/F
DCM
IHD
IHD
IHD
DCM
DCM
IHD
DCM
DCM
DCM
.
s
.
cm"
TPG,
mm
Hg
479
196
351
464
281
936
14
11
23
29
13
39
f
15
189
11
769
267
25
LVEF
0.20
0.20
0.30
0.30
0.30
0.15
0.20
0.18
0.20
*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 for
arterial and mixed venous oxygen content. The experimental
period of spontaneous breathing
procedure started with a control
at an inspiratory fraction of oxygen of 30% via a tightfitting face
mask in a nonrebreathing system. After baseline hemodynamic
measurements, NO (40 ppm) was added to the system for 10 min
followed 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 by
inhalation through a mouthpiece, using a high-efficiency nebu¬
lizer (see below).
NO Administration and Monitoring
The delivery system for NO to the breathing gas8 consisted of
mass-flow-regulators controlling the flow of NO mixed in
nitrogen (1,000 ppm; AGA Gas AB; Solna, Sweden) and an
oxygen/air mixture, respectively. A soda-lime-absorber placed
close to the patient on the inspiratory limb was used for
scavenging of nitrogen dioxide (N02). N02 measurements with
ultraviolet technique (Binos NO; Leybold-Horaeus GmbH;
Hanau, Germany) in breathing gas to the patient has shown NOs
values well below 0.5 ppm at the NO and oxygen concentration
used in the present study (40 ppm and 30%, respectively). The
level of inhaled NO was monitored continuously using electro¬
chemical fuel-cell-technique (City Technology; London, UK).
two
Prostacyclin Administration
The nebulizer used for inhalation of PGI2 (Maxin MA-2;
Clinova Medical AB; Malmo, Sweden) (Fig 1) is a high-efficiency
nebulizer; 68% of the particles have a mean mass diameter <4
jxm. The delivery rate is low output 0.2 to 0.3 mL/min, and the
flow of aerosol with a driving pressure of 5 bar is 4.5 L/min. Lung
deposition is 90% and lung retainment is 50% according to the
manufacturer. PGI2 was prepared in a glycine buffer (0.188%
glycine, 0.147% sodium chloride, pH 10.5) immediately before
use to a concentration of 10 ixg/mL. Each patient received 2 to 3
mL of PGI2 solution (20 to 30 ixg).
ratio was also calculated for each drug. Arterial and mixed venous
oxygen saturation (Sa02 and Sv02) were measured as well as
Statistical Analysis
extraction
a
PaO£. The intrapulmonary shunt fraction and whole body-oxygen
were calculated using standard formulas.
dyne
Data are presented as mean±SEM. Data were compared using
two-way analysis of variance for repeated measurements. The
CHEST / 114 / 3 / SEPTEMBER, 1998
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1998 by the American College of Chest Physicians
781
Figure 1. Nebulizer
differential effect of PGI2 as compared with NO were evaluated
using the analysis of variance interaction analysis.23 A p value
<0.05 was considered to indicate statistical
significance.
(Maxin MA-2).
obtained for patient 7 due to a severe tricuspid valve
Individual data on the effects of inha¬
insufficiency.
lation on
MPAP, PCWP, TPG, and PVR are shown
Figure 2.
Effects of Inhaled NO 40 ppm on Central
Hemodynamics (Table 2)
During inhalation of NO, PCWP increased
in
Results
Patient characteristics prior to inclusion are shown
Table 1. Mean values for central hemodynamic
variables during control and during PGI2 and NO
inhalation are given in Table 2. No CO values were
in
Table
SV, mL
.
s
cm
.
s
cm-
P/S
TPG, mm Hg
Pa02, kPa
Sa02, %
Sv02, %
02 extr, %
IPSF, %
Control
NO
Control
PGI,
87±8
80±3
43±4
24±2
10±2
3.7±0.3
50±10
437±87
1,633 ±127
0.27±0.05
19±3
15±1
98±0.4
58±5
41±5
6.2±1.5
89±8
80±3
87±6
81±2
42±4
24±2
10±2
3.6±0.4
47±9
431±91
1,650 ±138
0.26±0.05
18±3
13±1
97±0.7
56±5
42±6
9.0±2.1
87: :6
78: :4
39: :4t
29: :3f
9: :2
NS
NS
NS
NS
NS
4.0: :0.4f
51d :9
221 d :55|
1,484:! 156
0.16:! 0.04J
10:! ¦M
12 d 3
95 d 1
59d 5
6
14.2d :3.0|
..¦§
*Mean±SEM. P/S=PVR/SVR ratio;
40±4f
29±3f
9±2
3.7+0.4
51±10
250±67j
1,668±182
0.15±0.04{
ll±2j
15±1
98±0.4
58±5
42±5
6.1±1
02 extr= whole body oxygen extraction; IPSF=intrapulmonary shunt fraction; NS=
fp<0.05 control vs NO, control vs PGI2.
}p<0.01 control vs NO, control vs PGI2.
§p<0.05 NO vs PGI2.
782
MPAP decreased (-7%) as well as
PVR (-43%), and PVR/SVR ratio
2.Effects of Inhaled NO (40 ppm) and Inhaled PGI2 (10 pg/mL) on Central Hemodynamics*
HR, beats/min
MAP, mm Hg
MPAP, mm Hg
PCWP, mm Hg
CVP, mm Hg
CO, L/min
PVR, dyne
SVR, dyne
(+21%) while
(-42%),
TPG
NO
vs
PGI9
NS
NS
NS
NS
NS
NS
NS
NS
NS
not
significant.
Clinical
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1998 by the American College of Chest Physicians
Investigations
MPAP
mmHg
PCWP 40
Hg
80
mm
60
30
40
20
20
.
-
-v
PGI2
NO
PC! 2
NO
TPG
mmHg
v
10H
-V-
PVR 1000
dynes x
40
s x
cm-5
30
750-
20-
500
250-
.!.
NO
C
PGI2
C
Figure 2. Individual data on the effects of inhaled NO
|xg/mL) on MPAP, PCWP, TPG, and PVR.
(.44%). Inhaled
NO caused
or SVR.
no
MAP, CVP, CO, SV,
changes
in
HR,
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 increase
in CO ( + 11%).
Oxygenation Parameters
During inhalation of PGI2 or NO, no changes in
Sa02, Sv02, oxygen extraction, or Pa02 were ob¬
served. The intrapulmonary shunt was significantly
increased during PGI2 inhalation.
NO
C
PGI2
(40 ppm) and inhaled PGI9 (prostacyclin, 10
Discussion
In the present study, we have compared the
effects of inhaled aerosolized PGI2 (concentration in
solution 10 |ULg/mL) with those of inhaled NO (40
ppm) on central hemodynamics in heart transplant
candidates with congestive heart failure and elevated
PVR. The main findings were that inhaled PGI2
induced a pulmonary vasodilation, with a decrease in
PVR, MPAP, and TPG, comparable to that induced
by inhaled NO. Furthermore, inhaled PGI2 caused
no significant effect on SVR. It is not immediately
obvious why inhaled PGI2, in contrast to inhaled
NO, induced a slight (11%) but significant increase
in CO. Previous in vitro studies have suggested that
PGI2 may exert a mild positive inotropic effect2425
which, 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
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1998 by the American College of Chest Physicians
783
a minor "spill-over" of PGI2 to the systemic circula¬
tion, in turn unloading the failing left ventricle (LV).
patients are required to establish whether, in
such
a spill-over effect of inhaled PGI2 is real or
fact,
More
not.
Evidence that inhalation of aerosolized PGI2 may
induce a selective pulmonary vasodilation was first
in a canine model of
provided by Welte et al28
Inhaled
PGI2 has also been
hypertension.
pulmonary
shown to reduce pulmonary arterial pressure and
improve oxygenation in both adults and infants with
respiratory distress syndrome.19'2229 We have re¬
described the effects of incremental concen¬
cently
trations of inhaled PGI2 (2.5, 5, and 10 [xg/mL) in
patients with postoperatively elevated PVR after
heart surgery or heart transplantation.17 In that
study, inhaled PGI2 induced a selective dose-depen¬
dent decrease in PVR and the TPG with no effects
on systemic vasculature and with a maximal effect
seen at an inhaled concentration of 10 ixg/mL. The
selective pulmonary vasodilatory effect of NO is well
described in both animal and human studies.9'3031
NO (5 to 80
Gradually increased doses of inhaled
PVR in
decrease
to
documented
have
been
ppm) with chronic
hypertension, in
pulmonary
patients
heart
cardiac surgical patients, after
transplantation,
and in patients supported with ventricular assist
devices after heart surgery.1011'32'33 In a recent
the effects of incremental doses
study, we evaluated
of inhaled NO (5, 10, 20, and 40 ppm) on PVR in
heart transplant candidates with elevated PVR.8 We
found that inhaled NO at a concentration of 20 ppm
was the lowest mean dose to cause a maximal
reduction in PVR, even though a few patients re¬
40 ppm.
quired
The use of NO for evaluation of heart transplant
candidates with pulmonary hypertension has been
described previously not only by us8 but also by
others.34-35 The decrease in PVR in those studies was
associated with an increase in PCWP. The mecha¬
nism behind this NO-induced increase in PCWP in
patients with left heart failure is unknown. It is
not caused by an NO-induced negative
probably effect
as NO is most likely inactivated by
inotropic
LV and NO donors
hemoglobin before it reaches the
such as sodium nitroprusside or nitroglycerin do not
exert a negative effect on myocardial contractility.
We therefore hypothesized that inhaled NO causes a
redistribution of blood from precapillary to postcap-
capacitance vessels with a conse¬
illary pulmonary
quent increase in LV end-diastolic volume and filling
in LV
pressure.8 This would have caused an increase
in
LV
our
in
but
not
stroke volume a normal
patients
with severely depressed LV function. A small in¬
crease in the capacity of postcapillary capacitance
vessels and LV end-diastolic volume, induced by
784
NO, might cause a large increase in PCWP due to
the increased stiffness of the failing LV. This hypoth¬
esis is supported by the finding that NO induces a
greater vasodilation of postcapillary compared with
vessels in patients with ARDS and high
precapillary
PVR.36 This hypothesis was further supported by a
recent study of Hare et al,37 in which the effects of
inhaled NO on LV filling pressure were studied in
patients with LV failure receiving an LV assist
device. When the pump delivered a fixed systemic
flow, the selective reduction in PVR by NO in¬
creased left atrial pressure, ie, inhaled NO increases
LV filling pressure by increasing pulmonary venous
volume. In the present study, an increase in LV
filling pressure was seen, both for inhaled PGI2 and
inhaled NO, suggesting that the mechanism behind
the 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 and
inhaled PGI2 act to a greater extent on the postcap¬
with the precapillary portion of the
illary compared
vascular
bed.
pulmonary
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.
IV vasodilators is accom¬
Pulmonaryavasodilation by decrease
in SVR, with no
by corresponding
panied
decrease in the PVR/SVR ratio and a decrease in
arterial pressure.8 This systemic hypotension limits
the use of IV nonselective vasodilators in the evalu¬
ation of heart failure patients with elevated PVR,
especially in those with ischemic heart disease, and
also in the postoperative treatment of these patients
after heart transplantation.8'33-38 In contrast, inhala¬
tion of PGI2 and NO produces a rapid and reversible
pulmonary vasodilation without concomittant sys¬
temic
hypotension.817'33the
In recent
studies,
pulmonary hemodynamic
effects of inhaled NO have been compared with
those of inhaled aerosolized PGI2 in patients with
ARDS22 and severe pulmonary hypertension.39
Walmrath et al22 demonstrated in 16 patients with
ARDS that inhaled NO and inhaled PGI2 reduce
MPAP, 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 of
MPAP or PVR as demonstrated by Olschewski.39
One can thus conclude from the data of those reports
and the present study that the efficacy of inhaled
PGI2 to improve pulmonary hemodynamics in pa¬
tients with high PVR, irrespective of the underlying
disease, is at least comparable to that seen with
inhaled NO.
In the present study, it was observed that inhala¬
tion of PGI2 induced a slight increased pulmonary
Clinical
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1998 by the American College of Chest Physicians
Investigations
shunt that could be explained by an increase in lung
water in these patients with severe cardiac failure,
because of the increase in PCWP, in combination
with a prolonged period in the supine position.
Indeed, some patients also developed clinical signs
of pulmonary congestion during NO and PGI2 inha¬
lation that was associated with the development of
pronounced V wavesnoon the PCWP tracing.
Inhaled PGI2 has toxic effects or toxic metab¬
olites and requires only standard systems for nebu¬
lizing therapy. Possible side effects of PGI2 are
and tachycardia induced by an
profound hypotension
overdose of the agent. Systemic effects of PGI2
inhalation have been reported only with inhaled
concentrations of PGI2 100 times greater than those
reported in the present study.40 Inhibition of platelet
aggregation is another possible side effect of PGI2
inhalation that may increase the risk of intraoperative
and postoperative bleeding. However, no effects on
were demonstrated during pro¬
platelet aggregationinhalation
in an animal setting,41
(8
h)
PGI2
longed
but should be studied also in humans. A major
concern has also been the effect of the highly
alkaline glycine buffer PGI2 solution on global bio¬
chemical and cellular composition of the alveolar
epithelial lining fluid. This was investigated in an
lamb model in which inhaled PGI2 for
experimental
8 h did not cause signs of acute pulmonary toxicity.41
In conclusion, a brief period of inhaled PGI2
provides a simple, pulmonary selective test of the
PVR in heart transplant
reversibility of an elevated
candidates, which is comparable to the effects of
inhaled NO with respect to both pulmonary vascular
and systemic effects. The advantages of inhaled PGI2
in comparison to NO is its atoxicity and simple
technology for its administration.
1
2
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Investigations
Comparison of Inhaled Nitric Oxide and Inhaled Aerosolized
Prostacyclin in the Evaluation of Heart Transplant Candidates With
Elevated Pulmonary Vascular Resistance
Åsa Haraldsson, Niels Kieler-Jensen, Ulla Nathorst-Westfelt, Claes-Håkan
Bergh and Sven-Erik Ricksten
Chest 1998;114; 780-786
DOI 10.1378/chest.114.3.780
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