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Correspondence to: Barbara A. Cockrill, MD, Pulmonary and Critical Care Unit, Massachusetts General Hospital, 32 Fruit St, Boston, MA 02114; e-mail: bcockrill{at}partners.org
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Abstract |
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Study design: Micromanometer and balloon-tipped right heart catheterization were performed. Inhaled NO, IV nitroprusside, and sublingual nifedipine were administered sequentially while patients breathed > 90% oxygen.
Setting: Cardiac catheterization laboratory in a tertiary care teaching hospital.
Patients: Fourteen patients with severe pulmonary hypertension unrelated to left ventricular dysfunction.
Measurements and results: During NO inhalation, mean systemic arterial pressure (MAP) was unchanged, but pulmonary artery (PA) pressure ([mean ± SEM] 49 ± 2 mm Hg vs 44 ± 2 mm Hg; p < 0.01), pulmonary vascular resistance (PVR; 829 ± 68 vs 669 ± 64 dyne · s · cm-5; p < 0.01) and RV end-diastolic pressure (RVEDP; 12 ± 1 vs 10 ± 1 mm Hg; p < 0.01) decreased. Stroke volume index (SVI; 31 ± 2 vs 35 ± 3 mL/m2; p < 0.05) increased, and the first derivative of RV pressure at 15 mm Hg developed pressure (RV +dP/dt at DP15) was unchanged. During nitroprusside administration, MAP decreased (105 ± 5 vs 76 ± 5 mm Hg; p < 0.01), PA was unchanged (48 ± 2 vs 45 ± 3 mm Hg; p = not significant), and PVR decreased (791 ± 53 vs 665 ± 53 dyne · s · cm-5; p < 0.01). RV +dP/dt at DP15 increased (425 ± 22 vs 465 ± 29 mm Hg/s; p < 0.05), but SVI was unchanged. Nifedipine decreased MAP (103 ± 5 vs 94 ± 5 mm Hg; p < 0.01), PA and PVR were unchanged, RVEDP increased (12 ± 1 vs 14 ± 2 mm Hg; p < 0.01), and RV +dP/dt at DP15 decreased (432 ± 90 vs 389 ± 21 mm Hg/s; p < 0.05).
Conclusions: Inhaled NO is a selective pulmonary vasodilator in patients with chronic pulmonary hypertension that improves cardiac performance without altering RV contractility. Nitroprusside caused a similar degree of pulmonary vasodilation. In contrast to inhaled NO, nitroprusside caused systemic hypotension associated with an increase in RV contractility. Acute administration of nifedipine did not cause pulmonary vasodilation, but RVEDP increased and RV contractility decreased.
Key Words: inotropism • nifedipine • nitric oxide • nitroprusside • pulmonary hypertension
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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The effects of inhalation of NO on myocardial function are not well documented, but are of particular interest in light of observations that suggest that endogenous NO has negative inotropic effects and may be an intermediary in the cardiac dysfunction seen in sepsis.9 10 We and others have shown that LV filling pressures increase during NO inhalation in patients with severe heart failure,5 and this effect is associated with a deterioration in LV performance.11
Currently, the treatment of patients with isolated pulmonary hypertension remains problematic.12 The use of calcium-channel antagonists and epoprostenol are recent advances that have improved the outlook for patients primary pulmonary hypertension; however, both calcium-channel antagonists and epoprostenol are nonselective vasodilators, and their use may be limited by systemic vasodilation. IV epoprostenol improves survival in patients with primary pulmonary hypertension but requires continuous IV infusion, and catheter-related complications may occur in > 10% of patients.13 Calcium-channel antagonists are effective in a minority of patients and have negative inotropic effects, which may limit their use in patients with right ventricular (RV) dysfunction.14 15 Lung and heart-lung transplantation is an option for suitable candidates, but its application is limited because of a shortage of donors.
If long-term administration of NO is considered, any negative inotropic effect of NO would be particularly important in patients with isolated pulmonary hypertension. In 1991, a median survival of only 2.8 years after diagnosis was reported for patients with primary pulmonary hypertension, with RV failure the most significant predictor of mortality.16 In the current study, we examined the effects of inhaled NO on pulmonary hemodynamics and right heart function in patients with severe pulmonary artery hypertension unrelated to LV dysfunction. These effects were compared with the effects of IV nitroprusside and sublingual nifedipine. Patients were studied while breathing oxygen to assess the additional vasodilating properties of these agents beyond those caused by the reversal of hypoxic pulmonary vasoconstriction.17 18
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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25 mm Hg at rest was required
for study entry. Chronic pulmonary emboli were excluded by normal or
low probability ventilation/perfusion nuclear scintigraphy in all
patients. Five patients had primary pulmonary hypertension, 6 had
pulmonary hypertension associated with collagen vascular disease, 2 had
pulmonary hypertension associated with hepatic cirrhosis, and 1 patient
had veno-occlusive disease. The diagnosis of veno-occlusive disease was
made clinically before the study, and was subsequently confirmed on
autopsy. The study was approved by the Massachusetts General Hospital
Subcommittee on Human Studies. All patients gave informed consent
before the study.
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The following hemodynamic variables were recorded: heart rate; right
atrial pressure, high-fidelity RV pressure, pulmonary artery pressure,
pulmonary artery wedge pressure, and systemic arterial pressure. The
position of the pulmonary artery catheter was confirmed by fluoroscopy
and by the detection of a blood oxygen saturation of > 95% in blood
drawn from the distal port of the wedged catheter. The rate of change
in RV pressure (RV dP/dt) was determined by electronic differentiation.
Cardiac output was determined by the Fick oxygen technique. Oxygen
consumption was measured with an MRM-2 oxygen consumption monitor
(Waters Assoc; Rochester, MN) at baseline on room air. Measurement of
oxygen consumption was repeated at the conclusion of the study and did
not differ significantly from the initial measurement. Thus, oxygen
consumption was assumed to be constant throughout the study. Derived
variables were calculated by standard formulas as follows:
 | (1) |
 | (2) |
 | (3) |
Blood Gas Measurements
Oxygen saturations were determined on a co-oximeter (model 482;
Instrumentation Laboratories; Lexington, MA), and blood gases and pH
were analyzed on a blood gas analyzer (model 1630; Instrumentation
Laboratories). Pulmonary shunt fraction was determined by the standard
formula:
 | (4) |
Gas Delivery System
All gas mixtures were delivered by a nonrebreathing circuit
consisting of a large bore aerosol tubing and a modified continuous
positive airway pressure mask (Respironics Inc; Murrysville, PA). Gas
entry into the system was controlled by two standard high-flow
flowmeters (Timeter Instruments; Lancaster, PA) in parallel. One
flowmeter delivered 100% oxygen and the other a mixture of NO gas (800
ppm by volume in N2; Airco; Riverton, NJ) and
room air obtained from a standard low-flow blender (Bird Blender; Bird;
Palm Springs, CA). Flow from each flowmeter was titrated to achieve a
total flow of 45 L/min at > 90% oxygen concentration adding either
0, 20, 40, or 80 ppm NO. High flow was used to reduce the residence
time of NO with oxygen to minimize the oxidation of NO to nitrogen
dioxide (NO2). The inspired concentration of NO
and NO2 was measured by chemiluminescence (model
14A; Thermo Environmental Instruments; Franklin, MA) and by polarimetry
(Hudson Oxygen Meter; Temecula, CA). NO2 levels
were < 1 ppm at all doses of NO. Exhaled gases were scavenged and
discarded to atmosphere. Blood methemoglobin levels were determined
spectrophotometrically19
at baseline and during the
inhalation of NO at 80 ppm.
Study Protocol
All measurements were made with the patient supine breathing
through a face mask under the following sequential conditions: room
air, > 90% oxygen, NO at 80 ppm by volume (ppm) in addition to
> 90% oxygen, a second period of > 90% oxygen without NO, IV
sodium nitroprusside plus > 90% oxygen, a third period of > 90%
oxygen alone, and lastly, the administration of sublingual nifedipine
plus > 90% oxygen. Measurements were taken 5 min after the beginning
of each study period, or 5 min after the administration of the final
dose of medication. The nitroprusside infusion was titrated to a
systolic BP of 100 mm Hg, or a maximum dose of 500 µg/min. Ten
milligrams of nifedipine was given sublingually every 10 min until the
systolic BP was reduced to 100 mm Hg, or a maximum dose of 30 mg was
reached.
Statistics
All results are expressed as mean ± SEM. Comparisons of the
effects of oxygen alone are made by paired t test. One
patient was unable to tolerate room air because of hypoxia; therefore,
the comparison between room air and oxygen excludes one patient.
Comparisons of the effects of NO, nitroprusside, and nifedipine were
made by two-way analysis of variance for repeated measures followed by
Fisher’s protected least-significant difference test, (StatView,
version 5.1.2; SAS Institute Inc; Cary, NC). The Wilk-Shapiro
test was used to test the normality of the data before analysis of
variance. Values are compared with the previous baseline, unless
otherwise noted. Comparisons of patients categorized by response to NO
were by 
2 test. A p value of 
0.05 was
considered significant.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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Nitric Oxide Inhalation
Inhalation of 80 ppm NO with > 90% oxygen reduced the pulmonary
artery pressure by 10 ± 3% (p < 0.001), the transpulmonary
gradient by 13 ± 4% (p < 0.003), pulmonary vascular
resistance by 19 ± 4%, (p < 0.001), and the ratio of
pulmonary to systemic vascular resistance by 22 ± 4% (p < 0.001;
Table 3 ). RVEDP decreased by 17 ± 5%,
(p < 0.001), and stroke volume index increased by 12 ± 4%
(p = 0.008). Heart rate, cardiac index, mean arterial pressure, and
pulmonary artery wedge pressure were unchanged.
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Nifedipine Administration
After the sublingual administration of nifedipine (24 ± 1 mg),
mean arterial pressure fell 8 ± 1% (p < 0.001), and heart rate
increased 11 ± 3% (p < 0.001). The ratio of pulmonary to
systemic vascular resistance increased 21 ± 7% (p < 0.01),
as did RVEDP (11 ± 4%; p < 0.001). Pulmonary artery pressure,
pulmonary vascular resistance, transpulmonary gradient, cardiac index,
and stroke volume index did not change with nifedipine (Table 3)
.
Effects of NO, Nitroprusside, and Nifedipine on RV Contractility
and Relaxation
There were no changes in peak positive rate of change in right
ventricular pressure (RV dP/dt), RV dP/dt at 15 mm Hg developed
pressure(RV +dP/dt at DP15), or peak negative RV dP/dt during NO
inhalation. Nitroprusside infusion increased peak positive RV dP/dt
25 ± 12% (p < 0.001) and RV +dP/dt at DP15 10 ± 6%
(p < 0.001). There was no change in peak negative RV dP/dt with
nitroprusside infusion. The administration of nifedipine caused a
decrease in RV +dP/dt at DP15 (9 ± 3%; p < 0.001); other
measured indexes of myocardial contractility and relaxation were
unchanged (Table 4
and Fig 1
).
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Characteristics of Patients Who Responded to NO
The pulmonary artery pressure, pulmonary vascular resistance, and
RV dP/dt at a developed pressure of 20 mm Hg in individual patients
receiving 100% oxygen, 80 ppm inhaled NO and oxygen, IV nitroprusside
and oxygen, and oral nifedipine and oxygen are shown in Figure 1
. A
decrease in mPAP of 10% was arbitrarily used to define a pulmonary
vasodilator response to treatment. The baseline pulmonary artery
pressure was lower in patients who responded to NO (49 ± 1 vs
56 ± 3 mm Hg, p 0.05), but there was no difference in pulmonary
artery pressure between responding and nonresponding patients while
breathing oxygen (48 ± 3 vs 51 ± 4 mm Hg). A vasodilator response
was seen in five of the six patients with collagen vascular disease,
but in only one of the five with primary pulmonary hypertension and
none of the two patients with cirrhosis. The single patient with
pulmonary veno-occlusive disease had a 25% fall in pulmonary artery
pressure with NO. All four of the patients who responded to
nitroprusside infusion had responded to inhaled NO. There were no
differences in demographics or baseline hemodynamics between those
patients who responded to inhaled NO but not to IV nitroprusside and
those who responded to both agents.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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Hemodynamic Effects
Of the agents studied, only inhaled NO caused selective pulmonary
vasodilation associated with augmented RV stroke volume and reduced
RVEDP. In contrast, at doses that lowered pulmonary vascular resistance
to a similar degree, nitroprusside caused systemic arterial hypotension
as well as a decrease in RV preload, consistent with its known effect
as a balanced vasodilator.20
The short-term administration
of sublingual nifedipine did not cause pulmonary vasodilation.
Nifedipine administration was associated with an increase in RVEDP
without any change in stroke volume. The lack of a pulmonary
vasodilator response to the relatively low dose of nifedipine has been
reported: higher doses are usually required to demonstrate pulmonary
vasodilation in the few patients who do respond.14
The increase in RVEDP in the absence of an increase in stroke volume
even at this low dose suggests that nifedipine may have an adverse
effect on RV myocardial function.
Inhaled NO has previously been reported to reduce the pulmonary artery pressure in patients with chronic pulmonary hypertension who were not receiving supplemental oxygen.4 21 Inhaled NO is also known to reverse hypoxic pulmonary vasoconstriction.17 In the current study, pulmonary vasodilation in response to supplemental oxygen was noted: both pulmonary artery pressure and transpulmonary gradient fell when oxygen was administered, despite the fact that oxygen saturation was > 90% on room air. Therefore, the current study differs from previous reports in that we observed additional pulmonary vasodilation when inhaled NO was added to a high inspired concentration of oxygen. Thus, inhaled NO appears to have vasodilating actions that are in addition to that of reversal of hypoxic vasoconstriction.
The target for NO in pulmonary vascular smooth muscle is thought to be the heme receptor of cytoplasmic soluble guanylate cyclase, where binding of NO leads to an increase in the conversion of guanosine triphosphate to cyclic guanosine monophosphate.22 The relaxation effect of the increase in intracellular cyclic guanosine monophosphate in smooth muscle cells appears to be mediated by both an active extrusion of intracellular calcium and promotion of the phosphorylation of calcium channels. Phosphorylation leads to the inactivation of the calcium channels, resulting in a decrease in both voltage- and receptor-mediated calcium influx into the cell. Our observation that the vasodilator response to inhaled NO exceeds that of oxygen alone supports the hypothesis that some of the vasomotor effects of oxygen in the pulmonary circulation are endothelium independent and, as has been suggested by the studies of Madden et al,23 the location of the hypoxia sensor is within the smooth muscle cell.
Effects on RV Contractility
There is increasing evidence, both in vitro and
in vivo, that NO has negative inotropic effects. Isolated
cardiac myocyte contraction is attenuated by NO gas.24
Production of NO by NO synthase-3 within cardiac myocytes is associated
with reduced contractility during endotoxemia.25
NO may
also mediate the myocardial depressant effects of other
cytokines.26
Endogenous NO reduces myocardial
contractility and reduces myocardial lactate formation during
myocardial ischemia in dogs.9
Furthermore, Hare et
al10
have demonstrated that the inhibition of NO synthase
augments the positive inotropic response to intracoronary dobutamine
infusion in heart failure patients. This suggests that local NO
production in the heart inhibits the positive inotropic effect
associated with dobutamine infusion.
The possibility that inhaled NO affects myocardial function is less certain. NO is rapidly bound to and inactivated by hemoglobin, and therefore should have no systemic effects.27 In patients with severe heart failure, inhalation of NO reduces the transpulmonary gradient but is associated with an increased pulmonary artery wedge pressure and no change in stroke volume.5 Loh et al11 reported that inhaled NO increased LV end-diastolic pressure and decreased stroke volume in patients with left heart failure. Both of these observations are consistent with a negative inotropic effect.
The current study demonstrates that inhaled NO given at doses sufficient to lower pulmonary vascular resistance has no effect on RV contractility. Inhaled NO lowered pulmonary artery pressure and RVEDP and improved stroke volume. There was no change in indexes of RV contractile function or isovolumic relaxation, including RV +dP/dt at DP15. This likely reflects the extremely short half-life of NO in the presence of hemoglobin and the fact that, when given by inhalation, NO does not reach cardiac myocytes. Thus, the beneficial hemodynamic effects of breathing NO in patients with pulmonary hypertension appear to be related to an improvement in cardiac performance caused by a decrease in RV afterload, not a change in myocardial contractility.
IV nitroprusside, in contrast, was associated with an increase in RV contractility. The increased contractility is likely related to an increase in sympathetic nervous system activation, as indicated by the increase in heart rate that occurred during nitroprusside infusion. Despite the increase in contractility, RV performance was unchanged during nitroprusside infusion, probably because of the simultaneous fall of RV preload caused by systemic venodilation.20
We observed that the administration of sublingual nifedipine caused a decrease in RV contractility associated with a rise in RVEDP. In vitro, nifedipine blocks transmembrane calcium transport in myocardium and results in depression of myocardial contractility.28 In humans with severe LV dysfunction, Fifer et al29 observed a negative inotropic effect of nifedipine. In that study, sublingual nifedipine caused a decrease in peak LV dP/dt, associated with an increase in LV end-diastolic pressure. In patients with pulmonary hypertension, Packer et al30 found that both nifedipine and verapamil administration lowered pulmonary artery pressure; however, both were associated with worsening RV performance as indicated by an increase in right atrial pressure with no change in cardiac output. Our observation that RV dP/dt decreased after sublingual nifedipine administration supports and extends the studies of Fifer et al28 and Packer et al.30 We also measured RV dP/dt at a constant developed pressure to verify that our observation of a decrease indicated a negative inotropic effect regardless of the simultaneous change in ventricular preload.31 The negative inotropic effects of calcium-channel agonists may limit their utility in some patients with pulmonary hypertension and RV dysfunction. However, in those patients in whom the pulmonary vasodilator effects predominate, the negative inotropic effect on the RV may be offset by the decrease in RV afterload. Indeed, improvement in RV function has been observed with the long-term use of calcium-channel antagonists in patients with a pulmonary vasodilator response.32
Cause of Pulmonary Hypertension and Effect of NO
The single patient with veno-occlusive disease had a 15% decrease
in pulmonary artery pressure, which was associated with improvement in
RV function and no change in clinical status or oxygenation. This
response may indicate that there is NO-responsive tone in the pulmonary
venules as well as the arterioles. If only the arterial circulation had
undergone vasodilation, pulmonary edema would likely have developed
because of increased pulmonary capillary pressure. Inhaled NO may
provide a short-term therapy in this difficult to treat disorder.
Limitations of the Study
Several potential limitations to this study should be considered.
The investigators in this study were not blinded, and the order in
which the treatments were given was not randomized. Because of the
obvious and possibly dangerous hemodynamic effects of nitroprusside, we
did not want to administer this drug blindly. Given the short
half-lives of both NO and nitroprusside and that the protocol called
for at least a 5-min period of oxygen alone between measurements, it is
unlikely that randomizing the sequence of administration would have
changed the outcome. Nifedipine, which has a longer half-life, was
given last by design because its effects would be expected to influence
subsequent measurements.
Because a low dose of nifedipine was administered and only the short-term effects were recorded, we cannot compare the effects of NO with a fully titrated dose of this calcium-channel antagonist. All of the 14 patients did go on to enter prolonged high-dose calcium-channel blocker trials according to the protocol of Rich et al.14 Only two patients responded with a fall in pulmonary artery pressure. It is intriguing that both of these patients also had responded to inhaled NO. A vasodilator response to inhaled NO predicts a response to IV epoprostenol.21 It is likely that a response to inhaled NO will identify the subset of patients who are more likely to respond to high-dose calcium-channel antagonists.33 34
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Conclusions |
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Footnotes |
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{altfoot}*From the Pulmonary and Critical Care Unit (Drs. Cockrill and Ginns), Respiratory Care Department (Dr. Kacmarek), Cardiology Unit (Drs. Fifer and Semigran), and Department of Anesthesia and Critical Care (Drs. Bigatello and Zapol), Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Supported in part by grant HL43297 from the National Heart, Lung, and Blood Institute, National Institutes of Health (Dr. Zapol).
Received for publication September 20, 1999. Accepted for publication June 8, 2000.
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