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From the Division of Respiratory and Critical Care Physiology and Medicine, Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA.
Visiting scientist from Chung Shan Medical
and Dental College, Taichung, Taiwan.
Visiting scientist from
Chang Gung Memorial Hospital, Taipei, Taiwan.
Correspondence to: Karlman Wasserman, MD, PhD, FCCP, St. John’s Cardiovascular Research Center, Harbor-UCLA Medical Center, RB-2, Box 405, Torrance, CA 90509; e-mail: kwasserm{at}ucla.edu
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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E] to carbon dioxide output
[CO2]) is increased in patients with
primary pulmonary hypertension (PPH) consequent to an increase in
physiologic dead space and alveolar ventilation. We wished to see
whether the E/CO2
ratio correlated with the abnormality in pulmonary hemodynamics in PPH
patients and whether it changed in response to prostacyclin
infusion. Methods: Following right-sided heart catheterization, 10 patients with severe PPH were studied in the coronary-care unit while hemodynamic and gas exchange measurements were measured simultaneously before and after infusion with epoprostenol (Epo), a prostacyclin analog. Studies were performed at baseline and during IV infusion of two to three increasing dosages of Epo in 10 PPH patients (NYHA class III-IV). Four patients had radial artery catheters for simultaneous blood gas measurements. Nine healthy subjects who were matched by sex, height, and weight underwent gas exchange analyses only.
Results: The mean (± SD)
E/CO2 ratio was
higher in PPH patients than in control subjects (50.7 ± 9.7 vs
30.6 ± 3.8; p < 0.001). Thirteen measurements made in four
patients showed that the
E/CO2 ratio
correlated with the physiologic dead space/tidal volume ratio
(r = 0.78; p = 0.002). The
E/CO2 ratio
measurement at baseline correlated significantly with total pulmonary
vascular resistance (TPVR) (r = 0.70; p = 0.02) but
not with mean pulmonary artery pressure (mPAP) or cardiac index. During
Epo infusion, the
E/CO2 ratio decreased
with increasing dosage in 6 of 10 patients, with no change or slight
increases in the 4 remaining patients. Considering all doses, the
E/CO2 ratio decreased
significantly in response to the short-term administration of Epo. The
decrease tended to parallel the pattern of decrease in TPVR, but the
changes in both variables were too small to provide a statistically
significant correlation. The mPAP did not change significantly in
response to Epo infusion, although TPVR did change at the highest
dosage.
Conclusions: In patients with severe PPH, the
E/CO2 ratio
correlated significantly with TPVR but not with mPAP or cardiac index.
The E/CO2 ratio
decreased systematically from baseline with the dose of Epo in some but
not all patients. The
E/CO2 ratio and TPVR
decreased significantly in response to Epo when all doses were
considered. Further studies are needed to elucidate whether noninvasive
gas exchange measurements may be clinically useful in the evaluation of
the severity of pulmonary vascular disease and the effectiveness of
pulmonary vasodilator therapy.
Key Words: cardiac output • physiologic dead space/tidal volume ratio • pulmonary vascular resistance • ventilation-perfusion mismatching • ventilatory equivalent for CO2
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The dyspnea that accompanies PPH takes place during exercise. It can be attributed to at least the three following factors that increase ventilatory drive: (1) inefficiency of ventilation resulting from reduced perfusion to well-ventilated lung; (2) metabolic acidosis secondary to inadequate cardiac output (O2 flow) in response to the metabolic stress3 ; and (3) arterial hypoxemia that may be marked if the increase in right atrial pressure forces venous blood through a patent foramen ovale (PFO) into the left atrium.4
The management of PPH has been revolutionized by the continuous IV administration of epoprostenol (Epo), an analog of prostacyclin that can reduce pulmonary arterial pressure and pulmonary vascular resistance.5 In order to ascertain the efficacy of Epo in a dose that can be administered without side effects (eg, hypotension, joint pain, and headache), it is customary to evaluate the degree of tricuspid regurgitation (TR) by echocardiography6 7 and, less frequently, to perform right-sided heart catheterization.8 Because of the potential morbidity and cost associated with right-sided heart catheterization,9 it is impractical to repeat this procedure as often as needed to evaluate the response to therapy and to readjust the dose to obtain maximal therapeutic effects.
Since inefficiency of ventilation results from decreased perfusion of
the ventilated lung (ie, increased physiological dead space
ventilation [VD/VT]), a
high ventilatory response relative to metabolic rate would be expected.
We hypothesized that this high ventilatory response measured as the
ratio of minute ventilation (E) to carbon
dioxide output (CO2)
under steady-state conditions should correlate with some aspect of
pulmonary hemodynamics. We also postulated that improved perfusion to
the ventilated lung resulting from Epo therapy should result in a
decreased
E/CO2
ratio. Thus, the
E/CO2
ratio might be useful in categorizing the severity of decreased
perfusion to the ventilated lung, and the change in
E/CO2
ratio might be useful to evaluate the effectiveness of a drug for
treating patients with PPH.
If a simple noninvasive measurement, such as the
E/CO2
ratio, could be shown to be useful in evaluating pulmonary vascular
disease, it might serve to supplement or replace other methods
currently used to monitor clinical course and treatment. In this study,
we related the resting
E/CO2 ratio
to simultaneous changes in central hemodynamics measured during
right-sided heart catheterization and compared the acute effect of IV
infusion of Epo in PPH patients on these measurements.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Protocol
All patients underwent right-sided heart catheterization with 7F
triple-lumen, flow-directed, thermodilution catheters (Swan-Ganz;
Baxter Edwards; Irvine, CA) in the catheterization laboratory
and then were transferred to the coronary-care unit, where they
remained at rest in the supine position breathing room air.
Patients were familiarized with the face mask (Cosmed srl; Rome, Italy) that was used for making gas-exchange measurements. The patient wore the face mask only for the last 5 min of each 15-min dosing period during which measurements were made. No patient complained about the face mask or had discomfort when wearing it.
Sterile, lyophilized Epo sodium powder (Glaxo Wellcome; Research Triangle Park, NC) was dissolved in sterile glycine buffer (pH, 10.5) and was filtered immediately before administration. Saline solution was infused continuously with the use of a portable infusion pump (CADD-1 model 5100 HF; Sims Deltec; St. Paul, MN) through a peripheral or subclavian vein catheter. Each dose was administered over a 15-min period. Gas exchange and hemodynamics were measured during the last 5 min of the baseline period and during each dosing period. The initial Epo dose was started at a level of 2 ng/kg/min (except for one subject who was started at 1 ng/kg/min) and increased at 15 min by a further 2 ng/kg/min (except for two subjects who were increased by 1 ng/kg/min). The dosage administered was determined on an individual basis by the cardiologist’s clinical evaluation. A total of two doses were studied in seven patients and three doses were studied in three patients before the study was ended because of symptoms or falling systemic arterial pressure.
Measurement
ECG rhythm and finger pulse oximetry oxyhemoglobin saturation
(Biox 3740 Pulse Oximeter; Ohmeda; Louisville, CO) were measured
continuously. The mean systemic arterial pressure (mSAP) was measured
at each level of dosing with an automated brachial artery pressure cuff
(STPB 680; Colin Medical Instrument Co; Komaki City, Japan) at the end
of each 15-min period. Cardiac output was measured by the
indicator dilution technique using iced saline solution injected into
the right atrium and sensing the temperature change in the pulmonary
artery with a thermocouple at the tip of a flotation catheter.
Pulmonary arterial pressure was measured with a strain gauge attached
to the pulmonary artery port of the catheter. Total systemic vascular
resistance (TSVR) and total pulmonary vascular resistance (TPVR) were
calculated from mSAP and mean pulmonary artery pressure (mPAP) divided
by cardiac output, respectively. Because it was not possible to obtain
what was regarded to be a valid pulmonary artery occlusion pressure
measurement to estimate left atrial pressure in all patients, TPVR was
calculated rather than pulmonary vascular resistance. Oxygen uptake,
E, CO2,
tidal volume, and respiratory frequency were measured with a portable
gas analyzer (model K4; Cosmed srl). These measurements were
transmitted by telemetry to a site outside of the coronary-care unit.
In four patients, blood samples were taken from a radial artery catheter for arterial blood gas and pH measurements before Epo therapy was started and at minute 13 and minute 15 of each dosing period.
Healthy Subjects
Sex- (two men, seven women), age-, height-, and
weight-compatible healthy nonsmoking subjects, without histories of
cardiopulmonary disease, were recruited for gas exchange monitoring at
rest, after obtaining informed consent. Repeated measurements were made
over time following the protocol used for the PPH patients except for
the absence of drug infusion and central hemodynamic measurements.
Statistical Analysis
Changes from the baseline for each Epo dosing period were used
for calculation and analysis. The results are reported as the mean
± SD for key variables. In the patients, paired two-tailed
t tests were used to compare changes from baseline. Unpaired
two-tailed t tests were used to compare PPH patients with
healthy subjects. Pearson’s correlation coefficients and regression
equations were used to assess the relationships between and among gas
exchange and hemodynamic variables during baseline and Epo infusion
periods. Comparisons with p of < 0.05 were considered to be
significant.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The average cardiac index and stroke index before Epo dosing (baseline) were relatively low (1.9 ± 0.8 L/min/m2 and 21.7 ± 10.2 mL/beat/m2, respectively) with a wide range of values. At baseline, the mPAP was quite high (69.4 ± 15.1 mm Hg) and, accordingly, so was the average TPVR (25.6 ± 16.1 mm Hg/L/min).
Relating
E/CO2 Ratio to
Pulmonary Hemodynamics
The patients’
E/CO2 ratio
values were higher than those of the control subjects (50.5 ± 9.3 vs
30.6 ± 3.8, respectively; p < 0.001). In the control subjects,
the E/CO2
ratio did not change significantly over the time that matched the
baseline and the two Epo dosing periods (31.6 ± 5.0, 30.8 ± 4.6,
and 31.0 ± 4.5, respectively).
Since the
E/CO2 ratio
is increased in clinical states in which the ventilated lung is poorly
perfused, we sought to determine which aspects of pulmonary
hemodynamics, if any, correlated with the increase in
E/CO2 ratio
in PPH patients. Thus, we plotted the baseline
E/CO2 ratio
as a function of mPAP, cardiac index, and TPVR (Fig 1
). The E/CO2
ratio correlated significantly only with TPVR (Fig 1
, lower
panel). There was a tendency toward reduction of the
E/CO2 ratio
with increases in the cardiac index (Fig 1
, middle panel).
In contrast to the relationship between
E/CO2 ratio
and TPVR, there was no significant correlation between
E/CO2 ratio
and mPAP (Fig 1
, upper panel).
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E/CO2 Ratio and
Pulmonary HemodynamicsE/CO2
ratio, TPVR, cardiac index, and mPAP is shown in Figure 2
. Those patients with PFOs are shown as open symbols in the figure to
distinguish them from patients without PFOs (solid symbols). We
thought that they should be so distinguished because some of the drug
dose may bypass the pulmonary circulation and pass directly into the
systemic circulation, lowering mSAP to a greater degree than mPAP. This
may increase blood flow through the PFO and cause the
E/CO2 ratio
to increase in response to Epo, as illustrated in one PFO patient (Fig 2
, top left, A). Similarly, calculated pulmonary
blood flow may be spuriously high in the PFO patients because some of
the iced saline solution injected into the right atrium to measure
cardiac output may pass directly into the left atrium. Thus, the
pulmonary hemodynamic data shown in open symbols must be interpreted
cautiously.
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E/CO2 ratio
have a pattern similar to that of TPVR with increasing doses. This is
not true of mPAP. The three patients with PFOs and one other subject
showed increases or no change in
E/CO2 ratio
as related to dosing (Fig 2
, top left, A). There
was general agreement between the
E/CO2
ratio and the TPVR. The subject with the largest
E/CO2
ratio had the largest TPVR. Thus, it is conceivable that the
E/CO2
ratio might identify, noninvasively, those patients who might get a
good response to therapy.
As shown in Table 2
, there was no significant reduction in mPAP at any
dose level and when all dose levels were combined. However, TPVR was
significantly reduced at the highest dose and when all dose levels were
combined. In contrast, the
E/CO2 ratio
was significantly reduced in response to Epo only when all doses were
considered. While the
E/CO2 ratio
trended downward for the group as a whole, the reductions did not reach
statistical significance because some subjects did not respond or
changed only slightly (Fig 2)
. When the three subjects with the PFOs
were removed from the analysis (lower half of Table 2
; n = 7), the
E/CO2 ratio
was found to decrease significantly in response to the highest dose and
to all doses of Epo combined. The trend to decrease was also present
for the lowest dose, but it was not significant (p = 0.07).
The changes in
E/CO2 ratio
in response to Epo therapy as compared to changes in TPVR, cardiac
index, and mPAP are shown in Figure 3
for each of the 10 patients. Lines are drawn from the baseline
measurement, which is shown as the intersection of the two dotted zero
lines. Most of the points relating
E/CO2
ratio to the change in cardiac index and of
E/CO2
ratio to TPVR are in the quadrants of Figure 3 showing improvement
in both variables. However, the data do not lend themselves to a
significant correlation because of the variable response to dose,
subject to subject.
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E/CO2 Ratio and
VD/VTE/CO2 ratio
was compared to VD/VT for these four subjects
(total of 13 measurements; Fig 4
), they correlated well (r = 0.791; p < 0.01), although
the sample size is small. In response to Epo infusion, blood gas values
(ie, pH, PaCO2,
and PaO2) did not change
appreciably. However,
E/CO2
ratio and VD/VT, both
calculations reflecting gas exchange efficiency, decreased
significantly (Fig 4)
.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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E/CO2
ratio) reflects the ventilatory efficiency of gas exchange. The stable
gas exchange ratio (RER) shown in Table 2
indicates that patients were
in a gas exchange steady state during their studies. A higher
E/CO2
ratio describes a greater ventilatory requirement for eliminating the
CO2 produced by aerobic metabolism and defines a
reduced ventilatory efficiency. The reduced ventilatory efficiency is
caused by an increase in physiologic dead space, as shown in Figure 4
,
and a reduced PaCO2
set-point (ie, the level of
PaCO2 regulated by the
ventilatory control mechanism; Table 3
).11
12
These studies demonstrate that the
E/CO2 ratio
is elevated in PPH patients. To correlate the degree of abnormality in
the E/CO2
ratio with pulmonary hemodynamics, we had available direct measurements
of pulmonary artery pressure and thermodilution cardiac output
measurements made simultaneously with the gas exchange measurements.
Thus, we could calculate TPVR in all patients. We did not have good
pulmonary artery occlusion pressure measurements to estimate left
atrial pressure in all patients because the occlusion was not always
satisfactory and there could be anastomoses with the bronchial
circulation distal to the site of occlusion, causing spuriously
elevated occlusion pressures. Therefore, TPVR rather than pulmonary
vascular resistance was calculated. Of the three variables (mPAP,
cardiac index, and TPVR),
E/CO2
correlated significantly only with TPVR; the correlation was positive,
as would be expected given the significance of the two measurements
with respect to the pulmonary vascular bed (Fig 1)
. Thus, a patient
with a higher
E/CO2 ratio
would be the patient with the higher pulmonary vascular resistance.
It was difficult to make a comparison of the change in
E/CO2 ratio
with the change in TPVR, or with any other hemodynamic measurement,
because of the variable response, subject to subject. Thus, some
patients had reduced TPVRs and
E/CO2
ratios, and some did not (Fig 2)
. Sequential measurements showed good
agreement, particularly for
E/CO2 ratio
(Fig 2
, top left, A). While these measurements
may change in the same direction in response to dosing, the magnitude
is variable from subject to subject (Fig 3)
. But, in general, the
subject with the greater reduction in TPVR in response to acute dosing
with Epo also had the greater reduction in
E/CO2
ratio. The overall acute effect of therapy on pulmonary hemodynamics
and ventilatory efficiency is shown in Table 2
and in Figures 3
, 4
.
Figure 3 shows the
E/CO2 as
related to mPAP, change in cardiac index, and TPVR. If random
relationships prevail, the
E/CO2
ratio plotted against the changes in each of the three hemodynamic
variables will fall equally in the four quadrants of this plot. The
points distribute randomly only for the
E/CO2
ratio when related to the mPAP. For the
E/CO2
ratio, as related to the change in cardiac index and TPVR, most
points fall in the quadrant that shows improvement in both.
The statistical analysis for the changes in response to acute Epo
dosing is shown in Table 2
. mPAP did not change with Epo at any dose in
these acute studies. Cardiac output increased at all doses. TPVR
decreased only at the highest dose.
E/CO2 ratio
decreased with Epo administration, but the improvement is statistically
significant only when all doses are considered or when patients with
PFOs are excluded. Because the patients with PFOs tended to increase
their
E/CO2
ratio (three measurements increased, two decreased, and one had no
change) in contrast to the population as a whole, we envisioned that
part of their IV Epo dose might enter the systemic circulation
directly, thereby decreasing systemic vascular resistance and,
consequently, reducing left atrial pressure below right atrial
pressure. This would divert some of their venous return to the systemic
circulation, depriving their lungs of blood that they would ordinarily
receive if the Epo infusion had not directly entered into their
systemic circulation through their PFOs. Gorcsan et al13
had identified a PFO in 29% of patients (12 of 41 patients) with
severe pulmonary hypertension (both PPH and secondary pulmonary
hypertension). Thus, our incidence of PFO was similar to that in this
report. If we separately analyzed the
E/CO2
ratio with dosing in the seven patients without PFOs, we obtain
statistically significant reductions for the last dose and all doses
combined, but only a trend in the case of the first dose (p = 0.07;
Table 2 ).
As shown in Figure 4
, the improvement in
E/CO2 ratio
paralleled the improvement in VD/VT following
dosing with Epo. This supports the concept that a reduction in the
E/CO2 ratio
reflects an improvement in blood flow to the ventilated lung.
This study demonstrates that the magnitude of the abnormality in
resting
E/CO2 ratio
reflects the magnitude of the abnormality in pulmonary vascular
resistance in PPH patients. The failure to show a correlation between
E/CO2 ratio
and mPAP is not surprising because the latter depends not only on the
degree of pulmonary vasculopathy, but also on the degree of right
ventricular hypertrophy in response to the increase in pulmonary
vascular resistance. Because the degree of right ventricular
hypertrophy appears to be quite variable in response to a given
increase in pulmonary vascular resistance, and perhaps because mPAP
could increase just to a limited level before the tricuspid valve
becomes incompetent, mPAP might not be as precise an indicator of
severity of disease as TPVR. Thus, Rich et al14
used the
change in pulmonary vascular resistance, and not mPAP, as a measure of
favorable drug response.
In our patients, mPAP did not change significantly with treatment
despite a reduction in calculated TPVR (Table 2)
. Thus, a change in
mPAP itself may be a poor early indicator of acute improvement in
pulmonary vascular resistance, particularly soon after treatment is
started.9
The changes in mPAP also did not correlate with
changes in TPVR because the latter resulted primarily from the increase
in cardiac output. However, the correlation of
E/CO2 ratio
with TPVR and its change with treatment suggests that this measurement
of gas exchange efficiency may be useful to evaluate the efficacy of a
drug in improving lung perfusion, even in the short term. Barst et
al15
showed that the 6-min walk distance could be used as
a measurement to demonstrate improvement in patients with PPH in
response to Epo therapy. However, they did not show which aspects of
exercise pathophysiology improved in response to the drug treatment in
these patients.
In summary, in our patients, the
E/CO2 ratio
is increased in proportion to TPVR, but not in proportion to mPAP. The
E/CO2 ratio
also was found to decrease in response to effective pulmonary
vasodilator therapy. Further studies might clarify and elucidate how
noninvasive gas exchange measurements might be used to replace or
complement other more complex, expensive, and invasive techniques for
evaluating the severity of pulmonary vascular disease and the
effectiveness of pulmonary vasodilator therapy.
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Footnotes |
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CO2 = carbon dioxide output;
VD/VT = physiological dead space fraction of
tidal volume; E = minute ventilation Supported in part by the Milly Liang Liu, MD, and Steve CK Liu, MD, Research Fund and by Glaxo Wellcome.
Received for publication January 6, 2000. Accepted for publication September 13, 2000.
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References |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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