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Methods to improve the yield of right heart catheterization in pulmonary hypertension
Ambalavanan Arunachalam, Neal F. Chaisson, Adriano R. Tonelli
PII: S2590-1435(20)30002-6
DOI: https://doi.org/10.1016/j.yrmex.2020.100015
Reference: YRMEX 100015
To appear in: Respiratory Medicine: X
Received Date: 3 June 2019
Revised Date: 11 December 2019
Accepted Date: 17 February 2020
Please cite this article as: A. Arunachalam, N.F. Chaisson, A.R. Tonelli, Methods to improve the yield
of right heart catheterization in pulmonary hypertension, Respiratory Medicine: X (2020), doi: https://
doi.org/10.1016/j.yrmex.2020.100015.
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1
Abstract word count: 111
Manuscript word count: 3,556
Methods to Improve the Yield of Right Heart Catheterization in
Pulmonary Hypertension
Ambalavanan Arunachalam MD: Assistant Professor, Division of Pulmonary,
Critical Care and Sleep, Tufts Medical Center, Boston, MA, USA.
aarunachalam@tuftsmedicalcenter.org
Neal F. Chaisson MD: Staff, Department of Pulmonary, Allergy and Critical Care
Medicine. Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA.
chaissn@ccf.org
Adriano R. Tonelli MD MSc: Staff, Department of Pulmonary, Allergy and Critical
Care Medicine. Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA.
tonella@ccf.org
Running head: Provocative tests during RHC
Address for correspondence:
Adriano Tonelli MD
9500 Euclid Avenue A-90
Cleveland, Ohio, 44195
Tel: +1 (216) 444-0812
Fax: +1 (216) 445-6024
Email: tonella@ccf.org
2
Keywords: Right heart catheterization, pulmonary hypertension, exercise test, fluid
challenge, pulmonary vasodilator test.
3
Contributions of authors:
Ambalavanan Arunachalam MD: Participated in the conception, design, writing
and critical revision of the manuscript for important intellectual content and final
approval of the manuscript submitted.
Neal F. Chaisson MD: Participated in the writing and critical revision of the
manuscript for important intellectual content and final approval of the manuscript
submitted.
Adriano R. Tonelli MD MSc: Participated in the conception, design, writing and
critical revision of the manuscript for important intellectual content and final
approval of the manuscript submitted. Dr. Tonelli is the guarantor of the paper,
taking responsibility for the integrity of the work, from inception to published
article.
4
Conflict of interest statements:
Ambalavanan Arunachalam MD: The author has no significant conflicts of interest
with any companies or organization whose products or services may be discussed in
this article.
Neal F. Chaisson: The author has participated in the advisory board of Actelion and
Bayer and is a speaker for Gilead and Bayer.
Adriano R. Tonelli MD MSc: The author has no significant conflicts of interest with
any companies or organization whose products or services may be discussed in this
article.
5
Abbreviations:
AV: arteriovenous.
CO: cardiac output.
HVPG: Hepatic venous pressure gradient
HFpEF: heart failure with preserved ejection fraction.
mPAP: mean pulmonary artery pressure.
PAWP: pulmonary artery wedge pressure.
PAH: pulmonary arterial hypertension.
PH: pulmonary hypertension.
PLR: passive leg raising.
PVR: pulmonary vascular resistance.
TPR: total pulmonary resistance.
6
Abstract:
Right heart catheterization (RHC) is needed to diagnose pulmonary
hypertension (PH). Traditional hemodynamic determinations may be insufficient to
identify early stages of the disease and the mechanism of PH, confidently allocate
patients to the pre- and/or postcapillary groups of the disease and guide certain
treatment decisions (e.g. use of calcium channel blockers). In this review, we discuss
the role of established (pulmonary vasodilatory, exercise and rapid fluid infusion
challenges) and promising maneuvers (passive leg raising, intrathoracic pressure
estimation, temporary exclusion of arteriovenous dialysis accesses and dobutamine
infusion) that help interrogate the pulmonary vasculature during RHC, with a focus
on describing rationale for use, indications, contraindications, protocols and
implications of different responses.
7
Introduction:
The proceedings of the 6
th
World Symposium on pulmonary hypertension
(PH) define PH by a resting mean pulmonary artery pressure (mPAP) > 20 mmHg
1
.
Right heart catheterization (RHC) is needed to diagnose PH and distinguish between
the two major hemodynamic types of the disease (i.e. pre- and postcapillary PH)
1
(Table 1). While RHC is the gold standard for PH diagnosis, there is growing
recognition that traditional hemodynamic determinations may be insufficient to
identify early stages of the disease, confidently allocate patients to the pre- and/or
postcapillary groups of the disease
2
, and guide treatment decisions (e.g. use of
calcium channel blockers).
A multicenter study noticed that a third of patients referred to PH centers
were initially misdiagnosed, leading to inappropriate treatment
3
. One example of
potential misdiagnosis includes the assumption that a resting pulmonary artery
wedge pressure (PAWP) ≤ 15 mmHg is conclusively associated with precapillary PH
4
. In fact, Robbins et al. showed that 22% of the patients initially diagnosed with
pulmonary arterial hypertension (PAH) were reclassified as having post-capillary
PH after a rapid fluid challenge
5
. This misclassification was initially suspected in the
AMBITION trial
6
, where investigators modified the clinical and hemodynamic
inclusion criteria to refine the selection of patients with PAH. In the revised
protocol, the PVR was increased from 3 to 3.75 Wood units when the PAWP was ≤
12 mmHg and from 3 to 6.25 Wood units when the PAWP was between 13 and 15
mmHg
6
. Importantly, patients excluded from the final analysis (based on the
8
revised criteria) had higher rates of clinical failure, lower tolerability and attenuated
treatment response
7
.
Certain maneuvers during RHC facilitate a better understanding of the
cardiopulmonary hemodynamics, leading to a better characterization of PH (figure
1). For instance, a pulmonary vasodilator challenge can demonstrate the presence of
pulmonary vascular reactivity which impacts treatment and may provide prognostic
information
8
. An exercise challenge can unmask early stages of pre-
9,10
and
postcapillary PH
11-13
. A fluid challenge can reveal the presence of occult
postcapillary PH
11,13
. Several other maneuvers (e.g. passive leg raising (PLR),
intrathoracic pressure estimation, temporary exclusion of arteriovenous (AV)
dialysis accesses, dobutamine challenge, etc) appear promising and are currently
under investigation. In general, these complementary tests do not appear to add
significant risk to those of resting RHC
14
.
In this manuscript, we discuss the role of established and promising
maneuvers that interrogate the pulmonary vasculature during RHC, with a focus on
describing the rationale for their use, indications, contraindications, protocols and
implications of different responses (Table 2). Our objective is to survey selected
maneuvers and present a practical approach, recognizing that we provide a “bird
eye view” and not an in depth review of each test, which could engender separate
reviews. We also acknowledge that there is a limited understanding of the normal
physiological response and great degree of controversy in how to perform and
interpret these maneuvers. In spite of these limitations, this manuscript succinctly
provides a clinically useful framework on how to improve the yield of the RHC in PH.
9
Established tests:
1. Vasodilator testing:
A) Rationale for use:
Pulmonary vasodilator testing is used to identify PAH patients with
reversible vasoconstriction. Patients with PAH, particularly with the idiopathic or
anorexigen-induced form of the disease, who have a pronounced reduction in the
mPAP may benefit from calcium channel blockers
15
. In addition, a few studies have
linked the degree of acute response to pulmonary vasodilators with outcomes
15,16
.
B) Indications:
- Vasodilator testing is recommended in patients with idiopathic, heritable or
drug-induced PAH; to identify long-term calcium channel blockers responders who
have improved survival over other forms of PAH
17
.
- Further research is needed to determine whether a vasodilator challenge
can provide additional information a) in patients with combined pre and
postcapillary PH, who are considered for medications that target the nitric oxide
pathway; b) to assess the effect of pulmonary vasodilators in the event of acute right
ventricular failure during surgical interventions; c) to support the diagnosis or
assess the response to prostacyclin analogues in patients with pulmonary
venoocclusive disease.
C) Contraindications:
- When used to determine long-term response to calcium channel blockers:
10
- Patients with right ventricular failure or hemodynamic instability in whom
calcium channel blockers are not an option.
- For other potential indications:
- Use with caution in patients with a) left-sided heart disease given risk of
pulmonary edema and b) clinical suspicion of pulmonary venoocclusive
disease / pulmonary capillary hemangiomatosis.
D) Protocol:
Inhaled nitric oxide, intravenous epoprostenol, intravenous adenosine and
inhaled iloprost can be used to test pulmonary vasoreactivity (table 3). Current
guidelines suggest inhaled nitric oxide as the preferred agent
1
given its short half-
life (few seconds)
18
and minimal side effects. Its administration requires a nitric
oxide delivery system, usually managed by a respiratory therapist. In our practice, a
respiratory therapist delivers nitric oxide 40 ppm through a nasal cannula
transported by a flow of at least 4 L/min of either room air or oxygen (based on the
patient’s baseline oxygenation). Hemodynamic determinations are obtained just
before and at 5 minutes of continuous nitric oxide inhalation
15
.
For all the maneuvers described in this manuscript, particular attention
should be paid to common causes of error during RHC; i.e. PAWP and cardiac
output (CO) measurements. An incomplete balloon occlusion could overestimate
PAWP values
19
. Repositioning the pulmonary artery catheter (to a more distal
portion or contralateral pulmonary artery) or using half-balloon inflation generally
helps obtain a reliable PAWP
19
. Cardiac output should be ideally measured with
direct Fick methodology, where oxygen consumption is measured and arterial and
11
mixed venous blood are used for determining arterial and venous oxygen contents.
Wide limits of agreement were reported when comparing CO measured by
thermodilution or indirect Fick versus the “gold standard” direct Fick methodology
20
. Noninvasive methodologies to measure CO are evolving and may be of value in
the future
21-24
.
E) Interpretation:
A positive vasodilator response is defined as a decrease in mPAP of ≥ 10
mmHg, to a value ≤40 mmHg, without a decrease in CO
1
. Based on these criteria,
Sitbon et al.
16
noted a positive vasodilator tests in 12.6% of patients with idiopathic
PAH; of whom about half (6.8%) were long-term calcium channel blocker
responders.
Although still controversial, investigators have associated a more
pronounced response to inhaled nitric oxide with better outcomes in patients with
PAH
8
. Subjects that respond better to this gas have a different phenotype and likely
genotype (e.g. vascular smooth muscle contraction genes are enriched in
vasodilator-responsive patients)
25
. It is tempting to hypothesize that responders to
nitric oxide who are not candidates for calcium-channel blocker or failed this
treatment, may benefit from medications that target this pathway.
A marked increase in PAWP during pulmonary vasodilator challenge is
suggestive of left heart disease
26
. Interestingly, some patients with combined pre-
and postcapillary PH may experience a decrease in PVR during nitric oxide
inhalation
27
. It remains unclear if this response may help guide therapeutic
decisions.
12
2. Exercise testing:
A) Physiologic rationale for use:
A resting RHC may be insufficient for patients who have dyspnea during
activities and mPAP < 20 mmHg. Exercise increases CO and therefore the blood flow
through the pulmonary vasculature. On account of vascular recruitment and
vasodilation, this rise in flow marginally increases the mPAP and PAWP, with a
slight drop in total pulmonary resistance (TPR= mPAP/CO)
28,29
. An increase in TPR
30,31
or mPAP/workload during exercise is associated with exercise intolerance
32-34
and could represent early pulmonary vascular disease, left heart disease, lung
disease or their combination
29
.
B) Indications:
- Study patients with dyspnea of unclear origin or symptoms out of
proportion to the degree of pulmonary or cardiac disease
29
.
- Unmask occult pulmonary vascular or left heart disease in patients
suspected of having PH
2
.
- Help differentiate group 1 from group 2 PH in patients with ambiguous or
borderline determinations (i.e. PVR around 3 Wood units and PAWP 12-15 mmHg)
29,35
.
- Assess the degree of right ventricular contractile reserve, to assist with
prognosis and treatment escalation
36-38
.
C) Contraindications:
- Similar contraindications to those traditionally described for exercise
testing in other cardiovascular and pulmonary conditions
39,40
. These include clinical
13
signs of decompensated heart failure, unstable ischemic heart disease, uncontrolled
cardiac arrhythmias, symptomatic severe aortic stenosis, acute pulmonary
embolism, uncontrolled asthma, acute respiratory failure, acute myocarditis or
pericarditis, and severe PH at rest with a low CO or history of syncope with exertion.
In addition, exercise testing might not be appropriate in subjects unable to
cooperate or who have orthopedic impairments that limit the intensity / duration of
the exercise.
D) Protocol:
Dynamic exercise using stationary cycle ergometers with electronic brakes is
recommended
41
. Exercise protocols vary significantly among institutions and
operators (e.g. supine versus upright bicycles, incremental ramp versus step
protocol, submaximal versus maximal exercise)
1,41,42
. Both peak and immediately
(first seconds) post-exercise measurements provide the most valuable information.
Vascular pressures rapidly recover after exercise
43
. Table 4 describes our exercise
protocol during RHC.
E) Interpretation:
Controversy remains regarding the proper interpretation of exercise
hemodynamics. Hemodynamic criteria that supports the diagnosis of exercise PH
include a) peak mPAP > 30 mmHg and peak TPR > 3 Wood units during exercise
10,29
, b) linearized slope of multiple mPAP and CO determinations > 3 Wood units
43
(figure 2), and c) change in peak minus resting mPAP over the respective change in
CO > 3 Wood units
44
. These 3 criteria have high diagnostic accuracy when tested
against healthy controls
45
, but lack diagnostic concordance
45
. A peak mPAP > 30
14
mmHg and peak TPR > 3 Wood units during exercise appear more sensitive than the
linearized slope of multiple mPAP and CO determinations to identify exercise PH
46
.
The 6
th
World symposium in PH did not reintroduce exercise PH in their
proceedings given uncertainties regarding the clinical definition
1
.
The most common cause of exercise PH is left ventricular diastolic
dysfunction, and it appears that exercise is more sensitive than fluid challenge in
detecting this disorder
11
. Nevertheless there is no consensus on how to define
exercise-induced LV dysfunction
1,13,47
, and adequate measurement of PAWP during
exercise might be difficult due to pulmonary artery catheter displacement
(incomplete wedging), motion artifact and respiratory swings
1
. That said, a ratio of
PAWP over workload normalized to body weight > 25.5 mmHg/W/kg
48
or a
linearized slope of multiple PAWP and CO determinations > 2 Wood units has been
associated with early / occult heart failure with preserved ejection fraction (HFpEF)
49,50
(figure 2).
3. Rapid fluid administration:
A) Physiological rationale for use:
Rapid fluid infusion increases the left ventricular end-diastolic volume,
potentially unmasking HFpEF
5,11,51
. Given therapeutic implications (e.g.
development of pulmonary edema), it is important to exclude occult group 2 PH in
patients suspected of having PAH
13,52
. Patients with a higher risk of left ventricular
remodeling/stiffening and hence occult HFpEF include elderly females, patients
with metabolic syndrome or scleroderma
53
. For instance, in patients with
15
scleroderma-associated PH, rapid fluid administration reclassified one quarter of
patients as having postcapillary instead of precapillary PH
53
.
B) Indications:
- Identify occult or early HFpEF in high-risk groups such as older patients
with metabolic syndrome, obesity or scleroderma.
- Test patients with mildly elevated pulmonary pressures to assess whether
they have occult or early stage HFpEF.
- Adequately classify patients with ambiguous phenotypic characteristics that
overlap between PH group 1 and group 2.
C) Contraindications:
- Patients with signs and symptoms of volume overload and elevated baseline
PAWP, pronounced hypoxemia, severe arterial hypertension, marked left
ventricular systolic and/or diastolic dysfunction and decompensated right
ventricular failure (given the pericardial constraint, a rapid increase in the right
ventricular preload can further displace the interventricular septum leftwards, with
decrease in left ventricular preload and output)
54
.
D) Saline infusion protocol:
Rapid saline infusion is widely available and easy to administer. We infuse
500 ml of normal saline (0.9% sodium chloride) over 5 minutes using the side arm
port of the introducer. We typically use an 8-8.5 F introducer with a 7-7.5 F
pulmonary artery catheter. A rapid infusion is critical, as a slow administration
allows fluid redistribution to the interstitial space, risking a false negative test
55
.
E) Interpretation:
16
Similar to exercise, there is no consensus on the threshold to define an
abnormal response following rapid fluid infusion. Age and gender affect the rise in
PAWP after rapid fluid administration
51
. In general, healthy volunteers maintain a
PAWP < 15 mmHg after the rapid infusion of 500 ml of normal saline
56
. Meanwhile,
patients with HFpEF have a steeper rise in PAWP than healthy individuals
51
and a
PAWP ≥18 mmHg after rapid fluid infusion is considered abnormal
13,56
. Unlike
exercise, fluid bolus had a minimal effect on heart rate and blood pressure
5
.
Promising tests, in which further research is needed.
4. Passive leg raising:
A) Physiologic rationale for use:
Passive leg raising is a simple maneuver that increases the cardiac preload by
shifting blood (around 300 mL)
57
from the venous system of lower extremities
towards the heart
58
. It has the advantage of transiently increasing the cardiac
preload without actively administering fluids. PLR has been reported to increase
PAWP
59,60
with variable CO response. The effect of PLR on pulmonary
hemodynamics has not been thoroughly investigated, but might be similar to rapid
fluid challenge
61
.
B) Indications:
- Similar to fluid challenge; nevertheless this maneuver can be used in
subjects with contraindications to fluid challenge
61
.
C) Contraindications:
- PLR may not be effective in subjects using compression stockings or who
17
have intra-abdominal hypertension or deep venous thrombosis of the lower
extremities.
D) PLR protocol:
Once supine resting measurements are taken, we place the patient in a semi-
recumbent position, in order to load the venous system of the lower extremities
57,61
. After adopting a supine position we elevate the legs 45 degrees using a custom
wedge. Repeat hemodynamic measurements are obtained during the first minute of
leg elevation, since PLR effects can rapidly dissipate
60,62
.
E) Interpretation:
The effects of PLR are mostly unknown in patients with PH; however, they
likely resemble (probably less pronounced) those of rapid fluid challenge. It
remains unclear if a PAWP >15-18 mmHg during PLR can be used to identify occult
or early HFpEF.
5. Estimation of intrathoracic pressure using an esophageal balloon:
A) Physiologic rationale for use:
Pulmonary vascular pressures measured during RHC are a function of the
thoracic intravascular and intrathoracic (pleural) pressures. Using RHC alone, it is
impossible to delineate how much each component contributes to the recorded
pulmonary pressures. In healthy subjects the pleural pressure at functional residual
capacity is around -3 to -5 mmHg, due to the opposing elastic recoil of lungs and
chest wall
63
. This pressure can be estimated with an esophageal balloon catheter
64
and may be higher (positive numbers) in subjects with obesity and/or advanced
18
chronic obstructive disease. Increases in pleural pressure can lead to false positive
diagnosis of PH and postcapillary PH).
B) Indications:
- Delineate the contribution of intrathoracic pressure to the pulmonary
hemodynamic determinations.
C) Contraindications:
-Bleeding diathesis, nasal or esophageal conditions (i.e. strictures, varices)
that would preclude or increase the risk of complications from placing the
esophageal probe.
D) Protocol:
We introduce the esophageal balloon catheter via the nasogastric route and
advance it to 60 cm. We inflate the balloon with 0.5 mL of air and withdraw the
catheter slowly until observing negative pressure deflections during inspiration
65
.
To validate measurements, we verify identical excursions of esophageal and airway
pressures while breathing with an occluded airway
66
. While the patient is breathing
quietly, we simultaneously measure the esophageal pressure along with mPAP or
PAWP over the course of 5 consecutive breaths. The transmural mPAP and PAWP
are obtained by subtracting the esophageal pressure from the intravascular
determinations.
E) Interpretation:
In conditions in which the pleural pressure is higher, the mPAP and PAWP
might be overestimated. Overestimation of mPAP and PAWP can overdiagnose PH
and postcapillary PH, respectively. In overweight subjects we showed that an
19
unadjusted PAWP led to a misclassification of one-third of patients as having
postcapillary PH
67
. The PVR calculation is not directly affected by changes in
intrathoracic pressure, since both mPAP and PAWP are affected by the same degree.
Further research is certainly needed to validate these important findings.
6. Temporary arterio-venous dialysis access exclusion:
A) Physiologic rationale for use:
The introduction of permanent AV accesses is common in patients with
chronic kidney disease who are dependent on renal replacement therapy
68
.
Vascular accesses include AV fistulae (autogenous) and grafts (commonly made of
polytetrafluoroethylene)
69
. The most frequently used anastomosis in AVF is the
artery (side) to vein (end) technique
70
. Most common types include the radial-
cephalic (distal forearm), brachial-cephalic (proximal forearm) and brachial-basilic
(upper arm) AVF
69
. In general, forearm fistulae have lower flows than the upper
arm ones
71-73
.
The creation of an AV access generates hemodynamic effects that include a
decrease in systemic vascular resistance and increase in CO, stroke volume and
pulmonary pressures
74-76
. The relationship between AV access flow and CO is direct
but complex (third-order polynomial regression model)
72,77
. When the fistula flow
increases ≥ 1.5 L/min or the proportion of fistula flow over CO (cardiopulmonary
recirculation) is ≥ 20%, there is a higher risk of developing high CO heart failure
and/or PH
78
.
B) Indications:
- Determine the impact of an AV shunt on pulmonary hemodynamics.
20
C) Contraindications:
- Brief periods of AV access exclusion / occlusion (up to 5 minutes) appear to
be safe
79
.
D) Protocol:
The methodology to exclude a dialysis AV access is not clearly defined. We
obtain full hemodynamic determinations before and after a minute of excluding the
AV access. If the AV access is in the forearm (radiocephalic), then an arm cuff is
inflated above the elbow at 40 mmHg above the arterial systolic blood pressure. If
the AV access is in the upper-arm (brachiocephalic) then we digitally compress the
central part of the fistula or the arterial flow proximal to the anastomosis. We aim
for a temporary but complete loss of the palpable thrill
77
. Studies that included a
temporal compression (either manual or with sphygmomanometer) of the AV
access for evaluation of dialysis associated steal syndrome or PH, reported no
significant complications of this maneuver
80-83
.
E) Interpretation:
High CO heart failure is more common when the AV access flow is ≥ 2 L/min.
When the AV access is excluded the preload decreases, with a reduction in CO and
mPAP
77,83
. Exclusion of the AV access can indicate the fistula contribution towards
high CO heart failure and mPAP. Patients usually have a rapid decrease in CO and
PAP, that could be followed by a more pronounced drop in mPAP over time
84
. In
patients with pre and/or postcapillary PH, a temporary compression will inform on
the impact an elevated CO has on the mPAP, but the precise impact on PAWP and
PVR needs further investigation
85
. High vascular access flow should be monitored
21
regularly with clinical assessments (signs of congestive heart failure), access flow
measurements (with ultrasonography), and echocardiographic assessments (left
and right ventricular size and function and estimated right ventricular systolic
pressure)
86
.
7. Dobutamine infusion:
A) Physiologic rationale for use:
In healthy subjects, an increase in CO causes a modest increase in mPAP and
decrease in PVR because of passive distension of zone 1 pulmonary vessels and
active flow-mediated vasodilation
87,88
. A dobutamine infusion increases the
ventricular inotropy and CO, raising the mPAP when the pulmonary circulation has
a reduced vascular compliance. A dobutamine infusion can help assess the right
ventricular contractility reserve, particularly in subjects who cannot exercise.
B) Indications:
- Assess the pulmonary vasodilatory and right ventricular contractile reserve.
C) Contraindications:
-Hypertrophic cardiomyopathy with left ventricular outflow tract
obstruction, atrial tachyarrhythmias, history of ventricular tachycardia, unstable
angina or recent myocardial infarction, and uncontrolled systemic hypertension.
Dobutamine infusion is relatively contraindicated in patients receiving beta-
blockers as the inotropic effect may be attenuated.
D) Protocol:
We infuse dobutamine through the side port of the introducer, starting at 5
mcg/kg/min and increasing in a stepwise fashion to 10, 20, 30 and 40 mcg/kg/min
22
at 3-minute intervals. We continue the infusion until reaching the maximum
dobutamine dose or development of side-effects. Other investigators use a
maximum dobutamine dose of 10-20 mcg/kg/min or lower based on achieving a
predefined target heart rate (e.g. 120 beats/min)
89
or developing side effects
89,90
.
One group of investigators added a Trendelenburg position at 30 degrees, in
addition to dobutamine infusion
90
, to increase the ventricular preload.
E) Interpretation:
A disproportionate increase in mPAP for the rise in CO reflects a decrease in
the pulmonary vasodilatory reserve
90
. Domingo et al. administered dobutamine at
10 mcg/kg/min in combination with Trendelenburg to patients with PAH. When
compared to controls, patients with PAH had a lower increase in CO but a higher rise
in mPAP, suggesting a lower right ventricular and pulmonary vascular reserves
90
.
Sharma et al. reported a reduced right ventricular contractile reserve in PAH
patients using low-dose dobutamine stress echocardiography
89
.
Conclusions:
Established and promising methodologies during right heart catheterization
stand to provide critical information to improve the diagnosis, optimize treatment
selection and impact prognosis. These maneuvers need to be considered in cases of
unexplained dyspnea, normal or borderline pulmonary pressures, ambiguous
phenotype, and at the time of initial PH diagnosis
23
Table 1: Hemodynamic types of pulmonary hypertension
Definition
Characteristics
Clinical groups
PH
mPAP
>
2
0
mmHg
All
Pre
-
capillary PH
mPAP > 20 mmHg
PAWP ≤ 15 mmHg
PVR ≥ 3 Wood units
1. Pulmonary arterial hypertension
3. PH due to lung diseases and/or
hypoxia
4. Chronic thromboembolic PH
5. PH with unclear and/or multifactorial
mechanisms
Post
-
capillary PH
•Isolated post-capillary PH
•Combined post-capillary and
pre-capillary PH
mPAP
>
2
0
mmHg
PAWP > 15 mmHg
PVR ≤ 3 Wood units
PVR > 3 Wood units
2. PH due to left heart disease
5. PH with unclear and/or multifactorial
mechanisms
Modified from reference
1
. Abbreviations: mPAP = mean pulmonary artery
pressure, PAWP = pulmonary artery wedge pressure, DPG = diastolic pressure
gradient, PVR = pulmonary vascular resistance
24
Table 2: Established and promising maneuvers to challenge the pulmonary
circulation.
Maneuver
s
Indication
s
Benefit
s
Risk
s
Established tests
Vasodilator testing Identify the presence of
pulmonary vasoreactivity
Recognize patient that may
respond to calcium channel
blockers
Pulmonary edema in patients
with left heart disease (rare)
Exercise Recognize occult pulmonary
vascular or left heart disease
Characterize
ambiguous or
borderline pulmonary artery
and PAWP determinations
Identify specific origins of
dyspnea
Those associated with exercise
testing
Fluid
administration Identify occult or early HFpEF
Characterize ambiguous or
borderline pulmonary artery
and PAWP determinations.
Easier to perform than exercise
challenge
Pulmonary edema in patients
with left heart disease
Promising tests, in which further research is needed
Passive leg raising Identify occult or early HFpEF
Can be used in subject with
contraindications to fluid
challenge
None
Esophageal
balloon
Identify interactions
between intrathoracic
pressure and pulmonary
hemodynamics
Accurately determines
pulmonary hemodynamics in
obese or other subjects with
elevated pleural pressures.
Epistaxis, gaging, vomiting,
sore throat.
Temporary
arterio-venous
dialysis access
occlusion
S
uspicion
of
high
cardiac
output heart failure
secondary to AV dialysis
access
Determine the impact of an AV
shunt on pulmonary
hemodynamics
Brief periods of AV access
exclusion / occlusion appear to
be safe
Dobutamine
infusion
Determine the right
ventricular contractile
reserve
Can be used in subjects who are
unable to exercise to assess
response of the RV
May worsen h
ypertrophic
cardiomyopathy with left
ventricular outflow tract
obstruction and arrhythmias,
Abbreviations: AV: arteriovenous, HFpEF: heart failure with preserved ejection
fraction.
25
Table 3: Medications for pulmonary vasodilator testing
Medication
Route
Initial dose
Maximum
dose
Duration
Onset
of
action
Half
-
life
Adverse
effects
Consideration
s
Nitric Oxide
16,91
Inhaled
10 ppm 80 ppm 5-10 min Few seconds Few seconds Rebound PH
(unlikely with
short
administration
)
Pulmonary
edema in
postcapillary
PH
Short-acting,
minimal systemic
side effects, does
not increase
intrapulmonary
shunting, requires
a respiratory
therapist,
relatively cheap
but needs a
delivery system
Epoprostenol
91-93
Intravenous 2 ng/kg/min 12 ng/kg/min
(increments of
2 ng/kg/min)
10-15 min Few minutes 4-6 min Headache,
flushing, jaw
pain, nausea,
dizziness,
hypotension,
diarrhea
Intravenous
infusion, increases
CO and pulmonary
shunt, more
expensive
Adenosine
94,95
Intravenous 50 μg/kg/min 500
μg/kg/min
2 min Few seconds 5-10 s Systemic
hypotension,
bradycardia,
bronchospasm,
chest pain,
atrivoentricula
r block
Increases CO and
systemic shunt,
relatively cheap,
easily available
Iloprost
96,97
Inhaled 2.5 μg/inh 20μg/inh 15-30min Several
minutes
20-30min Headache,
flushing, jaw
pain, dizziness,
hypotension
Inhaled route,
longer plasma half-
life
Modified from Tonelli et al.
15
and Galie et al (web table 4).
98
26
Table 4: Exercise protocol summary
Before exercise
During exercise
After exercise
-
Review
medical history
and
medications
- Evaluate indications and
contraindications for exercise
testing.
- Recognize presence of lung
diseases that may cause pronounced
respiratory variation
- Recognize the presence of atrial
fibrillation and/or other arrhythmia
- Oxygen supplementation to match
usual requirements or keep oxygen
saturation ≥ 90%.
- Jugular or brachial vein approach is
preferred.
- Zero reference level at the mid-
thoracic line, 4
th
anterior intercostal
space.
- Perform a full hemodynamic
evaluation in the exercise position
(with feet on the pedals), including a
careful assessment of the validity/
reproducibility of the PAWP
determination.
- Pressure measurements are
obtained both at end-expiration and
across respiratory cycles *
-
Zero
reference level
should be maintained.
- Obtain hemodynamic
assessments during each
stage of exercise.*
- Measure cardiac output
with thermodilution
unless Fick cardiac output
can be measured.
-Increase the work load
by 20 Watts every 2
minutes (step protocol).
- Stop exercise if
diagnostic criteria for
exercise PH or left
ventricular diastolic
dysfunction associated PH
are clearly achieved.
Alternatively we continue
the exercise until
exhaustion or achieving
absolute / relative
indications for
terminating the exercise
99
.
-
Obtain mPAP and
PAWP immediately
after exercise (to
minimize motion
artifacts).
- Full hemodynamic
assessment at 1
minute of recovery.
*We measured pulmonary vascular pressures both at end-expiration and as the average across
respiratory cycles. Some authors recommend averaging the vascular pressures to reduce the impact
respiratory swings on the determinations
29,41
. We use both approaches and respectively compare
using the same methodology, pulmonary pressure values obtained during exercise with those at rest.
Abbreviations: mPAP = mean pulmonary artery pressure, PAWP = pulmonary artery wedge
pressure.
27
Figure legends:
Figure 1: Complementary tests during right heart catheterization.
Abbreviations: PH: pulmonary hypertension, PLR: passive leg raising, RV: right
ventricle
Figure 2: Mean pulmonary artery and pulmonary artery wedge pressure over
cardiac output during exercise.
In black, we show the mean pulmonary artery pressure (mPAP) over cardiac output
linear slope with a normal response (solid line, slope of 2 Wood units) and
pulmonary hypertensive response to exercise (shaded line, slope of 4 Wood units).
The peak TPR is 2.5 Wood units in the first case and 3.9 Wood units in the second.
The change in peak minus resting mPAP over the respective change in CO was 2
Wood units in the first case and 4 Wood units in the second.
In grey, we show the pulmonary artery wedge pressure (PAWP) over cardiac output
linear slope with a normal response (solid line, slope of 1 Wood units) and a
disproportionate elevation of PAWP during exercise (dotted line, slope of 2.5 Wood
units).
28
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• Misclassification between pre- and post-capillary pulmonary hypertension can
occur with traditional resting hemodynamic evaluation.
• Provocative maneuvers during right heart catheterization help better characterize
the hemodynamic alteration.
• We discuss the role of various maneuvers, describing the rationale for use,
indications, contraindications, protocols and implications of different responses.
Conflict of interest statements:
Ambalavanan Arunachalam MD: The author has no significant conflicts of interest with any
companies or organization whose products or services may be discussed in this article.
Neal F. Chaisson: The author has participated in the advisory board of Actelion and Bayer and
is a speaker for Gilead and Bayer.
Adriano R. Tonelli MD MSc: The author has no significant conflicts of interest with any
companies or organization whose products or services may be discussed in this article.