Variability in Hemodynamic Evaluation of Pulmonary Hypertension at Large Referral Centers

Abstract

Despite consensus guidelines for right heart catheterization (RHC) in the diagnosis of pulmonary arterial hypertension (PAH), considerable differences exist in the performance of RHC, interpretation of hemodynamic data, and frequency of RHC performance in patients with established disease. These differences may lead to variability in diagnosis or treatment of PAH. We sought to gather information on the standard practice of RHC for the diagnosis and management of PAH from experienced pulmonary vascular disease specialists. We developed a semiquantitative online survey of diagnosis and treatment patterns of pulmonary hypertension and distributed it to physicians at pulmonary hypertension centers in the United States. Thirty of 50 physicians completed the survey: 20 pulmonologists and 10 cardiologists, all of whom reported treating >100 patients with PAH in the past year. All respondents perform RHC in ≥90% of patients with suspected PAH. All physicians determine the pulmonary wedge pressure at end expiration; however, only half of respondents personally review tracings. Physicians differed in frequency of vasodilator testing (8 of 24 performed testing in >90% of patients with PAH), fluid challenge and exercise (19 of 30 performed testing in <25% of patients with PAH for both). Most physicians (70%) report repeating RHC between 6 months and 1 year after PAH treatment initiation. Variability exists in the interpretation of hemodynamic tracings and performance of vasodilator, fluid, and exercise challenges in the management of PAH by experienced physicians in the United States. Additional consensus guidelines delineating appropriate adjunctive testing to standardize the diagnosis of PAH are needed.

INTRODUCTION

Right heart catheterization (RHC) is the gold-standard procedure for the diagnosis and classification of pulmonary hypertension (PH).^1,2 RHC is necessary to diagnose pulmonary arterial hypertension (PAH) and is recommended for all patients suspected of having PAH before the initiation of any PAH-specific therapy. Consensus guidelines state that RHC should include measurement of pulmonary artery pressure, pulmonary wedge pressure, cardiac output, and oxygen saturations in the central veins, cardiac chambers, and pulmonary artery; calculation of pulmonary vascular resistance; and performance of vasodilator testing in patients with PAH to accurately diagnose and categorize PH and to guide therapy (Table 1).¹ Evidence is lacking for some specialized tests commonly performed during right heart catheterization (e.g., exercise testing and fluid challenge), and although consensus recommendations exist,¹ adherence to these recommendations and application of these tests in clinical practice is unknown. In addition, differences in measurement and assessment of certain variables during right heart catheterization (e.g., measurement of pulmonary wedge pressure at end-exhalation versus the electronic mean) between centers can create heterogeneity in hemodynamic assessment and thus in final diagnosis of PH. Furthermore, no practice guidelines exist to delineate the best practice for repeating hemodynamic assessment in routine PH surveillance or after change in clinical status or therapy for PH. A standardized, rigorous approach to RHC is important for multicenter clinical trials and PH registries.

Table 1.

Hemodynamic assessment in the evaluation of pulmonary arterial hypertension

Measured variables

Right atrial pressure

Right ventricular pressure

Pulmonary artery pressure (systolic, diastolic, mean)

Pulmonary artery occlusion or wedge pressure, left atrial pressure, or left ventricular end-diastolic pressure

Oxygen saturations (inferior vena cava, superior vena cava, pulmonary artery, systemic artery)

Heart rate

Systemic blood pressure

Derived variables

Cardiac output/index

Pulmonary vascular resistance

Response to acute vasodilator

Note: Adapted from the American College of Cardiology Foundation Task Force and American Heart Association Expert Consensus Document on Pulmonary Hypertension.¹

Our objective was to gather information on the standard practice of RHC for the diagnosis and management of PAH from experienced pulmonary vascular disease specialists in the United States. We hypothesized that significant variability in standard practice of right heart catheterization would exist among expert physicians.

METHODS

Survey instrument and study population

We developed a semiquantitative online survey instrument with 82 questions designed to collect information about practice patterns in the diagnosis, treatment, and management of patients with PAH. The survey was developed and data were collected and managed using REDCap, a secure, web-based application designed to support data capture for research studies.³ The survey was designed for physicians experienced in the treatment of adults with pulmonary vascular disease, and respondents were asked how RHC was performed at their center; specific hemodynamic variables used to make the diagnosis of PAH; methods for provocative testing during right heart catheterization with vasodilators, fluid challenge, and exercise testing; and how frequently repeat RHC was performed to assess response to therapy in PAH. The survey contained additional questions not included in these results, and the full contents of the survey are found in the Supplemental Material, available online. The survey instrument and study design were approved by Vanderbilt University's institutional review board (protocol 110492) before survey distribution.

The web-based survey was sent via e-mail to 50 physicians who specialize in the treatment of adults with PAH in the United States. We identified eligible physicians as those listed at centers participating in a large observational US registry.⁴ Only one physician per treatment center was included.

Survey mechanics

A link to the survey was sent via e-mail to 50 specialists treating PAH on July 6, 2011. A reminder e-mail was sent to physicians who had not yet completed the survey 1 month later. Informed consent was waived, because we did not collect identifying information. Physicians were required to answer a question that acknowledged their participation in this research study (survey question 1, Supplemental Material, available online). Respondents did not have to answer all questions to submit the survey. For several questions, respondents were able to select multiple answers as applicable to their practice.

Data analysis

Survey data were collected in REDCap and exported into SPSS, version 19 (IBM, Armonk, NY). Surveys with less than 75% of questions completed were not included in the final analysis. Response rate was calculated by dividing the number of unique completed surveys by the number of e-mail addresses on the participant list (n = 50). Results are reported as number (%) unless otherwise noted.

RESULTS

General characteristics

Thirty surveys meeting our criteria for inclusion were returned, representing a 60% response rate. Two-thirds of responding physicians were pulmonologists, one-third were cardiologists, and the respondents had a mean of 16.5 years (range, 6–30 years) experience treating PAH. All responding physicians reported at least 100 patients at their center receiving PAH-specific therapies, with 12 respondents reporting 250–500 patients and 5 reporting more than 500 patients. Twenty-three centers (77%) had more than 50 patients receiving continuous prostaglandin therapy.

Hemodynamic assessment

At centers surveyed, nearly all patients undergo hemodynamic assessment with right heart catheterization before initiation of PAH-specific therapy: 90%–99% of patients (n = 10, 33%) or 100% of patients (n = 20, 67%). RHC is performed by the respondent or a colleague (70%) or a select group of experienced cardiologists (53%), with only 50% of respondents independently reviewing hemodynamic tracings (multiple answers accepted). All respondents indicated that pulmonary wedge pressure (PWP) is determined at end expiration; however, 10% also indicated that they use the mean of inspiratory and expiratory PWP values, and 7% use the value determined by the computer as the final wedge measurement. A minority of respondents (37%) obtain a wedged saturation to help confirm an accurate PWP. Routine measurement of left ventricular end-diastolic pressure (LVEDP) is performed for a minority of patients, with 70% of respondents obtaining an LVEDP in less than 25% of patients. Only three centers reported measuring LVEDP in 75%–99% of patients.

Nearly two-thirds of centers (n = 18) derive cardiac output (CO) using both thermodiluation and the Fick method; only 4 respondents (13%) use a measured maximal oxygen consumption for the Fick calculation. Nineteen respondents indicated they use a minimum pulmonary vascular resistance (PVR) cutoff as a consideration when starting PAH therapy: 17 of 19 use a cutoff PVR >3 Wood units, one uses a cutoff PVR >2.5 Wood units, and one uses a cutoff PVR >4 Wood units.

Vasodilator testing, exercise testing, and fluid challenge

Of the 24 physicians responding to questions regarding vasodilator testing, 38% report using acute vasodilator testing in less than 50% of patients with PAH, and 33% report using vasodilator testing in all or nearly all (>90%) of patients with PAH. Agents used for acute vasodilator challenge include inhaled nitric oxide (iNO; 87%), adenosine (7%), intravenous prostacyclin derivative (3%), or inhaled prostacyclin derivative (3%). For clinicians limiting use of vasodilator challenges to certain groups of patients, vasodilator challenges were commonly not performed for patients with scleroderma (30%), portopulmonary hypertension (33%), congenital heart disease (30%), human immunodeficiency virus infection (7%), and drug/toxin-associated PAH (3%).

Intravenous fluid challenge during hemodynamic assessment is uncommon (Table 2): 63% of respondents perform fluid challenge in less than 25% of patients with PAH, and 27% reported not performing fluid challenge during right heart catheterization for PAH. Exercise testing in patients without PH at baseline (mean pulmonary artery pressure [mPAP], <25 mmHg) is uncommon but used more frequently than fluid challenge (Table 2). There was no consensus on the definition for exercise-induced PAH, although the majority of centers (17 of 25) who perform exercise testing use an mPAP >30 mmHg. The remaining centers use other values: mPAP >35 mmHg, mPAP >40 mmHg, an mPAP cutoff that varied depending on age, and a cutoff based on changes in other variables (CO, PVR, and PWP compared with baseline).

Table 2.

Fluid challenge and exercise testing in pulmonary arterial hypertension (PAH)

Patients with PAH, %	Performing fluid challenge, %	Performing exercise testing, %a
0	27	3
1–24	63	63
25–49	7	13
50–74	0	3
75–99	3	7
100	0	3

Seven percent of respondents reported performing exercise testing only in specific populations (unexplained exertional dyspnea, scleroderma, and research trial).

Assessing response to PAH treatment with RHC

Table 3 shows the assessments routinely performed to evaluate the efficacy of PAH therapy. RHC is routinely performed by 67% of respondents and is more common than cardiopulmonary exercise testing (10%) and cardiac magnetic resonance imaging (MRI; 17%). Table 4 shows when clinicians repeat RHC assessment in PAH. RHC is performed within 1 year of starting therapy in 70% of centers and is repeated after changing or adding therapy in 60% of centers.

Table 3.

Assessments routinely performed to evaluate the efficacy of pulmonary arterial hypertension (PAH) treatment

Assessment	Responding physicians using that assessment, %
Patient symptoms	100
Physical examination	97
WHO functional classification	100
Six-minute walk test	97
Brain natriuretic peptide	90
Echocardiogram	97
Cardiac MRI	17
Cardiopulmonary exercise test	10
Right heart catheterization	67
Othera	7

Note: WHO: World Health Organization; MRI: magnetic resonance imaging.

Other assessments listed included Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) score and Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR).

Table 4.

Interval for repeating right heart catheterization

Response	Respondents, %
After 3 months of initial treatment	10
After 6 months of initial treatment	23
After 1 year of initial treatment	37
Annually	27
After adding or changing therapy (at any point)	60
Only if patient is worsening	47
Never	0
Other^a	20

^a Other responses included if diagnostic/therapeutic dilemma, 4 months, every 2 years, and if patient being prepared for liver or lung transplantation.

DISCUSSION

The results of this survey demonstrate differences in the diagnostic evaluation of PAH using RHC among clinicians at large PH centers in the United States. Although noninvasive methods evaluating the pulmonary vasculature and right ventricular function exist, invasive hemodynamic assessment by RHC is essential for the diagnosis of PAH. In addition, repeated hemodynamic assessment may be performed to assess disease progression or response to therapy, although no consensus recommendations exist regarding the frequency of follow-up measurements. Consistent and accurate measurement of pulmonary artery pressure, PWP, and/or LVEDP and derivation of PVR are critical for guiding treatment of PAH. Practice variability in RHC for assessment of PAH between centers can contribute to heterogeneity in the classification of PAH, which has implications for PAHregistries and clinical trials.

RHC is performed before starting PAH therapy for the vast majority of patients, with all respondents indicating more than 90% of patients had invasive hemodynamic assessment before starting therapy. Because the diagnosis of PAH requires invasive hemodynamics to exclude pulmonary venous hypertension (World Health Organization [WHO] group 2 PH),^1,2 it is notable that one-third of respondents indicated that a small percentage of patients initiated PAH therapy without RHC. It is not known from this survey whether these patients initiated PAH therapy before presenting to a PH center, were too ill to undergo RHC, or there were other clinical factors that influenced the decision to begin PAH therapy without invasive hemodynamic assessment.

Accurate measurement of the PWP can be challenging, especially for patients with severe pulmonary disease or obesity, for whom large swings in intrathoracic pressure with respiration can lead to significant variation in values. In addition, inaccurate assessment of PWP due to “overwedging” or partial occlusion can lead to an overestimation of the true PWP, potentially misclassifying the cause of PH.^5,6 The vast majority of physicians in our survey used end-expiratory values to determine PWP as suggested by consensus guidelines;^1,2 however, a minority of physicians reported also using the mean of inspiratory/expiratory PWP or an electronic mean PWP. Although most compared PWP with LVEDP when available, LVEDP was measured in less than 25% of patients with PAH at most centers. Strikingly, only half of physicians reported personally reviewing the RHC tracings.

Careful interpretation of hemodynamic waveforms is a critical practice in the evaluation of pulmonary vascular disease.⁷ Interobserver variability in the interpretation of hemodynamic waveforms is common. Clinicians in this study relied primarily on PWP as an estimation of left ventricular filling pressure, a critical assessment for distinguishing PAH from WHO group 2 PH; however, numerous studies have highlighted the limitations of this approach. In a prospective analysis of 61 patients referred for evaluation of PH, Ryan et al.⁸ showed that use of the digitized mean PWP resulted in misclassification of patients as having PAH. In their study, the digitized mean PWP was significantly lower than the PWP measured at end-expiration, and the end-expiration PWP was a more reliable surrogate for LVEDP. In a large cohort of patients with PH, Halpern and Taichman⁹ have reported that PWP frequently underestimates LVEDP and that nearly half of patients classified as having PAH may be misclassified without simultaneous evaluation of LVEDP. The reliance on PWP, especially the electronic mean PWP, and lack of personal review of tracings may contribute to misclassification of PAH even by experienced clinicians. Even with careful review, any given PWP value need be considered in context with other clinical and physiologic variables to most accurately distinguish PAH from group 2 PH, a recommendation highlighted in the Nice guidelines.²

The 2013 Nice classification does not include PVR in the definition for PH,² although PVR was included in the definition of PAH, which is consistent with other consensus statements.¹ Our results suggest that the majority of PH practitioners at referral centers continue to use a PVR cutoff of >3 Wood units when considering PAH therapies. Although the PVR in most cases of PAH will be substantially higher than this cutoff value, there are some instances in which PAH may be present with normal or mildly elevated PVR (e.g., high-output states such as portopulmonary hypertension).¹

Determination of acute vasodilator response is an important part of the evaluation for PAH, because patients with PAH who have a positive response have improved long-term outcomes.^10–12 In accordance with consensus guidelines,^1,2 most respondents to this survey use iNO for acute vasodilator challenge. Over a third of physicians in this survey report using vasodilator testing in less than half of patients with PAH. In particular, patients with scleroderma, portopulmonary hypertension, and congenital heart disease often did not undergo vasodilator testing. The Nice guidelines² recommend vasodilator testing only for patients with IPAH, because vasodilator responders in other subgroups of PAH are uncommon.^13–16 Although “responders” may be uncommon in these other groups, some studies suggest that acute vasodilator response may help with prognosis in congenital heart disease^17,18 and portopulmonary hypertension.¹⁶ One-third of respondents in this survey reported assessing vasodilator response in nearly all (>90%) of patients with PAH. It is unclear whether this practice will change with the recommendations from the Nice guidelines, which were not available at the time of this survey.

Current guidelines do not recommend routine use of exercise testing during RHC in the assessment of PAH.^1,2 Although some centers perform exercise testing frequently, most centers surveyed use exercise testing in a minority of patients with PAH. We did not query clinicians about how they determine which patients receive exercise testing. Progression of exercise-induced PAH (mPAP >30 mmHg) to overt PAH has been reported only in patients with scleroderma,¹⁹ indicating that this may be an important group in which to consider exercise testing if resting mPAP is not elevated. The lack of consensus regarding what constitutes exercise-induced PAH reflects the heterogeneity of criteria and protocols reported in the literature.²⁰

Fluid challenge during RHC to elicit latent pulmonary venous hypertension (PVH), discussed in a recent summary statement on group 2 PH,²¹ is routinely performed in a minority of centers. However, there is increasing evidence that this simple test may be useful in identifying latent PVH,^22,23 with over 20% of patients exhibiting an increase in PWP >15 mmHg after rapid infusion of 500 mL normal saline.^22,24 Given that exercise testing and fluid challenge are not commonly performed at most PH centers, additional study of these maneuvers in patients with PAH and group 2 PH to define sensitivity and specificity is needed before firm consensus recommendations and widespread adoption of this practice should occur.

There are no current recommendations on the frequency of repeat hemodynamic assessment following treatment initiation in patients with PAH. PH specialists in this survey routinely measure invasive hemodynamics in patients with PAH between 6 and 12 months after initiation of PAH-specific therapy and after changes in treatment. This highlights the important role of follow-up RHC in patients with PAH even in an era with improving options for noninvasive evaluation of PH (e.g., brain natriuretic peptide testing, cardiac MRI, and echocardiography).

Responding physicians in this survey were experienced and represented PH centers with moderate-to-large cohorts of patients with PAH, with over half of the represented centers actively treating more than 250 patients with PAH therapies. The results of this survey may not apply to physicians at smaller centers or those outside the United States. Other limitations are the inclusion of partially completed questionnaires and potential for bias, because physicians knew they were being studied and may have adjusted their responses. Although the majority of surveys were fully completed, the inclusion of questions with less than a 100% response rate may lead to over- or underestimation of certain variables. Nonetheless, the survey offers important information on practice patterns by experienced PH physicians.

Conclusions. This survey highlights differences in the use of RHC by expert clinicians in the United States that may contribute to heterogeneity in the diagnosis and management of PAH. Standardization of RHC practices, including specialized testing such as exercise and fluid challenge, is an important consideration for future consensus guidelines and clinical trial groups.

Footnotes

ACKNOWLEDGMENTS

We thank the pulmonary hypertension centers and physicians who took the time to respond to the survey.

Source of Support: This work was supported by Clinical and Translational Science Award UL1TR000445 from the National Center for Advancing Translational Sciences and by National Institutes of Health 5 K08 HL093363 (to ARH).

Conflict of Interest: MEP has served as an advisory board member for Gilead. ARH receives research funding from Pfizer and serves as a consultant for Actelion, Pfizer, and United Therapeutics. IMR serves as an advisory board member for Actelion, Gilead, and United Therapeutics and is currently receiving institutional grants from Actelion, Gilead, United Therapeutics, GeNo, and Aries. All other authors: none declared.

References

McLaughlin

Archer

Badesch

. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009;53:1573–1619.

Hoeper

Bogaard

Condliffe

. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013;62:D42–D50.

Harris

Taylor

Thielke

Payne

Gonzalez

Conde

. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42:377–381.

McGoon

Krichman

Farber

. Design of the REVEAL registry for US patients with pulmonary arterial hypertension. Mayo Clin Proc 2008;83:923–931.

Leatherman

Shapiro

. Overestimation of pulmonary artery occlusion pressure in pulmonary hypertension due to partial occlusion. Crit Care Med 2003;31:93–97.

Morris

Chapman

Gardner

. Frequency of technical problems encountered in the measurement of pulmonary artery wedge pressure. Crit Care Med 1984;12:164–170.

Mueller

Chatterjee

Davis

. ACC expert consensus document. Present use of bedside right heart catheterization in patients with cardiac disease. J Am Coll Cardiol 1998;32:840–864.

Ryan

Rich

Thiruvoipati

Swamy

Kim

Rich

. Current practice for determining pulmonary capillary wedge pressure predisposes to serious errors in the classification of patients with pulmonary hypertension. Am Heart J 2012; 163:589–594.

Halpern

Taichman

. Misclassification of pulmonary hypertension due to reliance on pulmonary capillary wedge pressure rather than left ventricular end-diastolic pressure. Chest 2009;136:37–43.

10.

Sitbon

Humbert

Jais

. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;111:3105–3111.

11.

Rich

Kaufmann

Levy

. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76–81.

12.

Rich

Brundage

Levy

. The effect of vasodilator therapy on the clinical outcome of patients with primary pulmonary hypertension. Circulation 1985;71:1191–1196.

13.

Elliott

Glissmeyer

Havlena

. Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. Circulation 2006;113:2509–2515.

14.

Klings

Hill

Ieong

Simms

Korn

Farber

. Systemic sclerosis-associated pulmonary hypertension: short- and long-term effects of epoprostenol (prostacyclin). Arthritis Rheum 1999;42:2638–2645.

15.

Simonneau

Fartoukh

Sitbon

Humbert

Jagot

Herve

. Primary pulmonary hypertension associated with the use of fenfluramine derivatives. Chest 1998;114: 195S–199S.

16.

Ricci

Melgosa

Burgos

. Assessment of acute pulmonary vascular reactivity in portopulmonary hypertension. Liver Transplant 2007;13:1506–1514.

17.

Post

Janssens

Van de Werf

Budts

. Responsiveness to inhaled nitric oxide is a predictor for mid-term survival in adult patients with congenital heart defects and pulmonary arterial hypertension. Eur Heart J 2004;25:1651–1656.

18.

D'Alto

Romeo

Argiento

. Pulmonary vasoreactivity predicts long-term outcome in patients with Eisenmenger syndrome receiving bosentan therapy. Heart 2010; 96:1475–1479.

19.

Condliffe

Kiely

Peacock

. Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med 2009;179: 151–157.

20.

Kovacs

Berghold

Scheidl

Olschewski

. Pulmonary arterial pressure during rest and exercise in healthy subjects: a systematic review. Eur Respir J 2009;34:888–894.

21.

Fang

DeMarco

Givertz

. World Health Organization Pulmonary Hypertension group 2: pulmonary hypertension due to left heart disease in the adult—a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2012;31:913–933.

22.

Fox

Shimony

Langleben

. High prevalence of occult left heart disease in scleroderma-pulmonary hypertension. Eur Respir J 2013;42(4):1083–1091.

23.

Fujimoto

Borlaug

Lewis

. Hemodynamic responses to rapid saline loading: the impact of age, sex, and heart failure. Circulation 2013;127:55–62.

24.

Robbins

Hemnes

Pugh

. High prevalence of occult pulmonary venous hypertension revealed by fluid challenge in pulmonary hypertension. Circ Heart Fail 2014;7:116–122.