Fluid loading during the hemodynamic evaluation of pulmonary hypertension: a cross-sectional study

Introduction

Pulmonary hypertension (PH) is a condition characterized by a mean pulmonary artery pressure (mPAP) >20 mmHg during right heart catheterization (RHC) (1). PH is classified into five different clinical categories based on the underlying cause of disease: group 1—pulmonary arterial hypertension (PAH); group 2—PH due to left heart disease (PH-LHD); group 3—PH due to lung disease or hypoxia; group 4—PH due to chronic thromboembolic disease; and group 5—PH due to unclear or multifactorial causes (2,3). PH-LHD is the most common type of PH (4) and is characterized by elevated left-sided filling pressures (5). The 6^th World Symposium on PH (WSPH) categorized the hemodynamic phenotypes of PH-LHD as: (I) isolated postcapillary PH: pulmonary artery wedge pressure (PAWP) >15 mmHg and pulmonary vascular resistance (PVR) <3 Wood units (WU); and (II) combined pre- and post-capillary PH (CpcPH): PAWP >15 mmHg and PVR ≥3 WU (2).

Provocative testing such as exercise and fluid challenge may be used to unmask occult PH-LHD (5,6). Even though exercise is more physiologic, fluid challenge is more practical (5,7). In fact, the recent PH proceedings recommend fluid challenge over exercise for technical reasons (5). An increase in PAWP to >18 mmHg during fluid challenge supports the diagnosis of postcapillary PH (5). There is still uncertainty about the clinical value of fluid challenge, particularly in patients with PAWP between 13–15 mmHg, and the specific hemodynamic determinations and thresholds that support the diagnosis of PH-LHD.

In the present study, we hypothesized that other hemodynamic variables are better associated with parameters indicating PH-LHD rather than the currently used PAWP cutoff of >18 mmHg (5). Our objective was to test several hemodynamic variables during fluid challenge to assess whether they have a better association with the pretest probability of PH-LHD; and the value of fluid challenge in patients with PAWP between 13–15 mmHg, which is a pressure range above normal but below the threshold of >15 mmHg to define postcapillary PH (5). The pre-specified variables that we tested were PAWP, PAWP/cardiac output (CO) and right atrial pressure to pulmonary arterial wedge pressure ratio (RAP/PAWP) (8) during the fluid challenge or their absolute change from baseline. We present this article in accordance with the STROBE reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-23-59/rc).

Methods

Study subjects and design

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This single-center cross-sectional study with the incorporation of retrospective data was approved by Cleveland Clinic Institutional Review Board (No. 19-104) and written informed consent was waived due to the retrospective analysis. Between April 2013 and January 2019, we included all consecutive patients who underwent rapid fluid challenge testing during RHC and had: (I) normal pulmonary pressures; (II) PH (mPAP >20 mmHg) with intermediate or high pretest probability of having PH-LHD (to determine whether they had occult postcapillary PH) (5); (III) PH with PAWP between 13–15 mmHg (regardless of the number of risk factors for PH-LHD; (IV) PAWP >15 mmHg (usually 16–18 mmHg) with limited risk factors for left heart disease (LHD); or (V) patients with inadequate response to PAH medications with suspicion of PH-LHD. Patients who failed to show improvement in World Health Organization (WHO) functional class and/or had clinical worsening after treatment with PAH-specific therapies were deemed to have inadequate treatment response (9).

The rationale for including patients with PAWP >15 mmHg, in the absence of strong clinical suspicion of PH-LHD, was due to the frequent overestimation of PAWP in the setting of elevated intrathoracic pressure in patients with obesity (10). In fact, we previously showed that when adjusting for esophageal pressure there was a reduction in isolated postcapillary PH from 60% to 8% and CpcPH from 34% to 11% (10). We excluded patients who could not tolerate a total of 500 mL of normal saline due to the development of symptoms, or underwent fluid challenge for other reasons: e.g., to assess the effect on CO in patients with a low preload state, or post-exercise as part of a specific clinical research study protocol (11).

RHC and fluid challenge

RHC was performed in the outpatient setting by a single operator (Tonelli AR) (10,12). The mPAP and PAWP were measured at end-expiration, using electronic calipers and waveform tracings of three respiratory cycles. CO was measured by thermodilution.

After baseline measurements were obtained, 500 mL of normal saline (0.9%) at room temperature were administered over the course of 5 minutes through the side port of an 8.5-French introducer, with the tip located in the superior vena cava. The fluid bag was pressurized at 200 mmHg to facilitate a rapid infusion. Immediately after the end of the fluid administration we recorded a full set of hemodynamic measurements (6).

Other data reported

We collected data from our electronical medical records on clinical characteristics, cardiovascular risk factors, N-terminal pro-B type natriuretic peptide (NT-proBNP), six-minute walk test, and echocardiographic determinations.

Statistical analysis

Continuous data are presented as mean ± standard deviation (SD), or median [interquartile range (IQR)] as appropriate. Normality was tested visually with Q-Q plot and by the Kolmogorov-Smirnov test. Categorical data are summarized as discrete values and percentages [n (%)]. The PAWP and PAWP/CO change was calculated as the difference between the values obtained at the end of fluid administration and baseline determinations. Continuous and categorical variables were compared across the groups using t-test or analysis of variance (ANOVA) and Chi-square, respectively. Paired data were contrasted with paired t-test or Wilcoxon signed-rank test based on normality. Associations between variables were tested using linear regression. We included consecutive patients that met inclusion/exclusion criteria during the study period (convenience sample). All P values are two-tailed and a value of <0.05 was considered significant. All the hemodynamic data was available. In specific analyses like correlation, we excluded cases with a missing variable used in the comparison. Additionally, sensitivity analyses were performed removing patients with PAWP >15 mmHg. The statistical analyses were performed using the statistical package IBM SPSS, version 22 (IBM; Armonk, NY, USA).

Results

Patient characteristics

During the study period, 917 patients underwent RHC while 174 consecutive patients with a qualifying fluid challenge were included (Table 1 and Figure 1). Mean ± SD age was 63.7±13.0 years, of whom 123 (71%) were women. RHC was done due to abnormal echocardiogram (n=90, 52%), unexplained dyspnea with suspicion of PH (n=42, 24%), suggestion of worsening PH (n=22, 13%), hemodynamic assessment before PAH treatment changes (n=14, 8%), and abnormal echocardiogram during liver transplant evaluation (n=6, 3%).

Figure 1 Patient selection flowchart. Patients that did not tolerate 500 mL of rapid fluid administration had either dyspnea (n=2) or atypical chest pain (n=1) at about half the planned normal saline bolus dose. RHC, right heart catheterization.

Baseline hemodynamic determinations

At baseline, the mean ± SD PAWP was 11±5 mmHg, with a PAWP/CO ratio of 2.1±1.1 WU and a RAP/PAWP ratio of 0.54±0.27 (Table 2). The baseline PAWP was <13, 13–15 and >15 mmHg in 103 (59%), 37 (21%) and 34 (20%) patients, respectively. Only 15 (9%) patients had a PAWP >18 mmHg.

Effect of fluid loading on hemodynamic determinations

The 500 mL of normal saline administered resulted in 5.8±1.3 mL/kg of fluid. Fluid loading resulted in significant changes in several hemodynamic determinations (Table 2). The absolute increase in PAWP was 6.9±3.6 mmHg. The PAWP change was inversely associated with baseline PAWP (unit: mmHg, constant: 9.2, β: −0.20, R²: 0.09, P<0.001). In fact, the increase in PAWP was 7.5±3.5, 6.9±3.3 and 4.8±3.6 mmHg, for patients with a baseline PAWP of <13, 13–15 and >15 mmHg, respectively (P=0.001). Remarkably, the PAWP with fluids was >18 mmHg in 24 (23%) patients with baseline PAWP <13 mmHg and 30 (81%) patients with baseline PAWP 13–15 mmHg. All patients (n=19) with baseline PAWP between 16 and 18 mmHg had a PAWP >18 mmHg during fluid administration.

The absolute change in PAWP with fluids was directly but weakly associated with age (unit: year, constant: 3.4, β: 0.05, R²: 0.04, P=0.01), female gender (female: 1, constant: 5.5, β: 2.0, R²: 0.06, P=0.001), and systolic blood pressure (unit: mmHg, constant: 2.4, β: 0.03, R²: 0.05, P=0.003), while it was inversely associated with body mass index (BMI) (unit: kg/m², constant: 9.2, β: −0.07, R²: 0.03, P=0.04). No significant association was noted between change in PAWP with fluids and left atrial volume index (P=0.86), left ventricular (LV) mass index (P=0.75), right ventricular function (P=0.17), or mitral regurgitation (MR) severity (P=0.12).

The PAWP/CO had an absolute increase of 1.06±0.91 WU. The absolute change in PAWP/CO with fluids was predominantly driven by the absolute change in PAWP (unit: WU, constant: 3.8, β: 2.9, R²: 0.52, P<0.001) and less by the change in CO (unit: L/min, constant: 1.28, β: −0.37, R²: 0.13, P<0.001). The PAWP/CO slopes are not provided because as we have only two time points (baseline and with fluids) and since the CO minimally and inconsistently increased with fluids, the values are not reliable. The RAP/PAWP ratio was 0.58±0.23 with fluids, with an absolute increase of 0.05±0.28 when compared to baseline.

Effect of fluid loading in the hemodynamic classification of PH

At baseline, 52 (30%) patients had no PH, 43 (25%) had precapillary PH, 23 (13%) had postcapillary PH, 11 (6%) had combined pre and postcapillary PH and 45 (26%) had undifferentiated PH (mPAP >20 mmHg, PAWP ≤15 mmHg and PVR <3 WU). With fluid challenge and using a cutoff of >18 mmHg to identify the presence of postcapillary PH, 6 (3%) patients had no PH, 23 (13%) had precapillary PH, 58 (33%) had postcapillary PH, 28 (16%) had combined pre and postcapillary PH and 59 (34%) had undifferentiated PH (mPAP >20 mmHg, PAWP ≤18 mmHg and PVR <3 WU) (Figure 2).

Figure 2 Bar graphs representing patients’ PH classification at baseline and after fluid challenge based on the 6th World Symposium on PH hemodynamic phenotypes. Cutoff of PAWP >18 mmHg was used to identify the presence of postcapillary PH. PH, pulmonary hypertension; CpcPH, combined pre and postcapillary pulmonary hypertension; FC, fluid challenge; PAWP, pulmonary artery wedge pressure.

Fluid loading and pretest probability of PH-LHD

The association between PAWP and PAWP/CO response to fluid loading and the pretest probability of PH-LHD (5,13) is shown in Table 3. The PAWP at baseline, with fluids, its absolute change or the percentage of patients that achieve a value >18 mmHg, were not associated with age, number of cardiovascular risk factors, left atrial enlargement or degree of LV diastolic dysfunction on echocardiogram. All PAWP determinations were higher in patients with any degree of MR. The PAWP with fluids and its absolute change from baseline were higher in patients with ≥ mild increase in LV mass index. The PAWP/CO with fluids and its absolute change from baseline were higher with increasing age groups; while PAWP/CO at baseline and with fluids were higher in the presence of MR and LV diastolic dysfunction. The RAP/PAWP with fluids (but not the absolute change) was only higher in patients with mild to moderate MR, compared to no MR, but there was no statistical association with other markers of pretest probability of PH-LHD.

Sensitivity analyses

At total of 140 patients had a PAWP ≤15 mmHg, age 63.1±13.0 years and 96 (69%) were women. In this cohort, the PAWP was 9.6±3.5 mmHg at baseline and 17.0±4.6 mmHg after fluids with an increase of 7.4±3.4 mmHg. Similarly, the absolute change in PAWP with fluids was directly but weakly associated with age (unit: year, constant: 3.8, β: 0.06, R²: 0.05, P=0.01), female gender (female: 1, constant: 5.8, β: 2.2, R²: 0.09, P<0.001), and systolic blood pressure (unit: mmHg, constant: 3.3, β: 0.03, R²: 0.04, P=0.01), while it was not significantly associated with BMI (P=0.59) or echocardiographic variables tested. The effect of fluid loading on hemodynamics (Table S1) or the associations of hemodynamic changes with fluids and the pretest probability of PH-LHD (Table S2) were similar for the group of patients with PAWP ≤15 mmHg that for the entire cohort.

Discussion

In the present study, we included a relatively large number of patients who underwent RHC for PH evaluation and had a fluid challenge. We noted a median absolute increase in PAWP of 7 mmHg, with a change inversely associated with baseline PAWP. About a quarter of patients with baseline PAWP <13 mmHg and about 80% of those with PAWP 13–15 mmHg achieved a PAWP >18 mmHg with fluids. Patients that achieved a PAWP >18 mmHg with fluids, or the change in PAWP, PAWP/CO or RAP/PAWP with fluids had limited associations with parameters related with PH-LHD (5).

Diagnosing PH-LHD in compensated patients can be challenging, since the PAWP could be temporarily ≤15 mmHg when there is adequate blood volume. Hence, compensated PH-LHD patients may show normal hemodynamics, isolated precapillary PH (in those with combined pre and postcapillary PH) or undifferentiated PH. In this context, a hemodynamic challenge such as exercise (14-16) or rapid fluid infusion (5) is recommended. In patients with heart failure with preserved ejection fraction there is a steeper rise in PAWP with fluids (17) and a PAWP ≥18 mmHg is considered abnormal (5,18).

Since there is no gold-standard to determine the presence of PH-LHD, we incorporated known variables associated with this condition and supported by the 6^th WSPH proceedings (5). Overall, the value of the fluid challenge appears limited with unclear hemodynamic determinations to track or thresholds to consider. From our data, it is evident that most of the patients (80%) who have a baseline PAWP between 13 and 15 mmHg have an increase in PAWP with fluids to >18 mmHg (a positive test by current recommendations), questioning the utility of challenging this group of patients and introducing the observation of whether we should be using a PAWP of >12 mmHg during baseline hemodynamic determinations to identify postcapillary PH instead of the current cut-off of >15 mmHg (19). One of the benefits of fluid challenge could potentially be in identifying patients who might experience harm from PAH treatment since it can estimate the effect of an eventual increase in LV preload, that could occur with pulmonary vasodilator therapies, rather than strictly categorizing patients into PH groups 1 and/or 2.

Moghaddam et al. described that a positive fluid challenge led to reclassification of 20% of patients to PH-LHD, and affected treatment decisions in 6.5% of the cases (20). Similarly, Robbins et al. showed that 22% of 207 patients previously diagnosed as PAH, were reclassified as PH-LHD after fluid loading, using a PAWP threshold of >15 mmHg to define a positive fluid challenge (21). Our current data questions the value of fluid challenge to define PH-LHD since it predominantly identified subjects with already high PAWP at baseline (>12 mmHg). The degree of increase in PAWP with fluids was only weakly associated with a few clinical and echocardiography variables associated with LHD. The PAWP/CO change did not substantially outperform the absolute PAWP change, probably because of the relatively small increase in CO with fluids (mean increase of 0.6 L/min).

We acknowledge that our study has limitations. It is a single-center, retrospective cohort study at a tertiary care center that may have overestimated the prevalence of occult PH-LHD. Although the protocol for fluid administration is generally similar among studies, the actual flow may vary based on the relation between the introducer and pulmonary arterial compliance (PAC) diameters, administration site and use of pressurized system, etc. In addition, the determination of PAWP may be subject to errors; however, we followed a strict protocol to establish a valid PAWP measurement (22).

Conclusions

The absolute change in PAWP, PAWP/CO or achieving a PAWP >18 mmHg with rapid fluid loading do not have a robust association with the pretest probability of PH-LHD. Patients with PAWP between 13–15 mmHg commonly have PAWP elevations >18 mmHg with rapid fluid loading, questioning the use of fluid challenge in this group of patients, and raising the observation of whether we should be using a PAWP of >12 mmHg during baseline hemodynamic determinations to identify postcapillary PH, instead of the current cut-off of >15 mmHg.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-23-59/rc

Data Sharing Statement: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-23-59/dss

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-23-59/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-23-59/coif). ART serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from September 2021 to August 2023. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by Cleveland Clinic Institutional Review Board (No. 19-104). The consent to participate was waived due to the retrospective analysis.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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