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Am J Respir Crit Care Med
Am J Respir Crit Care Med
ajrccm
American Journal of Respiratory and Critical Care Medicine
1073-449X
1535-4970
American Thoracic Society

38668713
202402-0359VP
10.1164/rccm.202402-0359VP
Viewpoint: Turning the Air Blue
“This Patient Needs a Doctor, Not a Guideline!” The Zone of Uncertainty in Pulmonary Arterial Wedge Pressure Measurement
https://orcid.org/0000-0002-2541-4221
Rayner Samuel G. 1
https://orcid.org/0000-0001-9045-7722
Tedford Ryan J. 2
https://orcid.org/0000-0001-5716-248X
Leary Peter J. 1
https://orcid.org/0000-0003-2193-602X
Mak Susanna 3
https://orcid.org/0000-0001-6188-8072
Houston Brian A. 2
1 Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, Washington;
2 Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina; and
3 Division of Cardiology, Mount Sinai Hospital, Toronto, Ontario, Canada
Correspondence and requests for reprints should be addressed to Samuel G. Rayner, M.D., University of Washington Center for Lung Biology, Box 358052, 850 Republican Street, Seattle, WA 98109-4714. E-mail: srayner@uw.edu.
24 4 2024
15 9 2024
24 4 2024
210 6 712714
15 2 2024
24 4 2024
Copyright © 2024 by the American Thoracic Society
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern (dgern@thoracic.org).

National Heart, Lung, and Blood Institute 10.13039/100000050 K08HL166696-01 R01HL152724 R01HL159886 R33HL142539 R61HL167848
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pmcPulmonary arterial wedge pressure (PAWP) is used to discriminate pulmonary hypertension (PH) into pre- and post-capillary disease (1). This is a crucial distinction. Patients with pre-capillary PH (particularly Group 1 PH) have access to a multitude of approved therapies. In contrast, patients with a post-capillary component are generally not offered PH-specific therapy, which has not shown benefit in this population and may cause harm (1).

Given its importance, debate has been rekindled about both the “correct” way to measure PAWP and the optimal threshold for identifying post-capillary disease (currently >15 mm Hg). These discussions leverage results collected by thoughtful colleagues; however, the very presence of this debate underscores a larger point that is often missed in these discussions themselves—namely, that PAWP measurement is imperfect, and it is quite unlikely that a single PAWP cutoff will reliably dichotomize patients with PH in a way that reflects true physiology and predicts response to therapies. By way of background, we highlight sources of imprecision and controversy in PAWP measurement and discuss how heterogeneity in patient physiology further complicates these considerations. Ultimately, we advocate that future PH guidelines formally acknowledge the “Zone of Uncertainty” that exists (Figure 1A).

Figure 1. The Zone of Uncertainty. (A) In patients with pulmonary hypertension (PH), variability and imprecision in measuring the pulmonary arterial wedge pressure (PAWP), combined with heterogeneity in patient physiology, leads to (B) the Zone of Uncertainty, wherein PAWP particularly lacks precision to reliably discriminate the presence or absence of post-capillary PH. The use of ancillary data, although always important, is especially so within these bounds. LV = left ventricle; LVEDP = left ventricular end-diastolic pressure; LVH = left ventricular hypertrophy; MRI = magnetic resonance imaging.

First, how to report PAWP in relation to the respiratory cycle has reemerged as a source of controversy, stemming from the acknowledgment that PAWP conflates vascular pressure and transmitted intrathoracic pressure. In control subjects, intrathoracic pressure is slightly negative at functional residual capacity and decreases several millimeters of mercury further with inspiration (2, 3). Although guidelines recommend reporting PAWP at end exhalation, when intrathoracic pressure best approximates atmospheric pressure, they acknowledge that averaging over the respiratory cycle may be appropriate for patients with large intrathoracic pressure swings from obesity, hyperventilation, active respiratory muscle use, or dynamic hyperinflation (1, 4). Recent editorials advocate extending this practice to report PAWP averaged across the respiratory cycle for all patients (2). This approach would improve consistency between centers and procedures but may exacerbate imprecision at the individual patient level. Averaging may underestimate PAWP in patients with predominantly active inspiration and would still overestimate it in the setting of persistently increased intrathoracic pressure because of obesity or air-trapping. Ultimately, in patients with obesity, both end-expiratory and averaged PAWP overestimate values corrected using esophageal manometry to estimate intrapleural pressure (5).

In addition to the respiratory cycle, the location within the cardiac cycle where PAWP is reported influences the results. Averaging PAWP over the cardiac cycle may underestimate the PAWP value obtained at ventricular end diastole, immediately preceding the C-wave (3). The opposite is true when large V-waves are present, following left ventricular systole in situations of poor left atrial compliance or mitral valve disease. Providers do not routinely average V-waves into reported PAWP, even when noted. If the goal is to have PAWP perfectly estimate left ventricular end-diastolic pressure (LVEDP), then excluding V-waves is appropriate. If the goal is to quantify the total contribution of pulmonary venous pressure to PH, excluding the systolic component of pulmonary venous pressurization may underestimate post-capillary disease.

Uncertainty in PAWP measurement begins with leveling the transducer. Pulmonary vascular pressures are recorded relative to atmospheric pressure, with the midthorax recommended as the zero-reference level that best approximates the left atrium (1, 6). Accuracy in estimating this plane from external landmarks is unknown and may be nontrivial, with every centimeter of vertical leveling difference producing a difference of 0.78 mm Hg in PAWP. Relatedly, PAWP is accurate only if complete pulmonary arterial occlusion is achieved. In a study with experienced operators, wedge-blood oximetry suggested that 50% of initially “elevated” PAWPs were nonocclusive, with subsequently confirmed PAWP lower in 64% of these cases (7).

Suggestions to improve detection of post-capillary PH by using LVEDP or lowering the PAWP threshold for isolated pre-capillary PH from ⩽15 to ⩽12 mm Hg would, unfortunately, not resolve the aforementioned issues. The LVEDP is subject to similar measurement variability from respiratory swings and leveling concerns. Reducing the threshold will not address patient heterogeneity, and improved detection of Group 2 PH would come at the cost of excluding some Group 1 patients from treatment.

Overall, we believe that PAWP measurement lacks the precision and discrimination necessary to provide a singular cutoff for PH classification. Efforts to standardize PAWP measurement are crucial, but, ultimately, it is unlikely that a single method will reach the “truth” in all circumstances, in every center, and across a heterogeneous patient population. This imprecision, although generally understood at expert centers, is not reflected in guidelines, which has a ripple effect for insurance approval, study inclusion, and patient care. We believe that it is time to formally acknowledge that a Zone of Uncertainty exists in PAWP measurement, wherein Group 2 PH should be recognized as a possibility but not a certainty. The upper limit of normal PAWP is considered 12 mm Hg (1, 3), a threshold that also separates PH patients by prognosis and cardiac comorbidities (8), and progression to overt post-capillary PH (9). An upper bound of 18 mm Hg would capture the majority of patients within published registries of pre-capillary PH (10), who frequently have PAWP over 15 mm Hg but rarely over 18 mm Hg (4). Therefore, we cautiously suggest a range from 12 to 18 mm Hg as the initial bounds of the Zone of Uncertainty.

More work is needed to justify the cutoffs proposed. Furthermore, it is crucial to acknowledge that these thresholds will not cleanly separate all patients. Indeed, patients with Group 2 PH may have PAWP below 12 mm Hg after brisk diuresis, and (perhaps less commonly) patients with pre-capillary PH may have PAWP above 18 mm Hg from measurement imprecision or physiology such as pericardial constraint. Nonetheless, these cutoffs communicate where uncertainty is highest, offering a practical guide to clinicians and researchers. Codifying a Zone of Uncertainty in future guidelines could reduce disease misclassification, encouraging providers to always use PAWP in conjunction with ancillary clinical data (Figure 1B). At any value, PAWP should always be interpreted in the context of the entire clinical picture and reevaluated when incongruent. Agreeing that uncertainty exists, using the full range of our tools, and avoiding a binary cutoff will lead to better care for our patients.

Supported by NHBLI grants K08HL166696-01, R01HL152724, R01HL159886, R33HL142539, and R61HL167848.

Originally Published in Press as DOI: 10.1164/rccm.202402-0359VP on April 24, 2024

Author disclosures are available with the text of this article at www.atsjournals.org.
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