- Email: [email protected]
The Relationship of Pleural Manometry With Postthoracentesis Chest Radiographic Findings in Malignant Pleural Effusion
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The Relationship of Pleural Manometry With Postthoracentesis Chest Radiographic Findings in Malignant Pleural Effusion
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Amit Chopra, MD; Marc A. Judson, MD; Peter Doelken, MD; Fabien Maldonado, MD; Najib Rahman, DPhil;
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and John T. Huggins, MD
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Both elevated pleural elastance (E-PEL) and radiographic evidence of incomplete lung expansion following thoracentesis have been used to exclude patients with a malignant pleural effusion (MPE) from undergoing pleurodesis. This article reports on a cohort of patients with MPE in whom complete drainage was attempted with pleural manometry to determine the frequency of E-PEL and its relation with postthoracentesis radiographic findings.
BACKGROUND:
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Seventy consecutive patients with MPE who underwent therapeutic pleural drainage with pleural manometry were identified. The pressure/volume curves were constructed and analyzed to determine the frequency of E-PEL and the relation of PEL to the postthoracentesis chest radiographic findings.
METHODS:
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E-PEL and incomplete lung expansion were identified in 36 of 70 (51.4%) and 38 of 70 (54%) patients, respectively. Patients with normal PEL had an OR of 6.3 of having complete lung expansion compared with those with E-PEL (P ¼ .0006). However, 20 of 70 (29%) patients exhibited discordance between postprocedural chest radiographic findings and the pleural manometry results. Among patients who achieved complete lung expansion on the postdrainage chest radiograph, 9 of 32 (28%) had an E-PEL. In addition, PEL was normal in 11 of 38 (34%) patients who had incomplete lung expansion as detected according to the postthoracentesis chest radiograph.
RESULTS:
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E-PEL and incomplete lung expansion postthoracentesis are frequently observed in patients with MPE. Nearly one-third of the cohort exhibited discordance between the postprocedural chest radiographic findings and pleural manometry results. These findings suggest that a prospective randomized trial should be performed to compare both modalities (chest radiograph and pleural manometry) in predicting pleurodesis outcome. CONCLUSIONS:
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CHEST 2019;
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lung entrapment; malignant pleural effusion; pleural elastance; pleural manometry; pleurodesis
KEY WORDS: Q6
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CLE = complete lung expansion; CXR = chest radiograph; E-PEL = elevated pleural elastance; ILE = incomplete lung expansion; MPE = malignant pleural effusion; P/V = pressure/volume AFFILIATIONS: From the Department of Medicine (Drs Chopra, Judson, and Doelken), Division of Pulmonary and Critical Care Medicine, Albany Medical Center, Albany, NY; Department of Medicine (Dr Maldonado), Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN; Oxford Centre for Respiratory Medicine (Dr Rahman), Oxford Respiratory Trials Unit, University of Oxford, Cambridge, UK; and the Department of Medicine (Dr Huggins), Division of Pulmonary,
Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC. FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Amit Chopra, MD, Department of Medicine, Division of Pulmonary and Critical Care Medicine, MC-91, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208; e-mail: Q5 [email protected] Copyright Ó 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2019.08.1920
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Pleurodesis and indwelling pleural catheter placement are acceptable treatment options for the management of malignant pleural effusion (MPE).1 In patients with expandable lung, both an indwelling pleural catheter and chemical pleurodesis are recommended as first-line therapy according to current American Thoracic Society guidelines. Adequate pleural apposition is a prerequisite to achieving successful pleurodesis in MPE. The current British Thoracic Society guidelines recommend demonstration of pleural apposition on a chest radiograph (CXR) following pleural fluid removal as a criterion for pleurodesis in MPE.2 A previous study by Lan et al3 showed that pleurodesis was uniformly unsuccessful in those patients with MPE who had elevated pleural elastance (E-PEL). Although both failure
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of complete drainage and E-PEL are contraindications for pleurodesis, there are currently no data examining the prevalence of E-PEL in patients with MPE who undergo an attempt at complete pleural drainage; in addition, the relation of the pressure/volume (P/V) curve and the postthoracentesis CXR findings have not previously been explored. The current prospective observational study compared postdrainage CXR findings vs pleural manometric findings in patients with MPE undergoing attempted complete pleural drainage. The goals of this study were: (1) to determine the prevalence of E-PEL in patients with MPE; and (2) to compare pleural manometry findings vs postthoracentesis CXR findings.
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Materials and Methods
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We retrospectively reviewed consecutive patients with a diagnosis of MPE based on positive pleural cytology findings who underwent an attempt at complete pleural drainage and had concomitant pleural manometry. A postthoracentesis anteroposterior view CXR was obtained immediately following thoracentesis. Each postprocedural CXR was reviewed independently by a dedicated thoracic radiologist. Postprocedural CXRs were evaluated for: (1) complete lung expansion (CLE-CXR), which was defined as > 90% pleural apposition on the frontal view; and (2) incomplete lung expansion (ILE-CXR), defined as # 90% pleural apposition, or drainage-related pneumothorax (pneumothorax ex vacuo) on a frontal view CXR.4
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Q7
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Pleural manometry was performed with an electronic acquisition system and damped water manometer as previously described.5 To measure pleural pressures and pleural space elastance PEL at the time of thoracentesis, the patient was placed in an upright sitting position with the arms resting on a level surface. The manometer was attached to a three-way stopcock on the pleural catheter to allow repeated measures of pleural pressure during fluid removal. When using a water manometer, the zero-pressure level was set where the catheter entered the chest wall. The initial mean pleural pressure was measured after approximately 20 mL of pleural fluid was removed. Mean pleural pressure was measured during periods of tidal breathing and assessed over four to five respiratory cycles representing quiet breathing. During subsequent fluid removal, the pleural pressure was measured after each aliquot of 100 to 250 mL
of pleural fluid. Pleural fluid drainage was discontinued if the following conditions occurred: (1) the mean pleural pressure declined below –20 cm H2O; (2) the patient reported significant chest pain; or (3) no further pleural fluid could be drained.
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The P/V curves were constructed for analysis, and PEL was calculated. The last pleural pressure measurement was considered valid by Q8 documenting the presence of fluid on thoracic ultrasound, or at least 50 mL of pleural fluid was removed. E-PEL was defined as the presence of either a monophasic P/V curve with PEL > 14.5 cm H2O/L, or a biphasic P/V curve in which the terminal portion of the biphasic P/V curve had PEL > 14.5 cm H2O/L.4 A monophasic P/V curve with PEL # 14.5 cm H2O/L represents normal PEL. Validation of the last mean pleural pressure is necessary because the pleural pressure may be artifactually low because of the local deformation forces around the catheter tip.5-7 Statistical analysis was performed by using SigmaPlot version 11.0 (Systat Software, Inc.). Continuous variables are presented as mean, median with SD, and 5th to 95th percentile range. Categorical variables are expressed as percentages and interquartile ranges. The differences between the two groups were evaluated with either an unpaired Student t test or Mann-Whitney rank sum test, depending on the characteristics of the distribution of the variable tested. For categorical data, 2 2 contingency tables were constructed, and the data were analyzed by using a two-tailed c2 test. P values < .05 were considered statistically significant.
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Results Seventy consecutive patients who had undergone therapeutic thoracentesis and concomitant pleural manometry were identified. Table 1 presents the demographic and tumor characteristics of the study cohort. Fifty-seven of 70 (81.4%) patients had an adenocarcinoma. A non-lung primary tumor was detected in 51 of 70 (72.8%) patients. The 70 patients who had undergone therapeutic thoracentesis and concomitant pleural manometry constituted the cohort
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that was analyzed. Selection of patients undergoing pleural manometry was determined by the capability of the clinician to perform the procedure and not by using clinical or radiographic data.
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Postthoracentesis CXRs were available in all 70 patients and showed complete expansion in 32 of 70 (46%). Thirty-eight of 70 (54%) patients had either incomplete drainage (25 of 70 [36%]) or a drainage-related pneumothorax (13 of 70 [18%]).
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TABLE 1
] Demographic Characteristics and Tumor Type in Patients With Malignant Pleural Effusion Undergoing Thoracentesis With Pleural Manometry (N ¼ 70)
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Characteristic
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Age, mean, median (range), y
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Q15
Value 59, 61 (37-78)
Ethnicity White
42 (60%)
Black
28 (40%)
Male
19 (27%)
Female
51 (73%)
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0
51 (73%)
30 20
240
Non-adenocarcinoma
13 (19%)
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250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275
Normal PEL was observed in 34 of 70 (49%) patients. Of these 34 patients, 32 (94%) had a monophasic P/V curve with PEL # 14.5 cm H2O/L (Fig 1A). Two patients with normal lung expansion had an unusual “inverted” biphasic P/V curve with an initial high PEL and a normal terminal PEL. This outcome may occur in situations in which PEL is initially transiently elevated because of lobar atelectasis that resolves with pleural fluid removal. For the purposes of our analyses, we interpreted the two patients with the inverted biphasic P/V curves as representing normal PEL. Elevated PEL was detected in 36 of 70 (51%) patients. Nine of 36 (25%) had a monophasic P/V curve with PEL > 14.5 cm H2O/L (mean, 21.8; SD, 4.1; median, 20.8; range 18.2-31.6) (Fig 1B). Twenty-seven of 36 (75%) patients had a biphasic P/V curve with PEL for the initial portion of the curve (E1) # 14.5 cm H2O/L (mean, 8.8; SD, 3.1; median, 8.6; range, 3.3-8.6) and PEL for the terminal portion of the curve (E2) > 14.5 cm H2O/L (mean 41.4; SD, 27.9; median, 33.3; range, 15.3-129.0) (Fig 1C). There was no statistically significant difference in age, race, sex, tumor origin, or tumor cell type between the normal and E-PEL groups (Table 2) or those with CLECXR and ILE-CXR (Table 3). The mean pleural fluid volume drained was statistically significantly greater (P ¼ .04) in the normal PEL group (1,589 mL) compared with the E-PEL group (1,180 mL). Figure 2 and Table 4 outline the relation between the postthoracentesis CXR findings and pleural
Pressure (cm H2O)
57 (81%)
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3,000
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4,000
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B
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0
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–10
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–20
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0
1,000
2,000 Volume (mL)
3,000
4,000
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C 30
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Pressure (cm H2O)
Adenocarcinoma
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2,000 Volume (mL)
Tumor cell type
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Tumor origin 19 (27%)
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–20
Non-lung
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–10
Lung
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Sex
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2,000 Volume (mL)
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Figure 1 – A, Monophasic pressure/volume curves with PEL < 14.5 cm H2O/L. B, Monophasic pressure/volume curves with PEL > 14.5 cm H2O/L. C, Biphasic pressure/volume curves with an initial PEL # 14.5 cm H2O/L and a terminal PEL > 14.5 cm H2O/L. PEL ¼ pleural elastance.
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Pressure (cm H2O)
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manometry results. Patients with normal PEL had a significantly statistically higher rate of CLE on CXR (23 of 34 [68%]) compared with those with E-PEL (9 of 36 [25%]) (P < .005). Patients with E-PEL had a statistically significantly higher rate (P ¼ .002) of ILECXR (27 of 70 [38.5%]) than those with normal PEL
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TABLE 2
] Comparison of the Demographic Data, Pleural Fluid Effusion Size, Tumor Origin, and Tumor Cell Type Between the Normal and Elevated Pleural Elastance Groups
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Normal Pleural Elastance
Variable Age, y*
59, 61 (37-78)
64, 64 (44-84)
65
56
339
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340
Sex, % Male
29
25
342
Female
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75
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.79
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Tumor origin, % Lung
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33
Non-lung
79
67
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Adenocarcinoma
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349
Non-adenocarcinoma
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22
1,589, 1,510 (733-2,509)
1,180, 1,088 (500-2,280)
Pleural fluid removed, mL*
399
.29
348
352
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347
351
.14
.46
Tumor cell type, %
350
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395
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P Value
Ethnicity, %
Black
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Elevated Pleural Elastance
White
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*Mean, median (range).
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(11 of 70 [15.7%]). Patients with normal PEL had an OR of 6.3 of having CLE-CXR compared with those with E-PEL (P ¼ .0006). Concordance between the PEL and postthoracentesis CXR criteria for pleurodesis was found in 50 of 70 (71%) cases; 20 of 70 (29%) patients had discordance between these two criteria. Eleven of 38 (34%) patients with ILE-CXR had normal PEL, whereas 9 of 32 (28%) patients with CLE had E-PEL. TABLE 3
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Discussion In this analysis of 70 patients with MPE who underwent pleural drainage with pleural manometry, the postthoracentesis CXR findings and pleural manometry each identified a contraindication to pleurodesis in approximately 50% of the cohort. The prevalence of ILE-CXR was 54% in this study cohort and was higher than reported in previous studies
Between the Complete Lung Expansion and Incomplete Lung Expansion Groups
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Variable
Complete Lung Expansion
Incomplete Lung Expansion
369
Age, y*
62, 64 (38-79)
61, 62 (36-90)
370
Ethnicity, %
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White
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66
Black
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34
31
24
376
Female
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Lung
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29
Non-lung
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71
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.80
424
.27
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.51
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.65
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Tumor cell type, % Adenocarcinoma
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81
Non-adenocarcinoma
16
19
1,589, 1,510 (733-2,509)
1,262, 1,192 (305-2,300)
Pleural fluid removed, mL*
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.74
437 438
.06
439 440
*Mean, median (range).
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432
379
382
415 416
P Value
Tumor origin, %
378
381
413 414
422
Sex, % Male
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425
375 377
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] Comparison of the Demographic Data, Pleural Fluid Effusion Size, Tumor Origin, and Tumor Cell Type
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that pleural manometry findings accurately predict the success of pleurodesis in MPE.3 In that study, 14 of 57 (25%) subjects had E-PEL. Subjects with PEL < 19 cm H2O/L had a 98% (42 of 43) pleurodesis success rate, whereas those with PEL > 19 cm H2O/L had a 100% (14 of 14) pleurodesis failure rate.3 However, these findings were never replicated in a larger study. A major limitation of that study was that PEL was calculated over the first 500 mL of pleural fluid drainage, and there was a lack of evaluation of the entire P/V curve. This approach may represent a cohort of patients with a monophasic P/V curve and might have missed patients who have a biphasic P/V curve with high terminal PEL and thereby underestimated the frequency of E-PEL. In addition, the follow-up period for pleurodesis success was short and measured only at 1 month by using CXR.
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30 No. of Patients
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Normal PEL
Complete lung expansion Incomplete lung expansion Figure 2 – Distribution of postdrainage chest radiograph with respect to pleural manometry findings. See Figure 1 legend for expansion of abbreviation.
(range, 2%-30%).8-10 The degree of variability in ILECXR across various series may be due to heterogeneity in the accepted degree of pleural apposition (50%-90%) on the postdrainage CXR to determine chemical pleurodesis eligibility.8-15 Interestingly, the studies that required a higher degree of pleural apposition (> 90%) to define lung expansion had higher prevalence rates of ILE-CXR than studies with less rigorous degrees of apposition on CXR. Our higher rate of ILE-CXR compared with that of previous studies may be explained by our requirement of at least 90% apposition of visceral and parietal pleura apposition to define adequate pleural fluid drainage. The prevalence of E-PEL in MPE was approximately 50% in the current study. If the prevalence of E-PEL with MPE is closer to 50% (as seen in the current cohort), the manometry and post-pleural drainage CXR findings reported could explain the low pleurodesis success rates (< 50%) and suggest a plausible explanation for the lower pleurodesis success rates in the published literature.8,9,14-17 To our knowledge, there are no published data available describing the prevalence of E-PEL in patients with MPE during an attempt to completely drain an MPE. One previous study reported
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Elevated PEL
TABLE 4
Nearly one-third of patients had discordance between postdrainage CXR and pleural manometry findings. These results suggest that the post-pleural drainage findings on CXR alone are inadequately sensitive and inadequately specific to detect E-PEL. Our analysis supports the premise that performing pleural manometry during thoracentesis may provide additional information in terms of predicting the outcome of pleurodesis procedures. We believe that comparison of these two criteria with pleurodesis outcomes will need to be addressed.
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The explanation for the discordance between these two criteria for pleurodesis of patients with MPE remains unclear. The postthoracentesis CXR may show incomplete lung expansion while the PEL is normal because either: (1) drainage was prematurely stopped due to a mechanism other than unexpandable lung, such as the presence of pleural adhesions not allowing complete drainage or chest pain due to the catheter irritating the diaphragm; or (2) the PEL may be falsely normal in cases of drainage-related pneumothorax. In Q10 the current study, drainage-related pneumothorax was present roughly in one-fifth of the cases, but approximately one-third of patients had drainagerelated pneumothorax with normal PEL. A proposed mechanism for drainage-related pneumothorax may be the result of air entry from the lung into the pleural
Normal Pleural Elastance (n ¼ 34) 23
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Incomplete lung expansion
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Elevated Pleural Elastance (n ¼ 36)
Complete lung expansion
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] Postdrainage Chest Radiograph With Respect to Pleural Manometry Findings (N ¼ 70)
Chest Radiograph Findings
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space from the development of a pressure-dependent alveolar-pleural fistula.4 Air-leaks through these fistulas may elevate the pleural pressure into normal physiological ranges, resulting in “pseudonormalization” of PEL and P/V curves. In addition, the presence of air entry into the drainage system may interfere with an accurate reading of pleural pressures.
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The current study has several limitations. First, the study cohort consisted of patients from a single center and may not be generalizable to all patients with MPE. Second, we did not explore the mechanisms responsible for the discordance between the ILE-CXR and E-PEL results in the study cohort. Although such an evaluation may be useful in determining the eligibility for pleurodesis in patients with MPE who exhibit discordance, it could not be performed in our retrospective analysis. We hypothesize that in future prospective studies that incorporate the success rate of pleurodesis, distinguishing the cause for the discordance may be impactful in establishing more
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reliable eligibility criteria for pleurodesis. Finally, our assessment of lung expansion following pleural drainage was rudimentary as we relied on the postthoracentesis CXRs alone; however, such an assessment is similar to previous studies.
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Conclusions
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The present investigation suggests that 50% of patients with MPE have an abnormality in lung expansion as detected according to pleural manometry and CXRs. Incomplete lung expansion on postthoracentesis CXR and E-PEL are both considered as a contraindication to pleurodesis. However, we found significant discordance between these two criteria. These results suggest that pleural manometry may have a role in addition to the postthoracentesis CXR in selecting patients for pleurodesis; however, confirmation of this conjecture would require a study similar to ours plus an analysis of pleurodesis outcomes.
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Acknowledgments
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Author contributions: J. T. H. is the guarantor of the paper and takes responsibility for the integrity of the work as a whole, from inception to published article. All authors contributed to the writing of the manuscript.
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Financial/nonfinancial disclosures: The authors have reported to CHEST the following: M. A. J. served as a consultant for Biogen; and has received institution grant support from Novartis and Mallinckrodt Pharmaceuticals. J. T. H. has served as a consultant/advisory board member for iBIOS (idiopathic pulmonary fibrosis), Roche/ Genentech (idiopathic pulmonary fibrosis [nintedanib]), and Boehringer Ingelheim (idiopathic pulmonary fibrosis [pirfenidone]). F. M. has received an unrestricted research grant from Centurion. None declared (A. C., P. D., N. R.).
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Other contributions: The authors acknowledge the contributions of Dr Steven A. Sahn for his valuable contribution to this paper.
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effusion: British Thoracic Society Pleural Disease Guideline 2010. Thorax. 2010;65(suppl 2):ii32-ii40. 3. Lan RS, Lo SK, Chuang ML, et al. Elastance of the pleural space: a predictor for the outcome of pleurodesis in patients with malignant pleural effusion. Ann Intern Med. 1997;126(10):768-774. 4. Heidecker J, Huggins JT, Sahn SA, et al. Pathophysiology of pneumothorax following ultrasound-guided thoracentesis. Chest. 2006;130(4):1173-1184. 5. Doelken P, Huggins JT, Pastis NJ, et al. Pleural manometry: technique and clinical implications. Chest. 2004;126(6):1764-1769. 6. Agostoni E. Mechanics of the pleural space. Physiol Rev. 1972;52(1):57-128. 7. Lai-Fook SJ. Pleural mechanics and fluid exchange. Physiol Rev. 2004;84(2):385-410. 8. Davies HE, Mishra EK, Kahan BC, et al. Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: the TIME2 randomized controlled trial. JAMA. 2012;307(22):2383-2389. 9. Thomas R, Fysh ETH, Smith NA, et al. Effect of an indwelling pleural catheter vs talc pleurodesis on hospitalization days in patients with malignant pleural effusion: the AMPLE Randomized Clinical Trial. JAMA. 2017;318(19):1903-1912. 10. Dresler CM, Olak J, Herndon JE 2nd, et al. Phase III intergroup study of talc poudrage vs talc slurry sclerosis for
malignant pleural effusion. Chest. 2005;127(3):909-915.
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11. Robinson LA, Fleming WH, Galbraith TA. Intrapleural doxycycline control of malignant pleural effusions. Ann Thorac Surg. 1993;55(5):1115-1121.
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12. Kennedy L, Rusch VW, Strange C, et al. Pleurodesis using talc slurry. Chest. 1994;106(2):342-346.
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13. Villanueva AG, Gray AW Jr, Shahian DM, et al. Efficacy of short term versus long term tube thoracostomy drainage before tetracycline pleurodesis in the treatment of malignant pleural effusions. Thorax. 1994;49(1):23-25.
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14. Putnam JB Jr, Light RW, Rodriguez RM, et al. A randomized comparison of indwelling pleural catheter and doxycycline pleurodesis in the management of malignant pleural effusions. Cancer. 1999;86(10):1992-1999. 15. Bhatnagar R, Keenan EK, Morley AJ, et al. Outpatient talc administration by indwelling pleural catheter for malignant effusion. N Engl J Med. 2018;378(14):1313-1322. 16. Van Meter ME, McKee KY, Kohlwes RJ. Efficacy and safety of tunneled pleural catheters in adults with malignant pleural effusions: a systematic review. J Gen Intern Med. 2011;26(1):70-76. 17. Wahidi MM, Reddy C, Yarmus L, et al. Randomized trial of pleural fluid drainage frequency in patients with malignant pleural effusions. The ASAP Trial. Am J Respir Crit Care Med. 2017;195(8):10501057.
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The Relationship of Pleural Manometry With Postthoracentesis Chest Radiographic Findings in Malignant Pleural Effusion
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Both elevated pleural elastance (E-PEL) and radiographic evidence of incomplete lung expansion following thoracentesis have been used to exclude patients with a malignant pleural effusion (MPE) from undergoing pleurodesis. This article reports on a cohort of patients with MPE in whom complete drainage was attempted with pleural manometry to determine the frequency of E-PEL and its relation with postthoracentesis radiographic findings.
BACKGROUND:
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Seventy consecutive patients with MPE who underwent therapeutic pleural drainage with pleural manometry were identified. The pressure/volume curves were constructed and analyzed to determine the frequency of E-PEL and the relation of PEL to the postthoracentesis chest radiographic findings.
METHODS:
23 24 25 26 27
E-PEL and incomplete lung expansion were identified in 36 of 70 (51.4%) and 38 of 70 (54%) patients, respectively. Patients with normal PEL had an OR of 6.3 of having complete lung expansion compared with those with E-PEL (P ¼ .0006). However, 20 of 70 (29%) patients exhibited discordance between postprocedural chest radiographic findings and the pleural manometry results. Among patients who achieved complete lung expansion on the postdrainage chest radiograph, 9 of 32 (28%) had an E-PEL. In addition, PEL was normal in 11 of 38 (34%) patients who had incomplete lung expansion as detected according to the postthoracentesis chest radiograph.
RESULTS:
28 29 30 31 32 33 34 35
E-PEL and incomplete lung expansion postthoracentesis are frequently observed in patients with MPE. Nearly one-third of the cohort exhibited discordance between the postprocedural chest radiographic findings and pleural manometry results. These findings suggest that a prospective randomized trial should be performed to compare both modalities (chest radiograph and pleural manometry) in predicting pleurodesis outcome. CONCLUSIONS:
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CHEST 2019;
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lung entrapment; malignant pleural effusion; pleural elastance; pleural manometry; pleurodesis
KEY WORDS: Q6
45 ABBREVIATIONS:
48 49
52 53 54 55
77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 101
47
51
75 76
100
46
50
73 74
Q4
CLE = complete lung expansion; CXR = chest radiograph; E-PEL = elevated pleural elastance; ILE = incomplete lung expansion; MPE = malignant pleural effusion; P/V = pressure/volume AFFILIATIONS: From the Department of Medicine (Drs Chopra, Judson, and Doelken), Division of Pulmonary and Critical Care Medicine, Albany Medical Center, Albany, NY; Department of Medicine (Dr Maldonado), Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN; Oxford Centre for Respiratory Medicine (Dr Rahman), Oxford Respiratory Trials Unit, University of Oxford, Cambridge, UK; and the Department of Medicine (Dr Huggins), Division of Pulmonary,
Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, SC. FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Amit Chopra, MD, Department of Medicine, Division of Pulmonary and Critical Care Medicine, MC-91, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208; e-mail: Q5 [email protected] Copyright Ó 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2019.08.1920
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Pleurodesis and indwelling pleural catheter placement are acceptable treatment options for the management of malignant pleural effusion (MPE).1 In patients with expandable lung, both an indwelling pleural catheter and chemical pleurodesis are recommended as first-line therapy according to current American Thoracic Society guidelines. Adequate pleural apposition is a prerequisite to achieving successful pleurodesis in MPE. The current British Thoracic Society guidelines recommend demonstration of pleural apposition on a chest radiograph (CXR) following pleural fluid removal as a criterion for pleurodesis in MPE.2 A previous study by Lan et al3 showed that pleurodesis was uniformly unsuccessful in those patients with MPE who had elevated pleural elastance (E-PEL). Although both failure
112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127
of complete drainage and E-PEL are contraindications for pleurodesis, there are currently no data examining the prevalence of E-PEL in patients with MPE who undergo an attempt at complete pleural drainage; in addition, the relation of the pressure/volume (P/V) curve and the postthoracentesis CXR findings have not previously been explored. The current prospective observational study compared postdrainage CXR findings vs pleural manometric findings in patients with MPE undergoing attempted complete pleural drainage. The goals of this study were: (1) to determine the prevalence of E-PEL in patients with MPE; and (2) to compare pleural manometry findings vs postthoracentesis CXR findings.
166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182
128
183
129
184
Materials and Methods
130 131
We retrospectively reviewed consecutive patients with a diagnosis of MPE based on positive pleural cytology findings who underwent an attempt at complete pleural drainage and had concomitant pleural manometry. A postthoracentesis anteroposterior view CXR was obtained immediately following thoracentesis. Each postprocedural CXR was reviewed independently by a dedicated thoracic radiologist. Postprocedural CXRs were evaluated for: (1) complete lung expansion (CLE-CXR), which was defined as > 90% pleural apposition on the frontal view; and (2) incomplete lung expansion (ILE-CXR), defined as # 90% pleural apposition, or drainage-related pneumothorax (pneumothorax ex vacuo) on a frontal view CXR.4
132 133 134 135 136 137 138 139 140 141 142
Q7
143 144 145 146 147 148 149 150 151 152
Pleural manometry was performed with an electronic acquisition system and damped water manometer as previously described.5 To measure pleural pressures and pleural space elastance PEL at the time of thoracentesis, the patient was placed in an upright sitting position with the arms resting on a level surface. The manometer was attached to a three-way stopcock on the pleural catheter to allow repeated measures of pleural pressure during fluid removal. When using a water manometer, the zero-pressure level was set where the catheter entered the chest wall. The initial mean pleural pressure was measured after approximately 20 mL of pleural fluid was removed. Mean pleural pressure was measured during periods of tidal breathing and assessed over four to five respiratory cycles representing quiet breathing. During subsequent fluid removal, the pleural pressure was measured after each aliquot of 100 to 250 mL
of pleural fluid. Pleural fluid drainage was discontinued if the following conditions occurred: (1) the mean pleural pressure declined below –20 cm H2O; (2) the patient reported significant chest pain; or (3) no further pleural fluid could be drained.
156 157 158 159 160 161 162 163 164 165
187 188
The P/V curves were constructed for analysis, and PEL was calculated. The last pleural pressure measurement was considered valid by Q8 documenting the presence of fluid on thoracic ultrasound, or at least 50 mL of pleural fluid was removed. E-PEL was defined as the presence of either a monophasic P/V curve with PEL > 14.5 cm H2O/L, or a biphasic P/V curve in which the terminal portion of the biphasic P/V curve had PEL > 14.5 cm H2O/L.4 A monophasic P/V curve with PEL # 14.5 cm H2O/L represents normal PEL. Validation of the last mean pleural pressure is necessary because the pleural pressure may be artifactually low because of the local deformation forces around the catheter tip.5-7 Statistical analysis was performed by using SigmaPlot version 11.0 (Systat Software, Inc.). Continuous variables are presented as mean, median with SD, and 5th to 95th percentile range. Categorical variables are expressed as percentages and interquartile ranges. The differences between the two groups were evaluated with either an unpaired Student t test or Mann-Whitney rank sum test, depending on the characteristics of the distribution of the variable tested. For categorical data, 2 2 contingency tables were constructed, and the data were analyzed by using a two-tailed c2 test. P values < .05 were considered statistically significant.
153 154 Q9 155
185 186
189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208
Results Seventy consecutive patients who had undergone therapeutic thoracentesis and concomitant pleural manometry were identified. Table 1 presents the demographic and tumor characteristics of the study cohort. Fifty-seven of 70 (81.4%) patients had an adenocarcinoma. A non-lung primary tumor was detected in 51 of 70 (72.8%) patients. The 70 patients who had undergone therapeutic thoracentesis and concomitant pleural manometry constituted the cohort
2 Original Research
that was analyzed. Selection of patients undergoing pleural manometry was determined by the capability of the clinician to perform the procedure and not by using clinical or radiographic data.
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Postthoracentesis CXRs were available in all 70 patients and showed complete expansion in 32 of 70 (46%). Thirty-eight of 70 (54%) patients had either incomplete drainage (25 of 70 [36%]) or a drainage-related pneumothorax (13 of 70 [18%]).
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TABLE 1
] Demographic Characteristics and Tumor Type in Patients With Malignant Pleural Effusion Undergoing Thoracentesis With Pleural Manometry (N ¼ 70)
222 224
Q14
225
Characteristic
226
Age, mean, median (range), y
227 228 229 230 231
Q15
Value 59, 61 (37-78)
Ethnicity White
42 (60%)
Black
28 (40%)
Male
19 (27%)
Female
51 (73%)
280 282 284
0
51 (73%)
30 20
240
Non-adenocarcinoma
13 (19%)
241 242
250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275
Normal PEL was observed in 34 of 70 (49%) patients. Of these 34 patients, 32 (94%) had a monophasic P/V curve with PEL # 14.5 cm H2O/L (Fig 1A). Two patients with normal lung expansion had an unusual “inverted” biphasic P/V curve with an initial high PEL and a normal terminal PEL. This outcome may occur in situations in which PEL is initially transiently elevated because of lobar atelectasis that resolves with pleural fluid removal. For the purposes of our analyses, we interpreted the two patients with the inverted biphasic P/V curves as representing normal PEL. Elevated PEL was detected in 36 of 70 (51%) patients. Nine of 36 (25%) had a monophasic P/V curve with PEL > 14.5 cm H2O/L (mean, 21.8; SD, 4.1; median, 20.8; range 18.2-31.6) (Fig 1B). Twenty-seven of 36 (75%) patients had a biphasic P/V curve with PEL for the initial portion of the curve (E1) # 14.5 cm H2O/L (mean, 8.8; SD, 3.1; median, 8.6; range, 3.3-8.6) and PEL for the terminal portion of the curve (E2) > 14.5 cm H2O/L (mean 41.4; SD, 27.9; median, 33.3; range, 15.3-129.0) (Fig 1C). There was no statistically significant difference in age, race, sex, tumor origin, or tumor cell type between the normal and E-PEL groups (Table 2) or those with CLECXR and ILE-CXR (Table 3). The mean pleural fluid volume drained was statistically significantly greater (P ¼ .04) in the normal PEL group (1,589 mL) compared with the E-PEL group (1,180 mL). Figure 2 and Table 4 outline the relation between the postthoracentesis CXR findings and pleural
Pressure (cm H2O)
57 (81%)
249
3,000
288
4,000
289 290
B
291 292 293 294 295
10
296 297
0
298
–10
300
–20
302
299 301
0
1,000
2,000 Volume (mL)
3,000
4,000
303 304 305
C 30
306
20
308
307
Pressure (cm H2O)
Adenocarcinoma
248
2,000 Volume (mL)
Tumor cell type
239
247
1,000
Tumor origin 19 (27%)
246
287
–20
Non-lung
245
285
–10
Lung
244
283
0
236
243
281
10
235
238
279
20
286
233
237
277 278
Sex
232 234
276
30
309
10
310
0
312
–10
314
311 313
–20 0
1,000
2,000 Volume (mL)
3,000
4,000
Figure 1 – A, Monophasic pressure/volume curves with PEL < 14.5 cm H2O/L. B, Monophasic pressure/volume curves with PEL > 14.5 cm H2O/L. C, Biphasic pressure/volume curves with an initial PEL # 14.5 cm H2O/L and a terminal PEL > 14.5 cm H2O/L. PEL ¼ pleural elastance.
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223
A
Pressure (cm H2O)
221
Q19
315 316 317 318 319 320 321 322 323 324
manometry results. Patients with normal PEL had a significantly statistically higher rate of CLE on CXR (23 of 34 [68%]) compared with those with E-PEL (9 of 36 [25%]) (P < .005). Patients with E-PEL had a statistically significantly higher rate (P ¼ .002) of ILECXR (27 of 70 [38.5%]) than those with normal PEL
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TABLE 2
] Comparison of the Demographic Data, Pleural Fluid Effusion Size, Tumor Origin, and Tumor Cell Type Between the Normal and Elevated Pleural Elastance Groups
332 333 334 335 336 337
387
Normal Pleural Elastance
Variable Age, y*
59, 61 (37-78)
64, 64 (44-84)
65
56
339
35
44
340
Sex, % Male
29
25
342
Female
71
75
345 346
393
396
.79
397 398
Tumor origin, % Lung
21
33
Non-lung
79
67
400 401
Adenocarcinoma
85
78
349
Non-adenocarcinoma
15
22
1,589, 1,510 (733-2,509)
1,180, 1,088 (500-2,280)
Pleural fluid removed, mL*
399
.29
348
352
391 392 394
347
351
.14
.46
Tumor cell type, %
350
389 390
395
341
344
P Value
Ethnicity, %
Black
343
388
Elevated Pleural Elastance
White
338
402 .54
403 404 405
.04
406
*Mean, median (range).
407
353 354 355 356 357 358 359 360 361 362 363 364 365 366
408
(11 of 70 [15.7%]). Patients with normal PEL had an OR of 6.3 of having CLE-CXR compared with those with E-PEL (P ¼ .0006). Concordance between the PEL and postthoracentesis CXR criteria for pleurodesis was found in 50 of 70 (71%) cases; 20 of 70 (29%) patients had discordance between these two criteria. Eleven of 38 (34%) patients with ILE-CXR had normal PEL, whereas 9 of 32 (28%) patients with CLE had E-PEL. TABLE 3
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Discussion In this analysis of 70 patients with MPE who underwent pleural drainage with pleural manometry, the postthoracentesis CXR findings and pleural manometry each identified a contraindication to pleurodesis in approximately 50% of the cohort. The prevalence of ILE-CXR was 54% in this study cohort and was higher than reported in previous studies
Between the Complete Lung Expansion and Incomplete Lung Expansion Groups
368
Variable
Complete Lung Expansion
Incomplete Lung Expansion
369
Age, y*
62, 64 (38-79)
61, 62 (36-90)
370
Ethnicity, %
372 373 374
White
53
66
Black
47
34
31
24
376
Female
69
76
Lung
34
29
Non-lung
66
71
383 384 385
420 421 423
.80
424
.27
426 427 428 429
.51
430 431 433
.65
434 435
Tumor cell type, % Adenocarcinoma
84
81
Non-adenocarcinoma
16
19
1,589, 1,510 (733-2,509)
1,262, 1,192 (305-2,300)
Pleural fluid removed, mL*
436
.74
437 438
.06
439 440
*Mean, median (range).
4 Original Research
417 418
432
379
382
415 416
P Value
Tumor origin, %
378
381
413 414
422
Sex, % Male
380
411 412
425
375 377
410
419
] Comparison of the Demographic Data, Pleural Fluid Effusion Size, Tumor Origin, and Tumor Cell Type
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that pleural manometry findings accurately predict the success of pleurodesis in MPE.3 In that study, 14 of 57 (25%) subjects had E-PEL. Subjects with PEL < 19 cm H2O/L had a 98% (42 of 43) pleurodesis success rate, whereas those with PEL > 19 cm H2O/L had a 100% (14 of 14) pleurodesis failure rate.3 However, these findings were never replicated in a larger study. A major limitation of that study was that PEL was calculated over the first 500 mL of pleural fluid drainage, and there was a lack of evaluation of the entire P/V curve. This approach may represent a cohort of patients with a monophasic P/V curve and might have missed patients who have a biphasic P/V curve with high terminal PEL and thereby underestimated the frequency of E-PEL. In addition, the follow-up period for pleurodesis success was short and measured only at 1 month by using CXR.
40
442 443
35
444
30 No. of Patients
445 446 447 448 449 450 451
25 20 15 10
452
5
453 454 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489
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455
Q16
Normal PEL
Complete lung expansion Incomplete lung expansion Figure 2 – Distribution of postdrainage chest radiograph with respect to pleural manometry findings. See Figure 1 legend for expansion of abbreviation.
(range, 2%-30%).8-10 The degree of variability in ILECXR across various series may be due to heterogeneity in the accepted degree of pleural apposition (50%-90%) on the postdrainage CXR to determine chemical pleurodesis eligibility.8-15 Interestingly, the studies that required a higher degree of pleural apposition (> 90%) to define lung expansion had higher prevalence rates of ILE-CXR than studies with less rigorous degrees of apposition on CXR. Our higher rate of ILE-CXR compared with that of previous studies may be explained by our requirement of at least 90% apposition of visceral and parietal pleura apposition to define adequate pleural fluid drainage. The prevalence of E-PEL in MPE was approximately 50% in the current study. If the prevalence of E-PEL with MPE is closer to 50% (as seen in the current cohort), the manometry and post-pleural drainage CXR findings reported could explain the low pleurodesis success rates (< 50%) and suggest a plausible explanation for the lower pleurodesis success rates in the published literature.8,9,14-17 To our knowledge, there are no published data available describing the prevalence of E-PEL in patients with MPE during an attempt to completely drain an MPE. One previous study reported
490 491 492 493 494 495
Elevated PEL
TABLE 4
Nearly one-third of patients had discordance between postdrainage CXR and pleural manometry findings. These results suggest that the post-pleural drainage findings on CXR alone are inadequately sensitive and inadequately specific to detect E-PEL. Our analysis supports the premise that performing pleural manometry during thoracentesis may provide additional information in terms of predicting the outcome of pleurodesis procedures. We believe that comparison of these two criteria with pleurodesis outcomes will need to be addressed.
497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526
The explanation for the discordance between these two criteria for pleurodesis of patients with MPE remains unclear. The postthoracentesis CXR may show incomplete lung expansion while the PEL is normal because either: (1) drainage was prematurely stopped due to a mechanism other than unexpandable lung, such as the presence of pleural adhesions not allowing complete drainage or chest pain due to the catheter irritating the diaphragm; or (2) the PEL may be falsely normal in cases of drainage-related pneumothorax. In Q10 the current study, drainage-related pneumothorax was present roughly in one-fifth of the cases, but approximately one-third of patients had drainagerelated pneumothorax with normal PEL. A proposed mechanism for drainage-related pneumothorax may be the result of air entry from the lung into the pleural
Normal Pleural Elastance (n ¼ 34) 23
9
Incomplete lung expansion
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547 548 549 550
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529 530
546
Elevated Pleural Elastance (n ¼ 36)
Complete lung expansion
527 528
545
] Postdrainage Chest Radiograph With Respect to Pleural Manometry Findings (N ¼ 70)
Chest Radiograph Findings
496
551
space from the development of a pressure-dependent alveolar-pleural fistula.4 Air-leaks through these fistulas may elevate the pleural pressure into normal physiological ranges, resulting in “pseudonormalization” of PEL and P/V curves. In addition, the presence of air entry into the drainage system may interfere with an accurate reading of pleural pressures.
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The current study has several limitations. First, the study cohort consisted of patients from a single center and may not be generalizable to all patients with MPE. Second, we did not explore the mechanisms responsible for the discordance between the ILE-CXR and E-PEL results in the study cohort. Although such an evaluation may be useful in determining the eligibility for pleurodesis in patients with MPE who exhibit discordance, it could not be performed in our retrospective analysis. We hypothesize that in future prospective studies that incorporate the success rate of pleurodesis, distinguishing the cause for the discordance may be impactful in establishing more
560 561 562 563 564 565 566 567 568 569 570 571 572 573
reliable eligibility criteria for pleurodesis. Finally, our assessment of lung expansion following pleural drainage was rudimentary as we relied on the postthoracentesis CXRs alone; however, such an assessment is similar to previous studies.
606 607 608 609 610 611 612
Conclusions
613
The present investigation suggests that 50% of patients with MPE have an abnormality in lung expansion as detected according to pleural manometry and CXRs. Incomplete lung expansion on postthoracentesis CXR and E-PEL are both considered as a contraindication to pleurodesis. However, we found significant discordance between these two criteria. These results suggest that pleural manometry may have a role in addition to the postthoracentesis CXR in selecting patients for pleurodesis; however, confirmation of this conjecture would require a study similar to ours plus an analysis of pleurodesis outcomes.
614 615 616 617 618 619 620 621 622 623 624 625 626 627 628
574
629
575
630
576
Acknowledgments
577
Q17
Author contributions: J. T. H. is the guarantor of the paper and takes responsibility for the integrity of the work as a whole, from inception to published article. All authors contributed to the writing of the manuscript.
Q11 Q12
Financial/nonfinancial disclosures: The authors have reported to CHEST the following: M. A. J. served as a consultant for Biogen; and has received institution grant support from Novartis and Mallinckrodt Pharmaceuticals. J. T. H. has served as a consultant/advisory board member for iBIOS (idiopathic pulmonary fibrosis), Roche/ Genentech (idiopathic pulmonary fibrosis [nintedanib]), and Boehringer Ingelheim (idiopathic pulmonary fibrosis [pirfenidone]). F. M. has received an unrestricted research grant from Centurion. None declared (A. C., P. D., N. R.).
Q13
Other contributions: The authors acknowledge the contributions of Dr Steven A. Sahn for his valuable contribution to this paper.
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effusion: British Thoracic Society Pleural Disease Guideline 2010. Thorax. 2010;65(suppl 2):ii32-ii40. 3. Lan RS, Lo SK, Chuang ML, et al. Elastance of the pleural space: a predictor for the outcome of pleurodesis in patients with malignant pleural effusion. Ann Intern Med. 1997;126(10):768-774. 4. Heidecker J, Huggins JT, Sahn SA, et al. Pathophysiology of pneumothorax following ultrasound-guided thoracentesis. Chest. 2006;130(4):1173-1184. 5. Doelken P, Huggins JT, Pastis NJ, et al. Pleural manometry: technique and clinical implications. Chest. 2004;126(6):1764-1769. 6. Agostoni E. Mechanics of the pleural space. Physiol Rev. 1972;52(1):57-128. 7. Lai-Fook SJ. Pleural mechanics and fluid exchange. Physiol Rev. 2004;84(2):385-410. 8. Davies HE, Mishra EK, Kahan BC, et al. Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: the TIME2 randomized controlled trial. JAMA. 2012;307(22):2383-2389. 9. Thomas R, Fysh ETH, Smith NA, et al. Effect of an indwelling pleural catheter vs talc pleurodesis on hospitalization days in patients with malignant pleural effusion: the AMPLE Randomized Clinical Trial. JAMA. 2017;318(19):1903-1912. 10. Dresler CM, Olak J, Herndon JE 2nd, et al. Phase III intergroup study of talc poudrage vs talc slurry sclerosis for
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12. Kennedy L, Rusch VW, Strange C, et al. Pleurodesis using talc slurry. Chest. 1994;106(2):342-346.
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13. Villanueva AG, Gray AW Jr, Shahian DM, et al. Efficacy of short term versus long term tube thoracostomy drainage before tetracycline pleurodesis in the treatment of malignant pleural effusions. Thorax. 1994;49(1):23-25.
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14. Putnam JB Jr, Light RW, Rodriguez RM, et al. A randomized comparison of indwelling pleural catheter and doxycycline pleurodesis in the management of malignant pleural effusions. Cancer. 1999;86(10):1992-1999. 15. Bhatnagar R, Keenan EK, Morley AJ, et al. Outpatient talc administration by indwelling pleural catheter for malignant effusion. N Engl J Med. 2018;378(14):1313-1322. 16. Van Meter ME, McKee KY, Kohlwes RJ. Efficacy and safety of tunneled pleural catheters in adults with malignant pleural effusions: a systematic review. J Gen Intern Med. 2011;26(1):70-76. 17. Wahidi MM, Reddy C, Yarmus L, et al. Randomized trial of pleural fluid drainage frequency in patients with malignant pleural effusions. The ASAP Trial. Am J Respir Crit Care Med. 2017;195(8):10501057.
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