The study protocol was approved by the Institutional Review Board of Chonnam National University Hospital (IRB No. CNUHH-2020-190). A waiver for informed consent was obtained from the IRB. We have complied with the latest version of the Declaration of Helsinki (2013).

This is a multicenter retrospective study from 2 tertiary medical centers (Chonnam National University Hwasun Hospital and Chonnam National University Hospital, Republic of Korea). Pericardiocentesis was performed in 486 patients from January 2015 to January 2020. Among these, 156 were diagnosed with cancer within 5 years and being followed up by oncologists. After excluding 23 patients who did not have analyzable pre- or post-pericardiocentesis echocardiograms, a total of 133 were included in the analysis. The study population was divided into 2 groups: CP and non-CP.

Clinical information, including medical history and clinical symptoms, was obtained from each patient's medical record. Chest X-rays, 12-lead electrocardiograms (ECGs), serologic studies including complete blood counts, liver/renal function tests, and C-reactive protein (CRP), were performed for all patients. Chest computed tomography (CT) was performed in all patients on the day of or within 1 month of pericardiocentesis. Pericardial enhancement, thickening, or direct pericardial invasion was assessed by trained radiologists. Significant pericardial enhancement and thickening were defined as appearance of obviously contrast-enhanced parietal and visceral pericardial layers which can be distinguished from pericardial effusion. Echocardiography was performed at rest, in the left lateral decubitus position, by 2 trained sonographers using 2 digital echocardiographic equipment systems (Vivid E9 and E95; Vingmed Ultrasound, Horten, Norway), following the guidelines and diagnostic criteria of the American Society of Echocardiography and the European Association of Cardiovascular Imaging. In all cases, the left ventricular ejection fraction (LVEF) was measured using the modified biplane Simpson's method. The intraobserver and interobserver variabilities of Simpson's method were 4±5% and 5±4%, respectively. Other conventional measurements were performed in all cases. The size of PE was determined using a semiquantitative method to measure the depth of the pericardial space in diastole: scanty (not measurable), small (<10 mm), moderate (<20 mm), and large (>20 mm). Cardiac tamponade was defined by several echocardiographic criteria such as diastolic right atrial and right ventricular collapse, cardiac swinging motion, respiratory mitral inflow variation >25%, plethora of the inferior vena cava (IVC), and several clinical criteria such as arterial hypotension and/or tachycardia, which were relieved by pericardial fluid drainage and pulsus paradoxus.9)

Image-guided (echocardiography and fluoroscopy) pericardiocentesis was performed by experienced cardiologists. A puncture needle was introduced into the pericardial space through the subxiphoid or intercostal route. An 8.5F-multihole pigtail catheter was introduced into the pericardial space for continuous drainage of pericardial fluid. The pericardial fluid underwent routine analysis (differential cell count, chemistry, microbiology, and pathology). After pericardiocentesis, echocardiography and chest radiography were performed to ensure correct catheter position and to identify acute mechanical complications (pericardial hematoma, pneumopericardium, pneumothorax, etc.). The catheter was retained until the drainage volume decreased to <50 mL for 24 hours. Follow-up echocardiography was then performed, and the catheter was removed if the residual PE volume was small (deepest pocket <10 mm).

Follow-up echocardiography was performed in the same way as pre-pericardiocentesis echocardiography. A diagnosis of CP was made when patients had features of elevated jugular venous pressure and at least one of the following: respirophasic ventricular septal shift, increase in early diastolic mitral inflow velocity (E velocity) >25% with expiration, medial mitral annular early diastolic velocity (medial e′ velocity) >8 cm/s and is higher than the lateral e′ velocity, prominent expiratory diastolic flow reversal in the hepatic veins, and IVC plethora.10)

Statistical Package for the Social Sciences (SPSS) software (version 22.0; IBM Corp., Armonk, NY, USA) and R statistical software version 3.5.2. (R Foundation for Statistical Computing, Vienna, Austria) were used for all statistical analyses. All numerical variables are presented as mean value±standard deviation and were compared using an independent samples t-test or one-way analysis of variance. All categorical variables are shown as numbers and percentages, and they were compared using the χ² or Fisher's exact test to determine significance. To identify relation between CP and overall survival, Kaplan-Meier survival analysis was used. Logistic regression analysis was performed to determine the significant predictive factors of CP. Cox proportional hazard model was used to calculate the hazard ratio (HR) and the 95% confidence interval (CI) and to identify independent predictors of overall survival. Variables with p<0.15 in the univariable analysis were selected for the multivariable analysis. Interruption of cancer therapy was not considered for the logistic regression analysis, because it could not affect development of CP: interruption was determined in the oncologists' outpatient clinic after index hospitalization for pericardiocentesis. Significant multicollinearity between medial and lateral e′ velocity (variance inflation factor 16.536, 14.821, respectively) was detected. We chose medial e′ velocity over lateral e′ velocity, because medial e′ velocity is regarded as a more valuable echocardiographic parameter when determining constrictive physiology.10) For Cox proportional hazard model, continuous variables were converted to dichotomous variables with the median value. All statistical tests were 2-tailed, and a p value <0.05 was considered significant.

Pericardiocentesis was successful in all patients without significant acute mechanical complications. Of 133 patients 49 (36.8%) patients developed CP on follow-up echocardiography after pericardiocentesis. Table 1 shows the clinical characteristics of all included patients. There were no significant differences in the mean age, sex distribution, or prevalence of other general cardiovascular risk factors between the non-CP and CP groups, but a history of chest radiation therapy (RTx) was more frequent in the CP group. Fever (≥38.0°C) was observed more frequently in the CP group. ST segment elevation was observed only in the CP group, although this was uncommon. Of 133 patients 72 (54.1%) patients had overt cardiac tamponade, without significant differences between the 2 groups. After pericardiocentesis, cancer therapy was interrupted more frequently in the CP group.

The underlying primary cancers of these patients are summarized in Table 2. Ninety (67.7%) patients had thoracic cancers. The most common underlying malignancy was lung cancer in both groups. The second most common malignancy was breast cancer, followed by lymphoma, esophageal cancer, colon cancer, leukemia, and thymic cancer. The prevalence of any primary cancer was not significantly different between the 2 groups.

Chest CT and echocardiographic findings before pericardiocentesis are presented in Table 3. On chest CT, both abutting of a malignant mass to the pericardium and pericardial contrast-enhancement were more frequent in the CP group. In cases with pericardial enhancement (n=52) positive pericardial fluid cytology was observed in 37/52 patients (71.2%), while abutting of a malignant mass to the pericardium was observed in 31/52 (59.6%). On pre-pericardiocentesis echocardiography, LVEF did not show significant differences. Among the other functional parameters, inspiratory E velocity was significantly higher in the CP group, along with higher medial e′ velocity. Medial e′ velocity was significantly lower than lateral e′ velocity in the non-CP group (6.5±2.3 vs. 7.1±2.4, p<0.001), while there were no significant differences between medial e′ velocity and lateral e′ velocity in the CP group. Respirophasic ventricular septal shift was infrequently observed in both groups, but the incidence was much higher in the CP group. There were no significant differences in mitral inflow variation or IVC plethora in either group. Pericardial adhesions (often accompanied by pericardial thickening) and loculated PE were more commonly observed in the CP group.

Table 4 presents the serum and pericardial fluid findings. The serum CRP levels were markedly higher in the CP group. Positive pericardial fluid cytology was observed more frequently in the CP group. The total pericardial fluid leukocyte count was significantly higher in the CP group, but differential leukocyte counts were not available. Other laboratory findings such as erythrocyte count, protein, glucose, and lactate dehydrogenase (LDH) levels showed no significant differences between the 2 groups, although the LDH levels were markedly elevated in both groups. The adenosine deaminase (ADA) levels were somewhat increased in both groups without significant differences between the 2, while polymerase chain reaction for tuberculosis was negative for all patients. The pericardial fluid culture results were negative in all patients.

Table 5 illustrates the predictors of CP after pericardiocentesis. Using multivariable logistic regression analysis, following variables were found to be statistically significant predictors of CP: pericardial enhancement on CT, presence of a malignant mass abutting the pericardium, high medial e′ velocity on pre-pericardiocentesis echocardiography, and high serum CRP levels. No other echocardiographic signs of CP or other signs of pericardial inflammation, such as fever, ST segment elevation, or pericardial fluid leukocyte counts were shown to be significant for predicting CP. The type of primary cancer and a history of chest RTx were also not significant predictors.

Figure 1 shows Kaplan-Meier curve for overall survival of the patients after pericardiocentesis. Table 6 presents the results of Cox proportional hazards regression analysis for predictors of all-cause death. In the multivariable-adjusted model, development of CP after pericardiocentesis, interruption of cancer therapy after pericardiocentesis, lung cancer, presence of a malignant mass abutting the pericardium, medical e′ velocity >7 cm/s were independent predictors of all-cause death after pericardiocentesis. Serum CRP >3.58 mg/dL was inversely associated with all-cause death.