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Original research
Contemporary biochemical analysis of normal pericardial fluid
  1. Massimo Imazio1,
  2. Andrea Biondo2,
  3. Davide Ricci3,
  4. Massimo Boffini3,
  5. Emanuele Pivetta4,
  6. Antonio Brucato5,
  7. Carla Giustetto1,6,
  8. Gaetano Maria De Ferrari1,6,
  9. Mauro Rinaldi3
  1. 1 University Cardiology, Cardiovascular and Thoracic Department, AOU Città della Salute e della Scienza di Torino, Torino, Italy
  2. 2 Cardiovascular and Thoracic Department, University of Torino, Torino, Italy
  3. 3 Cardiac Surgery, Cardiovascular and Thoracic Department, AOU Città della Salute e della Scienza di Torino, Torino, Italy
  4. 4 Emergency Medicine and High Dependency Unit, Cancer Epidemiology Unit and CPO Piemonte, Department of Medical Sciences, University of Torino, AOU Città della Salute e della Scienza di Torino, Torino, Italy
  5. 5 Dipartimento di Scienze Biomediche e Cliniche 'Sacco', University of Milano, Milano, Italy
  6. 6 Department of Medical Sciences, University of Torino, Torino, Italy
  1. Correspondence to Massimo Imazio, University Cardiology, Cardiovascular and Thoracic Department, AOU Città della Salute e della Scienza di Torino, Torino 10141, Italy; massimo_imazio{at}yahoo.it; massimo.imazio{at}unito.it

Abstract

Objective Biochemical analysis of pericardial fluid (PF) is commonly performed for the initial assessment of PF, and the results are usually interpreted according to Light’s traditional criteria for the differential diagnosis of transudates versus exudates. However, Light’s criteria have been formulated for the biochemical analysis of pleural fluid. The aim of the present paper is to evaluate the normal composition of PF in candidates for cardiac surgery.

Methods Cohort study with analysis of PF from candidates for cardiac surgery. Exclusion criteria were previous pericardial disease or cardiac surgery, prior myocardial infarction within 3 months, systemic disease (eg, systemic inflammatory diseases, uremia) or drug with potentiality to affect the pericardium.

Results Fifty patients (mean age was 67 years; 95% CI 64 to 71, 29 males, 58.0%) were included in the present analysis. Levels of small molecules were similar in blood and PF. Total proteins in PF was, on average, 0.5 times lower than corresponding plasma levels (p=0.041), while the level of pericardial lactate dehydrogenase was, on average, 1.06 times higher than plasma (p=0.55). Moreover, mononuclear cells were more concentrated in PF than plasma (p=0.17). Traditional Light’s criteria misclassified all PFs as exudates.

Conclusions Traditional Light’s criteria misclassified normal PFs in candidates for cardiac surgery as exudates. This study suggests their futility for the biochemical analysis of PF in clinical practice.

  • pericardial fluid
  • biochemical analysis
  • transudate
  • exudate
  • diagnosis

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Introduction

Biochemical analysis of pericardial fluid (PF) is commonly performed for the initial assessment of pericardial effusion after pericardiocentesis, and it is recommended by international guidelines.1 2

Results are interpreted according to Light’s traditional criteria for the differential diagnosis between transudates and exudates. However, Light’s criteria have been formulated for the biochemical analysis of pleural fluid stating cut-off points for the diagnosis of pleural exudates (at least one of the following criteria should be satisfied: fluid/serum protein ratio >0.5, fluid/serum lactate dehydrogenase (LDH) ratio >0.6 and fluid LDH >2/3 of the upper limit for serum levels).3

However, limited data are available on the normal composition of PF and suggest that the assumption that PF composition is similar to pleural fluid is probably wrong since normal PF may have greater levels of proteins, LDH and lymphocytes than expected.4 5

The aim of the present paper is to evaluate the normal composition of PF in candidates for cardiac surgery, and its implications for PF analysis in clinical practice.

Methods

Study design and patients

Cohort study including candidates for cardiac surgery from November 2017 to May 2018 in our centre (tertiary referral centre for myopericardial diseases in Italy). The study protocol has been approved by the institutional ethical committee (AOU Città della Salute e della Scienza di Torino).

All patients performed clinical evaluation with chest radiography, echocardiography and coronary angiography according to clinical practice. Exclusion criteria were previous pericardial diseases or cardiac surgery or pericardial effusion before cardiac surgery, prior myocardial infarction within 3 months, systemic diseases (eg, systemic inflammatory diseases, uremia) or drugs with potentiality to affect the pericardium. Patients with previous cardiac surgery were excluded because of potential difficulties in draining PF and potential changes of the normal pericardium. Informed consent was obtained before surgery. After induction of anaesthesia and opening of the chest, the pericardium was opened according to cardiac surgery plan minimising trauma and bleeding and collecting PF for biochemical analysis. Simultaneous collecting of venous blood sample allowed contemporary study of blood biochemical analysis. All samples were analysed using standard laboratory techniques. The corresponding author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a worldwide basis to the BMJ Publishing Group and its Licensees to permit this article to be published in HEART editions and any other BMJPGL products to exploit all subsidiary rights.

Statistical analysis

Descriptive results are reported as mean (SD) or median (IQR) for continuous variables, and as numbers and percentages for categorical variables. Continuous data are reported as mean and 95% CI. Comparison between groups was done by a two-tailed Student’s t-test or by Wilcoxon-Mann-Whitney test or Χ2 test with Fisher correction for categorical data, as appropriate. Light’s criteria were applied to PF analysis.

A p value <0.05 was considered to show statistical significance. Analyses were performed by MedCalc Statistical Software V.18 (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2018) and Stata 13.1 (StataCorp, College Station, Texas, USA).

Results

Patients and pericardial fluid analysis

Two hundred and forty patients were screened and evaluated for inclusion in the present study (figure 1). One hundred and twenty-seven patients were excluded because of meeting at least one exclusion criterion. One hundred and thirteen patients were eligible to be included in the present study, and PF was collected. Pericardial sample was not sufficient or contaminated by blood in sixty-three patients. At the end, 50 samples from 50 patients (mean age 67 years, 95% CI 64 to 71, with 29 males, 58.0%) were suitable for the analysis of normal PF. Baseline data of the studied population are reported in table 1. Results of the biochemical analysis of PF are reported in table 2 and figure 2.

Figure 1

Studied population (screened, eligible, excluded and included patients). *Forty-two patients were excluded because of cardiac surgery reoperation, and 85 patients for meeting other exclusion criteria; †Forty-three patients had no pericardial fluid to drain, and 20 patients had pericardial fluid contaminated by blood.

Figure 2

Histograms of both serum and pericardial measures of proteins (g/dL), albumin (g/dL), LDH (U/L) and total cholesterol (mmol/L). LDH, lactate dehydrogenase.

Table 1

Baseline data of the studied population

Table 2

Analysis of pericardial fluid (n=50 patients)

Levels of small molecules were similar in blood and PF. Total proteins in PF was, on average, 0.5 times lower than corresponding plasma levels (p=0.041), while the level of pericardial LDH was, on average, 1.06 times higher than plasma (p=0.55). Moreover, mononuclear cells seem to be more concentrated in PF than plasma (p=0.17).

According to Light’s criteria, 50 of 50 PFs (100.0%) met biochemical criteria for the diagnosis of exudate, and no analysed pericardial effusions met biochemical criteria for the diagnosis of transudate (figure 3). No differences were found in the composition of PF in patients with or without coronary artery diseases (table 3).

Figure 3

Fluid to serum ratio for total proteins and LDH, and biochemical analysis of fluid LDH levels. The red lines identify cut-off levels for the differential diagnosis of transudate/exudate according to Light’s criteria. LDH, lactase dehydrogenase.

Table 3

Comparison of pericardial fluid analysis in patients with or without CAD

Discussion

The main result of the present analysis of normal PF from candidates to cardiac surgery is that, although PF is at least partially an ultrafiltrate of plasma (as confirmed by similar concentrations of small molecules in PF and plasma with ratio around 1.0), LDH concentrations are higher than plasma and thus Light’s criteria cannot be used for the correct differential diagnosis of transudate versus exudate.

The biochemical analysis of PF showed that small molecules (eg, urea, uric acid, glucose and creatinine) are similarly concentrated in PF and plasma. On the contrary, LDH has higher levels than expected in PF suggesting that PF is not simply an ultrafiltrate of plasma.

For this reason, all samples of ‘normal pericardial fluid’ met pleural fluid biochemical criteria for an exudate according to Light’s criteria. On this basis, an important outcome of the study is that normal pericardial effusion has been shown to be under the category of exudate according to Light’s criteria.

Limited data are available on the composition of normal PF with the largest study reporting the analysis of 30 cases from candidates to cardiac surgery and consistent with the current analysis.4 5

In our study, the levels of total proteins in PF was, on average, 0.5 times lower than corresponding plasma levels, while the level of pericardial LDH was, on average, 1.06 times higher than plasma. Moreover, mononuclear cells are more concentrated in PF than plasma, and this finding can be explained by a high content of mesothelial cells within the normal PF affecting also the content of proteins and LDH.

The explanation of these differences can only be speculated (eg, preferential leakage from the adjacent myocardium, presence of mesothelial cells in PF), but this study clearly suggests that PF is not simply an ultrafiltrate of plasma and Light’s classification criteria are invalid in case of normal pericardial effusions, thus challenging the current classification of pericardial transudate/exudate using these criteria.

In clinical practice, additional criteria have been proposed to solve Light’s criteria misclassification of cardiac transudates: total proteins and albumin gradients, and cholesterol PF/serum ratio.6 7

Additional studies are needed to clarify the potential utility of these criteria for the analysis of PF in normal and pathological cases.

Potential limitations of the present study are especially represented by the collection of PF from patients candidates to cardiac surgery rather than healthy donors, but these limitations are shared by previous studies and cannot be overcome for obvious ethical reasons. Nevertheless, the exclusion criteria and the selection of stable patients should provide a sample of patients very close to a healthy donor. An additional limitation may be the lack of comparison with pathological PFs but this comparison was beyond the aim of the paper. Although we had more patients with samples that were not suitable for analysis (n=63) compared with patients who had PF analysis (n=50), this should not be considered as a real study limitation since we included very carefully selected cases that could be analysed with sufficient PF and without blood contamination.

In conclusion, an important outcome of the study is that normal pericardial effusion has been shown to be under the category of exudate according to Light’s criteria. Pericardial effusion is not simply an ultrafiltrate of plasma and has higher concentrations of LDH and cells than expected by a simple transudate according to Light’s criteria. If applied, pleural effusion criteria for transudate/exudate will classify most ‘normal’ PFs as exudate. On this basis, the application of Light’s criteria is only misleading and should be abandoned in clinical practice.

Key messages

What is already known on this subject?

  • Biochemical analysis of pericardial fluid (PF) is commonly performed for the initial assessment of pericardial effusion after pericardiocentesis, and it is recommended by international guidelines following Light’s criteria.

  • However, Light’s criteria have been formulated for the biochemical analysis of pleural fluid stating cut-off points for the diagnosis of pleural exudates.

  • Limited data are available on the normal composition of PF and suggest that the assumption that PF composition is similar to pleural fluid is probably wrong.

What might this study add?

  • In this cohort study of candidates for cardiac surgery, we evaluated the normal composition of PF in such patients using Light’s criteria for fluid analysis.

  • Fifty patients (mean age was 67 years; 95% CI 64 to 71, 29 males, 58.0%) were included in the present analysis.

  • Traditional Light’s criteria misclassified all PFs as exudates.

How might this impact on clinical practice?

  • This paper suggests the futility of the use of Light’s criteria for the biochemical analysis of PF in clinical practice and also questions the utility of making differential diagnosis between exudates and transudates according to these criteria.

References

Footnotes

  • Contributors All authors have participated and contributed to the manuscript providing a final approval for submission.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval Ethical Committee—AOU Città della Salute e della Scienza di Torino.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.