“What to do with all that fluid

“What to do with all that fluid
“What to do with all that fluid?” A focused review on the diagnosis and management of pleural effusions Jean Du Plessis Internal Medicine and Respirology Ridge Meadows Hospital

Outline (1) A brief review of the mechanisms of normal and abnormal pleural fluid accumulation Imaging in pleural effusions “Should I do a thoracentesis?” Pleural fluid investigations: Initial testing Follow-up testing depending on initial test results

Outline (2) A brief review of specific etiologies of pleural effusions: Parapneumonic and empyema Malignant Complicated transudates Congestive heart failure Hepatic hydrothorax

Pleural effusions Definition: They are common
“…an excess of fluid in the pleural cavity, usually resulting from an imbalance in the normal rate of pleural fluid production or absorption, or both.” They are common 1 – 1.5 million new cases in US each year More than 50 recognized causes Most common: CHF, pneumonia, cancer BMJ 2015;351:h4520 N Engl J Med 2018;378:740-51

Pleural anatomy and physiology
“The pleural space” – defined by the visceral pleura and the parietal pleura Visceral pleura – covers the lungs Parietal pleura – covers the chest wall, diaphragm, and mediastinum The pressure in the pleural space is slightly negative -3 to -5 cmH2O Combination of elastic recoil in lung and tendency towards expansion of the chest wall at FRC N Engl J Med 2018;378:740-51

The exact physiological function of the pleural space in humans remains unclear… Serves as an elastic serous membrane  allow changes in lung shape with respiration Prevents atelectasis  negative pleural pressure at FRC maintains a positive transpulmonary pressure Humans do well after obliteration of pleural space i.e. pleurodesis N Engl J Med 2018;378:740-51

Both visceral and parietal pleura involved in maintaining homeostasis About 0.26mL/kg contained within EACH pleural cavity ~18ml in 70kg person N Engl J Med 2018;378:740-51

Fluid primarily produced and absorbed in the parietal pleura Dependent on the balance hydrostatic and oncotic pressures between systemic and pulmonary circulations Lymphatic vessels on parietal pleura responsible for fluid resorption Flow rate in these vessels increase by factor of ~20 in response to pleural fluid formation Clinically significant effusion only seen once these mechanisms overwhelmed N Engl J Med 2018;378:740-51

Imaging in pleural effusions
THREE main modalities available: X-ray, computed tomography, ultrasound Chest X-ray usually performed FIRST  CT chest often comes next (better delineate fluid versus consolidation, volume of pleural fluid, loculations, etc.) Chest ultrasonography often only performed as part of thoracentesis procedure

THREE main modalities available: X-ray, computed tomography, ultrasound Chest X-ray usually performed FIRST  CT chest often comes next (better delineate fluid versus consolidation, volume of pleural fluid, loculations, etc.) Chest ultrasonography should be performed as part of the INITIAL ASSESSMENT of pleural effusions

Chest ultrasonography can more be effective in: Fluid quantification Detection of fluid septations Identifying exudative effusions Identifying malignant effusions N Engl J Med 2018;378:740-51

Chest ultrasonography can more be effective in: Fluid quantification Radiology 1994;191: 51 patients underwent sonography of the pleural space while supine Ultrasonographic results and results of lateral decubitus radiography were compared with actual effusion volumes Ultrasonographic measurements correlated statistically significantly better with actual effusion volume

Chest ultrasonography can more be effective in: Identifying exudative effusions AJR Am J Roentgenol 1992;159:29-33 Prospectively analyzed the ultrasonographic findings in 320 patients with pleural effusion of various causes Etiology of the effusions established on the basis of chemical, bacteriologic, and cytologic examination of pleural fluid; pleural biopsy; and clinical follow-up All patients had ultrasonography performed with no clinical information available to the radiologist Anechoic effusion: could be EITHER a transudate or an exudate Complex septated, complex non-septated, or homogeneously echogenic patterns were ALWAYS exudates (p < 0.01)

Chest ultrasonography can more be effective in: Identifying malignant effusions Thorax 2009;64: 52 consecutive patients with suspected MPE underwent thoracic ultrasound(TUS) and contrast-enhanced CT (CECT) TUS was used to assess pleural surfaces using previously published CT imaging criteria for malignancy, diaphragmatic thickness/nodularity, effusion size/nature and presence of hepatic metastasis (in right-sided effusions) A TUS diagnosis of malignant or benign disease was made blind to clinical data/other investigations TUS correctly diagnosed: malignancy in 26/33 patients (sens 73%, spec 100%, PPV 100%, NPV 79%) benign disease in 19/19

“Should I do a thoracentesis?”
“Classically” – perform a thoracentesis on ALL effusions >1cm in lateral decubitus view With ultrasonography, any pleural effusion that is reasonably visualized and accessible “Generally” - Yes, if feasible Any effusion accessible via ultrasonography usually need pleural fluid to help identify underlying etiology Diagnostic and Therapeutic indications…

Diagnostic Most newly detected pleural effusions should undergo diagnostic thoracentesis Exceptions: small amount of pleural fluid with secure diagnosis; clinically obvious heart failure without atypical features Therapeutic Symptom relief (i.e. dyspnea) Complicated pleural effusions (e.g. loculated parapneumonic pleural effusions) UpToDate

“But, what about placing a chest tube?” Depends on suspected underlying etiology Obvious clinical indications: e.g. complicated parapneumonic effusion, large pleural effusion completely filling hemithorax, etc. Personally – diagnostic thoracentesis first and attempt to drain as much fluid as possible up to 1500mL *Will address this more a little later…

Pleural fluid investigations
General goal to differentiate transudates and exudates Accomplished through Light’s Criteria – first established in 1972 Annals of Internal Medicine 77: , 1972 Prospective study of 150 “pleural effusions” Utility of pleural fluid cell counts, total protein, and LDH Three characteristics found – associated with over 70% of exudates and ONE transudate All, but ONE, exudate had at least one of the three characteristics

Light’s Criteria (any ONE of the following): pleural fluid total protein/serum total protein > 0.5 pleural fluid LDH/serum LDH > 0.6 Pleural fluid LDH >200 IU (or >67% the upper limit of normal of serum LDH level) Criteria correctly identifies nearly all exudates, BUT, misclassifies up to 25% of transudates especially in patients with congestive heart failure having received diuretics N Engl J Med 2018;378:740-51

“Well, is there anything better?” CHEST 1997; 111:970-80 Formal meta-analysis of studies that reported the diagnostic value of pleural fluid tests Eight studies; 1448 patients Pleural fluid tests: total protein, LDH, bilirubin, cholesterol, albumin Generally, similar diagnostic accuracies (except bilirubin) Paired and triplet test combinations have higher diagnostic accuracies

“Well, is there anything better?” CHEST 1997; 111:970-80 Two-test rule: pleural fluid cholesterol >45 mg/dL; pleural fluid LDH >0.45 upper limit of normal of serum LDH Three-test rule: pleural fluid total protein >29 g/L; pleural fluid cholesterol >45 mg/dL; pleural fluid LDH >0.45 upper limit of normal for serum LDH **Both require only ONE criterion to be present = exudate

“Well, is there anything better?” CHEST 1997; 111:970-80 Two-test and three-test rules had SIMILAR diagnostic accuracies compared to Light’s Criteria

“Well, is there anything better?” Not really…

Other Considerations… If clinically suspect transudate, but meets criterion for exudate (esp. in CHF patients): Serum-effusion albumin gradient ≥ 1.2 g/dL  transudate Serum-effusion total protein gradient ≥ 3.1 g/dL transudate Serum and pleural fluid NT-proBNP = similar Disease-specific testing Parapneumonic (glucose, pH); malignancy (cytology); chylothorax (triglycerides); hemothorax (hematocrit), etc. N Engl J Med 2018;378:740-51

What to test ALL pleural effusions for initially… LDH and total protein Exudate vs. transudate Cell count and differential Neutrophilic, lymphocytic, eosinophilic Gram stain, culture and sensitivity Parapneumonic effusion or empyema Glucose LOW suggestive of parapneumonic, RA, TB or malignant pH Cytology Malignant cells

**PLEASE ALWAYS SEND PLEURAL FLUID FOR ALL INITIAL INVESTIGATIONS**

Specific etiologies of pleural effusions
Parapneumonic effusion and empyema The MOST COMMON exudative effusion Mortality HIGHER in those patients with pneumonia complicated by parapneumonic effusion delays in drainage associated with SUBSTANTIALLY HIGHER mortality Both INCIDENCE of and MORTALITY due to parapneumonic effusion continue to rise ELDERLY often present with atypical symptoms Anemia, fatigue, failure to thrive Consider parapneumonic effusion in ALL elderly with pneumonia N Engl J Med 2018;378:740-51

Parapneumonic effusion and empyema Uncomplicated vs. complicated parapneumonic Complicated = positive gram stain or pH <7.2 or glucose < 3.3mmol/L USUALLY require drainage to achieve resolution Empyema = frank pus ALWAYS require drainage to achieve resolution Pocket Medicine, 5e

Poor prognostic factors: pus, positive gram stain, gluc <2
Poor prognostic factors: pus, positive gram stain, gluc <2.2, pH <7.15, LDH >3x ULN

Parapneumonic effusion and empyema The role of t-PA and DNase N Engl J Med 2011;365: (MIST2 Trial) 210 patients with pleural infection randomly assigned to receive one of four study treatments for 3 days: double placebo intrapleural tissue plasminogen activator (t-PA) and Dnase t-PA and placebo DNase and placebo

Parapneumonic effusion and empyema The role of t-PA and DNase N Engl J Med 2011;365: (MIST2 Trial) Primary outcome: change in pleural opacity, measured as the percentage of the hemithorax occupied by effusion, on chest radiography on day 7 as compared with day 1 Secondary outcomes: referral for surgery, duration of hospital stay, and adverse events

Parapneumonic effusion and empyema The role of t-PA and DNase N Engl J Med 2011;365: (MIST2 Trial) Results: ONLY t-PA – DNase group had significant improvements in mean change in pleural opacity, referral to thoracic surgery, and length of hospital stay No difference in adverse events

Parapneumonic effusion and empyema The role of t-PA and DNase Instillation technique Dosing: DNase 5mg and t-PA 10mg Each instilled into pleural space through the chest tube TWICE daily Clamp the chest tube for 1 hour after instillation; unclamp after 1 hour Medications can be instilled TOGETHER Was given separately in the MIST2 Trial

Parapneumonic effusion and empyema “What about chest tube size?” CHEST 2010; 137(3):536–543 405 patients with pleural infection enrolled in the MIST1 Trial Compared the combined frequency of death, surgery, and secondary outcomes in patients receiving chest tubes of differing size (<10F, 10-14F, 15-20F, >20F) also looked at pain in patient subset NO significant difference in the frequency of death or need for thoracic surgery; less pain with smaller bore chest tubes

Parapneumonic effusion and empyema “What about chest tube size?” Cardiovasc Intervent Radiol (2008) 31:135–141 Evaluated 93 small-bore chest tubes (range ~8-12F) in 82 patients Placed under image guidance (CT or US) Catheter dwell times, catheter outcome, pleural fluid outcome, reinsertion rates, and need for urokinase or surgery recorded Conclusion: small-bore chest tubes adequate for noninfected pleural collections; ~20% failure rate in empyemas

Parapneumonic effusion and empyema “When should I refer to surgery?” Is the avoidance of surgery the most important outcome measure? Definitive treatment of empyema in >90% of cases LOS ranging 5-7 days Mean LOS 12 days in t-PA – DNase group (MIST2) Planned randomized trial: evaluating tPA–DNase versus early VATS for the treatment of parapneumonic effusion or empyema N Engl J Med 2018;378:740-51

Malignant effusions The second leading of exudative effusions The majority arise from: lung cancer, breast cancer, lymphoma In lung cancer: 15% have an effusion at presentation 50% will develop and effusion during their course Associated with a poor prognosis; 4 – 7 month median survival To effectively treat malignant effusions, need to understand mechanism by which they cause dyspnea N Engl J Med 2018;378:740-51

Malignant effusions Mechanism of dyspnea in pleural effusions Pleural effusions only mildly increase shunt fraction  RARE to find substantial hypoxemia Dyspnea generally NOT due to lung collapse or a reduction in pulmonary function measures Dyspnea is a chest wall issue… Caused by the diaphragm being displaced caudally mechanically disadvantageous length-tension relationship N Engl J Med 2018;378:740-51

Malignant effusions Treatment Goals: improve quality of life – primarily by minimizing dyspnea – and to minimize pleural procedures and the need for repeated medical visits TWO main treatment options Tunneled pleural catheters Pleurodesis N Engl J Med 2018;378:740-51

Malignant effusions Treatment Two main questions (after initial thoracentesis): “Is the patient’s breathing better?” If not, look for other potential causes of dyspnea “Did the lung fully re-expand?” Yes – candidate for EITHER indwelling pleural catheter or pleurodesis No – candidate ONLY for indwelling pleural catheter N Engl J Med 2018;378:740-51

Indwelling Pleural Catheters
PROS CONS Significant improvement in dyspnea Placement in the outpatient setting The ability of patients to care for the catheter themselves Spontaneous pleurodesis in ~50% of patients Patients need to drain the catheter repeatedly until effusion resolves or death Infection related to the tunneled pleural catheter in ~5% N Engl J Med 2018;378:740-51

Indwelling Pleural Catheters
PleurX Placement Video (search “pleurx”)

Pleurodesis (talc) Significant improvement in dyspnea
PROS CONS Significant improvement in dyspnea Not having to manage a catheter In hospital for 3 to 5 days after the instillation of talc to effect pleural surface fusion A small risk of transient hypoxemia (nongraded talc) N Engl J Med 2018;378:740-51

Malignant effusions “So, which is better?” JAMA 2012;307(22): Unblinded randomized controlled trial comparing indwelling pleural catheter and talc pleurodesis in 106 patients with malignant pleural effusion Patients completed daily 100-mm line visual analog scale (VAS) of dyspnea over 42 days after intervention Dyspnea improved in both groups, with no significant difference in the first 42 days Talc pleurodesis group: more additional procedures Tunneled pleural catheter group: higher incidence of nonserious adverse events

Complicated transudates Mostly due to heart failure, cirrhosis, and nephrotic syndrome Often associated with high 1-year mortality rates (50%, 25%, and 46% respectively) In the majority of patients, managed by treatment of the underlying condition N Engl J Med 2018;378:740-51

Complicated transudates Congestive heart failure Due to an increase in pulmonary capillary pressure and a consequent leak into the pleural space Decompensated heart failure requiring diuretic treatment  87% have pleural effusions on CT Uncomplicated heart failure with pleural effusions  bilateral effusions in 73% of cases Initial response to diuretic treatment  89% no longer had a pleural effusion after 2 weeks of follow-up Eur Respir Rev 2016; 25: 303–316

Complicated transudates Congestive heart failure Although more commonly associated with left-sided failure, pleural effusion also occurs in right-sided heart failure most commonly small effusions appear to be most commonly right sided (58%) or bilateral (26%) Eur Respir Rev 2016; 25: 303–316

Complicated transudates Hepatic hydrothorax Present in ∼5% of patients with liver cirrhosis and ascites Most commonly right sided may be bilateral or exist solely on the left a predisposition of diaphragmatic defects affecting the right hemidiaphragm May occur in the absence of clinically apparent ascites Associated with a particularly poor prognosis Eur Respir Rev 2016; 25: 303–316

Complicated transudates Hepatic hydrothorax Managed with salt restriction and diuretic therapy In the presence of persisting fluid  a trans-jugular intrahepatic portosystemic shunt or liver transplant may be needed surgical repair of the diaphragm rarely used Fluid and protein loss is a significant concern with pleural fluid drainage Similar to ascites drainage Eur Respir Rev 2016; 25: 303–316

Complicated transudates Generally managed by treatment of the underlying condition Refractory effusions deserve prompt and aggressive pleural palliation Tunneled pleural catheters, pleurodesis, or both may be indicated for these patients* recommend careful discussion with relevant services N Engl J Med 2018;378:740-51

SUMMARY Pleural effusions are common and have a variety of potential causes Thoracic ultrasound should be considered as an early investigative tool in pleural effusions A thoracentesis is often (but not always) required as past of pleural fluid investigation There are effective tests available to help determine the etiology of pleural effusions Pleural effusions often cause dyspnea (but not always hypoxemia) There are well laid-out guidelines for the management of the most common cause of pleural effusions

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