Time Stamps

• Interpretation of Pleural Fluid Studies and Common Pleural Diseases
  
• Imaging Pearls and Thoracentesis Indications
  
• Deciding on Thoracentesis
  
• Light’s Criteria and Pseudo Exudates
  
• Pleural Fluid Studies: pH and Cell Differential
  
• Diagnosing and Treating Parapneumonic Effusions
  
• Malignant Pleural Effusions: Diagnosis and Management

Show Notes

• Pearl 1: Review of Pleural Effusions
  • Types of pleural effusions
    • Pleural effusions are a pathologic state in which more fluid accumulates between the visceral and parietal pleura than is physiologic.
    • Transudative pleural effusions occur due to increased hydrostatic and decreased oncotic pressure
    • Exudative effusions occur due to a process causing increased capillary permeability allowing complex materials entering the pleural space
  • Points to consider when discussing diagnostic thoracentesis
    • Laterality of the effusion: while bilateral effusions tend to be due to transudative processes, a new unilateral thoracentesis warrants diagnostic tap
    • Chronicity of the effusion: consider diagnostic thoracentesis for new unilateral pleural effusions or treatment refractory bilateral pleural effusions
      • Patient risk factors: consider diagnostic thoracentesis in patients with underlying malignancy, concern for infection, recent thoracic surgery
  • Do not anchor, up to 30% of pleural effusions have more than one etiology
  • Ultrasounding pleural effusions
    • Sensitive test which is easiest to do repeatedly at the bedside and can provide features of the effusion
• Pearl 2: Light’s Criteria and Pseudoexudates
  • Light’s criteria
    • Pleural fluid-to-serum protein ratio greater than 0.5
    • Pleural fluid-to-serum LDH ratio greater than 0.6
    • Pleural fluid LDH greater than 0.67 (ie, two-thirds) the upper limits of the laboratory’s normal serum LDH
  • Benefits to Light’s criteria is its simplicity and high sensitivity for exudative effusions. However, some caveats is that it duplicates its use of LDH and it can be inaccurate in patients on chronic diuretic therapy – pseudoexudates
  • Pseudoexudates
    • Effusions where the underlying etiology is transudative but is classified as exudative based on Light’s criteria. Some additional tests that may clue us that the effusion is transudative is:
      • SPAG (serum-pleural-albumin gradient) > 1.2 points towards transudates
      • SPPG (serum-pleural-protein-gradient) > 3.0 points towards transudates
      • NT-proBNP: If there is diagnostic uncertainty that the pleural effusion is of cardiac origin, pleural fluid NT-pro-BNP is a useful biomarker with high diagnostic accuracy. ***
  • Pleural fluid only three test confirmation
    • Classified pleural effusions using pleural protein, cholesterol and LDH without the use of serum tests.
      • protein > 3.0 g/dL
      • cholesterol > 45-55 mg/dL
      • LDH > 0.45-0.67 times the lab ULN.
    • May be useful in scenarios when the Light’s criteria is borderline positive or there is diagnostic uncertainty
• Pearl 3: Interpreting Pleural Fluid Studies
  • pH
    • Levels:
      • Normal pH ~ 7.60
      • Transudative effusions: pH 7.40-7.55
      • Exudative effusions: pH < 7.30;
    • Considerations of interpreting pH
      • Pleural fluid for pH testing should be collected anaerobically in a heparinized syringe and measured in a blood-gas machine.
      • Artificial elevation of pH can be due to air contamination in the sample.
      • Artificial reduction can be due to contamination with heparin or lidocaine.
      • If the fluid is really chronic and has been there for a long time and it’s cellular, the pH can be low even if without some active very infected process. ***
  • Cell count and differential
    • Elevated neutrophils (>50%) are seen in acute processes like parapneumonic effusions, empyema, PE
    • Lymphocytic predominance (>50%) is seen in TB, longstanding pleural effusions, CHF or malignancy.
      • Pleural fluid lymphocytosis > 90 percent suggests tuberculosis or lymphoma.
    • Pleural eosinophilia (>10%) could be due to a variety of causes: malignancy, infection, trauma, drugs, toxin, inflammation. It can signify recent air or blood in pleural space.
      • No diagnosis is ever obtained in as many as one third of patients with eosinophilic pleural effusion
    • Red blood cells: Ratio of pleural fluid to blood Hct > 0.5 is diagnostic of hemothorax
  • Gram stain and cultures
    • Positive Gram stain and cultures are generally diagnostic of a parapneumonic effusion, and frank pus is diagnostic of empyema.
    • Pleural fluid should be placed in blood culture bottles and a sterile container, because a small but well-conducted series showed a 20% absolute increase in microbiologic yield with this strategy
  • Adenosine deaminase
    • The most common diagnostic threshold used to establish a TB pleural effusion is a pleural fluid adenosine deaminase (ADA) level greater than 40 U/L.
    • ADA can also be elevated in hematologic malignancies like lymphoma, brucellosis, Q fever and rheumatoid arthritis
  • Glucose
    • Glucose concentration in pleural fluid should be the same as that of the blood. If glucose is low in pleural fluid, consider empyema, TB, malignancy or RA to name a few
  • pro-BNP
    • There is a high correlation between serum and pleural pro-BNP and so unless multiple etiologies are suspected, pleural pro-BNP may add little diagnostic value ***
    • If there is diagnostic uncertainty that the pleural effusion is of cardiac origin, pleural fluid NT-pro-BNP is a useful biomarker with high diagnostic accuracy.***
  • Triglycerides
    • A level > 110 mg/dl supports a chylothorax but a level < 50 rules it out
  • Amylase
    • When it is greater than the upper limit of normal, it suggests malignancy (<20 percent), pancreatic disease, esophageal rupture
• Pearl 4: Parapneumonic Effusions
  • Nearly 50% of bacterial pneumonias have associated pleural effusions, but most do not result in complicated effusions or empyemas.
  • Spectrum of parapneumonic effusions
    • Uncomplicated parapneumonic effusions: exudative, neutrophilic effusion, Gram stain and culture are negative, glucose level > 60 mg/dl, pH > 7.20.
    • Complicated parapneumonic effusions: glucose level < 60mg/dl, pH < 7.20, gram stain and culture may or may not be negative depending on the stage of disease, and loculations/septations may be seen on US.
    • Empyema: collection of bacteria or pus in the pleural space
  • Management of parapneumonic effusions
    • Antibiotics: Treatment of parapneumonic effusion includes appropriate antibiotic therapy (including anaerobic coverage) together with drainage of pleural fluid as indicated.
    • Chest tube placement: Pigtail chest tube is as good as large bore surgical chest tube
    • Enzymatic Treatment and MIST trials:
      • MIST 1: The intrapleural administration of streptokinase does not improve mortality, the rate of surgery, or the length of the hospital stay among patients with pleural infection.
      • MIST 2: Intrapleural t-PA–DNase therapy improved fluid drainage in patients with pleural infection and reduced the frequency of surgical referral and the duration of the hospital stay. Treatment with DNase alone or t-PA alone was ineffective.
• Pearl 5: Malignant Pleural Effusions
  • Suspicion of malignant pleural effusion (MPE) should be followed with drainage.
  • The yield for cytology is around 60%. The majority of MPEs will be detected within two attempts at sampling, so if the first tap is negative, do another.
  • If a diagnosis cannot be made with pleural fluid alone, a pleural biopsy is needed either via medical thoracoscopy from IP or VATS with thoracic surgery.
  • Management of recurrent MPEs
    • Repeated thoracentesis
      • Pros: Low risk procedure
      • Cons: Repeated thoracentesis requires repeated visits to the hospital.
      • It is reasonable to first trial pleural aspiration to assess symptomatic response prior to insertion of indwelling pleural catheters
    • Indwelling pleural catheter placement
      • If lungs are non-expandable and require intervention for symptomatic MPE, consider use of an indwelling pleural catheter rather than talc pleurodesis.
      • Pros:
        • simple to place
        • does not require repeated clinic/hospital visits,
      • Cons:
        • Psychological implications of having a semi-permanent tube drain inserted
        • Requires training for management
        • Higher risk for infection
    • Pleurodesis
      • In MPE patients with expandable lungs, talc slurry pleurodesis may improve quality of life, chest pain, breathlessness and pleurodesis rates.
      • Pros: Effective procedure
      • Cons: Invasive and painful procedure

Transcript

Dr. Christopher Kapp: I’ve said this multiple times and I can’t believe I’ve said this multiple times, being a proceduralist, but you just can’t shake the internist at heart. This is where your pretest probability for these things is so critical because especially in this age with healthcare trying to diminish healthcare utilization, choosing wisely for which tests you want to order.

Dr. Shreya Trivedi: That’s Dr. Chris Kapp, an interventional pulmonologist at Northwestern. Welcome to the Core IM 5 Pearls Podcast, bringing you high-yield evidence-based pearls. This is Dr. Shreya Trivedi.

Dr. Kalaila Pais: And this is Dr. Kalaila Pais, an internal medicine resident at Beth Israel Deaconess Medical Center. Today we’re talking about interpretation of pleural fluid studies.

Dr. Shreya Trivedi: In this episode, we will be really getting into the nitty gritty of pleural studies and what each test we send actually means.

Dr. Kalaila Pais: We’ll also touch on some common pleural diseases like parapneumonic effusions and malignant pleural effusions.

Dr. Shreya Trivedi: Yes, we have a lot to cover so let’s dive in!

Dr. Kalaila Pais: Pearl 1, a review of pleural effusions

Dr. Shreya Trivedi: What is the pathophysiology of pleural effusions and when should we think about thoracentesis?

Dr. Kalaila Pais: Pearl 2: deep dive into the Light’s criteria and pseudoexudates

Dr. Shreya Trivedi: What are some things to think about when using Light’s criteria and what are some other diagnostic tests which can augment its use?

Dr. Kalaila Pais: Pearl 3: Analyzing pleural fluid studies

Dr. Shreya Trivedi: How do we interpret common pleural fluid studies?

Dr. Kalaila Pais: Pearl 4: The spectrum of parapneumonic effusions

Dr. Shreya Trivedi: How do we identify and treat parapneumonic effusions?

Dr. Kalaila Pais: Pearl 5: Malignant pleural effusions?

Dr. Shreya Trivedi: How do we diagnose and manage malignant pleural effusions?

Pearl 1: Review of Pleural Effusions

Dr. Shreya Trivedi: Ok Kalaila, lets do a quick refresher on pleural effusions before we add some nuances to the testing.

Dr. Kalaila Pais: I would love to Shreya! So we can think of the pleural space as a potential space in the body between the parietal and visceral pleura. And fun fact: it is actually normal to have some fluid in the pleural space. How much?~ 1-3cc/kg.

Dr. Shreya Trivedi: So say we have a 200lb male, it can be physiologic to have up to a little more than 200cc of pleural fluid.

Dr. Kalaila Pais: Yep and the reason why that little bit of a fluid is there is because it acts as lubrication between the pleura of the lungs allowing the lungs to move freely.

Dr. Shreya Trivedi: The problem is when there is an excess build up of fluid to the point that it becomes pathologic. This is when we call it a pleural effusion.

Dr. Kalaila Pais: And on a AP CXR, we can see a meniscus forming/blunting of the costophenic angle on an AP CXR at around 200cc. And by 500cc, the meniscus can obscure the hemidiaphragm.

Dr. Shreya Trivedi: Yeah x-rays are great but POCUS can be even better. It is more sensitive, easy to do repeatedly at the bedside so you can follow the effusion over time. Dr. Kristina Montemayor, a pulmonary and critical care doctor at Johns Hopkins and one of the co-founders of the podcast Pulm PEEPs reminded how POCUS can be used to actually see features of the effusion itself.

Dr. Kristina Montemayor: As a resident I have called for a thoracentesis because it looked like there was complete whiteout of right lung and then I went with the IP fellow and we actually ultrasound it and it’s like, oh, this is not fluid. This is actually cancer and it’s solid component and there’s no fluid around it, but I wouldn’t have known that if I went and did an ultrasound or at the bedside.

Dr. Shreya Trivedi: Speaking of how useful POCUS can be, we will link an infographic on how to use POCUS to identify a pleural effusion in our show notes.

Dr. Kristina Montemayor: A lot of people when you’re talking about you have an effusion, they’re like, what is that? Is it in the lung itself? Is it outside of the lung? So I actually like to show them their actual image, whether it’s a chest x-ray or if they got the ct or even just showing them on our bedside ultrasound, this fluid here shouldn’t be here and you may be having your symptoms because of this. So here is a procedure that we can do. So I try to at least let them visualize what is abnormal and the amount of fluid that we potentially could take off and how that could help them from as Dave said, from a therapeutic standpoint is also from a diagnostic standpoint. Patients sometimes are like, wow, that much fluid was in me. I can’t believe that. Or they’re just surprised to see they’re like, what color is it?

Dr. Shreya Trivedi: Yeah this is the biggest thing I’ve changed in my practice is to show patients their images. Its day and night in terms of their understanding and the kinds of questions i get back and misconceptions i can clarify

Dr. Kalaila Pais: I know that we have all been taught and re-taught transudative vs exudative effusions. But, I really liked how our expert Dave Furfaro, one of the pulmonary and critical care doctors at Beth Israel Deaconess Medical Center and the other co-founder of Pulm PEEPs, made the distinction between the two.

Dr. Dave Furfaro: In transudate when that fluid is relatively simple, we’re really thinking about the hydrostatic and oncotic pressure and is there some reason that more fluid is just going across? And so those are things like heart failure or fluid over load from renal failure, low albumin states where you have low oncotic pressure and just sort of simple fluid builds up in that space. And then we think on the exudative side of more complex fluid, this is really when something’s happened to that barrier and it’s not functioning normally. So some sort of injury or inflammatory process, some pathologic state that’s leading more cells, more protein, more sort of complex material to go into that pleural space. And in either case, the buildup of fluid in that space can impact the lungs that are right there adjacent to the pleura and that’s why we care about them so much.

Dr. Shreya Trivedi: And just to lay out the menu of reasons why the patient may have a pleural effusions, we have to ask is it from volume overload (heart failure, hepatic hydrothorax, renal failure/nephrotic syndrome, or liver failure), is it related to an infection (parapneumonic vs empyema), is it related to malignancy or a pulmonary embolism and less common but still important to consider are hemothorax and TB. then there are the rare ones like chylous effusions, autoimmune related, urinothorax.

Dr. Kalaila Pais: And we will get more into those nuances in a bit. But when you have the x-ray or ultrasound the next step is to think about is it clear from the history its a transudative effusion that needs a bit diuresis or is it time i pull the trigger on a thoracentesis.

Dr. Christopher Kapp: So I think by and large in a new unilateral pleural effusion, everybody that can safely get a thoracentesis should probably get a thoracentesis.

Dr. Dave Furfaro: And then in that same vein, if I am having bilateral fusions and I am trying to treat it and I’m really not making any progress and it starts to make me question my underlying diagnosis that I might try to get a little bit more information. If there are some red flag features like the patient seems to really clinically have a bad pneumonia, and so even though there are two effusions there, one of them could be a monic, they might not be the same process. If someone has a known underlying malignancy and they could certainly have metastases in multiple parts of their body, then I’m going to go ahead and tap the larger one, the bigger one to try to get some diagnostic information.

Dr. Shreya Trivedi: So the takeaway is to ask yourself (1) is this a new unilateral effusion? (2) Is it a bilateral effusion that is not getting better with your interventions? (3) Are there any red flag symptoms like significant dyspnea, fever/weight loss hemoptysis where you really would want to work up the pleural effusion more.

Dr. Kalaila Pais: Something that really stuck with me after speaking with our discussant was how important it is not to anchor.

Dr. Christopher Kapp: I always have to tell myself, is to not anchor. Up to 30% of pleural effusions do have more than one etiology. So if you get your fluid studies back, that doesn’t necessarily mean there’s not something else going on.

Dr. Shreya Trivedi: The good old “two things can be true” lessons rears its head again and just to explicitly state some examples, a patient can have a malignant plerual effusion AND heart failure, they could have a parapneumonic effusion and a severe hypoalbuminemia say <1.5mg/dl contributing.

Dr. Kalaila Pais: Okay, so to recap, pleural effusions are pathologic states in which there is a buildup of excess fluid in the pleural space.

Dr. Shreya Trivedi: When classifying an effusion as transudative or exudative, think of the underlying physiology. If it is due to increased hydrostatic or low oncotic pressure, think transudative. And if there is concern for injury or inflammation, think exudative.

Dr. Kalaila Pais: When to tap an effusion is dependent on the individual patient but you should consider is this a new pleural effusion that has not been evaluated before, if it is bilateral or unilateral, and if there are any red flag signs.

Dr. Shreya Trivedi: And finally, do not anchor as up to 30% of pleural effusions can have more than one etiology. And I bet that number may be in the rise as our patients get more complicated.

Pearl 2: Light’s Criteria and Pseudoexudates

Dr. Kalaila Pais: Ok so say you get a thora on a patient, now time to interpret the study.

Dr. Shreya Trivedi: Typically id use the lights criteria but recently ive seen people also using PF3 aka only pleural fluid criteria with pleural cholesterol. Same so i think be helpful to go over the pros and limitations of each.

Dr. Kalaila Pais: Lets start with the Light’s criteria. Just a fun fact when i was researching that im blown away by: turns out Richard Light and submitted his prelim findings for the light’s criteria to the American Thoracic Society in 1971 which actually rejected him! He then submitted his manuscript to the Annals of Internal Medicine where it was accepted and is now a landmark study.

Dr. Shreya Trivedi: Wow can you imagine that? If that isn’t a motivator to believe in your work and passion, I don’t know what is. So, the Light’s criteria says if any of the following criteria are met, its an exudative fluid so a (1) pleural fluid to serum protein ratio > 0.5 (2) pleural fluid to serum LDH ratio > 0.6 and (3) pleural fluid LDH > ⅔ upper limit of normal for serum LDH.

Dr. Dave Furfaro (42:01): Lights criteria is wonderful, it works really well. I think the thing that it’s best at is identifying that it’s a transudate. So if you don’t meet any of those criteria, I feel really, really comfortable that this is a simple transudative effusion.

Dr. Kalaila Pais: So when light’s criteria calls something transudative we can feel confident in that but begs the Q, do feel that way with exudative fluid?

Dr. Dave Furfaro: It does have some flaws of maybe, I hate to say over calling exudates, but that is the criticism of it is that sometimes it can over a call exudates. The reason that it might have some propensity to do this is that you’re actually using LDH twice and so you are using this ratio and you’re using the higher limit of normal. And that can skew things quite a bit.

Dr. Shreya Trivedi: So if a patient has a high serum LDH, their pleural LDH may be greater than the upper limit of normal which points exudative, but the ratio of serum to pleural LDH ratio may less than 0.6 which points to transudative

Dr. Kalaila Pais: Yeah another critique of the Light’s criteria is a pseudoexudate which is an effusion where the underlying etiology is transudative but is classified as exudative based on the Light’s criteria.

Dr. Dave Furfaro: The other thing is that we know that people who have a lot of effusions are often overloaded. And if you’re on chronic diuretic therapy, you can, for lack of a better word, concentrate your pleural space. So fluid is going in, it has certain components, you’re slamming them with diuretics to get them to urinate more, and some of that fluid will get drained by the lymphatics and back into circulation and you sort of concentrate the fluid that’s left in the pleural space. And so in those cases, we sometimes call that like a pseudo exudative effusion.

Dr. Shreya Trivedi: So takeaway is that diuretics concentrate can pleural fluid, increasing protein and LDH levels which is humbling bc of course if our patient has HF or a hepatic hydrothorax and being diuresed and we get thora, we might go down a rabbit hole trying to work up an exudative fluid that actually a pseudoexudate

Dr. Kalaila Pais: I learnt that this actually can happen in up to 20-30% of effusions associated with liver or heart failure so definitely a common occurrence.

Dr. Shreya Trivedi: So how can we reclassify someone who may have a pseudoexudate by the lights criteria. There are 3 things to look at. The 1st two is peaking over to look at the difference in albumin and protein between the serum and pleural fluid

Dr. Kalaila Pais: Similar to SAAG calculation in cirrhosis, this is more formally known as protein gradient SPAG or serum-pleural-albumin gradient and the SPPG (serum-pleural-protein- gradient) for effusions.

Dr. Shreya Trivedi: Here, if the difference between protein levels in the serum and the pleural fluid is greater than 3.1 g per dL, or if the A serum-pleural effusion albumin gradient greater than 1.2 g per dL this can also can indicate that the pleural effusion is most likely a true transudative effusion.

Dr. Kalaila Pais: Okay so this makes sense thinking about the pathophysiology, because in a transudative effusion, the underlying mechanism is fluid moving through the membrane because of hydrostatic and oncotic pressure. So, you would expect that larger molecules like albumin and protein would remain in the serum, so there would be a greater difference in the serum-pleural protein or albumin gradient.

Dr. Shreya Trivedi: Great! I love it when we tie in the pathophys, it really helps cement the numbers and stats in place. The third and last thing that can help us objectively differentiate a pseudoexudate is the pleural pro-NTP, if its’ greater than 1500, then it is most likely due to heart failure. The idea is that if there is so much BNP in the blood it will “leak into” the pleural fluid.

Dr. Kalaila Pais: Great let’s transition to the pros and cons of the pleural fluid only rule. so this rule states that an effusion is exudative if the pleural protein > 3.0 g/dL, cholesterol > 45-55 mg/dL or LDH > 0.45-0.67 times the lab ULN. It’s great because it only uses pleural studies so you don’t need a serum level comparison. It also does not duplicate LDH.

Dr. Shreya Trivedi: Okay so you mentioned measuring pleural cholesterol, can you explain why it would be high in exudative effusions?

Dr. Christopher Kapp: There has been some pretty good data to suggest that a cholesterol level above 40 is consistent with exudate and below 25 is very consistent with transudate. I do send it a lot of the time. I think it can be useful in those situations where your borderline maybe one of light’s criteria is positive. So I think having that tests and if it’s really high, then it can really point to you that yeah, there’s some inflammation going on just because the pathophysiology of utilizing the cholesterol is thought to be related to degenerating cells and vascular leakage from increased permeability, and that is more consistent with kind of an exudative effusion

Dr. Kalaila Pais: So there are two schools of thought. 1 is that Dr. Kapp mentioned with pleural cells can synthesize cholesterol they get from degenerating cells for their own requirements, and cholesterol level rises in the pleural cavity. The second one states that because pleural cholesterol is derived from plasma, and pleural capillaries are more permeable in pleural exudate, plasma cholesterol could enter the pleural cavity.

Dr. Shreya Trivedi: Looking into it, the key difference is that pleural cholesterol in diagnosing exudative effusions has a high specificity of 96%. Compared to lights criteria which we discussed as a lower specificity for exudative effusions

Dr. Kalaila Pais: Okay so now that we have a good understanding of the two tests and some of the limitations, which one is better to use?

Dr. Christopher Kapp: I think the reason that lights criteria has stood the test of time for so long is it just works. And so there’s no reason to kind of debunk something that isn’t necessarily broken. If it’s not broke, why would we try to fix it? I think these other evaluations are great because we always want to improve upon ourselves. So I think the cholesterol was additive and I think the albumin gradient can be additive in the right patient, but I think that the reason that the lights criteria stood the test of time is just because of that reason. It just works.

Dr. Shreya Trivedi: Very well said. Okay, let’s summarize our learning points from this pearl. The Light’s criteria is a simple, easy to calculate test with a high sensitivity for exudative effusions. The caveats are that it uses LDH twice in it’s criteria and can be inaccurate in patients on chronic diuretic therapy resulting in a pseudoexudate.

Dr. Kalaila Pais: Yup, a pseudoexudate is an effusion where the underlying etiology is transudative but it is classified as exudative based on Light’s criteria. The 3 tools that we can use are the serum-pleural albumin, the serum-pleural protein gradient and NT-proBNP to help correctly classify the effusion.

Dr. Shreya Trivedi: And lastly, pleural fluid cholesterol levels will be elevated in exudative effusions due to cell degeneration and capillary permeability so grab a pleural cholesterol level to help identify an exudative effusion.

Pearl 3: Interpreting Pleural Fluid Studies

Dr. Shreya Trivedi: so we talked about pleural fluid LDH, protein, cholesterol, and proNT-BNP but there are a bunch of other tests we can send off to clue us in on what going on

Dr. Kalaila Pais: Yes I’m excited to discuss each test in a more nuanced way today. First up, pleural pH.

Dr. Shreya Trivedi: Just to remind everyone, a normal pleural pH is ~ 7.60. Most exudates effusions will have a pH of < 7.30.

Dr. Kalaila Pais: And, we will talk about parapneumonic effusions and empyemas, but if the pH is < 7.2 that confers a poor prognosis and indicates a high likelihood of the pleural space needing drainage with a chest tube.

Dr. Shreya Trivedi: Speaking of super low pH, i have definitely been tricked by a super low pleural fluid pH in a well-appearing patient eating a grilled cheese sandwich. Turns out it was local lidocaine used prior to the thora is acidic in nature and so when it comes in contact can falsely lower the pleural fluid pH. and on repeat dx throa, the pH came back normal.

Dr. Kalaila Pais: Yeah we can also see a falsely low pH if there is residual heparin in a syringe .

Dr. Shreya Trivedi: Also, the sample should be sent to the lab quickly, because delays can increase the pleural fluid pH.

Dr. Kalaila Pais: Studies have shown that sending pleural fluid samples that are delay of more than 1 hour can cause alterations in the pH, with significant changes observed at 4 and 24 hours.

Dr. Shreya Trivedi: Why don’t we move onto the cell count and diff. In normal pleural fluid there should be very few WBCs and only 0-1% will be neutrophils.

Dr. Kalaila Pais: If there a neutrophil predominance it signifies an acute process. Usually >50% neutrophils we are thinking empyema or parapneumonic effusion but the population matters. So in patients with a lung transplant patients, at about 21% neutrophil predominance can be seen with infection in those transplant lung patients

Dr. Shreya Trivedi: Another key takeaway is that neutrophils mean acute inflammation .. that does not always mean infection.

Dr. Kalaila Pais: Yeah for example, more than half of patients with a pulmonary embolism will have a neutrophil-predominant pleural effusion. PEs can be a very acute process.

Dr. Shreya Trivedi: Now what about lymphocytes? Usually there’s around 20% lymphocytes in pleural fluid. But again, if you see more than 50% you should be thinking of chronic processes

Dr. Dave Furfaro: Lymphocyte predominant is the most likely type of effusion for someone who has an idiopathic effusion. So somebody has recurrent effusions, we can’t figure out why. Lymphocyte predominant can be seen in malignancy. Certainly it can be seen in some sort of more indolent infections. Tuberculosis is being the classic one

Dr. Shreya Trivedi: And then pleural fluid lymphocytosis > 80-90 percent suggests tuberculosis,lymphoma, post-cardiac injury syndrome, chylothroax or a rheum process.

Dr. Kalaila Pais: And say you are worried about TB and have a lymphocytic predominnt effusion, youre next step is to likely add on an adenosine deaminase (ADA).

Dr. Christopher Kapp: ADA is an interesting test in the sense that I think in the right patient population it can be super, super helpful. So if you have a patient from an endemic area with TB and they have a pleural effusion, sending an A DA can be super helpful. If it’s elevated, it can help you cinch the diagnosis because culture data from an A FB from the pleural fluid is really low.

Dr. Shreya Trivedi: Yep in normal conditions ADA in pleural fluid is low and if an ADA <40 IU/L we can generally excude tuberculosis pleuritis.

Dr. Christopher Kapp: ADA can also be elevated in hematologic malignancies and lymphoma that have kind of invaded the pleural space and it’s an acute phase reactant. So if you send it in a patient with a low probability of tuberculosis, it’s probably not going to be super diagnostically helpful.

Dr. Kalaila Pais: Lets move on to eosinophils. There should be almost 0% of eosinophils in the pleural space. But if there is more than 10% in your pleural fluid, there are quite a few things it could possibly be.

Dr. Dave Furfaro: Eosinophils really can be from a grab bag of things, but anything that irritates or violates the pleura will lead eosinophils to be there. So somebody has a rib fracture, somebody has a pneumothorax, somebody has actually had a prior tap, there are certain types of malignancies or inflammatory conditions can do that.

Dr. Shreya Trivedi: And then I was also really surprised to hear that no diagnosis is ever obtained in as many as one third of patients with eosinophilic pleural effusions.

Dr. Kalaila Pais: That is definitely humbling. The last part of our cell count and diff is the number of RBCs.

Dr. Christopher Kapp: a lot of your pleural effusions are going to have a fair amount of red blood cells on ’em, but you really need a very high percentage or a very high number of red blood cells for that to be consistent with the hemothorax. The best test for that is actually to send a pleural fluid hematocrit, and if it’s greater than 50% of the serum hematocrit, then you’re looking at a likely hemothorax.

Dr. Kalaila Pais: So reiterate if we look at the ratio of pleural fluid to blood Hct and it’s > 0.5, this is diagnostic of a hemothorax.

Dr. Shreya Trivedi: Another cool trick we learnt is that when sending pleural fluid for culture, we should be placing these samples into blood culture bottles because it increases the microbiologic yield.

Dr. Christopher Kapp: There was a recent paper, it’s a couple years old now, but inoculating your blood culture bottles at the bedside before you send ’em to the lab improves your yield by about 10 to 12%. So it’s actually my practice now where I draw the fluid and then either myself or someone else who’s in the room just directly inoculates 10 ccs into the blood culture bottles just to improve your yield.

Dr. Shreya Trivedi: Okay we learnt about a lot of tests so let’s summarize some of our takeaways. A normal pleural pH is around 7.6 so levels below 7.3 suggest exudative effusions. However, don’t forget that samples contaminated with lidocaine or heparin can lower the pH and try to get the samples to the lab as soon as possible can have a falsely elevated pH.

Dr. Kalaila Pais: When we look at the cell differential of pleural fluids, greater than 50% neutrophils clues us into an acute process where elevated lymphocytes can suggest malignancy or even TB. If you are worried about TB, you can send an ADA.

Dr. Shreya Trivedi: Also, eosinophilic effusions can be due to anything that irritates the pleura and a pleural to serum Hct ratio of > 0.5 indicates a hemothorax.

Pearl 4: Parapneumonic Effusions

Dr. Shreya Trivedi: So we’ve learnt about all of the ways to test pleural fluid to give us little diagnostic clues. I think a great way to see how their interpretation can be put into practice is with how we diagnose and treat parapneumonic effusions.

Dr. Kalaila Pais: Oh yeah totally! A great example is distinguishing uncomplicated vs complicated parapneumonic effusions.

Dr. Dave Furfaro: an uncomplicated, you just have pneumonia there in the lung, the pleural space gets irritated. Yes, more protein and cells and things are pouring into there, but you don’t sort of have a frankly infected space. It’s just sort of next to this infected lung. And in those cases we feel a lot more comfortable trying to just treat the pneumonia and have the fluid maybe be drained once as we’re doing the diagnosis, but we’re just sort of monitoring it

Dr. Shreya Trivedi: And with these cases, when we check our pleural fluid biomarkers, we see an exudative, neutrophilic effusion because of the acute inflammation. But, because the fluid itself is not infected, we will have negative gram stain, negative cultures, a glucose level > 60 and a pH > 7.20.

Dr. Kalaila Pais: This is different from a complicated parapneumonic effusion which is when bacteria is introduced into the pleura. The reason we call this complicated is because it needs to be drained to resolve.

Dr. Shreya Trivedi: Oh man idk im dating myself but there was a time on FB where people update their relationship status as complicated and i cant help but think parallel that those complicated relationships needed drainage to help it out.

Dr. Kalaila Pais: Yep and idk if you can parallel for why you examine those complicated relationships but for those complicated effusions, since there is all this bacteria there, it makes less sweet aka low glucose <60 and things are sour so the pleural fluid pH will be below 7.20.

Dr. Shreya Trivedi: On pro-tip about the pleural glucose being low. The cutoff os <60 isnt a hard fast esp if you take your patient’s serum glucose into account.

Dr. Christopher Kapp: Now this is the situation where I think having a serum level is helpful because you want to see if the glucose level is significantly lower than the serum level. If you have a patient who has a glucose level in their serum of 400 and you have a glucose level in your pleural fluid of 70, then I think infection is going to be going higher on my list of potential diagnoses.

Dr. Shreya Trivedi: and annoyingly the Gram stain and cultures may be negative or positive depending on the stage of the disease or relationship. But if you do see loculations and septations on your bedside ultrasound, its clench the diagnosis

Dr. Dave Furfaro: If I see septations loculation in a really complex space, that’s going to be a complicated effusion. I don’t actually even care what the fluid characteristics look like. I can’t be positive that the fluid characteristics from one pocket are the same as another pocket. And so if it looks really complicated on my bedside ultrasound or on a CAT scan, I’m going to call that a complicated effusion.

Dr. Shreya Trivedi: And just to say explicitly, i appreciated hearing that esp if a complicated effusion with septations or loculation, a sample of fluid in one pocket may be different than another. Hence why we have higher bacteria in one pocket vs. another.

Dr. Kalaila Pais: And last but not least, if you tap an effusion and get frank pus, that is not just a complicated effusion, that is empyema

Dr. Shreya Trivedi: The treatment for complicated parapneumonic effusions and empyema has two main buckets: drainage of the pleural space with a chest tube and antibiotics therapy.

Dr. Dave Furfaro: I would make sure that those antibiotics have anaerobic coverage in them because almost thinking of this as an abscess. I at first have much lower threshold to add antibiotics that cover the broad spectrum bugs that we most worry about Pseudomonas and MRSA.

Dr. Kalaila Pais: And with the chest tubes for the paraneumonic effusion and empyema, sometimes we need some extra help with the drainage. That is where fibrinolytic therapy comes in. There was an age old debate about which therapy to use. Do you use TPA, Dornase or TPA and dornase? The Mist 2 trial gave us our answer.

Dr. Christopher Kapp: TPA DORNASE actually did improve both radiographic outcomes and decrease the need for surgery. There were no effect on mortality or hospital length of stay. The caveats to using TPA dornase I think are one, if you have a really thickened plural rind, it’s not going to be effective at decor cating or getting rid of that pleural rind. So the patient’s going to have some lung entrapment. These medicines are not going to fix that. Two, there was a very good retrospective review of a very large data set that looked at the safety of TPA doors. Essentially the bleeding rate is pretty low. It was somewhere between two and 4%. But if your odds ratio for bleeding from TPA dornase out of the pleural space goes up if you cannot stop anticoagulation. So in those situations you should really consider dose reducing or maybe not using it because obviously you don’t want to cause a pleural bleed in those patients.

Dr. Shreya Trivedi: So if we can, combination of TPA and dornase is preferred for our patients with complex effusions and empyema because it reduces the need for surgery. But, keep in mind that it will not be effective in patients with thickened pleural rind on CT or lung entreapment aka those where the lung cannot fully expand because of active disease.

Dr. Kalaila Pais: I think a good way to end this pearl is with a PSA that parapneumonic effusions are scary. The reason we care so much about them is because if we do not act in time, the patient of course could become very sick and septic, but also may ultimately require a VATS decortication which is a really painful and invasive procedure that could otherwise be avoided.

Dr. Christopher Kapp: I think the old adage of the sun never sets on a pleural effusion is probably only really applicable anymore to patients who you’re suspecting an empyema. So this is the consult that you see a pneumonia and a pleural effusion. This is the consult that probably should happen even if it’s four o’clock on a Thursday or on a Friday or even on the weekend. This is something that probably shouldn’t sit and wait, especially with some of the more advanced treatments we have. It should be acted upon quickly, certainly within 24 hours.

Dr. Shreya Trivedi: So to recap how distinguish and manage that effusion in someone with PNA. Parapneumonic effusions exist on a spectrum from uncomplicated (non-infected fluid near pneumonia) to complicated (bacteria in pleural space) to frank empyema (pus). You can distinguish between them using fluid biomarkers with complicated effusions have glucose <60, pH <7.20, but i appreciated learning if you see septations or loculation on ultrasound or CT, that may be enough to call it complicated.

Dr. Kalaila Pais: Treatment for complicated effusions and empyemas require chest tubes plus TPA-DNase therapy. And for the antibiotics in complicated or empyema, we do anaerobic coverage, and consider broader coverage for pseudomonas and MRSA.

Pearl 5: Malignant Pleural Effusion

Dr. Shreya Trivedi: Say we are worried about a malignancy, maybe coming in with a unilateral pleural effusion, some weight loss, other vague symptoms. We definitely want to drain it!

Dr. Christopher Kapp: There’s been some data that has been published about how much fluid to send, you want to send at least 50 ccs. In this day and age of needing next generation sequencing and molecular testing and things like that, it’s probably a good idea to send more than that.

Dr. Kalaila Pais: Yes and one protip our other discussant, Dr. Furfaro mentioned if we drain the effusion before a CT, it can better help us visualize any suspicious other findings on CT and of course the fluid can help with diagnosis.

Dr. Christopher Kapp: Your yield from your initial plural fluid cytology is generally speaking around 50 to 60 to 65%. If you’re in that 30 to 40% where you don’t get an answer, your second one, you will get an answer 25 to 30% of the time. So that second thoracentesis is usually the recommended thing. One, it can be diagnostic and over a quarter of cases, and two, you drain the patient dry and they feel better. And then if you still don’t have a diagnosis after that second one, then pursuing kind of a more definitive biopsy is recommended as long as it’s within the patient’s kind of plan and goals.

Dr. Kalaila Pais: And what is the definative biopsy? We can ask our proceduralists, whether it is medical thoracoscopy with IP or VATS with our thoracic surgery colleagues, to get a pleural biopsy.

Dr. Shreya Trivedi: Okay so once we have confirmed the diagnosis of a malignant pleural effusion, what do we do? Because unfortunately, a lot of these effusions can come back

Dr. Kalaila Pais: Yeah so we have a couple of ways to manage recurrent malignant pleural effusions.

Dr. Christopher Kapp: So I think the way that I counsel patients is I tend to be fairly conservative. I think we do a thoracentesis, we get a diagnosis of a malignant effusion. I tell patients almost universally that we should wait, see what happens, and then determine based on the rapidity with which the fluid comes back, if the fluid comes back quickly within a week, then at that point I’m talking to them about the various management option.

Dr. Kalaila Pais: And one of those mgmt options is repeat thoracentesis so we want patients give patients a headsup that they may have to come back once a week or every two weeks. That is definitely something to consider, especially for patients who have difficulty with transportation and mobility to the hospital, repeated thoracentesis can be quite a burden in an already very challenging situation. What other options are there for our patients?

Dr. Shreya Trivedi: Another option is an indwelling pleural catheter. These are soft silicone tubes that are inserted into the pleural space. They are not very visible, can be drained at home and are often a popular choice for patients with malignant pleural effusions.

Dr. Christopher Kapp: Sonal pleural catheter placement is ideal in the sense that it keeps you out of the hospital and it’s as simple as putting in a chest tube essentially, but about a four to 10% infection risk for the lifetime of the catheter. And most of the time it’s just colonization and you can treat through it and keep the catheter in, but sometimes it does lead to full blown pleural sepsis or it clogs the catheter up, so you have to remove it and potentially put a new catheter in and expose you to antibiotics. And then the other big thing I always tell patients is you can’t jump in a body of water or take a bath and you can’t lay on that side, generally speaking. So you really have to, I try to provide as much informed consent as possible.

Dr. Shreya Trivedi: I actually didn’t know that about not taking a bath with a pleural catheter because thats like a body of water and so only showers if the nurses pages us if they can shower. Not like our hospitals have baths for them.

Dr. Kalaila Pais: An alternative option is talc pleurodesis. This is when talc powder is inserted into the pleural space. It causes irritation of the pleura which ultimately results in the two pleura sticking together. This prevents fluid build up.

Dr. Christopher Kapp: So going back to Richard Light, he used to call giving a sclerosing agent, and these are some of the older sclerosis agents that were probably more painful, but he used to refer to it as tachy lordy syndrome, where the patient would get tachycardic and say, Lordy, lordy, lordy, which is very corny, but I think it does serve a purpose that it can cause some pretty significant inflammation in the pleural space. And so having an understanding of maybe how we’re going to manage pain prior to doing this and then counseling your patient like, yeah, this can cause a fairly significant pleuritic type pain. So I am usually injecting bupivacaine before I do any sort of pleurodesis because it’s a little longer lasting than lidocaine with a half-life. And then making sure as long as they can tolerate taking it, NSAIDs are generally speaking the best for this. If not, then you’re still going to want to hit it from multimodal. I know we always want to try to limit narcotic use in these cases, though sometimes, especially for a couple of days, immediately after the procedure, it’s probably warranted. But also lidoderm, lidocaine patches, topical therapies can be super effective in this patient population as well.

Dr. Shreya Trivedi: So to wrap up our last pearl. If you are worried about a malignant pleural effusion, you should tap the effusion. If your cytology comes back negative, try again because repeated thoracentesis usually increases your cytologic yield.

Dr. Kalaila Pais: When treating recurrent pleural effusions, we have a couple of options to choose from including repeated thoracentesis, indwelling pleural catheters and pleurodesis with a sclerosing agent.

Dr. Shreya Trivedi: But remember, that each procedure is not without side effects so it is important to have a transparent discussion with your patient regarding their goals of care and wishes.

References

• Mercer RM, Corcoran JP, Porcel JM, Rahman NM, Psallidas I. Interpreting pleural fluid results. Clin Med (Lond). 2019;19(3):213-217.
• Bintcliffe OJ, Hooper CE, Rider IJ, et al. Unilateral Pleural Effusions with More Than One Apparent Etiology. A Prospective Observational Study. Ann Am Thorac Soc. 2016;13(7):1050-1056.
• Light RW. The Light criteria: the beginning and why they are useful 40 years later. Clin Chest Med. 2013;34(1):21-26.
• Romero-Candeira S, Hernández L, Romero-Brufao S, Orts D, Fernández C, Martín C. Is it meaningful to use biochemical parameters to discriminate between transudative and exudative pleural effusions?. Chest. 2002;122(5):1524-1529.
• Mohan G, Bhide P, Agrawal A, Kaul V, Chaddha U. A practical approach to pseudoexudative pleural effusions. Respir Med. 2023;214:107279.
• Sharma K, Fultariya L, Reddy Mallimala P, Shah K, Sharma V. Comparison of the Efficacy of Light’s Criteria With Serum-Effusion Albumin Gradient and Pleural Effusion Glucose. Cureus. 2023;15(8):e43319. Published 2023 Aug 11.
• Janda S, Swiston J. Diagnostic accuracy of pleural fluid NT-pro-BNP for pleural effusions of cardiac origin: a systematic review and meta-analysis. BMC Pulm Med. 2010;10:58. Published 2010 Nov 20.
• Porcel JM, Light RW. Pleural Fluid Analysis: Are Light’s Criteria Still Relevant After Half a Century?. Clin Chest Med. 2021;42(4):599-609.
• Porcel JM, Light RW. Diagnostic approach to pleural effusion in adults. Am Fam Physician. 2006;73(7):1211-1220.
• Menzies SM, Rahman NM, Wrightson JM, et al. Blood culture bottle culture of pleural fluid in pleural infection. Thorax. 2011;66(8):658-662.
• Zhai K, Lu Y, Shi HZ. Tuberculous pleural effusion. J Thorac Dis. 2016;8(7):E486-E494.
• Janda S, Swiston J. Diagnostic accuracy of pleural fluid NT-pro-BNP for pleural effusions of cardiac origin: a systematic review and meta-analysis. BMC Pulm Med. 2010;10:58. Published 2010 Nov 20.
• Light RW. Parapneumonic effusions and empyema. Clin Chest Med. 1985;6(1):55-62.
• American Thoracic Society. Parapneumonic Effusions and Empyema.
• Rahman NM, Maskell NA, Davies CW, et al. The relationship between chest tube size and clinical outcome in pleural infection. Chest. 2010;137(3):536-543.
• Maskell NA, Davies CW, Nunn AJ, et al. U.K. Controlled trial of intrapleural streptokinase for pleural infection [published correction appears in N Engl J Med. 2005 May 19;352(20):2146]. N Engl J Med. 2005;352(9):865-874.
• Rahman NM, Maskell NA, West A, et al. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med. 2011;365(6):518-526.
• Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e142S-e165S.
• Roberts ME, Rahman NM, Maskell NA, et al. British Thoracic Society Guideline for pleural disease. Thorax 2023;78:1143-1156.
• Xia H, Wang XJ, Zhou Q, Shi HZ, Tong ZH. Efficacy and safety of talc pleurodesis for malignant pleural effusion: a meta-analysis. PLoS One. 2014;9(1):e87060. Published 2014 Jan 27.
• Sarodia BD, Goldstein LS, Laskowski DM, Mehta AC, Arroliga AC. Does pleural fluid pH change significantly at room temperature during the first hour following thoracentesis?. Chest. 2000;117(4):1043-1048.
• Ferreiro L, Toubes ME, Valdés L. Contribución del análisis del líquido pleural al diagnóstico de los derrames pleurales [Contribution of pleural fluid analysis to the diagnosis of pleural effusion]. Med Clin (Barc). 2015;145(4):171-177.
• Wahidi MM, Willner DA, Snyder LD, Hardison JL, Chia JY, Palmer SM. Diagnosis and outcome of early pleural space infection following lung transplantation. Chest. 2009;135(2):484-491.
• Romero Candeira S, Hernández Blasco L, Soler MJ, Muñoz A, Aranda I. Biochemical and cytologic characteristics of pleural effusions secondary to pulmonary embolism. Chest. 2002;121(2):465-469.

The post Pleural Effusions: 5 Pearls Segment appeared first on Core IM Podcast.