Today, Michael presented the case of a young woman with history of Sickle Cell Disease who presented with acute onset of CP, SOB, and pain, found to have new opacities on chest imaging and fevers concerning for Acute Chest Syndrome (ACS) with worsening symptoms requiring transfer for exchange transfusion.

Clinical Pearls

• Leading cause of death in patients with SCD is acute chest syndrome (ACS)
• ACS is defined as new radio density on chest imaging with fevers and/or respiratory symptoms.
• Most common causes of ACS are bone marrow/fat embolism and CAP
• There is no clinical/laboratory standard for diagnosing acute sickle cell crisis.
• Hydroxyurea can decrease crisis frequency, ACS events, need for transfusions, hospitalizations, and death.

DDx of liver injury in the setting of SCD

• Gallstones
• Hepatic sequestration
• Viral hepatitis
• Iron overload from transfusions
• Sickle cell intrahepatic cholestasis

Acute SCD complications

• Infections
• Severe anemia (due to splenic sequestration, aplastic crisis, or hyperhemolysis)
• Vaso-occlusive phenomena
  • Pain
  • Stroke
  • ACS
  • Renal infarction or med toxicity
  • Dactylitis/bone infarction
  • MI
  • Priapism
  • VTE

Acute chest syndrome

• Defined as a new radio density on chest imaging with fever (38.5) and/or respiratory symptoms
  • >2% decrease in SpO2 from a documented steady-state value on room air
  • PaO2<60 mmHg
  • Tahcypnea
  • Use of accessory muscles of respiration
  • Chest pain
  • Cough
  • Wheezing
  • Rales
• Leading cause of death for patients with SC disease
• Etiology of ACS in adults is commonly due to bone marrow or fat emboli followed by PNA
• 50% of patients with SCD will have an episode of ACS
• 80% of ACS episodes are associated with a vaso-occlusive pain episode
• Morality rate is 4.3%
• Clinical approach
  • Determine severity (affects treatment)
    • Mild
      • SpO2 >90% on RA
      • 1 lobe affected by infiltrates
    • Moderate
      • SpO2 >85%
      • 2 lobes affected
    • Severe
      • Respiratory failure à mechanical ventilation
      • 3 lobes affected
    • Treatment
      • Acute episode
        • Pain control
        • IVF (prevent hypovolemia but also avoid volume overload because it can worsen ACS)
        • Blood transfusion:
          • Mild ⇒ no transfusion
          • Moderate ⇒ simple transfusion
          • Severe ⇒ exchange transfusion (Goal Hg =10, HgS <30%)
        • Antibiotics
          • For CAP and atypicals x 7 days
        • Supplementary O2
        • Incentive spirometry
        • DVT ppx
      • Prevention
        • Hydroxyurea (decreased incidence of ACS by 50%)
          • Not good for acute episode
        • Chronic transfusion therapy
          • For those with > 2 episodes of moderate to severe ACS in 24 months despite hydroxyurea therapy

Tim presented a young man with no medical history presenting with a chronic cough with intermittent trace hemoptsis. Other than this cough and mild shortness of breath when he exerted himself, this pt had no other symptoms. A CXR revealed bilateral pleural effusion, and upon thoracentesis, milky fluid drained out with an elevated triglyceride content consistent with a chylothorax. Subsequent biopsy of a lymph node revealed a diagnosis of follicular lymphoma!

Since we are talking about pleural effusion, Light’s Criteria will inevitably come up. For both real life (and boards!) purposes, know this criteria really well!

Light Criteria:

• SENSITIVE but NOT SPECIFIC for exudative effusions.

Any one of these criteria = exudative

• Fluid protein/Serum protein > 0.5
• Fluid LDH/Serum LDH > 0.6
• Fluid LDH > 2/3 upper limit of normal of serum LDH

False positive is possible in certain settings:

• Chronic diuretic use can falsely elevate fluid LDH (KNOW THIS)
• Transudative effusion that’s been sitting there chronically can appear exudative like

The following tests can help us distinguish between a falsely positive exudative effusion from a true exudative effusion:

• Pleural cholesterol > 45 mg/dL has high sensitivity and specificity for exudative effusions.
• Can also use serum albumin – fluid albumin < 1.2g/dL to confirm exudative effusion

Pleural Fluid Analysis: Clues

Upon performing a thoracentesis, certain characteristics can potentially give us some clues to the etiology of the effusion…

Fluid Color

Fluid WBC Count

Fluid Predominant Myelocyte Type

Lastly, how do you diagnose a chylothorax and what are some potential causes?

Chylothorax

• Definition: Triglyceride > 110 mg/dL = slam dunk
  • 50 – 110: Less clear, cannot rule out, obtain liproprotein analysis. If presence of chylomicron is detected, likely chylothorax
  • < 50: Less likely
• Non-traumatic
  • Malignant: Lymphomatous is most common, can also be other cancers i.e. lung, mediastinal mets, sarcoma, leukemia
  • Non-malignant: Idiopathic, benign tumors, protein losing enteropathy, thoracic aortic aneurysm, TB, Sarcoid, amyloidosis, thyroid goiter, tuberous sclerosis, congestive heart failure, mitral stenosis
• Traumatic
  • Surgical is most common
  • External trauma
  • Trivial “trauma:” Stretching while yawning, coughing, hiccupping, sneezing (I’m not kidding)

Management of a malignant pleural effusion, as seen in this case, can be potentially challenging. After the patient was discharged, his pleural effusion on the right recurred within 3 days and completely filled up his right lung!

Several options are available for management of malignant pleural effusions. The decision is complicated and will goals of care discussion

• Indwelling pleural catheter
  • Advantage: Pt managed, can drain at home
  • Disadvantage: Catheter related complications
• Pleurodesis
  • Talc, slurry or poudrage, is the preferred agent. 60-90% success rate in reducing recurrence at 30 days.
  • Doxycycline can also be used but not as popular any more
  • Advantage: Eliminates the potential space for fluid reaccumulation
  • Disadvantage: Pain, potential for surgical failure, invasive
• Combination: Talc + IPC
• Pleurectomy

Katie presented a case of an elderly man with history of non-anuric ESRD on HD three times a week, NIDDM2, CMML, Klinefelter Syndrome, HTN, chronic anemia, and prior GIB secondary to gastric AVM who presented with shortness of breath. Earlier during the day he was at the transfusion center where he received a unit of PRBC. He was restless after the transfusion but he refused to stay for post-transfusion monitoring. He has been compliant with dietary restrictions and his HD sessions, but that evening after he went home, he started having difficulty breathing and hence he came to the ED. He was significantly hypertensive on presentation, and he went into respiratory failure requiring NIPPV. CXR revealed significant bibasilar pulmonary infiltrates c/w pulmonary edema. After diuresis and dialysis, his symptoms resolved. This presentation is consistent with transfusion associated circulatory overload, or TACO!

Let’s use this case to go over different types of transfusion reaction since you:

• Will encounter this during your career
• Will definitely get paged about this on nights
• Might encounter the more rare but potentially life-threatening reactions

Transfusion Reaction

• Common presentation
  • Fever (defined as > 1 degree Celsius from baseline)
    • Stable: Likely febrile non-hemolytic transfusion reaction
      • Tylenol, slow rate of infusion, observe
    • Unstable
      • ABO incompatibility
      • Bacterial contamination
      • Hemolytic transfusion reaction
      • TA Graft vs Host Disease (4-30 days after, delayed rxn, attack by immunocompetent donor lymphocytes on an immunocompromised recipient’s antigen presenting tissues. In immunocompetent recipients, reaction can occur if recipient is heterozygous for an HLA for which the donor is homozygous)
    • Urticaria:
      • Mild allergic reaction to plasma protein, common, resume transfusion at slower rate, anti-histamine PRN.
    • Dyspnea or hypoxia
      • Assess for anaphylaxis
        • Yes: Treat for anaphylactic allergic reaction
        • No: Consider circulatory overload
          • E/O vol overload, diuretic responsive: TACO (transfusion related circulatory overload)
          • Signs of instability, diuretic non-responsive: Suspect TRALI
        • Hemolysis 1-4 weeks after transfusion: Delayed hemolytic transfusion reaction, usually very mild

TACO

Epidemiology: 1% of transfusions in general, higher in the ICU.

Pathophysiology: Circulatory overload leading to pulmonary edema

Risk Factors

• Preexisting renal or cardiac dysfunction
• Higher transfusion volume
• Small stature
• Low body weight
• Extremes of age
• Female
• White
• Hypoalbuminemia

Presentation

• Development of respiratory distress or hypertension during or within 6 hours of completing a transfusion.
• May see concurrent headache
• Hypoxia, HTN, tachycardia, wide-pulse pressure, JVD, S3, crackles/wheezing

Diagnosis

• Clinical
• Nt-proBNP elevated but non-specific

Management

• Stop transfusion
• Oxygen
• Diuresis
• Report to transfusion service or blood bank. Get consultation for future transfusions i.e. smaller units, lower volume, or only during dialysis

TRALI

Epidemiology

• Rare, estimated 1 in 12000, leading cause of transfusion related mortality in the US
• Seen in all age groups and both sexes

Pathophysiology

• Not completely understood, but thought to be a neutrophil mediated reaction in setting pre-existing endothelial injury in the lungs, or antibodies to HLA

Risk Factors

• ICU patients
• Multiparous female donors (OR 4.5)
• Heme malignancies
• Chronic EtOH
• Liver dysfunction
• Tobacco use
• Positive fluid balance
• Mechanical ventilation
• Note: Transfusion of older blood products was once thought to be a risk factor, but disproved by multiple RCTs around 2010-2012.

Presentation

• During or within 6 hours after blood product transfusion
• Hypoxia, pulmonary infiltrates on exam, fever, hypotension
• May see elevated peak/plateau airway pressures in vented patients
• Non-responsive to diuretics
• ARDS like picture, sometimes diagnosis can be unclear, recent nomenclature of transfused ARDS.
• May have coexisting TACO

Diagnosis

• Clinical

Management

• Stop transfusion
• Notify blood bank/transfusion service
• Oxygen/ventilatory support, ARDS protocol (lower tidal volume) has generally been used
• Hemodynamic support, pts often hypovolemic, give fluids, pressors if needed.
• Corticosteroid historically has been used with inconsistent results

Prognosis

• Mortality as high as 41-67% in ICU population. Non-ICU patients have much lower morality, 5-17%. Almost all will recover their resp function, and they can still safely receive blood transfusions in the future.

Prevention

• Identify implicated donor
• Irradiate blood products for immunocompromised recipients
• Avoid transfusion of blood product from a relative
• Blood donated by men has lower incidence for unclear reasons

Thanks to Barnie for presenting the case of a middle-aged woman who was admitted with acute onset of SOB, found to have submassive PE.

Clinical Pearls:

• Risk stratification tools are helpful in estimating the pre-test probability of PE.  The best and most validated is Wells criteria.
  • YEARS items is a newer tool that was studied in an RCT in the Netherlands and found to lower the number of CTPA scans ordered by 14% without a significant impact on rates of missed PE diagnoses.
• For patients at low risk of PE according to Wells, PERC is useful in ED or outpatient setting to rule out PE without ordering a d-dimer (see graphic below).
• Age-adjusted d-dimer is age x 10 for patients older than 50 years.  This accounts for the increase in d-dimer baseline related to aging.  ADJUST-PE trial showed that age-adjusted d-dimer leads to higher specificity without subsequent VTE.
  • Studies have shown an 11.6% reduction in CTPA scans with the use of this correction factor without an appreciable increase in missed diagnoses of PE.
• Think of PE in three broad categories:
  • Massive PE = hemodynamically unstable ⇒ anticoagulation + thrombolysis
  • Submassive PE = hemodynamically stable + RV strain ⇒ anticoagulation + thrombolysis
  • Low risk PE = hemodynamically stable, no RV strain ⇒ anticoagulation.  Use the PESI score to determine if your patient can be treated outpatient.
• Remember that the most common EKG finding in PE is normal sinus rhythm!  The most common abnormal  EKG finding is sinus tachycardia.  S1Q3T3 pattern is only seen in 10% of patients with PE.

Diagnosis:

Suggested algorithm for diagnostic work up of suspected PE:

Remember that the scoring tools above are only there to add to your clinical judgment, not replace it!

Recent study in the Lancet looked at the utility of a different diagnostic algorithm, using the three most predictive items on Wells together with d-dimer.  Compared to Wells, this diagnostic tool led to a 14% reduction in unnecessary CTPA!

Treatment:

• Remember that clot burden does not factor into the treatment categories of PE.  Low clot burden in a patient with baseline cardiopulmonary disease can still lead to hemodynamic compromise and would be considered massive PE.
• Submassive PE treatment is an area of much debate.  A famous trial (PEITHO trial) in 2014 randomized 1006 patients to receive heparin + placebo vs heparin + tenecteplase (European version), and found a >50% reduction in combined death and cardiovascular collapse at 7 days but a > four-fold increase in risk of major bleed including intracranial hemorrhage.  Subsequent meta-analyses (and this one) found that the risk of major bleeding was highest in people >65 years of age.  So treatment decisions here are tricky and require consulting multiple services!

Signs of RV strain: 

• EKG findings:
  • S1Q3T3: this is a sign of cor pulmonale and can be seen in a number of conditions in addition to PE
    • Bronchospasm (really bad asthma)
    • ARDS
    • Pneumothorax
• Echo findings:
  • Elevated RVSP
  • Septal bowing
  • McConnell’s sign (regional wall motion abnormality sparing the RV apex)
    • Not sensitive but helpful in distinguishing RV strain due to chronic pulmonary HTN from RV strain due to acute PE
  • Increased RV size
  • Decreased RV function
  • Tricuspid regurgitation
• Labs
  • Elevated troponin
  • Elevated BNP