All posts by alp37

VA AM Report 12.8.17: Limitations of the blood smear & MAHA v2.0

Case summary: Our hearts exploded with happiness when our awesome ICU team presented a fascinating mystery case– a 54M with chronic low back pain and hypertension who presented with acute abdominal pain and was found to have anemia, thrombocytopenia and renal failure.

Top pearls:

  1. We discussed the limitations of smear and how obtaining a repeat smear, especially in cases where hemolysis is of persistent concern or where there are findings that might interfere with accuracy (e.g. other dysmorphic features that obscure schistocytes), can be useful diagnostically.
  2. The PLASMIC score (see Katie’s sick-nasty post on TTP and the PLASMIC score here) is a new diagnostic scoring system that can risk-stratify patients who should receive plasma exchange while awaiting ADAMTS13 results.
  3. Recall malignant hypertension as cause of MAHA!

Diagnostic approach to hemolytic anemia: stolen from one of my favorite Chief blogposts ever (no longer searchable?!) by the estimable Lekshmi Santhosh

RBC hemolysis results from damage to the RBC membrane. SEVERE damage leads to intravascular hemolysis. Less severe damage leads extravascular hemolysis.

  1. Intravascular hemolysis = RBCs lysed within the vasculature!

o   Causes include:

  • Shearing: MAHAs or defective mechanical heart valves
  • Complement mediated destruction: PNH, some drug reactions, ABO incompatibility, rarely AIHA from cold agglutins (IgM)
  • RBCs destroyed in the vasculature–>hemoglobinemia–>hemoglobinuria. NOT seen in extravascular hemolysis. Chronic heme loss in the urine leads to concomitant Fe deficiency anemia!

2. Extravascular hemolysis = RBCs destroyed/phagocytosed by macrophages in the liver, spleen, bone marrow, and lymph nodes.

o   Causes include:

  • Immune hemolytic anemia: RBCs coated in IgG, complement, or IgM+complement are phagocytosed in liver, spleen. Partial membrane phagocytosis–>microspherocytes! Coombs positive.
  • RBC membrane deformities: poorly deformable RBCs get stuck in sinusoids/cords of Billroth then phagocytosed. Ex: hereditary spherocytosis, G6PD def, thalassemia
  • All components of RBCs are recycled, including Fe, so you don’t get an Fe deficiency anemia

Hemolysis Labs – seen in intra and extravascular hemolysis

  • Reticulocyte count
  • Indirect bilirubin
  • Schistocytes on smear (in MAHAs)
  • Direct Antibody Test (Coombs): for immune mediated hemolytic anemia. Detects IgG or complement on RBCs. In IgM mediated hemolysis, will only detect complement bound to IgM, not the IgM itself!
  • LDH: released from lysed RBCs.
  • Free Hg binds to haptoglobin reducing its serum concentration.

o   Combo of increased LDH  + reduced haptoglobin = 90 percent specific for diagnosing hemolysis

o   Combo of a normal LDH + haptoglobin >25 mg/dL =  92 percent sensitive for ruling out hemolysis

Classic NEJM paper on blood smears:

Malignant hypertension and hemolytic anemia

  • Just a reminder that malignant hypertension can mimic TTP/HUS, and distinguishing between the two is important because it guides therapy!
  • Pathophysiology: Malignant hypertension causes vascular wall damage, fibrin and platelet deposition in both the systemic and renal blood vessels. This luminal narrowing can lead to erythrocyte fragmentation and platelet destruction.
  • Overlap: Confusingly, TTP, HUS and atypical HUS can all be independently associated with hypertension, especially if there is severe renal dysfunction. In addition, malignant hypertension can mimic TTP/HUS, AND some case series have shown that even patients with low ADAMTS13 have ALTERNATIVE causes of their hemolysis

    Great TTP review: 

    George, J. (2010) How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood 116: 4060–4069.

    TTP/HUS vs malignant hypertension:


VA Morning Report 12.5.17: Syncope, hypoglycemia, and aortic dissection potpourri

Case summary: Thanks to the incomparable Matt Schwede, who presented the case of a 64M with PMH back pain, dermatitis NOS, current EtOH and prior heroin/meth/cocaine abuse, who presented with syncope and hypoglycemia, as well as chest pain radiating to the back and was found to have a troponin of 15 and high-grade LAD lesion on LHC.

Top pearls:

  1. Hypoglycemic unawareness occurs most commonly in patients with long-standing DMT1 or 2 on insulin; it is more common in those with recently improved glycemic control and is often precipitated by recurrent iatrogenic hypoglycemia.
  2. Other medications and conditions can blunt or mask hypoglycemic awareness, including beta blockers and sedating medications.
  3. A unifying diagnosis for aortic dissection and elevated troponin is dissection of the R coronary artery leading to EKG evidence of inferior MI.


Etiologies of reduced hypoglycemic awareness

  • Recall the tragic death of Julia Roberts’s character in Fried Green Tomatoes!
  • A reminder about Whipple’s triad:
    • symptoms consistent with hypoglycemia
    • low plasma glucose
    • relief with glucose administration
  • Symptoms: usually idiosyncratic, but patients learn to detect their own unique flavor
    • Neurogenic/autonomic- palpitations, tremor, hunger, sweating
    • Neuroglycopenic- behavioral changes, slowed cognition, seizure, coma, death
  • What causes reduced hypoglycemic awareness?
    • Iatrogenic antecedent hypoglycemia causes a) reduced counter regulatory mechanisms (e.g. epinephrine, which triggers glycogenolysis) and b) reduced sympathoadrenal response, which normally generates the sympathetic physiologic symptoms (e.g. palpitations, tremors).
      • Sleep and exercise can also impair these pathways (both affect catecholamines, cortisol).
      • Studies have shown that even 1-2 weeks of avoiding hypoglycemic episodes can restore hypoglycemic awareness.
      • Risk factors: duration of disease and improved metabolic control
    • Beta blockade, alpha blockade, other sedating medications can also impact patients’ ability to recognize the autonomic/neuroglycopenic symptoms
    • Finally, ganglionic blockade, cervical cord injury, and sympathectomy blunt the physiologic response!

Aortic dissection pearls

  • This patient described his chest pain as radiating to the back, which was initially concerning for aortic dissection.
  • Is D-dimer useful in the diagnosis of acute aortic dissection?
    • CT and MRI are 100% sensitive and 95-10)% specific for diagnosis
    • TEE is 86-100% sensitive
    • D-dimer is 51.7-100% sensitive; some commentators have concluded that it is NOT useful because it would only reliably rule out low-risk patients, which would not include most patients in whom you’re suspecting aortic dissection (e.g. with chest pain)
  • We discussed the common complications of aortic dissection:
    • Coronary ischemia secondary to coronary dissection-
      • most commonly the R coronary (with EKG showing inferior MI)
      • Goop made the astute point that L coronary involvement may lead to out-of-hospital death and thus may be under-reported in case series!
    • aortic rupture
    • tamponade
    • stroke
    • visceral ischemia
    • circulatory collapse

Two great reviews of aortic dissection here and here.


VA Morning report: Pomalidomide strikes again

Case summary: Thanks to Serge for presenting a 60M with PMH multiple myeloma on pomalidomide, who presented to Heme/Onc clinic with hypoxia (77% on RA) due to pomalidomide-associated pneumonitis.

Top pearls:

  1. In a patient with hypoxia on pulse oximetry who is asymptomatic and appears well, ensure you rule out the many causes of pulse oximeter malfunction: poor signal, delay, interference.
  2. We were reminded of the increased morbidity of cocci in those of Filipino and African American descent.
  3. It is difficult to sort out the alphabet soup of cancer drug nomenclature, but it can be helpful to at least look up the class of a given medication in order to know its side effects (e.g. immunocompromise with traditional chemotherapy versus autoimmune phenomenon with immunotherapy)
  4. Pomalidomide is a new kid on the block for multiple myeloma. It most commonly causes cytopenias and predisposes patients to VTE (for which they’re on prophylactic aspirin). However, the VA has seen its fair share of rare complications, including PCP pneumonia and now pneumonitis!

 What can make your pulse oximeter inaccurate? 

Harken back to first principles of how pulse ox works…

  1. Oxyhemoglobin and deoxyhemoglobin absorb infrared and red wavelengths in different amounts.
  2. The pulse oximeter senses minute color changes in pulsating arterial blood and calculates how many oxygen molecules are bound to hemoglobin (=oxygen saturation)
  3. Problems arise due to…
  • Poor signal (cannot detect arterial pulsation)- poor perfusion (e.g. shock or peripheral arterial disease), dark nail polish, patient movement (e.g. shivering)
  • Delay- pulse oximetry averages a signal over time, so can have delay in detecting acute change
  • Carbon monoxide (falsely elevated O2 sat)- probe cannot distinguish CO-bound Hgb from O2-bound
  • Methemoglobinemia (O2 sat stuck at 85%)- a clue is probe will read stable 85% O2 sat no matter what
  • Other- some IV dyes (e.g. methylene blue), external factors (e.g. nerve stimulators) can also cause interference

Recall that disseminated cocci is more common in certain patient subgroups

Patients at increased risk of disseminated (rather than localized) cocci include:


  • patients of African or Filipino descent
  • patients who are pregnant
  • patients with cell-mediated immunodeficiency (eg, use of immunosuppressant medications, infection with human immunodeficiency virus [HIV], or receipt of a transplanted organ)
  • NB: vulnerability is not associated with outdoor occupations or activities, and we have not yet identified immunologic mechanisms!


Oncology drug nomenclature

Specificity is useful and important, as type dictates complications (e.g. immunocompromise w/ chemo versus autoimmune phenomenon w/ immunotherapy)

  • Endocrine therapy (e.g. tamoxifen in ER/PR+ breast cancer)- target cells expressing hormone receptors
  • Chemotherapy (e.g. doxorubicin)- target all rapidly dividing cells
  • Targeted therapy (e.g. trastuzumab for HER2 or imatinib for BCR-ABL) – target specific molecule involved in cancer cell growth
  • Immunotherapy- 
    • Monoclonal antibodies (e.g. nivolumab)- target immune checkpoints like CTLA-4 or PD-1
    • Adoptive cell transfer (e.g. CAR-T)- transfused T-cells
  • Pomalidomide technically targets angiogenesis but exerts its anti-cancer effects via impeding cytokine production, immunomodulation and alterations in the tumor microenvironment.



VA ICU Report 10.6.17: Pseudomonas double-coverage + post-arrest neurologic prognostication

Case summary: We discussed the case of 83M with PMH ESRD on HD, CAD s/p CABG, AIN on prednisone, who had a PEA arrest secondary to hypoxemia in the setting of multifocal pneumonia, who developed post-arrest myoclonus and was ultimately transitioned to comfort care. Thanks to Jill Goslinga, Neuro intern extraordinaire, for bringing up tons of great questions and pearls.

Top pearls: 

  1. Data support double-coverage (beta-lactam and aminoglycoside) for Pseudomonas in patients who are critically ill and at risk for multi-drug resistant organisms. Once sensitivities are known, you can narrow appropriately.
  2. Although neurologic prognostication is extremely variable, some 72H coma exam findings are predictive of poor neurologic outcome. These include absent or extensor motor response on day three and/or absent pupillary or corneal reflexes on day three.
  3. James Frank reminded us that nodules on a chest CT should make you expand your infectious differential beyond classic bacterial pathogens, particularly in immunocompromised patients– think carefully about mycobacteria (tuberculous and nontuberculous), endemic fungi (histo, cocci), and (rarely) PCP.

Pseudomonas double-coverage: just the facts

  • These are pearls I’ve learned from Jen Babik’s fantastic “Fever in the ICU” lectures.

Why do we talk about “double-coverage” for Pseudomonas?

1. Concern about resistant Pseudomonas: give 2 ABX EMPIRICALLY to expand the spectrum.

2. Idea of synergy between 2 active ABX: usually beta-lactam + (aminoglycoside or FQ).

  • 2012 metaanalysis showed NO mortality benefit, including for septic shock or neutropenic patients

3. Hope that 2 ABX prevents development of resistance.

  • No evidence that combination therapy prevents development of resistance and may increase superinfection rate.

…So when should we double-cover?

  1. In critically ill patients (like this patient) who have risk factors for multi-drug resistant organisms, consider empiric coverage with 2 ABX with anti-pseudomonal activity. Then narrow pending cultures and susceptibilities.
  2. Check your local sensitivities: the most recent SFVA Pseudomonas sensitivities from 1/2017 (non-urine and urine) can be found here!
  • Note that most studies are observational, non-blinded and have lots of heterogeneity (e.g. different ABX combinations).
  • Also note that these data likely DON’T apply to specific sub-populations at greatly increased risk of resistant organisms (e.g. cystic fibrosis patients).

Jen Babik’s “Fever in the ICU” lectures

Pseudomonas: Paul and Leibovici, CID 2013.(PMID 23580731)

Neurologic prognostication post-arrest

  • We discussed how this is one of the most humbling areas of medicine, as it is incredibly variable and difficult to predict.
  • Thanks so much to Jill Goslinga for digging into the data on the most important neurologic exam findings we and our Neuro colleagues use in our assessment.
  • Two systematic reviews have concluded that two clinical criteria have been found to be 100 percent specific for poor outcome:
    • Absent or extensor motor response on day three
    • Absent pupillary or corneal reflexes on day three
  • A JAMA Rational Clinical Exam review noted 5 clinical signs that strongly predict death or poor neurological outcome:
    • absent corneal reflexes at 24 hours (LR, 12.9; 95% confidence interval [CI], 2.0-68.7),
    • absent pupillary response at 24 hours (LR, 10.2; 95% CI, 1.8-48.6),
    • absent withdrawal response to pain at 24 hours (LR, 4.7; 95% CI, 2.2-9.8),
    • no motor response at 24 hours (LR, 4.9; 95% CI, 1.6-13.0),
    • no motor response at 72 hours (LR, 9.2; 95% CI, 2.1-49.4).
  • Although myoclonic status is associated with poor neurologic outcome, seizures and non-epileptic myoclonus alone are not significant predictors of morbidity or mortality.
    • We often use EEG to evaluate for status for this reason

Neurology. 2006;67(2):203.

Lancet. 1998;352(9143):1808.

JAMA. 2004 Feb 18;291(7):870-9.

VA AM Report 10.2.17: Post-XRT presyncope

Case summary: Thanks to Max Brondfield for presenting the case of a 56M with PMH remote squamous cell carcinoma of the head and neck s/p chemoXRT, who presented with chronic, intermittent presyncope on exertion, found to have bilateral 100% carotid artery occlusion likely 2/2 prior neck XRT.


1. (Pre)syncope in the real world includes getting at least an ECG and orthostatic vital signs. Consider inpatient evaluation and monitoring in patients with cardiovascular disease, abnormal ECG or FH SCD, OR those with recurrent episodes.

2. Thanks to Gerald Hsu for giving us his mental breakdown of complications of radiation therapy. It depends on the geography and dose. Then, you can divide the complications of radiation into long- and short-term sequelae, though time courses are variable.

3. Thanks to Goop for reminding us that carotid ultrasound is not a high value test in the evaluation of syncope and is part of the Choosing Wisely campaign as a consequence.

Syncope (or presyncope) in the real world

  • We discussed that for practical purposes, we tend to lump “presyncope” with syncope given the difficulty in distinguishing between these two entities in real life.
  • See here for a great prior blog post going through the Ddx for syncope (props to C. Auriemma!)
  • Recall that all patients presenting with syncope should (at least) receive:
    • ECG
    • orthostatic vitals
  • Max brought up the complexities of evaluating syncope in the outpatient setting, particularly in urgent care/back-up clinic, especially with regard to who should be hospitalized and who should get more extensive work-up.
  • Features that would support hospitalization for further work-up and monitoring include:
    • cardiovascular disease
    • abnormal ECG
    • FH of sudden cardiac death
  • Importantly, patients with multiple episodes compared with an isolated event are more likely to have a serious underlying disorder, as was the case with this patient.
    • Props to Max for combing through the chart to see that the patient has presented multiple times before with similar symptoms and had had a fairly exhaustive but unrevealing work-up, which prompted him to search for more esoteric etiologies.
  • Carotid U/S (or MRA!) should not be a part of your first-pass work-up for syncope (this has been identified as low value care by the Choosing Wisely campaign)
    • Great JAHA study illustrating the low value of this testing strategy:
      • 16.5% of all Medicare beneficiaries with simple syncope underwent carotid imaging
      • 6.5% of all carotid ultrasounds ordered were for this low-value indication
      • Manual chart review of 313 patients at a large academic medical center who underwent carotid ultrasound for simple syncope over a 5-year period
        • Only 2% of the 313 patients imaged experienced a change in medications after a positive study
        • <1% of patients underwent a carotid revascularization procedure.
    • However, put prior neck XRT should be on your list of causes for early-onset neck vessel atherosclerosis (just as it is for early-onset coronary artery disease in patients who received chest XRT for breast cancer or Hodgkins lymphoma)

Am Fam Physician. 2011 Sep 15;84(6):640-650.

Side effects of XRT

  • When considering radiation complications, Gerald Hsu recommends thinking about:
    • 1) Geography- local/adjacent structures more likely to be affected
    • 2) Dose- higher doses more likely to cause side effects
    • 3) Keep in mind that time course can vary- patients can have late-onset radiation proctitis for example long after prostate XRT
  • Short-term: tissues swell during XRT–> edema, overlying skin changes
    • Abdominal- nausea/vomiting
    • Head and neck- mouth and throat sores
    • Thoracic- esophagitis
    • Pulm- pneumonitis
    • Pelvic- cystitis, proctitis
    • Usually subsides with time
  • Long-term: prior edema and inflammation–> fibrosis
    • Thoracic- cardiomyopathy
    • Pelvic- infertility
    • Head and neck- accelerated carotid artery atherosclerosis/stenosis, hypothyroidism
    • All- secondary cancers, especially skin cancers

Bhandare N, Mendenhall WM (2012) A Literature Review of Late Complications of Radiation Therapy for Head and Neck Cancers: Incidence and Dose Response. J Nucl Med Radiat Ther S2:009. doi:10.4172/2155-9619.S2-009


VA Morning report 9.25.17: Rapid-onset pleural effusion

Case summary: Thanks to Andrew Folick for presenting the high-yield case of a 72M with metastatic melanoma previously treated with both immune checkpoint (pembrolizumab) and BRAF (dabrafenib/trametinib) inhibitors and recent PE on dalteparin, who presented with rapid-onset pleural effusion.


  1. The differential for rapid-onset pleural effusion includes: transudative fluid, hemothorax, chylothorax…and ?reactive effusion from targeted therapies (see below for more details regarding pulmonary complications of these agents!).
  2. Technically, diagnosis of hemothorax on thoracentesis is established if pleural fluid has a Hct >15% or is >50% serum Hct. Practically, it is often based on clinical picture and whether the fluid appears bloody.
  3. Chronic transudative effusions can transition to “exudative” because the protein increases over time. 
  4. Don’t put a chest tube in a patient with a transudative pleural effusion! This inevitably leads to malnutrition and is a portal of entry for infection.

Pulmonary complications of targeted therapy

  • Immune checkpoint inhibitors (e.g. pembrolizumab)
    • Pneumonitis is uncommon (~5% of patients) but can be severe.
    • It’s a diagnosis of exclusion: rule out infection and malignancy-associated pnuemonitis, as well as radiation pneumonitis.
    • Can occur at any time during therapy.
    • 1/3 of patients are asymptomatic, and the most common presenting symptom is cough
    • Imaging characteristics vary widely. There are case reports of pleural effusion associated with a clinical diagnosis pneumonitis, but it’s unclear if this is a drug side effect or a “reactive” response to cancer cell death in response to therapy.Pneumo_antiPD1_PDL1_therapy

This is an especially good UptoDate article

Clin Chest Med. 2017 Jun;38(2):223-232.

  • BRAF inhibitors (e.g. dabrafenib/trametinib)
    • Respiratory complications are extremely rare with vemurafenib or dabrafenib monotherapy.
    • Pneumonitis occurred in 2.4% of patients (5/211) treated with trametinib monotherapy
    • The time course and symptoms of pneumonitis are similar to immune checkpoint inhibitors.

  • General treatment considerations for toxicities associated with targeted therapy
    • For grade 2 (moderate) immune-mediated toxicities, treatment with the checkpoint inhibitor should be withheld and should not be resumed until symptoms or toxicity is grade 1 or less. Corticosteroids (prednisone 0.5 mg/kg/day or equivalent) should be started if symptoms do not resolve within a week.
    • For patients experiencing grade 3 or 4 (severe or life-threatening) immune-mediated toxicities, treatment with the checkpoint inhibitor should be permanently discontinued. High doses of corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) should be given. When symptoms subside to grade 1 or less, steroids can be gradually tapered over at least one month.

VA AM report 9.19.17: DVT/PE version 3.0

Case summary: Thanks to Adam Tabbaa (double-double) for presenting a case of a 70M with PMH obesity presenting with LLE edema and dyspnea and found to have a PE that made our nerd-hearts sing!

Top pearls:

  1. Anti-coag clinic pearl: for patients with a positive LE ultrasound OR CTPE, getting that second confirmatory imaging study (e.g. either CTPE or LE ultrasound) can seem like overkill. However, for providers who follow patients longitudinally, this additional imaging is useful (e.g. for serial imaging comparison, to monitor clot burden when considering whether to come off of anticoagulation)
  2. The most recent CHEST VTE guidelines recommend DOACs (e.g. apixaban) as FIRST LINE for DVT/PE over vitamin K antagonists except patients with cancer-associated thrombosis (though clinical trials are underway to test DOACs in cancer).
  3. Per a recent NEJM study, there is little benefit to screening for malignancy in unprovoked PE.

Why get an ultrasound in addition to a CTPE? Can be helpful for providers who follow patients longitudinally!

  1. Serial imaging comparison
  2. Helps when trying to get patients OFF anticoagulation (can follow serial U/S)
  3. Helps if patient has subsegmental PE on CTPE (if have a DVT, this supports anticoagulation)

No benefit to screening for malignancy with CT abdomen/pelvis in unprovoked PE

  1. 854 patients randomized to limited cancer screening (basic blood testing, chest radiography, and screening for breast, cervical, and prostate cancer) versus limited + CT A/P. There was no significant difference between the two study groups in the mean time to a cancer diagnosis (4.2 months in the limited-screening group and 4.0 months in the limited-screening-plus-CT group, P=0.88) or in cancer-related mortality (1.4% and 0.9%, P=0.75).



  1. In AT10, the first-line recommended anticoagulant therapy includes dabigatran, rivaroxaban, apixaban, or edoxaban over vitamin K antagonists (VKA) or low molecular weight heparin (LMWH).
  2. The one exception is in patients with cancer-associated thrombosis. In this subset, AT10 recommends LMWH over VKA or DOACs with extended therapy.

PE Risk stratification

  1. Rely on vital signs, biochemical markers, TTE and imaging to risk stratify VTE patients.
  2. Note that degree of clot burden does not factor into risk stratification (as long as PE is segmental).
  3. Here is a nifty risk stratification algorithm.


Management of PE: An Update. J Am Coll Cardiol 2016;67;976-990.