9/11 PPMC report: PD-1 inhibitors, myocarditis

Thanks to Kari Torp for presenting a cool case of a middle aged woman with lung cancer who developed ventricular tachycardia after receiving pembrolizumab for NSCLC and was found to have pembrolizumab-mediated myocarditis.

Pearls

PD1 (programmed death-1) and CTLA4 inhibitors are relatively novel drugs used to treat a growing list of cancers (NSCLC, melanoma, Hodgkin’s lymphoma, head/neck cancers and others) under the umbrella of immune therapy.

These drugs basically unleash the immune system to fight cancers by blocking certain costimulatory molecules that would have kept T-cells quiet.

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Journal of Clinical Oncology

  • Most common side effects of immune therapy (PD1 or CTLA4)
    • fatigue
    • rash (30-40%), 3-4 weeks into treatment
    • colitis/diarrhea (~5-20%, esp CTLA4 agents), 6 weeks into treatment
    • pneumonitis (~5%), 3-4 months into treatment
    • Other: hepatitis, endocrinopathies, neurotoxicity (rare; transverse myelitis, MG), uveitis, and rarely myocarditis (<0.5%)
  • Myocarditis (and/or myositis) is more common with combined PD1 blockade (ex: nivolumab + ipilimumab)
  • Myocarditis should be treated with high dose steroids (1mg/kg), but may progress despite that even in the absence of underlying cardiac disease

We also touched briefly on the differential for elevated cardiac biomarkers in the absence of ACS and the differences between troponin I and T. See this old blog post for more info!

Finally- see reference #3 below for a review on myocarditis.

References

  1. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. NEJM 2016.

  2. Immune Checkpoint Blockade in Cancer Therapy. Journal of Clinical Oncology 2015.
  3. Myocarditis. Lancet 2011.

 

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9/5 HUP intern report: elevated troponins, myopericarditis

Thanks to Rachel Snyder for presenting the case of a young man with chest pain after a recent viral prodrome, who is thought to have a (likely viral) myopericarditis.

We talked about where troponins come from:

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Harrison’s Principles of Internal Medicine: STEMI

We talked about the kinetics of cardiac biomarkers.

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Harrison’s Principles of Internal Medicine: STEMI

PEARLS

  • Remember that the diagnosis of ACS depends on the right clinical setting, with appropriate EKG changes, and a rise and fall in troponin with at least one value above the 99th percentile
  • Note that CKMB rises within 4-6h of myocardial necrosis, but is far less sensitive and specific than troponin; it is no longer recommended in most situations, except possibly to diagnose reinfarction. It is released from both myocardial and skeletal muscle
  • Troponin is most sensitive because there’s more of it per gram of myocardium; it also rises within 4-6h and can stay elevated for 7-10 days after injury
  • An increase in troponin of >20% after a recent infarct suggests reinfarction
  • A quick note on Troponin I (TnI) vs T (TnT)
    • At Penn, TnI is used as a point-of-care (POC) test
    • TnT is renally cleared (so is TnI, but less so than TnI), so patients with ESRD may have low grade elevations which may add to the challenge of diagnosing ACS

Remember that many things other than ACS can cause troponin elevation

 

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Daubert et al 2010

Lastly- don’t forget the importance of the physical exam in ruling out tamponade, so make sure you do a pulsus if you’re worried about it! Here’s how to do it.

References

  1. Daubert et al. The utility of troponin measurement to detect myocardial infarction: review of the current findings. Vasc Health Risk Manag 2010.

9/6 (HUP): A Case of Longstanding Refractory Atrial Tachyarrhythmias with New Onset VT

We discussed a case of a middle-aged female with a strong family history of uncertain cardiomyopathy who had a personal history of atrial tachyarrhythmias since teenage years, presenting with monomorphic VT.

We reviewed a differential of arrhythmogenic myocardial diseases:

  • Arrhythmogenic Right Ventricular Cardiomyopathy
    • ventricular arrhythmias predominate
    • pathology involves fibrous/fibro-fatty changes in ventricular tissue
    • workup includes EKG (prolonged S wave upstroke, epsilon wave between QRS and T, inverted T in right precordial leads), TTE (increased RV dimensions, decreased RV systolic function, RV trabecular derangement), ambulatory EKG (PVCs), cardiac MRI (dyssynchronous RV with global dysfunction)
  • Cardiac Sarcoidosis
    • manifestations depend on location of granuloma formation
    • common presentations are conduction abnormalities (AV block, bundle branch blocks), tachyarrhythmias
    • workup includes EKG, TTE (LV base and interventricular septum commonly affected, ventricular aneurysms, LV dilation), cardiac MRI, PET, endomyocardial biopsy
      • cardiac MRI: early gad-enhancement indicates acute inflammation, late gad-enhancement indicates chronic inflammation/scar; high sensitivity and specificity for cardiac sarcoidosis
      • PET: indicates active disease
      • biopsy: low sensitivity, in part due to patchy involvement and difficulty accessing LV/septal base which are commonly involved
  • Amyloidosis
  • Myocarditis
    • infectious: very long list of possible suspects, commonly coxsackie or parvovirus
    • medication-induced: direct cardiotoxicity from meds or hypersensitivity reaction
    • hypereosinophilic syndromes
    • autoimmune: lupus myocarditis can present with symptoms similar to ACS
    • Giant Cell Myocarditis: can cause acute and fulminant disease
    • cardiotoxins: EtOH, cocaine, certain meds

If none of the above fit, as in our patient with a strong family history of cardiomyopathy, both atrial and ventricular tachyarrhythmias, chronic disease and lack of response to steroids…think about glycogen storage diseases! This patient ended up getting diagnosed with Danon Disease, which is an x-linked glycogen storage disease that causes severe cardiomyopathy with milder peripheral myopathy, and sometime ophthalmologic and intellectual deficits. Pathology demonstrates intracellular vacuoles and glycogen deposits.

Reference:

Danon Disease as an Underrecognized Cause of Hypertrophic Cardiomyopathy in Children
Zhao Yang, Colin J. McMahon, Liana R. Smith, Jeathrina Bersola, Adekunle M. Adesina, John P. Breinholt, Debra L. Kearney, William J. Dreyer, Susan W. Denfield, Jack F. Price, Michelle Grenier, Naomi J. Kertesz, Sarah K. Clunie, Susan D. Fernbach, James F. Southern, Stuart Berger, Jeffrey A. Towbin, Karla R. Bowles and Neil E. Bowles

8/29 (HUP): peripartum cardiomyopathy

haToday we discussed the case of a young woman (10 days postpartum) who presented with chest tightness, acute respiratory failure and ultimately shock, and was found to have new systolic heart failure felt to be due to peripartum cardiomyopathy.

Major physiologic changes in pregnancy

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Why is this important to medicine residents?
– the decreased [plasma protein] means that there is less oncotic pressure compared to normal, even in the weeks after delivery; this can predispose to pulmonary edema
– blood volume is expanded due to plasma > RBC expansion; and at the time of delivery, autotransfusion of blood from placenta and contracting uterus can mean an increased 500-1000cc of blood in the maternal circulation
– the increased renal blood flow and GFR mean that most mothers have a lower than normal Cr; so a Cr of 1 in a pregnant woman may reflect kidney injury
– pregnant (and PP women, for several weeks after delivery) are relatively vasodilated compared to non-pregnancy

Consider both typical + atypical causes in a pregnant/postpartum woman with dyspnea

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Arany et al. NEJM 2014.

This patient ultimately had a TTE which showed a (presumably new) EF of 10%. Diagnoses to entertain: 1) Peripartum cardiomyopathy; 2) Viral myocarditis; 3) Giant cell arteritis; 4) Unmasking of underlying CHF of other etiology

Peripartum cardiomyopathy

  • Often a diagnosis of exclusion given that there’s not (until recently at least) a definitive diagnostic test
  • 90% of cases happen in the 1st month postpartum but can also happen during the 3rd trimester
  • It affects between 1:300 and 1:3000 births worldwide, particularly those of African descent; Northern Nigeria and Haiti are ‘hotspots’ where the incidence is MUCH higher than other parts of the world
  • The etiology is still unclear, although there is growing evidence of a ‘vasculotoxic’ phenomenon mediated by prolactin (produced by pituitary) and soluble FLT1 (sFLT1, from placenta)–> thus there may be a role for prolactin suppressors like bromocriptine and/or discontinuation of lactation
  • Even in patients who recover their EF partially or completely (~50% of pts), there’s a high risk of recurrence of PPCM with subsequent pregnancies; these patients require close counseling and discussion with OB/GYN before deciding on subsequent pregnancies
  • ~30% of pts don’t improve, and some go on to require transplant; a worse EF at presentation predicts worse outcomes
  • Patients with underlying cardiac protein mutations (titin, etc) may have a predisposition to developing PPCM. See a recent NEJM article investigating relationships between PPCM and other causes of dilated CM.

Other pearls

  • Many common cardiac drugs used in non-pregnant adults can be used in pregnancy, with the exception of: amiodarone, atenolol and sotalol
  • Don’t forget coronary artery dissection as a rare cause of chest pain in pregnant/postpartum women
  • Fluid shifts in pregnancy can unmask underlying valve disease, particularly stenotic lesions like mitral stenosis, which can dramatically increase the risk of pulmonary edema (due to expanded blood volume, tachycardia, preeclampsia and the use of tocolytics)

References

  1. Arany et al. Peripartum cardiomyopathy. Circulation 2016.
  2. Lapinsky et al. 1995. Critical care in the pregnant patient. American Journal of Respiratory and Critical Care Medicine. 152, 2 (1995), 427–455.
  3. Bello, N. and Arany, Z. 2015. Molecular mechanisms of peripartum cardiomyopathy: A vascular/hormonal hypothesis. Trends in Cardiovascular Medicine. 25, 6 (2015), 499–504.

8/22 (HUP): controversies in the world of submassive PE

Today we discussed a middle aged woman with factor V Leiden who came in with dyspnea and was found to have a monster (seriously) saddle PE. We had the pleasure of having Dr. Jay Giri talk to us today about the evolving evidence in submassive PE management and the PE response team.

There was way too much discussed to put in one post, but I’ll try to distill the essentials.

PE risk stratification

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  • Low risk PEs (those with none of the features above) can be treated with just anticoagulation (and may not even need admission, depending on the situation)
  • High risk (‘massive’) PEs should usually be treated with fibrinolytics because they will otherwise almost certainly progress to death; uncontrolled bleeding is the main contraindication
  • Intermediate risk (‘submassive’) PEs are where the opportunity is ripe to prevent morbidity and mortality

Options for treating intermediate risk PE

  • Anticoagulation + systemic thrombolysis
  • Catheter directed intervention (thrombolysis, vacuum aspiration)
  • (much less commonly) surgical embolectomy

While it’s well-accepted that thrombolysis is the best option for massive PEs, the use of thrombolytics for submassive PEs has been the subject of intense study. Several trials and meta-analyses have looked at this question, so I’ll highlight a few:

  1. PEITHO: anticoagulation + tenecteplase vs anticoagulation alone in patients with submassive PE. The study confirmed that fibrinolytics decreased the risk of hemodynamic decompensation
    • This study was not powered to detect differences in mortality
    • The bleeding rate was ~2% in the lytic group; in subgroup analyses a lot of that was driven by patients >75 (see plot below)

      Screen Shot 2017-08-22 at 11.50.39 AM.png

      Meyer et al. NEJM 2014

  2. This 2014 JAMA meta-analysis looked at prospective randomized trials of thrombolysis in >2000 patients with submassive or massive PE
    • Thrombolysis reduced all-cause mortality by 44% with a NNT of 59 (p=0.01), an effect also seen among the subgroup with submassive PE
    • Also note (table below) that the NNH is only 18 for major bleeding (but NNH = 176 in patients <75!)
Screen Shot 2017-08-22 at 10.29.47 AM.png

Chatterjee et al. JAMA 2014

Overall, clinicians who deal with this frequently find themselves in the position of having to decide which patients with submassive PE might benefit from thrombolysis. Right now it’s a decision made without clear guidance, but younger age and fewer comorbidities (and patient preference) are likely to play big roles.

A few other pearls from today’s talk 

  • Why do older patients do so much more poorly with lytics? Many possibilities: underlying amyloid angiopathy, prior strokes (whether recognized or not), possible old unrecognized ICHs
  • Lytic therapy is known to decrease PA systolic pressures much more rapidly than just anticoagulation, but there may be a ‘catch up’ phenomenon, such that months after the incident PE, PASPs are approximately equivalent in patients treated with lysis vs just anticoagulation; this suggests that A/C works, just slower
  • Transthoracic echo is decent at estimating RV and PA pressures (as compared to RHC), but that close concordance falls apart at very high PA pressures (approximately >60)
  • If someone codes and you suspect it’s due to a massive PE, you could consider giving them emergent lytics, but those people rarely survive given the attendant high bleeding risks with CPR, anoxic brain injury, etc. The better thing may be to crash them on to VA ECMO, which in some series confers a higher survival rate
  • Some (albeit shaky) data exists that lower doses of tPA (50mg instead of 100mg) may be equivalent, since the entirety of the cardiac output flows through the pulmonary vasculature
  • Catheter directed lysis theoretically has a lower risk of major bleeding since the tPA dose (typically 8-24mg) is much lower than systemic lytic doses, but that lower bleeding risk hasn’t actually been proven

Finally, consider activating the PE response team for any patient who has a submassive or massive PE; the attending or fellow on-call can always be found on Penn Medicine on Call (UPHS homepage).

References

  1. Meyer et al. Recent advances in the management of pulmonary embolism: focus on the critically ill patient. Ann Intensive Care 2016.
  2. Piazza et al. Management of submassive pulmonary embolism. Circulation 2010.
  3. Submassive PE: are we treating it backwards? Pulmcrit/EMCrit.

 

8/8 (HUP): CCB toxicity

Thanks to Dr. Francis DeRoos for walking us through a case of a young woman who presented with shock, and was ultimately found to have overdosed on calcium-channel blockers.

First, we talked about the importance of (1) the physical exam and (2) the EKG in diagnosing and risk stratifying patients with toxic ingestions. Assessing the skin, pupils, and sweat/lack thereof can give you valuable clues. See the toxidromes post from a few months ago for more info.

Here’s a cute chart that illustrates that:

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Common toxidromes (source: http://www.sketchymedicine.com)

We also talked about various causes of drug-induced bradycardia:

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Lithium tends to cause bradycardia most commonly in patients with underlying cardiac disease. Amiodarone has particularly been known to cause bradycardia in concert with certain of the new HCV medications (sofosbuvir or daclatasvir), including slow VT!

CCB toxicity can cause a variety of ECG changes, including sinus bradycardia and varying degrees of AV blockade. Remember to look at the rhythm strip carefully to make sure you’re not missing complete heart block!

Treatment options for CCB toxicity

  1. Calcium: may improve inotropy and blood pressure. You can give either calcium gluconate (short acting, can give peripherally but lower Ca content) or calcium chloride (3x the Ca content of Ca gluconate, must give centrally given risk of tissue damage w/ extravasation).
  2. Pacing: unlikely to be of much benefit even in hemodynamically significant bradycardia, given that the CCB is still bathing cardiomyoctes with its negative chronotropic effect.
  3. Vasopressors: something (like norepinephrine) with inotropic and vasoconstrictive effects is best, but there’s no trial proving the superiority of one vs another. Large doses may be needed.
  4. High-dose insulin/euglycemic therapy: CCBs block the calcium-dependent release of insulin from pancreatic beta cells, while at the same time increasing glycogenolysis. Insulin is also postulated to have a positive inotropic effect, especially in these patients in whom CCBs are exerting a negative inotropic effect. Massive doses of insulin (to the tune of 0.5-1U/kg/hour) may be needed given (along with dextrose) to maintain euglycemia.
  5. Lipid formulations: intravenous lipid rescue (initially used for bupivicaine toxicity) can be used as a ‘lipid sink’ to bind up unbound CCB. This is not without risks, as it can cause lipemic serum and higher rates of pancreatitis!
  6. ECMO/CPB: with refractory shock, there is also a role for putting patients on ECMO while using adjunctive therapies (above) to support them

Lastly, the paper of the day– which suggests that earlier Lasix administration in patients with decompensated heart failure may have a mortality benefit! See their central illustration, which suggests that there is a critical period (<60 min) where early diuretic administration might be particularly beneficial:

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References

  1. Matsue, Y. et al. 2017. Time-to-Furosemide Treatment and Mortality in Patients Hospitalized With Acute Heart Failure. Journal of the American College of Cardiology. 69, 25 (2017), 3042–3051.
  2. Kerns, W. 2007. Management of β-Adrenergic Blocker and Calcium Channel Antagonist Toxicity. Emergency Medicine Clinics of North America. 25, 2 (2007), 309–331.
  3. Life in the fast lane. Calcium Channel Blocker Toxicity.

 

7/19 (HUP): ECMO ECMO ECMO

Thanks to Fenton McCarthy, cardiac surgery fellow, for an incredible talk on extracorporeal membrane oxygenation (ECMO) and to everyone in the audience for creating a robust discussion.

We highlighted big differences between ECMO and cardiopulmonary bypass:
1) Cardiopulmonary bypass is a modality used almost exclusively for short periods of time in the OR
2) While similar, bypass circuits have a blood reservoir whereas ECMO circuits don’t

There are two main flavors of ECMO:

  1. Veno-arterial (VA) ECMO (see below): used if you have a cardiac problem (cardiac arrest, myocarditis, MI, cardiomyopathy, post-cardiac surgery) to provide circulatory support
    Screen Shot 2017-07-19 at 1.48.04 PM.png

    VA ECMO: blood drains from a vein, gets oxygenated, and pumped back into an artery. It flows retrograde from the femoral artery up the aorta. Poorly oxygenated blood being pumped by the failing heart can mix with well-oxygenated retrograde blood from the ECMO catheter, creating differential regional hypoxemia, also known as “North South syndrome”

    2. Veno-venous (VV) ECMO (see below): used primarily for respiratory failure (refractory hypoxemia, ARDS, etc). Complications are much less common with VV ECMO than VA ECMO.

    Screen Shot 2017-07-19 at 1.56.39 PM.png

    VV ECMO: blood is drained from the SVC or IVC and returned to the venous system.

    With VV ECMO, catheters can either go into the internal jugular vein or femoral vein. There’s also a catheter called an Avalon catheter (google it!) which is a single ‘catheter within a catheter’ that only requires placement of a cannula in the right IJ, and even permits ambulation!

We talked about some contraindications to ECMO (malignancy, unrecoverable neurological injury, age >75 among others, prolonged (>60 min) cardiac arrest, etc), and some tips for medicine residents if your patient is being considered for ECMO:

  • Have one point person who knows the patient well be the one to talk to the ECMO fellow
  • Get the unit charge RN involved early
  • Get extra stuff (laundry carts, trash can, etc) out of the room to create space to work

The question always comes up: should I pre-emptively put in IJ or femoral central lines to make ECMO cannulation easier if things are headed that way?

The answer (as with so many things)is a little nuanced: if all they have is an IJ line, it’s advisable to put one in the other side because they will still need separate central access, and having to do so after they’ve been placed on ECMO comes with the theoretical risk of air embolism.

If groin ECMO access is being considered, you could put in bilateral femoral lines, but it really depends on the experience of the operator: to be helpful, the groin lines really need to be within 1-2cm of the groin crease.

How’s the evidence?

Lastly, we touched on the CESAR trial, which is really the only major/recent randomized trial that looked at whether ECMO has any benefit. The short answer: possibly yes, but it may not be a fair comparison because the ECMO group may have gotten better overall medical care than the ‘conventional therapy’ group

References

  1. Peek et al. CESAR: conventional ventilatory support vs ECMO for severe adult respiratory failure. PMC1766357
  2. Brodie D et al. ECMO for ARDS in adults. PMID 22316467
  3. Ventetuolo et al. Extracorporeal life support in critically ill adults. PMC4214087

A quick aside on hypothermia (the topic of our question-of-the-day)

Hypothermic patients can have sinus bradycardia, PVCs/PACs, atrial fibrillation and J-waves (also known as Osborne waves, see below). The height of the Osborne wave corresponds with the degree of hypothermia.

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It is true that ‘you’re not dead until you’re warm and dead’. As the following NEJM table shows, hypothermia with hemodynamic instability is an indication to consider ECMO or cardiopulmonary bypass in order to speed rewarming:

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Reference

Brown et al. Accidental hypothermia. NEJM. PMID 23150960.