POTD: Supratherapeutic INR

I’ve maybe had to think about this twice during residency and both times was like ??? so I figured I should at least learn a little about it.

Although slowly dying out in terms of popularity, some providers STILL put their patients on warfarin. One of the last conditions where warfarin is indicated over a DOAC is in the setting of a mechanical valve, which can be a clue into the patient’s past medical history if you see it on their medication list (or that their PCP is old school). And even this may change as data on DOAC’s continues to evolve. There are multiple reasons why warfarin is a very annoying drug to work with.

1)    Narrow therapeutic window – for most indications the target INR is between 2-3

2)    Variable dose response

3)    Multiple drug-diet and drug-drug interactions

4)    Requiring bridging therapy

The main benefit of warfarin is that in the event of bleeding or hemorrhage, there are easy and effective reversal agents.

So, what happens if you shotgun labs on a patient (as one does) and their INR returns at a higher level? Like 4? 7? 10?? It depends on the scenario.

Significant or Life-Threatening Bleeding – very obvious, no thought involved. Obviously do not wait for confirmatory testing before treating.

-       Stop warfarin

-       Give Vitamin K 10mg IV over 20-60min. Some considerations…

o   Vitamin K works by helping the body produce more coagulation factors (no, I won’t go over the mechanism). This takes more than a few hours and does not help immediately

o   If started on vitamin K the patient will usually be refractory to warfarin for some time, but this is less of a problem as a different (and likely better) anticoagulant can be started in the interim

-       4-factor prothrombin complex concentrate (PCC) – Kcentra (what we have at Maimonides). I think this will end up institution specific, but we do…

o   Fixed approach – does not depend on INR. After a lovely discussion with pharmacy, studies appear to show that it is just as effective but lowers cost as overall doses are lower. Preferred if you have a choice.

§  GI/ENT/life-threatening hemorrhage – 1500 IU

§  ICH – 2000 IU 

o   INR-based approach – start off with 1500 IU empirically then add SUPPLEMENTAL dose…

§  INR 2-4: total 25 IU/kg (max 2500)

§  INR 4-6: total 35 IU/kg (max 3500)

§  INR > 6: total 50 IU/kg (max 5000)

-       If no Kcentra, consider FFP (but it honestly sounds like you should never really consider FFP). Per UpToDate…

o   2U FFP. Check INR 15 min after infusion, if >1.5 give another 2IU. Repeat until INR < 1.5.

o   Consider Lasix if infusing large amounts

Luckily, the order set reflects this at Maimonides, and we don’t have to think about it here.

Not really a debate anymore, but Kcentra vs FFP? Kcentra…

-       Is more rapid and effective at correcting INR - ~30 min

-       Can be infused faster with less volume  less likely leading to fluid overload

-       Shorter preparation time

-       Does not require blood-type matching

-       FFP is cheaper though….      +1

For Urgent/Emergent procedures

-       Treat as above in discussion with surgeon or proceduralist

-       If it can wait, don’t need to treat as aggressively

Minor Bleeding (like epistaxis) – very complicated, decided by many factors and heavily decided by physician judgement. Some things to consider

-       Extent of bleeding and risk of progression

-       Previous bleeding history

-       Comorbidities (CKD, HTN)

-       Concomitant anti-platelet therapy

-       INR level

-       Thromboembolic risk of the patient (prosthetic valve, atrial fibrillation, history stroke/DVT/PE, etc.)

-       Therapy will range from holding warfarin, giving vitamin K, and treating as above

Now on to why I actually decided to make this POTD.

Asymptomatic Elevated INR – based on INR

-       INR > 10: oral vitamin K 2.5-5mg  response in 24-48 hours

o   Hold warfarin

o   No role for Kcentra or FFP

o   INR should be checked daily or every other day, repeat oral vitamin K as needed

-       INR 4.5-10

o   Hold warfarin (1-2 doses)

o   Can consider low dose oral vitamin K – 1 - 2.5mg. Again, consider SEVERAL factors

§  Risk of bleeding – older age, prior bleeding, higher INR  consider oral vitamin K

§  Risk of thrombosis

-       INR <4.5

o   Hold next dose of warfarin (or reduce dose, this is generally on the PCP though)

o   Needs more frequent INR checks in the immediate future

Does anyone NEED to be admitted for management of supratherapeutic INR? Likely not. Fortunately, or unfortunately, depends on our clinical judgement. Off the top of my head…

-       Consider calling PCP to ensure follow-up / PCP comfort

-       Consider risk of bleeding vs. risk thrombosis

-       Patient ability to follow up

-       The thousand other things we think about when deciding whether to admit or discharge patients

What about an elevated INR in a liver patient?

-       Do not treat like warfarin-induced elevated INR

-       Patients are usually at baseline PRO-THROMBOTIC from low levels of protein C and S (anticoagulation factors)

-       Nothing to really do for elevated INR in the cirrhotic patient – per UptoDate appears that most attempts to correct lead to adverse events (thrombosis, etc.)

TL;DR

-       Ensure proper patient follow-up for cases of asymptomatic supratherapeutic INR

-       INR > 10 – hold warfarin, consider 2.5 – 5mg oral vitamin K

-       INR 4.5-10 – hold warfarin, consider 1 – 2.5mg oral vitamin K

-       INR < 4.5 – hold a single dose and recheck INR (not in ED)

https://www.nuemblog.com/blog/supratherapeutic-inr

https://www.uptodate.com/contents/management-of-warfarin-associated-bleeding-or-supratherapeutic-inr#H21790898

http://www.emdocs.net/em-cases-liver-emergencies/

POTD: Rabies Part 2 Rabies Vaccination

The much anticipated part 2 on rabies. 

Onto the actual important part of this POTD: Rabies post-exposure prophylaxis (PEP). Who gets it and how?

Who: UptoDate keeps recommending contacting local health officials for recommendations which, less face it, generally isn’t happening.

-       Anyone with a known or likely exposure to rabies defined as…

o   Bite or saliva-containing scratch from an animal with rabies

o   An open wound or mucus membrane exposure to saliva, CSF, or CNS tissue from an animal with rabies

-       Empirically to anyone with suspected exposure (pretty open-ended) 

-       Exposure of keratinized skin to saliva, blood, feces DOES NOT count as an exposure

For domesticated animals

-       High risk: undocumented vaccination status, aggressive behavior

-       If animal (dog, cat, ferret) able to be observed/quarantined for 10 days, can hold off PEP until end of 10-day period

o   Animals almost universally show signs within 10 days of rabies

For wild animals

-       High risk: bat, raccoon, skunk, fox

o   Start PEP, discontinue if animal able to be tested promptly and is negative

-       Low risk: squirrel, chipmunk, mouse/rat, rabbit/hare

o   Do not start PEP

How: There are 2 components, (1) the rabies vaccine and (2) rabies immune globulin (RIG)

1)    Rabies vaccine – administered 1mL IM specifically in the deltoid region (not gluteus muscle, risk of sciatic damage/lower response to vaccine). Has a very specific dosing schedule

a.     If patient has received pre-exposure prophylaxis: 2 doses, Day 0 and Day 3

b.     If patient unvaccinated: 4 doses, Days 0, 3, 7, and 14

                                               i.     If immunosuppressed, a 5th dose is given on Day 28

c.     Day 0 is first day that rabies vaccine is given

d.     It can be helpful to write the dosing schedule on the discharge papers for future providers (speaking from experience)

2)    RIG – only indicated if patient has not received pre-exposure prophylaxis

a.     20 U/kg – as much as possible infiltrated around the wound with the rest delivered IM in the opposite deltoid of the vaccine arm.

b.     If no obvious wound, place all IM

PEP should be given regardless of delay from time of exposure

Are there any adverse events with vaccination? Depends on the vaccine…

-       Usually local skin reactions (pain, redness, swelling, induration) with possible mild systemic symptoms (fever, headache, GI symptoms)

-       Hypersensitivity or anaphylaxis  can switch to a different vaccine formulation if possible

-       Counseling should be given on these symptoms to prevent patient non-compliance with future doses

FAQ

1)    What if they patient doesn’t closely follow the dosing schedule?

Small deviations aren’t that important, and doses should be administered at the same intervals. For example, if day 7 dose is actually given on day 10, then the next dose should be scheduled on day 17 (or 7 days later), etc.

For more significant delays… consult ID? Seriously though, it likely involves antibody testing and titers, while attempting to follow the initial dosing patient was started on (maybe requires ID follow-up).

2)    What if patient received different formulations of rabies vaccine?

Just give them what you have and have them follow-up with their PCP or clinic for antibody titers. Theoretically the vaccines are interchangeable but not ideal.

3)    What if the patient is pregnant?

Not a contraindication, no evidence associated with fetal abnormalities or adverse pregnancy outcomes.

4)    If RIG was not initially administered? Like if a traveler returns from a foreign country and needs to have their scheduled doses at specifically YOUR emergency department

RIG can be administered on return if less than 7 days from initial vaccine administration. RIG should not be administered afterwards because it interferes with the normal immune response that the vaccine causes.

Last, but not least, general wound care like irrigation should always be performed along with tetanus. Antibiotics are a more nuanced discussion, and possibly a POTD for another day (although I lean towards providing a course for patients with animal bites in general).

TL; DR – and considerations for a busy, NY ED

-       If there was an exposure (actual bite, found in room with a bat) and patient is concerned – give PEP. No serious adverse events.

-       PEP = vaccines in a specific dosing regimen (0, 3, 7, 14, and maybe 28) and RIG (20U/kg) around the wound and the rest IM

-       Please write the dosing schedule with dates on the discharge papers. This makes this patient encounter incredibly easy for your fast track resident.

This is likely more than you ever wished to know about rabies. I learned a lot, like next time Mak needs the rabies vaccine I’ll make sure to give it in his arm instead of his butt.

https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-rabies?topicRef=16595&source=see_link

https://www.uptodate.com/contents/treatment-of-rabies?topicRef=8328&source=see_link

https://www.uptodate.com/contents/when-to-use-rabies-prophylaxis?sectionName=POST-EXPOSURE%20PROPHYLAXIS&topicRef=8303&anchor=H2&source=see_link#H2

https://www.uptodate.com/contents/rabies-immune-globulin-and-vaccine?topicRef=8328&source=see_link

POTD: Rabies Part 1

Rabies Vaccination

Hey all,

I’m mostly going to be doing POTD’s on topics I’ve accumulated throughout the year that I wanted to look into but never actually did. So, prepare for quite a few fast track complaints (unless I get a request for a topic – just e-mail/text me!).

Anyways, let’s talk about rabies. I’m sure everyone has heard or experienced a great rabies case in their career. No? That’s because since 1980 there has only been about 2-3 reported cases a year in the US, with ~30% of them related to US travelers returning abroad. It is an almost universally fatal disease if contracted but is also 100% preventable if an exposure is identified and given the proper prophylaxis.

So…briefly about rabies…

Epidemiology

-       Estimates 59,000 deaths worldwide, mostly due to inadequate control of rabies in domesticated animals

-       Transmission usually through exposure from saliva from an animal bite

o   No history of transmission from infected patients to healthcare personnel (though personally I look forward to the coming zombie apocalypse)

-       Normal reservoirs: ?dogs/cats to some extent, mostly bats, foxes, skunks, and raccoons

-       Incubation period: 1-3 months on average, though can occur several years later

Clinical Manifestations

-       Prodromal phase (~1 week): Non-specific low grade fever, chills, myalgias, malaise, fatigue, anorexia, sore throat, nausea, vomiting (COVID is that you?)

-       Clinical rabies: Encephalitic (80%) vs. Paralytic

o   Encephalitic = “classic” rabies

• Fever

•   Hydrophobia

•   Autonomic instability – hyperthermia, lacrimation, hypersalivation

•   Pharyngeal spasms and hyperactivity  stupor, coma, and death

• Agitation, aggression, combativeness

o   Paralytic = Less than 20%

•   Ascending paralysis not unlike Guillain-Barre Syndrome

•   As paralysis ascends, respiratory muscles lose tone and respiratory failure and death occurs

  After learning more about this, it’s possible some of us HAVE seen rabies and it’s never diagnosed…….. (I’ll definitely be putting it in my MDM from now on)

Diagnosis

-       As always, a good history and physical is paramount any of the above symptoms surrounding an animal bite is suggestive of rabies

-       Lab diagnosis – requires multiple samples from saliva, skin, serum, or CSF using multiple modalities (sensitivity of a single test not that high)  likely unimportant in the ED

-       Post-mortem – examining brainstem or other neural tissue directly

Differential – aka all of these are 1000% more likely than rabies

-       ANY OTHER CAUSE OF ENCEPHALITIS (West Nile, herpes, autoimmune, etc.)

-       Tetanus (another very common disease that we see frequently)

Treatment – almost universally ends in death. 29 well-documented cases of survival. Survival usually still causes severe neurological sequelae

-       The treatment is always proper prophylaxis

-       Palliation (not joking)

-       Supportive care/ICU level care and strategies = no good evidence/way above our level of care in the ED.

Hopefully you’ve learned a little more than you already did about rabies (although the key clinical symptom does appear to be hydrophobia). I, for one, will be splashing Mak with a little bit of water every day until he becomes agitated and then send him to the ED to be treated for rabies.