Alteplase and Frostbite

From Guide to YKHC Medical Practices

#1

Dosing of alteplase for frostbite is different than for STEMI/CVA/PE

  • It is most likely a smaller bolus (unless pt is greater than 90-100 kg).
  • The bolus is delivered over a longer period of time (15 min as opposed to 1-2 min).
  • It may be a smaller total dose, depending on the weight of the pt ( same maximum dose, but less total dose if patient is less than 95 kg).
  • And the total dose is administered over 6 hours and 15 min as opposed to 1-2 hours.

Frostbite

  • 0.15 mg/kg over 15 min followed by 0.15 mg/kg/hr x 6 hrs, max 100 mg

STEMI

  • >67 kg 15 mg over 1-2 min then 50 mg over 30 min then 35 mg over 1 hr , max total 100 mg
  • <67 kg 15 mg over 1-2 min then 0.75 mg/kg (not to exceed 50 mg) over 30 min then 0.5 mg/kg (not to exceed 35 mg) over 1 hr, max total 100 mg

CVA

  • >100 kg 9 mg over 1 min then 81 mg over 60 min
  • <100 kg 0.09 mg/kg over 1 min, then 0.81 mg/kg over 60 min

PE

  • cardiac arrest 50 mg, repeat if no ROSC in 2 min
  • HD unstable or HD stable massive 100 mg over 2 hours

***SUMMARY: LESS OR SAME DOSE OVER MORE TIME

#2

The prudent use of thrombolytics requires an understanding of risk/benefit which can be communicated to a consenting pt.
We ought to avoid a visceral response to the use of a potentially dangerous medication and look at the data.

*STEMI

The first piece of information we, as medical providers, want to know about the patient presenting with ACS symptoms is whether their EKG indicates a STEMI (admittedly there is much more to it). This is because we have been trained that “time is tissue,” and there exists a window of opportunity to administer thrombolytics to save lives and myocardium. The overwhelmingly cited data that is used to support the use of thrombolytics deals with mortality risk, and morbidity of disability from myocardial damage is listed secondarily. Therefore, thrombolytics have been accepted in medical practice for their mortality reduction, not necessarily their morbidity reduction. This is a different scenario than that of frostbite. But if we look at the mortality data, we may find it surprising. The data I am referencing is readily available on an UpToDate Search (Acute ST-elevation myocardial infarction: The use of fibrinolytic therapy) or by checking thennt.com (thrombolytics given for major heart attack (STEMI)) or can be found in our own YKHC guidelines for consent of the STEMI pt for thrombolytics.

Number needed to treat= NNT (the number of people who need to have an intervention in order for 1 person to receive stated benefit) Number needed to harm=NNH (the number of people who receive an intervention before 1 person suffers stated harm)

Thrombolytic mortality benefit in STEMI: 1 hr NNT=15, 2 hr NNT=25, 3 hr NNT=33, 9 hr NNT=50, 18 hr NNT=100 (per UTD figure 1) <6 hr NNT=43, 6-12 hr NNT=63, 12-24 hr NNT=200 (per thennt.com) <6 hr NNT=40, 6-12 hr NNT=60 ( per YKHC STEMI consent form)

Thrombolytic risk in STEMI CVA NNH=83 (41% fatal), ICH NNH=143, Major bleed with hemodynamic compromise NNH=55, moderate bleed requiring transfusion NNH=9 (per UTD) Hemorrhagic CVA NNH=250, Major bleeding episode NNH=143 (per thennt.com) Hemorrhagic CVA NNH=100 to 250, non life threatening bleeding NNH=100

A quick digestion of that data will likely illuminate the fact that administration of thrombolytics is not as black and white as a medical textbook would have you think. Ultimately, it is up to the patient to decide the risk they wish to take, hopefully in consultation with a provider who knows the data and can communicate it to the patient.

*CVA

In terms of thrombolytics, the first two pieces of information we, as medical providers, want to know about the patient presenting with CVA symptoms is their onset of symptoms and the results of their CT head without contrast (again, there is much more to it). This is because, again, we have been trained that “time is tissue,” and there exists a window of opportunity to administer thrombolytics. But this scenario is different than thrombolytics for STEMI. The overwhelmingly cited data that is used to support the use of thrombolytics for ischemic CVA deals with reduction of morbidity in terms of disability, not mortality. Therefore, thrombolytics have been accepted in medical practice for their morbidity reduction, which is more akin to the indication for frostbite. But if we look at the mortality data, we may find it even more surprising than thrombolytics for STEMI. The data I am referencing is readily available on an UpToDate Search (Approach to reperfusion therapy for acute ischemic stroke) or by checking thennt.com (Thrombolytics for Stroke and Tissue Plasminogen Activator (tPA) For Acute Ischemic Stroke).

Thrombolytic morbidity benefit in ischemic CVA: <3 hr NNT=10, <4.5 hrs NNT=20 (per UpToDate Approach to reperfusion therapy for acute ischemic stroke) None helped (per thennt.com Thrombolytics for Stroke) <3 hr NNT=10, 3-4.5 hrs NNT=19, 4.5-6 hrs NNT=50 (per thennt.com Tissue Plasminogen Activator (tPA) For Acute Ischemic Stroke))

Thrombolytic risk in ischemic CVA ICH NNH=18, angioedema NNH=12-100 Symptomatic ICH NNH=20 ((per thennt.com Thrombolytics for Stroke) Fatal ICH within 7 days of Rx NNH=40-50, 90 day all cause mortality NNH=71

A quick digestion of that data may make you look in the mirror and do a little soul searching. That certainly is not as black and white as the books and most of my professors and attendings made it sound in medical school or residency. That’s okay. The folks at thennt.com seem torn, too. They have posted conflicting results, so much so that one review lists their recommendation as a greenlight (in favor of) and the other as a red light (no benefit found). Once again, ultimately it is up to the patient to decide the risk they wish to take, hopefully in consultation with a provider who knows the data and can communicate it to the patient.

*Frostbite

And thus, we come to frostbite. We are therefore not talking about mortality reduction, we are talking about morbidity reduction by saving people’s hands, feet and digits. The data is admittedly weak. Dr Herrmann has done an excellent job of gathering the relevant research. And it is weak. But alas there is some evidence, and some that even applies to YKHC’s capabilities. We ought to set aside the articles that address intraarterial alteplase for education only. The articles with iv alteplase utilization used bone scanning prior to administration. The data can be reviewed: 75-80% digit salvage/save with no major side effects (4% minor side effects) Interestingly authors of most of the reviews recommend directed intraarterial alteplase despite the majority of major complications coming from said administration. There is anecdotal evidence of administration of iv alteplase in austere environments without untoward effects (Bethel or K2!)

Thrombolytics benefit for frostbite Digit salvage/save NNT=1.2

Thrombolytic risk in frostbite Major complications NNH=infinity (in the reported literature at this time)

There admittedly is not much to digest there, but alteplase appears to be effective and safe for frostbite at this juncture.

#3

We practice in an austere environment.

Summary

I know thrombolytics are scary. To watch someone die when you are trying to save them is one of the worst feelings that any of us can ever experience. But that does not mean that we should let our visceral response to a drug prevent us from: looking at the available evidence, reflecting on what we are already doing in our daily practice because of what we have accepted as the standard of care, and realizing the potential life altering power that we have. Frostbite can be absolutely permanently disabling. And if I ever draw the winter muskox hunt for Nunivak Island, happen to get stuck out in a blizzard, suffer hypothermia and severe frostbite to my bilateral hands or hands and feet, get rewarmed after rescue or self-rescue in the Mekoryuk clinic, and met the criteria for thrombolytics, you can bet I would elect to proceed with alteplase here in Bethel with the understanding that “time is tissue” and I would be heading to Anchorage for further care. If I would do it myself, then I ought to be offering that service to others.