Thrombolysis for early ischaemic stroke

The question of what to do with the patient who has presented within 4 hours of having a cerebral infarct is brought up in Question 22 from the first paper of 2013, "A 60-year-old male presents 2 hours after the onset of vertigo and loss of consciousness. CT brain is performed and shows right basilar and vertebral occlusion with no evidence of infarction. Discuss two possible definitive treatment strategies for this condition, including the indications and contra-indications of each." The official college answer to this question is actually quite good, and here only a rearrangement and tabulation of the same material is offered.

As far as published peer-reviewed literature for stroke in ICU goes, the best is probably the freely available article by Kirkman et al (2014), The bits about intraarterial thrombolysis for the college SAQ are taken from the recent (2013) multisociety consensus guidelines. The Oxford Textbook of Stroke and Cerebrovascular Disease (2014) also has a page on intraarterial thrombolysis. The promising area of endovascular clot retrieval is sufficiently interesting to merit its own page, and will be largely ignored here. For the purpose of answering CICM questions, one would be well advised to stick to local guidelines, represented by the Australian Stroke Foundation - specifically their  Clinical Guidelines for Stroke Management 2017. Unless otherwise stated, they are the definitive resource for this summary. From the land of non-peer-reviewed FOAM, the best recent entry is Chris Nickson's update for LITFL (2018).

Determining the need for thrombolysis

The local guidelines recommend the use of some sort of a validated scoring system for stroke. The National Institutes of Health Stroke Scale (NIHSS) is a particularly popular scoring system for the impairment resulting from stroke, with eleven items and a total possible score of 42 (where 0 is no deficit and 42 is essentially a GCS of 3). The full scoring system is available from multiple sources (here's a version from stroke.nih.gov) and a discussion of this system or comparison to other systems will not be pursued here in the interest of space and sanity. It is unlikely that the college will ever expect their trainees to accurate score the NIHSS score of a stroke patient as a part of a model answer. 

What's the point of all this? Well. It is universally agreed that one needs to confirm clinically that some sort of stroke is taking place, and going through an eleven-item checklist is a convenient way of forcing people to actually examine the patient. Thrombolysis is obviously not consequence-free (the risks of it are discussed elsewhere in the context of PE), and one would obviously prefer not to give it unless the stroke is likely to cause signficant disability. Clearly some sort of risk stratification system is in order.  However, it is not clear how the stroke severity score relates to the question of whether or not a stroke merits thrombolysis, and beyond confirming stroke, there is probably little utility.

Very severe stroke (NIHSS score 25 and above) is generally thought to make dangerous thrombolysis candidates because they are supposed to be at greater risk of haemorrhagic transformation, but large audits of stroke patient data  (Mazya et al, 2015) did not find much of a trend towards ICH. In contrast, the IST3 trial (2012)  found greater benefit in the more severe strokes, with NIHSS scores greater than 14 (the benefit in mild stroke was not as clear; there may even be a signal towards increased harm). Very mild stroke (NIHSS <4-6) is thought to be so mild as to derive little benefit (and all the risk) from thrombolysis, and so some guidelines (eg. these from WA, 2011) recommend thrombolysis only for strokes with an NIHSS score over 4. 

Definitive management options

The window for thrombolysis seems to be three hours according to the college answer to Question 22 from the first paper of 2013, though according to them "there is data suggesting use up to 4.5 hours may be beneficial". That probably refers to  Hacke et al (ECLASS III, 2008) who went as late as 4.5 hours post stroke. Modern Australian Stroke Foundation guidelines recommend 4.5 hours as the cut-off on the basis of the meta-analysis articles by Wardlaw et al (2014) and Emerson et al (2014).

A few interesting points about the acute management of stroke:

• The availability of a specialist acute stroke unit improves mortality and outcome. ICU admission does not.
• These people do poorly on a ventilator, as they seem to be at an increased risk of ventilator-associated pneumonia.
• There is no benefit from heparin infusion.
• You should tolerate a systolic blood pressure under 220mmHg systolic, or 120mmHg diastolic.

The table of acute reperfusion strategies and the abovelisted points are probably enough to conclude the reading for this topic, if the candidate is short of time.

If time is plentiful, the rationale and evidence for these recommendations are presented in the summary chapter on massive ischaemic stroke, and a series of digressions regarding acute stroke therapies are offered below. Furthermore, an entire summary chapter is dedicated to decompressive craniectomy in malignant MCA infaction syndrome.

A digression about intravenous thrombolysis

Instead of repeating the well known (or widely believed) truths about thrombolysis, one should focus on the ICU-centric features which come up in CICM fellowship exams.  The British Guidelines of 2008 and the local Stroke Foundation guidelines will fill in the rest. 

In brief, we give people alteplase because the NINDS Study demonstrated a neurological recovery benefit without any increased bleed-related mortality.  In doing this we follow the guidelines uncritically, even though the evidence for thrombolysis in stroke is fairly weak, and even though respected FOAMers caution us against embracing dogma. "Continued use of stroke thrombolysis outside the setting of RCTs is a cause for concern continued use of stroke thrombolysis outside the setting of RCTs is a cause for concern and should be considered an experimental therapy", advises Chris Nickson, though as he rightly points out "the amount of debate far exceeds it’s [sic] relative clinical importance!" 

Without extensively digressing on the evidence base in support of thrombolysis in stroke, it is important to acknowledge that the evidence is of poor quality, conflicting, and tainted by industry interference. It is also important to acknowledge the need for CICM trainees to pass CICM exams, which is most easily accomplished when one's exam answers are devoid of controversial opinions. The savvy exam candidate will, therefore, need be aware both of how poor the evidence is, and how strongly it is supported by large international bodies (LIFTL list the FDA, the AAN, the AHA, ACEP and the Australian Stoke foundation as supporting the use of thrombolysis). Once they have passed, the newly minted fellows of the college are invited to cultivate their own opinion on this topic. 

There are a few things one should know about thrombolysis in stroke:

A digression about intra-arterial thrombolysis

The whole intra-arterial thrombolysis issue has been a source of great interest, and the PROACT-II study had certainly made some heads turn, with recanalisation rates of 66% in the treatment group vs. 18% for the placebo patients. However, that was at the cost of a five-fold increase in intracranial haemorrhage (10% vs 2%, ...one in ten thrombolysed patients). The MELT trial investigators tried to replicate the (positive) outcomes of PROACT-II in 2007, and though the trial was aborted prematurely and the primary endpoint never reached statistical significance, their data were encouraging.