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. 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

Management Options for an Early Presentation of Ischaemic Stroke
Strategy Indications Contraindications
Intravenous Thrombolysis
  • Presentation within 4.5 (ideally, 3)  hours
  • Age over 18 and less than 80
  • Clinically significant stroke (NIHSS >4) is quoted as an indication by some guideline authors
  • History of head trauma in the last 3 months
  • History of stroke in the previous 3 months
  • Arterial puncture in a non-compressible site in the past 7 days
  • Platelet count less than 100
  • Any heparin within 48 hours of the stroke
  • Current anticoagulant therapy
  • Hypoglycaemia
  • Multilobar infarction (more than one-third of a cerebral hemisphere) on CT scan
  • High stroke severity (NIHSS > 25) is a relative contraindication for some guideline-writers
Intraarterial thrombolysis
  • Contraindication to systemic thrombolysis
  • Systemic thrombolysis  is considered likely to fail
  • Systemic thrombolysis has failed (after 1 hr)
  • A large vessel occlusion is present
  • Poor vascular access
  • Intracerebral haemorrhage
  • Cerebral malignancy (relative)
  • The delay to procure appropriate expert staff and equipment is prohibitive
Endovascular embolectomy
  • Presentation within 8 hours
  • Contraindication to systemic thrombolysis (or failure to respond to it)
  • Clot is in a large vessel
  • Contraindications to carotid or verterbal arterial access (eg. significant carotid atherosclerosis)
  • Peripheral vascular disease (i.e. difficult access)
  • Uncontrolled coagulopathy
  • Obvious and well-established infact on CT or MRI (thus, no point in embolectomy)
  • Contrast allergy

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 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:

Indications and Contraindications to Thrombolysis in Stroke
Indications Relative contraindications Absolute contraindications apart from acute bleeding
  • Age over 18 and less than 80
  • Onset of symptoms < 4.5 hours ago
  • Minor or rapidly improving stroke
  • Seizure at time of stroke
  • Major trauma in the past 14 days
  • GI bleeding in the last 21 days
  • Haematuria in the last 21 days
  • History of head trauma in the last 3 months
  • History of stroke in the previous 3 months
  • Arterial puncture in a non-compressible site in the past 7 days
  • Platelet count less than 100
  • Any heparin within 48 hours of the stroke
  • Current anticoagulant therapy,
  • Hypoglycaemia
  • Multilobar infarction (more than one-third of a cerebral hemisphere) on CT scan

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.

A digression about mechanical embolectomy

This is promising, but only applicable to a limited extent.

Initial interest in endovascular stroke management was considerable. For instance, the MERCI trial investigators enrolled all-comers to receive embolectomy (within 8 hours!) by use of the Merci Retriever device. As a marketing exercise for this device, the trial was a success; in spite of a 7.1% serious complication rate the technique was viewed as "safe" in the conclusion. In fact there are numerous such devices, and the campaign to sell each one has yielded some equally promising propaganda material. Unfortunately, like in the MERCI trial, the outcomes of all these studies compared poorly with historical controls.

In 2009, the American Journal of Neuroradiology has published a summary of their opinions and experiences regarding endovascular stroke management.

They concluded:

"despite higher rates of recanalization, the mechanical thrombectomy studies have demonstrated substantially lower rates of good outcomes compared with IV and/or intra-arterial thrombolytic trials."

This was sad. There is something heroic and noble-sounding about accessing the cerebral vessels to suck out the clot and save the brain. In spite of this rather negative reception, as well as consistently depressing outcome data, enthusiasts continued to experiment, and the technology matured. Rather than attempting to dress it up as a viable alternative to thrombolysis, the investigators have recently focused on identifying a patient group which would derive the greatest benefit from the technique.

References

Oh's Intensive Care manual: Chapter   51   (pp. 568)  Acute  cerebrovascular  complications by Bernard  Riley  and  Thearina  de  Beer. This chapter of Oh's has the distinction of having extremely few tables in it - there are only two, for an extremely long block of text.

The Internet Stroke Centre has an excellent summary of stroke syndromes.

Kammersgaard, Lars Peter, et al. "Short-and long-term prognosis for very old stroke patients. The Copenhagen Stroke Study." Age and Ageing 33.2 (2004): 149-154.

National Collaborating Centre for Chronic Conditions (Great Britain). "Stroke: national clinical guideline for diagnosis and initial management of acute stroke and transient ischaemic attack (TIA)." Royal College of Physicians, 2008.

Friedman, Howard S., W. J. Koroshetz, and N. Qureshi. "Tissue plasminogen activator for acute ischemic stroke." N Engl J Med. 1995;333(24):1581.

Trialists’Collaboration, Stroke Unit. "Organised inpatient (stroke unit) care for stroke." Cochrane database of systematic reviews 4 (2013).

Foerch, C., et al. "Survival and quality of life outcome after mechanical ventilation in elderly stroke patients." Journal of Neurology, Neurosurgery & Psychiatry 75.7 (2004): 988-993.

Bath, Philip MW, Robert Iddenden, and Fiona J. Bath. "Low-molecular-weight heparins and heparinoids in acute ischemic stroke a meta-analysis of randomized controlled trials." Stroke 31.7 (2000): 1770-1778.

Sherman, David G., et al. "The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison."The Lancet 369.9570 (2007): 1347-1355.

Wartenberg, Katja E. "Malignant middle cerebral artery infarction." Current opinion in critical care 18.2 (2012): 152-163.

Kasuya, Yusuke, et al. "Ventilator-associated pneumonia in critically ill stroke patients: frequency, risk factors, and outcomes." Journal of critical care 26.3 (2011): 273-279.

Nogueira, R. G., et al. "Endovascular approaches to acute stroke, part 2: a comprehensive review of studies and trials." American Journal of Neuroradiology30.5 (2009): 859-875.

Brinjikji, Waleed, et al. "Patient outcomes with endovascular embolectomy therapy for acute ischemic stroke a study of the national inpatient sample: 2006 to 2008." Stroke 42.6 (2011): 1648-1652.

Kidwell, Chelsea S., et al. "Design and rationale of the mechanical retrieval and recanalization of stroke clots using embolectomy (mr rescue) trial."International Journal of Stroke 9.1 (2014): 110-116.

Jansen, Olav, et al. "Neurothrombectomy for the treatment of acute ischemic stroke: results from the TREVO study." Cerebrovascular Diseases 36.3 (2013): 218-225.

Furlan, Anthony, et al. "Intra-arterial prourokinase for acute ischemic stroke: the PROACT II study: a randomized controlled trial." Jama 282.21 (1999): 2003-2011.

Sacks, David, et al. "Multisociety consensus quality improvement guidelines for intraarterial catheter‐directed treatment of acute ischemic stroke, from the American Society of Neuroradiology, Canadian Interventional Radiology Association, Cardiovascular and Interventional Radiological Society of Europe, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, European Society of Minimally Invasive Neurological Therapy, and Society of Vascular and ...." Catheterization and Cardiovascular Interventions 82.2 (2013): E52-E68.

Ogawa, Akira, et al. "Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke The Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) Japan." Stroke 38.10 (2007): 2633-2639.

Kirkman, Matthew A., Giuseppe Citerio, and Martin Smith. "The intensive care management of acute ischemic stroke: an overview." Intensive care medicine 40.5 (2014): 640-653.

Hacke, Werner, et al. "Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke." New England Journal of Medicine 359.13 (2008): 1317-1329.

Wardlaw, Joanna M., et al. "Thrombolysis for acute ischaemic stroke." The Cochrane database of systematic reviews 7 (2014): CD000213.

Emberson, Jonathan, et al. "Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials." The Lancet384.9958 (2014): 1929-1935.

Mazya, Michael V., et al. "IV thrombolysis in very severe and severe ischemic stroke Results from the SITS-ISTR Registry." Neurology 85.24 (2015): 2098-2106.

IST-3 Collaborative Group. "The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial." The Lancet 379.9834 (2012): 2352-2363.

Reiff, T., and P. Michel. "Reasons and evolution of non-thrombolysis in acute ischaemic stroke." Emerg Med J 34.4 (2017): 219-226.