Trials and guidelines for neurology and neurosurgery

This compilation of papers is probably not as useful as other better resources which compile this information, such as Critical Care Reviews and The Bottom Line. However, it is probably at least harmless. Wherever possible, the original paper is linked from the name of the study, and the Bottom Line review is linked from the year of publication.

Traumatic brain injury

DECRA - 2011 - decompressive craniectomy vs. standard care; n=155, Au/NZ/Saudi.  Mortality same (19% and 18%) but more severely disabled survivors (70% vs 51%)

BEST:TRIP - 2012 - ICP monitoring vs. clinical examination and imaging; n=324, in South America. No difference in mortality (39% vs 41%) nor the composite outcome

STITCH - 2015- early evacuation of parenchymal haematoma; n=170, worldwide. Better mortality (33% vs 15%) and less disability, but underpowered.

Eurotherm3235 - 2015 - prophylactic 33°-35°C until ICP controlled, multinational, but 55% of n=387 from the UK. Greater risk of death (54% vs 44%) and lower likelihood of a good functional outcome (25% vs 37%)

RESCUEicp - 2016 - decompression or thiopentone and standard care? n=408, in 20 countries. Mortality improved with craniectomy (26.9% vs. 48.9%), but it created more severely disabled survivors (and did not change the % of less disabled survivors)

POLAR -  2018 - prophylactic 33°-35°C, for 3-7 days - n=511 all around the world. No difference in mortality (48.8% vs 49.1%), not much effect on ICP, and more complications (pneumonia, ventilation days, bradycardia and noradrenaline use)

COBI - 2021 - but what if 20% saline, except continuous infusion? n=370, in France. No significant difference in mortality (15.9% vs 20.8%), ICP control or functional outcome. Probably better off as a bolus. 

Intracranial haemorrhage

INTERACT2 - 2013 - SBP under 140 vs SBP under180; n=2839, multinational. No difference in composite mortality or severe disability (52% vs 55.6%).

PATCH - 2016 - platelets within 90 minute of imaging; n=190 patients on antiplatelet agents (Netherlands, UK and France). Worse mortality (24% vs 17%).  

ATACH-2 - 2016 - SBP 110-130, vs SBP 140-180; n=1000 from many countries. No mortality difference (38.7% vs 37.7%), and the low BP group had more renal complications (9% vs 4%).

TICH-2 - 2018 - tranexamic acid within 8 hours; n=2325 (12 countries). No effect on mortality (22% vs 21%) or functional outcome, but haematomas expanded less, so at least the radiologist was happy.

Subarachnoid haemorrhage

BRANT - 1989 - The nimodipine trial. n=554 in UK; oral nimodipine for 21 days. Reduced rate of cerebral infarction (22% vs 33%). Subsequent work duplicated their effect size reasonably well, such that for nimodipine NNT = 8.

Bradford - 2013 - but what if magnesium? Mg²⁺ ~ 1.70 mmol/L, n=162 (Australia). Less vasospasm in the magnesium group, but not statistically significant.

ULTRA - 2021 - super-early tranexamic acid; n=955, in the Netherlands. No difference in chances of a good outcome: 60% vs 64% (but: rebleeding decreased, 10% vs 14%).

Ischaemic stroke

BP targets

• CATIS - 2014 - BP 140/90, or uncontrolled? n=4071, in China. No difference in composite of mortality and major disability (33.6% vs 33.6%).
• MAPAS - 2019 - looked at 3 different ranges of SBP; n=218, in Brazil. Best outcomes seen in the 160-180 range, but only after statistical trickery. No range was clearly superior.

Decompressive craniectomy for malignant MCA infarction:

• DESTINY - 2007 - n=32; in Germany. Improved survival (88% vs 47%) but stopped early because other trials were concurrently running
• DECIMAL - 2007 - n=38; in France. Improved survival (75% vs 22%) Stopped early because of slow recruitment.
• HAMLET - 2009 - n=64, in the Netherlands.  Better survival (absolute risk reduction was 38%)
• DESTINY II - 2014 - but what if older patients? n=112, over 60s,  in Germany. Better survival (mortality 33% vs 70%), but most of the survivors were severely disabled (60% vs 28% were modified Rankin score 3 or 4)

Endovascular clot retrieval trials:

• MR CLEAN - 2015 - ECR within 6 hours versus usual care; n=500 (Netherlands). No difference in mortality, but the survivors had better function  (32.6% vs. 19.1%)
• SWIFT PRIME - 2015 - ECR plus tPA vs. tPA alone, within 6 hours. n=196, in US and Europe Stopped early because of obvious benefit: better function in 60% vs. 35%
• EXTEND-IA - 2015 - ECR plus tPA vs. tPA alone, n=70 in Australia and NZ; also stopped early because ECR+tPA was clearly superior (better function in  71% vs. 40%)
• DEFUSE III - 2018 - what if ECR, but later? 6-16 hours, n=182, in the US. Rate of functional independence at 90 days was 45% vs 17%. Mortality also better (14% vs 26%)
• DAWN - 2018 - what if ECR, but even later? 6 to 24 hours, n=207, in the US.  Rate of functional independence at 90 days was 49% vs 13%. Mortality same (19% vs 18%)
• Yoshimura et al - 2022 - in very large strokes; n=203 (Japan). Better outcomes in 31% vs 12.7%, but also more serious haemorrhagic transformation (9% vs 4.9%)

Status epilepticus

HYBERNATUS - 2016 - added hypothermia to standard care? n=270, in France. No difference in good functional outcome (49% vs 43%). Fewer seizures though. 

CERTA - 2020 - continuous EEG? n=364, in Switzerland. Yes, they picked up more seizures, and changed the AEDs a lot more, but there was no difference in mortality (48.4% vs 48.9%, because 30% of the patients had hypoxic-ischaemic encephalopathy). 

Guidelines

Traumatic brain injury:

• Brain Trauma Foundation Guidelines are definitely a necessity. The time-poor reader may wish to skim the 2016 executive summary before they sit the written.
• The 2019 SIBICC consensus statement on three tiered treatment for ICP management in TBI is also a good single source of good ICP control recommendations
• CREVICE protocol for when you do not have ICP monitoring

Stroke and intracranial haemorrhage of various sorts:

• 2012 AHA guidelines for SAH
• 2017 AHA statement on what to do when the thrombolysis causes a bleed
• 2017 ESO guidelines for cerebral venous thrombosis
• 2018 SNIS Guidelines for endovascular clot retrieval
• 2019 update to 2018 AHA guidelines for ischaemic stroke
• 2021 ESO guidelines for BP management in stroke and ICH
• 2022 AHA guidelines for ICH 
• 2022 NICE guidelines for SAH

Spinal injury:

• 2015 EAST statement on clearing the C-spine
• 2022 ACS best practice guidelines

Status epilepticus:

• 2016 AES guidlines
• 2012 Neurocritical Care Society guidelines

Persistent unconsciousness

• 2018 AAN guidelines on disorders of consciousness

Various myopathies and neuropathies:

• 2014 ATS guideline on ICU-acquired weakness
• 2020 international myasthenia gravis consensus statement
• 2021 Guillain Barre consensus guideline
• not exactly the same thing, but ACCM/SCCM 2002 clinical practice guidelines for sustained neuromuscular blockade could probably fit in here

Examination of the unconscious patient

• Not really guidelines, but as CICM are so fixated on seeing people perform the oculocephalic reflex in the fellowship exam, the candidates should prepare to discuss it. Walker and O'Brien's 1990 paper "Neurological examination of the unconscious patient" is an excellent brief synopsis; it draws its inspiration from the 1980 edition of Plum and Posner's "The Diagnosis of Stupor and Coma", which is essentially the Old Testament for neurological examination of the critically ill. The time-poor candidate will probably be unable to make use of this textbook, but the paper needs to be read through at least once before the exam. The hypothetical exam candidate with infinite time resources may also benefit from exploring The Comatose Patient by Eelco Wijdicks (2014).