Head injury trials

1. Major Trials in Head Injury
and Learning Points
Presenter – Dr. Soumen Kanjilal
Moderated by – Dr. Kuntal Kanti Das

2. Overview
• Intracranial hypertension is an important secondary insult that follows TBI.
• Causes of increasing intracranial pressure (ICP)
• hematomas or contusions,
• diffuse brain swelling, and
• hydrocephalus.
• The rise of pressure within the cranial vault can compromise the cerebral
perfusion pressure (CPP), which can lead to ischemia.

3. Some Important Definitions
• Decompressive craniectomy :
• Umbrella term.
• Three main procedures performed for TBI are
• hemicraniectomy,
• bilateral hemicraniectomy, and
• bifrontal decompressive craniectomy.
Geoffrey T. Overview and Controversies, Trauma. Youmann and Winn’s Neurosurgery, 7th ED.2017

4. • Primary DC :
• refers to leaving the bone flap out after evacuation of an intracranial hematoma with
associated parenchymal swelling and injuries in the acute phase after TBI.
• Acute subdural hematoma (ASDH) is the most commonly described indication.
• Secondary DC :
• is a procedure performed as part of tiered ICP management protocols, aimed at controlling
intracranial hypertension and ensuring adequate CPP.
• A secondary DC can be performed early in treatment as a neuroprotective measure or can
be performed as a last-tier intervention for refractory severe intracranial hypertension.
Some Important Definitions
Geoffrey T., Overview and Controversies, Trauma. Youmann and Winn’s Neurosurgery, 7th ED.2017

5. Extended Glasgow Outcome Scale (GOSE)
1 Death D
2 Vegetative State VS
3 Lower severe disability SD-
4 Upper severe disability SD+
5 Lower moderate disability MD-
6 Upper moderate disability MD+
7 Lower good recovery GR-
8 Upper good recovery GR+
Jennett B, Bond M. Glasgow Outcome Scale Assessment of outcome after severe brain damage: A practical scale. Lancet.
1975;480:484.

7. DECRA Trial
• Aim of study - The clinical effectiveness of early neuroprotective secondary
DC for patients with diffuse TBI.
• Inclusion criteria :
• Within 72 hours of trauma
• Diffuse injury only (excluding mass lesion)
• ICP >20mm Hg for at 15minutes in 1 hour (continuously/ intermittently)
• All the patients received optimised sedation, Mannitol/Hyperstonic saline
infusion, Neuromuscular blockade, EVD, Normalisation of PaCO2.
DECRA in Diffuse TBI, D. James Cooper, N Engl J Med 2011;364:1493-502.

8. DECRA Trial
• Ramdomised groups :
• Group A– Surgery
• Bifrontal DC (without division of SSS/ falx cerebri)
• Group B – Conservative
• Barbiturates
• Hypothermia
• Results – measured as per GOS-E at 6 months
• Higher rates of unfavourable outcomes in surgical arm 70% to 50% in standard care
DECRA in Diffuse TBI, D. James Cooper, N Engl J Med 2011;364:1493-502.

9. Learning Points
1. Decreasing ICP does not always mean a better outcome for our patients.
2. The perception of the use of decompressive craniectomies in clinical practice
by neurosurgeons all over the world has gone well beyond the evidence
published.
• bone flaps of less than 12cms. is entirely insufficient to determine a significant ICP
decrease.
3. To reserve the procedure only for use in patients with intractably increased
ICP (e.g.,30 mmHg) for at least an hour.
Iaccarino C, Schiavi P, Servadei F. Decompressive craniectomies: time to discuss not the DECRA study but the
comments to the DECRA study. World neurosurgery. 2013;1(79):78-9.

10. RESCUEicp trial
• Randomised Evaluation of Surgery with Craniectomy for Uncontrollable
Elevation of Intracranial Pressure.
• Aim of the study: Clinical effectiveness of secondary DC as last tier therapy
for patients with sever TBI and refractory severe intracranial hypertension.
• Inclusion criteria:
• Severe TBI including mass lesions
• ICP> 25mm Hg for atleast 1 hr.
• Refractory to tiered ICP lowering agents
P.J. Hutchinson, A.G, Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension, N Engl J Med. 2016;375:1119-30.

11. P.J. Hutchinson, A.G, Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension, N Engl J Med. 2016;375:1119-30.
Initial treatment measures
Head elevation
Ventilation
Sedation
Analgesia
Paralysis (optional)
Monitoring
Central venous pressure
Arterial blood pressure
Intracranial pressure
Intracranial pressure >25 mm Hg
Continue stage 1 treatments
Barbiturates not permitted
Optional treatments that can
be added
Ventriculostomy
Inotropes
Mannitol
Hypertonic saline
Loop diuretics
Hypothermia
Intracranial pressure >25 mm Hg for 1–12 hr
Surgical group
Decompressive
craniectomy
Continue stage 1 and
2 treatments
Medical group
Continue stage 1
and 2 treatments
Barbiturates
permitted

12. RESCUEicp trial
• Randomised groups:
• Group A – Bifrontal DC with division of SSS and falx cerebri
Large Hemicraniectomy for unilateral hemispheric swelling or midline shift or
both.
• Group B – Barbiturate infusion was given only to patients who received medical therapy.
• Results : Assessed with the use of the Extended Glasgow Outcome Scale
(GOS-E) at 6 months after randomization.
• Mortality – 26.9% in surgical arm to 48.9% in conservative arm
• Prolonged vegetative state in patients in surgical arm (8.5% to 2.1%)
P.J. Hutchinson, A.G, Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension, N Engl J Med. 2016;375:1119-30.

13. Comparison between DECRA & RESCUEicp trials
DECRA RESCUEicp
• ICP above 20 mm Hg for 15 min over a 1-h period despite the
optimization of tier 1 treatments within the first 72 h of care
(early)
• ICP greater than 25 mm Hg for 1 to 12 h refractory to 2 tiers of
treatment within 10 d of admission (late).
• A single bilateral frontotemporal decompressive craniectomy
with dural opening either by cruciate incision bilaterally or by
a large L shaped incision without division of the falx or
sagittal sinus regardless of the location of the swelling.
• A large unilateral frontotemporoparietal hemicraniectomy (for
unilateral hemisphere swelling on imaging) or
• A large bilateral frontotemporoparietal craniectomy with a
wide dural opening and optional division of the falx anteriorly
• Surgery was offered as a second-tier treatment for elevated
ICP (aggressive approach).
• Surgery was offered only when all other treatment options
(with the exception of barbiturates) had failed.
• Mortality - 19% in the surgical group and 18% in the medical
group.
• Mortality - 26.9% in the surgical group and 48.9% in the
medical group
• Unfavourable outcomes occurred in 70% in the surgical group
and 51% in the medical group.
• Favourable outcomes occurred in 42.8% of the patients in the
surgical group and in 34.6% of those in the medical group.

14. Controversy
• “Favourable” or “Unfavourable” outcomes depends upon the “Dichotomization point”.
• Conventional assessment of outcome after TBI
• Favourable – if there is full independence at 6 months (GOSe grade 5-8) and
• Unfavourable – if there is death or severe disability (GOSe grade 1-4)
• RESCUEicp dichotomization :
• Favourable - GOSe grade 4-8
• Unfavourable - GOSe grade 1-3
Dr Chris Nickson , “Favourable” is in the eye of the beholder! September 8, 2019.Blog UT.
http://lifeinthefastlane. com.

15. Learning Points
• Decompressive craniectomy provides favourable outcomes in the setting of
refractory intracranial hypertension.
• Surgery may not offer an increase in the likelihood of recovering to the level of
functional independence outside the home.
• The percentage of patients with upper severe disability was 13.4% in the surgical
arm compared to 3.9% in the medical arm.
• In other words, decompressive craniectomy allows for functional independence
within the home of 10% of patients who would otherwise have died or been
dependent on others for their care.
Matthew Dorazio DO, David Slottje MD, David Wyler MD:Commentary on RESCUEicp; N Engl J Med 2016; 375:1119-1130.

16. RESCUE-ASDH Trial
• Randomised Evaluation of Surgery with Craniectomy for patients undergoing Evacuation of
Acute Subdural Haematoma.
• Aim : RESCUE-ASDH is a multi-centre, pragmatic, parallel group randomised trial
comparing craniectomy vs. craniotomy for acute subdural haematoma patients.
• Inclusion criteria :
• Adult head-injured patients (aged >16 years)
• Acute subdural haematoma on CT.
• The admitting neurosurgeon feels that the haematoma needs to be evacuated with a large bone
flap (recommended size ≥11 cm anteroposterior diameter) either by a craniotomy or
decompressive craniectomy.
RESCUE-ASDH Trial Protocol, ISRCTN87370545, Version 3.0, 13 July 2018

17. RESCUE-ASDH Trial Protocol, ISRCTN87370545, Version 3.0, 13 July 2018
Enrollment is officially over.
A total of 463 patients were
randomized.
Result - awaited

18. Eurotherm3235 Trial
• The Eurotherm3235 Trial was a pragmatic, multicentre randomised controlled trial (RCT) to examine the effects
of hypothermia (32–35 °C) on patient outcome after TBI.
• Aim : Does therapeutic hypothermia (TH) (32–35 °C) improve patient outcome and reduce mortality 6 months
after TBI as assessed by the Glasgow Outcome Scale – Extended (GOSE)?
• Inclusion criteria :
• Primary closed TBI.
• Raised ICP of > 20 mmHg for ≥ 5 minutes after first-line treatments with no obvious reversible cause (e.g. patient position, coughing,
inadequate sedation).
• ≤ 10 days from the initial head injury.
• Cooling device or technique available for > 48 hours.
• Core temperature of ≥ 36 °C (at the time of randomisation).
• An abnormal CT scan of the brain, defined as one that shows haematoma, contusion, swelling, herniation or compressed basal cisterns.
Andrews PJ, Sinclair HL, Rodríguez A, et al. Therapeutic hypothermia to reduce intracranial pressure after traumatic brain
injury: the Eurotherm3235 RCT. Health Technol Assess. 2018;22(45):1-134.

19. Eurotherm3235 Trial
• Exclusion criteria :
• Patient already receiving TH treatment.
• Administration of barbiturate infusion prior to randomisation.
• Unlikely to survive for the next 24 hours in the opinion of the ICU consultant or consultant neurosurgeon treating the
patient.
• Temperature of ≤ 34 °C at hospital admission.
• Pregnancy.
Andrews PJ, Sinclair HL, Rodríguez A, et al. Therapeutic hypothermia to reduce intracranial pressure after traumatic brain
injury: the Eurotherm3235 RCT. Health Technol Assess. 2018;22(45):1-134.

20. Eurotherm3235 Trial
• Pathophysiology :
• Blood brain Barrier :
• Brain water content is significantly reduced with hypothermia after focal cerebral ischaemia.
• Inflammation and oedema :
• Hypothermia reduces increases in tissue levels of superoxide, nitric oxide and the hydroxyl radical.
• Metabolism :
• hypothermia appears to lower metabolic and energy demands, which has potentially beneficial effects on
cytoplasmic adenosine triphosphate (ATP) and the maintenance of normal transmembrane ion and neurotransmitter
gradients.
• Intracellular calcium-dependent signalling :
• Temporary cerebral ischaemia inhibits the activity of calcium/calmodulin-dependent protein kinase II (CaMKII), a
key protein kinase that mediates synaptic strength, and this is attenuated by hypothermia.
Andrews PJ, Sinclair HL, Rodríguez A, et al. Therapeutic hypothermia to reduce intracranial pressure after traumatic brain
injury: the Eurotherm3235 RCT. Health Technol Assess. 2018;22(45):1-134.

21. Eurotherm3235 Trial
Andrews PJ, Sinclair HL, Rodríguez A, et al. Therapeutic hypothermia to reduce intracranial pressure after traumatic brain
injury: the Eurotherm3235 RCT. Health Technol Assess. 2018;22(45):1-134.

22. Eurotherm3235 Trial
• Results
• Induced hypothermia in addition to standard care did not result in improved
patient outcomes at 6 months after injury compared with standard care alone.
• The trial was stopped early -
• At best, a result of futility would be expected if the trial were to continue.
• There were signs of harm with the treatment being evaluated.
• TBI and with an ICP of > 20 mmHg, titrated therapeutic hypothermia successfully reduced
ICP but led to a higher mortality rate and worse functional outcome.
Andrews PJ, Sinclair HL, Rodríguez A, et al. Therapeutic hypothermia to reduce intracranial pressure after traumatic brain
injury: the Eurotherm3235 RCT. Health Technol Assess. 2018;22(45):1-134.

23. BEST:TRIP Trial
• Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure.
• Objective : The study was a multicentre, parallel-group trial, with randomized assignment to
intracranial pressure monitoring or imaging and clinical examination.
• Inclusion criteria :
• Patients with age > 13 years
• have a score on the Glasgow Coma Scale (GCS) of 3 to 8 (with a score on the GCS motor
component of 1 to 5 if the patient was intubated) or a higher score on admission that dropped to
the specified range within 48 hours after injury.
• Patients with a GCS score of 3 and bilateral fixed and dilated pupils were excluded.
Chesnut RM; A trial of intracranial-pressure monitoring in traumatic brain injury. New England Journal of Medicine. 2012
Dec 27;367(26):2471-81.

24. BEST:TRIP Trial
Chesnut RM; A trial of intracranial-pressure monitoring in traumatic brain injury. New England Journal of Medicine. 2012
Dec 27;367(26):2471-81.
• Three CT scans be obtained (at baseline, 48 hours, and 5 to 7 days) and standard supportive care
provided for each patient, with care to include mechanical ventilation, sedation, and analgesia.
• Ramdomised groups :
• Group A : Placement of intra-parenchymal ICP monitor
• Group B : Imaging– clinical examination
• Intracranial hypertension was treated by tiered algorithms, which were similar in both groups and
were titrated to ICP < 20 mmHg or utilized based on imaging and clinical examination.
• Results : the 6-month mortality was -
• 41% in imaging clinical examination group and
• 39% in the ICP monitoring group

25. CRASH trial
• Corticosteroid Randomisation After Significant Head Injury
• Objective - In adults with a head injury, if early corticosteroids compared to
placebo reduce death and disability.
• April 1999 to May 2004
• Inclusion:
• adults over 16 years with head injuries,
• who presented within 8 hours of injury with GCS ≤ 14
CRASH Trial Collaborators. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid
in adults with head injury—outcomes at 6 months. The Lancet. 2005 Jun 4;365(9475):1957-9.

26. CRASH trial
• Intervention
• Administration of methylprednisolone for 48 hours
• Loading dose of 2 g over 1 hour in 100 ml 0.9% NaCl
• Maintenance of 0.4 g per hour for 48 hours in 20 ml per hour 0.9% NaCl
• Control
• Identical regime of placebo
• Outcome : 10,008 patients
• Primary (at 2 weeks): Corticosteroid group 21% mortality vs placebo group 18% mortality.
• Secondary (at 6 months) : Corticosteroid group 25.7% mortality vs placebo group 22.3% mortality.
• Conclusion : Corticosteroids should not be used routinely in the treatment of head
injury.
CRASH Trial Collaborators. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid
in adults with head injury—outcomes at 6 months. The Lancet. 2005 Jun 4;365(9475):1957-9.

27. UPDATED RECOMMENDATIONS
• Level IIA–to improve mortality and overall outcomes
1. NEW–Secondary DC performed for late refractory ICP elevation is recommended to improve mortality and
favorable outcomes.
2. NEW–Secondary DC performed for early refractory ICP elevation is not recommended to improve mortality and
favorable outcomes.
3. A large frontotemporoparietal DC (not less than 12 x 15 cm or 15 cm in diameter) is recommended over a small
frontotemporoparietal DC for reduced mortality and improved neurological outcomes in patients with severe TBI.
• Level IIA–for ICP control
1. NEW–Secondary DC, performed as a treatment for either early or late refractory ICP elevation, is suggested to
reduce ICP and duration of intensive care, though the relationship between these effects and favorable outcome is
uncertain.
Hawryluk GW, Guidelines for the Management of Severe Traumatic Brain Injury: 2020 Update of the Decompressive
Craniectomy Recommendations. Neurosurgery. 2020 Sep 1;87(3):427-34.

28. Thank You