This document summarizes a journal club discussion of a randomized trial comparing outcomes of intracranial pressure monitoring versus clinical examination alone for patients with severe traumatic brain injury. Key points included that the trial found similar outcomes between the two groups in composite endpoints and mortality. However, the intracranial pressure monitoring group received more aggressive treatments such as barbiturates. There was skepticism around applying the results to clinical practice in the US due to differences in pre-hospital care, rehabilitation standards, and treatment protocols between the study locations and the US.

1. NCCU Journal Club
JOSHUA KORNBLUTH, MD
F E B 5 TH, 2 0 1 3

2.  Objective: to review a recent randomized trial of
intracranial pressure monitoring in sTBI
 To encourage thought and discussion of our own
practices
 To consider future directions
 Nothing for me to disclose

3. Study Overview
 Does intracranial pressure monitoring improve
outcomes in severe TBI?
 What is the current standard of care in America?
 Why does this question matter?
 Multicenter, 324 adult pts, severe TBI, randomized
to two separate protocols
 Looked at in-hospital events, survival time and 3-
and 6- month outcomes

5. You heard it from the BTF…

6. Study Overview
 Can we conduct this type of study in America?
 Highly unlikely, so let's take advantage of alternative
standards of care to investigate.
 Study Design
 Multicenter, parallel-group trial
 Random assignment to ICP-monitoring group vs imaging-
clinical examination group
 Study started in Bolivian hospitals, and additional hospitals
were added later to increase enrollment

7. Study Design – Inclusion Criteria
 Traumatic brain injury
 GCS < 8 on admission or within first 48 hours after
injury (Motor score ≤ 5 if intubated)
 Admission to study hospital within 24 hours of injury
 No foreign object in the brain parenchyma.
 Age > 12
 Randomized:
 within 24 hours of injury [for patients with GCS < 8 on admission] or
 within 24 hours of deterioration [patients deteriorating to GCS < 8
within 48 hours of injury
 Randomization stratified according to site, injury
severity score, and age

8. Study Design – Exclusion Criteria
 GCS of 3 with bilateral fixed and dilated pupils
 No consent
 Pregnant
 Prisoner
 No beds available in ICU
 No ICP monitor available
 Non-survivable injury
 Other (e.g., Pre-injury life expectancy under 1 year)
 Pre-existing neurological disability that would
confound outcome

9. Study Design - protocol
 Place patient on mechanical ventilation (VM)
 Place continuous SaPO2 and EtCO2 monitors
 Insert indwelling urinary catheter to monitor urine output
 Insert arterial catheter for arterial mean pressure monitoring
 Insert central venous catheter for infusion of solutions and
central venous pressure monitoring.
 Monitor neurological clinical status each hour
 Pupils
 GCS
 Brain CT
 To evaluate evolution 48 hours after the admission CT
 To evaluate evolution 5-7 days after the admission CT
 p.r.n.

10. Study Design – Standards of Critical Care
Clearly delineate standard basic Critical Care
• Head positioning 30º
• Head and neck in neutral position and aligned
• Avoid hyperthermia (Defined as central temperature > 38 º C)
• Non-drug measures (cooling)
• Dipirona (Metamizole sodium)
• Early enteral nutritional support
• Before 48 hours
• 25 Kcal/kg weight
• Pharmacologic prophylactic of post traumatic seizures (Phenytoin (IV or PO))
• Load and maintenance dose as is being giving in each hospital
• Gastric bleeding prophylaxis
• Ranitidine or Omeprazol
• Avoid decubitus lesions
• Deep venous thrombosis prophylaxis
• Frequent tracheal suctioning with sterile technique to prevent pulmonary infections

11. Study Design – ICP group
 Had parenchymal monitor ASAP (i.e. after
randomization and resolution of coagulopathy if
present)
 Position was not specified
 Treat if ICP≥20mmHg x 5min
 If CSF drainage indicated, EVD placed
 CPP goal 50-70mmHg

12. Study Design – Treatments (ICP Group)
 Treatments based on a “Therapeutic Intensity Level”
 If signs of intracranial HTN, clinical or imaging
 1 – hyperosmolar therapy (mannitol)
 5% NaCl only if hypotenisve, hypovolemic, hyponatremic
 2 – optional mild hyperventilation (pCO2 30-35mmHg)
 3 – Ventricular drainage if possible*

13. Study Design – Definitions (ICP Group)
 Intracranial Pressure Definitions:
 Treatable intracranial hypertension:
 ICP > 20 mmHg for > 5 minutes
 Treatment failure:
 ICP not reduced to ≤ 20 mmHg within 20 minutes after a
treatment intervention is initiated, and
 Persistent elevation in ICP > 20 mmHg requires increase in
therapeutic intensity level

14. Study Design – “Neuroworsening”
 Neuroworsening = Inc’d TIL
 1. Decrease in the motor GCS > 2
 2. New loss of pupil reactivity
 3. Interval development of pupil asymmetry of > 2mm
 4. New focal motor deficit
 5. Herniation syndrome
 Give mannitol 0.25-1mg/kg to sOSM<320
 Hyperventilate to pCO2 25-30
 If no response  thiopental x 3d
 Craniectomy for space-occupying lesions

15. Study Design – Imaging only Group
 After optimized sedation and analgesia,
hyperventilation and hyperosmotic therapy
should be started simultaneously if there is
evidence of edema on CT, as indicated as
following:
 1. Compressed peri-mesencephalic cisterns
 2. Midline shift
 3. Cortical sulcal compression / effacement
 Otherwise, same metrics and goals of ICP
monitored group
 Corticosteriods prohibited
 AED’s for prophylaxis >28d

16. Study Design - Outcomes
 Primary outcome – 21-point composite of survival,
duration and level of impaired consciousness, 3-
month GOSe and GOAT, 6-month GOSe and
neuropsych testing
 Secondary Outcomes – ICU LOS, number of days
that patients received at least 1 brain-specific
treatment, days of MV, treatment with high-dose
barbiturates, decompressive crani

17. Results

18. Results - Demographics

19. Results
 MVA’s accounted for most injuries (51% of
randomized pts)
 45% of pts were brought in by ambulance
 Remainder were transferred from other facilities
 Did not publish pre-hospital demographics or
interventions as these we not uniformly recorded

20. Results - Demographics
 24% of randomized patients had clinical decline to
GCS within eligibility criteria
 49% of patients had localizing signs on clinical exam
 33% of participants required surgical treatment of
mass lesions
 On initial CT, 85% had cisternal compression and
36% had >5mm midline shift

21. Results – Clinical Outomes

22. HR for death at 6mos =1.10,
slightly in favor of ICP group

25. Results – Subgroup Analysis
 Hospital LOS was slightly shorter in the ICE group (iqr 12 for
ICP, 9 for ICE)
 No significant differences in MV days, of non-neurologic
complications
 Except ICP-monitored pts had a higher incidence of decubitus ulcers
(12%vs 5%, P=0.03)
 Median time of ICP monitoring was 3.6d
 Incidence of Neuroworsening after randomization was 25% in
the entire study, and was similar in both groups
 Median interval for brain-specific treatments was longer in
ICE group
 Use of barbiturates was significantly higher in the ICP group
(24% vs 13%)
 HTS and HV were used more in the ICE group (72% vs 58%,
73% vs 60%)

26. Results
 Almost every variable, including LOS, mortality, anf
functional outcomes favored ICP monitoring with a
HR>1.
 The study was powered to detect statistical
significance of HR>1.5
 Subgroup analysis of HR accounting for Marshall CT
Classification

27. Results Summary
 Composite endpoints between the two groups were
similar (P=0.49)
 ICP group = 56
 ICE group = 53
 Mortality at 6 months (P=0.06)
 ICP group=39%
 ICE group=41%
 ICE group had more days of brain specific
treatments (hyperosmolar therapy, HV)

28. Discussion
 So what did the trial show?
 Clinicians act on ICP, without clinical correlate as
evidenced by the increased use of barbiturates
 Clinicians also act on clinical findings without
quantitative evidence of intracranial hypertension as
evidenced by more brain-specific treatments overall
in the ICE group.
 Is this because increased ICP could herald clinical
changes and early interventions abort herniation
events?
 Also, radiographic signs may not translate to the
parenchymal monitor.

29. Discussion - Skepticism
 South America – differences in pre-hospital, and post-
hospital care
 Less might survive to hospital or to hospital transfer
 Rehabilitation standards are different and may not
translate to the same cognitive recovery
 35%death in all groups after 14d
 Adjusted estimates of sTBI mortality in the US varies
from 41%-25% (J Neurotrauma. 2012 Jan 1;29(1):47-52., J Neurotrauma. 2012 Jan
1;29(1):47-52.)
 The “Thereapeutic Intensity Level” is a good overall
metric but others such as %responders to ICP-lowering
therapy has proven predictive and should have been
incorporated (J Neurosurg. 2011 May;114(5):1471-8)

30. Discussion - Skepticism
 Technology – parenchymal monitors as standard
 Triggers for treatment? – ICP>20 x 5 min vs
radiographic signs with or without clinical correlates
 ICP group – ICP triggers  ICP is too simplistic a
reflection of intracranial pathophysiology. No
account for CPP
 Clinical signs don’t always reflect global pressures
and vice versa
 No discussion of inclusion/exclusion of polytrauma
and surgical interventions

31. Discussion - Skepticism
 Variability in treatments (i.e. more mannitol and HV
in the ICE group) may be because the ICE group had
scheduled scans and interventions and the ICP group
had more event-related treatment triggers
 Conversely, that may explain why the ICP group had
more barbiturates and HTS

32. Discussion - benefits
 Very rigorous treatment algorithm for management
of elevated ICP (either qualitative or quantitative)
 Homogenous population across countries
 Both groups had intracranial HTN treated… that
isn’t in question
 In truth, this study did not test ICP monitoring, only
a very specific treatment algorithm to an ICP
threshold compared with clinical exam
 In the end, the neurologic exam might STILL be the
best tool in our disposal.

33. Further Discussion
 This was probably the only way that this type of trial
could be done
 Authors were careful not to compare South American
patients to our own, only report their findings
 The goal of therapies was to lower the average ICP
within the head – this doesn’t accurately reflect
mechanical compression and injury to diepnephalic
which may portend a worse prognosis. The clinical
signs of elevated ICP (pupil dilations, posturing,
coma) are directly related to these areas.

34. Further Discussion
 How would you alter the study?
 Could multimodal monitoring be the next step?
 Are composite endpoints more useful that single
variable? i.e. mortality? Return to work?
 Is a 6-month outcome long enough?
 Don’t forget that even the most rigorous study
cannot account for all possible variables and that this
data might not apply to every patient.