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NCCU Journal Club

JOSHUA KORNBLUTH, MD
F E B 5 TH, 2 0 1 3

 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

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

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

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

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

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.

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

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

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*

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

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

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

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

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

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

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

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%)

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

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)

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.

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)


 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


 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

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.

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.

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.

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Nccu journal club 2.5.13

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