“Normothermia for traumatic brain injury”
- A proposal for a cross-sectional study of
temperature management practice after TBI
in low-, middle- and high-income countries
A collaboration between:
ANZICS - CTG
The George Institute
The CRASH Collaborators
The ESICM
Dr Manoj Saxena,
University of New South Wales,
St. George Hospital, Kogarah,NSW.
3 separate hypotheses for
cooling after TBI
• Can immediate systemic hypothermia (3234°C) improve clinical outcomes? - POLAR
• Can delayed systemic hypothermia (32-34°C)
to control ICP improve clinical outcomes? EUROTHERM
• Can interventions targeted at normothermia
improve clinical outcomes
Does targeting normothermia
warrant further investigation?
• Acute ischaemic stroke data:
• Observational studies (n=180-400)
–
–
–
–
*Kammersgard (2002) Stroke; 33:1759-62
**Dippel (2003) Neurology 61: 677-79
Jorgensen 1996 Lancet; 347: 422-5
Azzimondi 1995 Stroke; 26: 2040-3
* = risk of a poor outcome rises by a factor of 2.2 for each degree
centigrade increase in body temperature (95% CI 1.4 to 3.5)
** = temperature decrease of 0.27ºC may reduce the relative risk of poor
outcome after acute ischemic stroke by 10-20%
Growth in
Road
Traffic
Fatalities
Mathers CD (2006) : PLoS Medicine (11) 13 e442
Methods of Cooling
- globally 10 million hospitalised with
TBI per annum
• Drugs eg paracetamol/NSAID
• Convective cooling eg fan
• Cold iv fluids/ice packs
• Conductive cooling eg application of ice/cooling
caps
• Cooling blankets
Cost
• Cooling catheters
Staff Expertise
Equipment
Complexity of intervention
Global applicability
The normothermia debate
• Normothermia is the current “default” therapy
– Experimental data
– Observational data
– Control arm of systemic hypothermia trials
• Surveys*
– Canadian/UK/ESICM
• Brain Trauma Foundation
• Systematic Review
*Johnstone NJ (2006) Resuscitation
*Jacka MJ (2007) Can J Neurol Sci
Systematic Review of cooling
therapies after TBI (35-37.5°C)
• Does maintaining temperature between
35 and 37.5°C improve outcome?
• Drug therapy:
– paracetamol, acetaminophen, NSAIDs
• Physical therapies:
– fans, iv saline, cooling blankets etc
Saxena M, Andrews PJD, Cheng A. Modest cooling therapies (35-37.5°C) for traumatic brain injury.
Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD006811. DOI: 10.1002/14651858.CD006811.pub2
Systematic Review of cooling
therapies after TBI (35-37.5°C)
No studies included in the review
10 RCTs evaluated
• only 4 placebo-controlled
• 9/10 mixed neurosurgical case series
– Physiological end-points
• 1 study was a placebo-controlled RCT
– Control group received cooling
– Outcome data missing in 40/96
• No evidence that these interventions improve
patient outcomes
Saxena M, Andrews PJD, Cheng A. Modest temperature reduction for traumatic brain injury.
Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD006811. DOI: 10.1002/14651858.CD006811
The normothermia debate
• Normothermia is the current “default”
therapy
– Control arm of systemic hypothermia trials
– Observational data
• Surveys*
– Canadian/UK/ESICM
• Brain Trauma Foundation
• Systematic Review
*Johnstone NJ (2006) Resuscitation
*Jacka MJ (2007) Can J Neurol Sci
1.
Systematic reviews of interventional data
a)
b)
c)
2.
Cross-sectional study on temperature management after TBI
(St George Medical Research Foundation Grant 2008)
a)
b)
c)
d)
3.
Site survey
George CCRDG retrospective study
ANZICS/George Institute point prevalence study (CTG endorsed 2008)
International study: ANZICS/George Institute/CRASH/ESICM
Phase 2b study (ANZCA Project Grant 2008) :
a)
b)
4.
Modest cooling (35-37.5°C) after head injury - Cochrane Injuries Group
(Cooling therapies after experimental models of TBI)
NSAIDS for TBI - Cochrane Injuries Group
Does iv paracetamol reduce body temperature after TBI?
Is iv paracetamol safe after TBI?
(Phase 3 study targeting normothermia after TBI)
Low-cost therapeutic thermal regulation in TBI
Research program
Why do we need a crosssectional study?
• Accurate, prospective description of practice
– Inform design of subsequent phase 2 and phase 3
trials
• Understanding global differences in
availability of resources
• ? Demonstrating heterogeneity of practice
Study design
•
Aim: To conduct an international, cross sectional study of the clinical
practice of temperature management in low-, middle- and high-income
countries in patients with TBI.
•
Objectives: During the first 7 days of admission to hospital/ICU:
1. To describe the methods used to measure body temperature.
2. To describe the target temperature prescribed.
3. To describe the achieved temperature in relation to the prescribed
target temperature.
4. To describe the intensity of drug and physical therapies used to
achieve the prescribed target temperature.
Inclusion criteria
• TBI requiring hospital/ICU admission
• Age > 16 years old
Data collection tool
• Modification of SAFE-TRIPS CRF
– Point Prevalence Programme (25-50
patients)
– Retrospective study (100-150 patients)
– Will need to be suitable for use across
different resource settings.
Data Collection
• Demographic
– Age
– Date and time of injury
– Mechanism
– Presence of ICP monitoring
– Post-resuscitation GCS
– Marshall score
Data Collection
• Temperature management
– Method of measurement
• Location, frequency,
– Target temperature specification
– Actual achieved temperature
– Interventions used to modify temperature
• Pharmacological
• Physical
Data analysis:
• Temperature data
– Time weighted mean
– Categorize as 0.5 C bands and present as
frequency bar chart
• Subgroup analysis based on target temperature
– Define pyrexia as single temperature > 38
C in any 24-hour period
Data Analysis
• Temperature data:
–
–
–
–
Pharmacological and physical therapies
Level 1: Drugs with anti-pyretic effects
Level 2: Simple physical therapies
Level 3: Complex physical therapies
– Frequency of use of therapy/total number of
patients each day
– Use of therapies within the target temperature
group
Outcomes
• Accurate prospective description of
interventions used to modify temperature in
low-, middle- and high-income countries.
• Valuable baseline information for planning
interventional studies to assess the efficacy of
normothermia after TBI
Feasibility
• ANZICS-CTG
– ATBIS
• George Institute
• CRASH collaborators
• ESICM
1.
Systematic reviews of interventional data
a)
b)
c)
2.
Cross-sectional study on temperature management after TBI
(St George Medical Research Foundation Grant 2008)
a)
b)
c)
d)
3.
Site survey
George CCRDG retrospective study
ANZICS/George Institute point prevalence study (CTG endorsed 2008)
International study: ANZICS/George Institute/CRASH/ESICM
Phase 2b study (ANZCA Project Grant 2008) :
a)
b)
4.
Modest cooling (35-37.5°C) after head injury - Cochrane Injuries Group
(Cooling therapies after experimental models of TBI)
NSAIDS for TBI - Cochrane Injuries Group
Does iv paracetamol reduce body temperature after TBI?
Is iv paracetamol safe after TBI?
(Phase 3 study targeting normothermia after TBI)
Low-cost therapeutic thermal regulation in TBI
Research program