Modest temperature reduction for traumatic brain injury
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of modest cooling therapies (with antipyretic drugs or physical cooling devices) when administered to patients (adult and children) admitted to hospital after TBI.
We define modest temperature reduction as any interventions carried out with the intention of reducing body temperature to no less than 35ºC (this excludes studies identified in the Cochrane review titled 'Therapeutic hypothermia for head injury' (Alderson 2004) as this review assesses the effect of interventions that reduce temperature to below 34 to 35ºC).
We wish to test the following hypotheses:
1) Modest cooling therapies reduce the risk of a poor outcome after traumatic brain injury. We define a poor outcome as the composite endpoint of death or severe disability.
2) Modest cooling therapies increase the risk of intracranial and extracranial bleeding.
3) Modest cooling therapies increase the risk of pneumonia or other serious infections.
Background
Traumatic brain injury (TBI) is a major cause of death and disability amongst a predominantly young population, with an estimated 10 million people experiencing severe TBI worldwide every year (Alexander 1992). It is an important issue that affects both developed and developing countries. There is, however, a significant lack of coherent evidence about effective therapies in the acute care of these patients.
Certain animal experimental data (Busto 1989; Gunn 1997) have suggested that cooling may reduce neuronal damage but this has yet to be demonstrated in the clinical setting of TBI. There are now some data to support the use of systemic hypothermia following cardiac arrest in adults (body temperature reduction to 32 to 34ºC) and perinatal birth asphyxia (body temperature reduction to 35ºC) in neonates (Bernard 2002; Gluckman 2005). Pathophysiologically, TBI differs from cardiac arrest and neonatal birth asphyxia in that the primary insult is direct neuronal trauma and this is frequently complicated by associated secondary insults. These include disorders of the airway, breathing and circulation that may result in episodes of hypoxia, hypercarbia and low cardiac output (most commonly due to haemorrhage and hypovolaemia). The trials of temperature reduction after cardiac arrest and neonatal birth asphyxia have not been replicated in patients with TBI and an existing Cochrane review (Alderson 2004) has concluded that there is no evidence that hypothermia (defined as interventions that reduce core body temperature to at least 34 to 35ºC) is beneficial in the treatment of TBI. In addition this review suggested that there is a statistically significant increase in pulmonary infections with the intervention of hypothermia compared to controls. Systemic 'therapeutic' hypothermia remains a complex intervention that could only be applied to the small proportion of the total global pool of patients suffering a TBI that eventually present to facilities that have intensive care services.
Interventions that may achieve a more modest temperature reduction than systemic hypothermia include drug therapy (for example, paracetamol, acetaminophen, non‐steroidal anti‐inflammatory drugs etc) and physical therapies (for example, bedside fans, tepid sponging, ice packs etc). It has been argued that more modest methods of reducing temperature may have greater general applicability to the total global population of patients that present to acute care services following TBI (Andrews 2006). Arguably these therapies may also be easier to initiate at an earlier stage after TBI. We define modest temperature reduction after TBI as any intervention(s) that is (are) carried out with the intention of reducing body temperature to no less than 35ºC. This includes interventions that are administered with the intention of lowering body temperature to below normal (< 36.5ºC), but above 35ºC, and, those interventions that are given to try and maintain normothermia (36.5 to 37.5ºC).
The Brain Trauma Foundation (BTF 2000) does not make recommendations regarding modest temperature reduction after TBI, reflecting the lack of evidence for this intervention. At present, modest measures of reducing temperature as outlined above are used in an ad hoc measure after TBI. Although some observational studies may support this approach (Xiao 2002), we would like to search for randomised controlled clinical trials that explore the effects of more modest temperature reduction on outcomes following TBI. This systematic review aims to assess the relationship between imposed modest changes in body temperature and outcome after TBI and determine whether there is any clear evidence that modest temperature reduction of any kind is beneficial, has no effect, or causes harm.
Objectives
To assess the effects of modest cooling therapies (with antipyretic drugs or physical cooling devices) when administered to patients (adult and children) admitted to hospital after TBI.
We define modest temperature reduction as any interventions carried out with the intention of reducing body temperature to no less than 35ºC (this excludes studies identified in the Cochrane review titled 'Therapeutic hypothermia for head injury' (Alderson 2004) as this review assesses the effect of interventions that reduce temperature to below 34 to 35ºC).
We wish to test the following hypotheses:
1) Modest cooling therapies reduce the risk of a poor outcome after traumatic brain injury. We define a poor outcome as the composite endpoint of death or severe disability.
2) Modest cooling therapies increase the risk of intracranial and extracranial bleeding.
3) Modest cooling therapies increase the risk of pneumonia or other serious infections.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) of interventions for reducing body temperature to no less than 35ºC versus control in patients with traumatic brain injury (TBI) that require hospital admission.
Types of participants
All patients admitted to hospital following a TBI (all severities are to be included).
Types of interventions
Any physical or drug therapy that reduces temperature to no less than 35ºC.
Examples of physical therapy include bedside fans, fluid or air‐filled devices applied to body surfaces (for example, blankets, neck‐collars, helmets or hoods), ice‐water lavage or intravenous fluid administration and intravenous cooling catheters.
Examples of drug therapies include acetaminophen, paracetamol, non‐steroidal anti‐inflammatory drugs, cyclo‐oxygenase‐2 inhibitors given by any route.
Types of outcome measures
Primary outcome
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Poor outcome at the end of follow up. This is defined as death or dependency as measured by the Glasgow Outcome Score, or an equivalent method in which it is clear how many people are dependent and how many are independent at the end of the follow up period. This is the most important outcome as the aim of treatment should not only be to prevent death, but also to improve the quality of the patient's survival.
Secondary outcomes
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Death from all causes during the follow up period.
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Further serious intracranial haemorrhage: this is defined as the need for operative intervention (for example, evacuation of subdural or extradural haematoma) occurring during the period of intervention.
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Extracranial haemorrhage: defined as the need for transfusion of greater than two units of packed cells within a 24 hour period occurring during the period of intervention.
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Pneumonia or other serious infections.
Search methods for identification of studies
Electronic searches
We will search the following electronic databases;
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Cochrane Injuries Group's specialised register
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Cochrane Central Register of Controlled Trials (CENTRAL)
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MEDLINE
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EMBASE
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National Research Register
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Zetoc
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Current Controlled Trials
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MetaRegister of controlled trials
We will base the electronic database searches on the following MEDLINE strategy adapted, as appropriate, for each database;
1.exp CRANIOCEREBRAL TRAUMA/
2.exp Cerebrovascular Trauma/
3.exp BRAIN EDEMA/
4.exp GLASGOW COMA SCALE/
5.exp GLASGOW OUTCOME SCALE/
6.exp UNCONSCIOUSNESS/
7.(glasgow adj3 scale$).ab,ti.
8.(Unconscious$ or coma$ or concuss$ or 'persistent vegetative state').ab,ti.
9.Rancho Los Amigos Scale.ab,ti.
10.((head or crani$ or cerebr$ or capitis or brain$ or forebrain$ or skull$ or hemispher$ or intra‐cran$ or inter‐cran$) adj3 (injur$ or trauma$ or damag$ or wound$ or fracture$ or contusion$)).ab,ti.
11.Diffuse axonal injur$.ab,ti.
12.10 or 11
13.4 or 5 or 6 or 7 or 8 or 9
14.12 and 13
15.(therapy or surgery or rehabilitation or diet therapy or drug therapy or Prevention & Control).fs.
16.12 and 15
17.1 or 2 or 3 or 14 or 16
18.exp Hypothermia/
19.exp Hypothermia, Induced/
20.exp Cryotherapy/
21.(hypotherm$ or cryotherap$).ab,ti.
22.((cool$ or cold) adj3 (therap$ or device$ or equipment)).ab,ti.
23.(temperature adj3 reduc$).ab,ti.
24.(intravenous adj3 (cold or cool$) adj3 (fluid$ or catheter$)).ab,ti.
25.((cool$ or cold$) adj3 (blanket$ or neck collar$ or helmet$ or hood$)).ab,ti.
26.ice‐water lavage.ab,ti.
27.or/18‐26
28.exp Analgesics, Non‐Narcotic/
29.(analgesic$ adj3 (non?narcotic$ or non?opioid$)).ab,ti.
30.exp Acetaminophen/
31.antipyretic$.ab,ti.
32.(Aspirin or Meclofenamate sodium or Niflumic acid or Tiaprofenic acid or Tolfenamic acid or Acemetacine or Naproxen or Diclofenac or Etodolac or Fentiazac or Etofenamato or Fenbufen or Fentiazac or Nimesulid or Flurbiprofen or Ibuprofen or Indomethacin or Sulindac or ketoprofen or Lonazolac or Piroxicam or Tenoxicam or Proglumetacina or acetaminophen or paracetamol or acetamidophenol or hydroxyacetanilide or apap or acamol or acephen or acetaco or acetaminophen or algotropyl or anacin‐3 or datril or n‐4‐hydroxyphenyl acetanilide or n‐acetyl‐p‐aminophenol or panadol or Tylenol or p‐acetamidophenol).ab,ti.
33.exp Anti‐Inflammatory Agents, Non‐Steroidal/
34.((analgesic$ or non?steroidal) adj3 anti?inflammator$).ab,ti.
35.(NSAID$ or anti?rheumatic$ or aspirin‐like).ab,ti.
36.or/28‐35
37.exp Body Temperature/
38.exp Body Temperature Regulation/
39.(body adj3 temperature).ab,ti.
40.(body adj3 (cool$ or cold$)).ab,ti.
41.or/37‐40
42.36 and 41
43.27 or 42
44.17 and 43
45.(randomised or randomized or randomly or random order or random sequence or random allocation or randomly allocated or at random or controlled clinical trial$).tw,hw.
46.clinical trial.pt.
47.45 or 46
48.exp models, animal/
49.exp Animals/
50.exp Animal Experimentation/
51.exp Disease Models, Animal/
52.exp Animals, Laboratory/
53.or/48‐52
54.Humans/
55.53 not 54
56.47 not 55
57.44 and 56
Other sources
Reference lists of selected studies and relevant reviews will be hand checked to find additional studies. We will also contact the authors of relevant studies to assist in the identification of unpublished studies, internal reports, and conference proceedings. We also plan to contact investigators, pharmaceutical companies and manufacturer's of cooling equipment that are pertinent to this field.
The searches will not be restricted by publication status, date or language.
Data collection and analysis
Trial identification and selection
The titles and abstracts will be screened independently by two authors (MS and AC), who will discard studies that are not applicable, however studies and reviews that might include relevant data or information on trials will be retained initially. The authors will independently assess retrieved abstracts, and, if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria. The reference lists of all relevant studies will also be searched.
Data extraction
Data extraction will be carried out independently by the same authors using standard data extraction forms. Non‐English language studies will be translated before assessment. Any further information required from the original author will be requested by written correspondence and any relevant information obtained in this manner will be included in the review. Disagreements will be resolved after consultation with a third author (PA).
General information that will be extracted will include: trial name, intervention being tested (dosage and route for drug therapy and physical cooling method for equipment), lowest body temperature attained, duration of intervention, time between initial injury and cooling starting and any neurological deterioration occurring after cooling started. The total number of patients randomised, total number of patients randomised to placebo group and total number of patients randomised to intervention groups will be recorded. We will also collect data on age, gender, mechanism of injury, associated extracranial injuries and duration from injury to presentation to hospital.
Specific information regarding the number of patients in each group with the following outcomes: death and dependency, death alone, intracranial haemorrhage, extracranial haemorrhage, and, pneumonia or other serious infections.
Assessment of methodological quality
The quality of studies to be included will be assessed independently by two authors, without blinding to authorship or journal using a checklist developed by the Cochrane Renal Group. Discrepancies will be resolved by discussion. The quality items to be assessed are allocation concealment, blinding (participants, investigators, outcome assessors and data analysis), intention‐to‐treat analysis and completeness of follow‐up. It may be unfeasible to blind participants and investigators if cooling equipment is being used.
Allocation concealment
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A. Adequate ‐ randomisation method described that would not allow investigator or participant to know or influence intervention group before eligible participant entered in the study.
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B. Unclear ‐ randomisation stated but no information on method of allocation concealment used is available.
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C. Inadequate ‐ method of randomisation used such as alternate medical record numbers or unsealed envelopes; any information in the study that indicated that investigators or participants could influence intervention group.
Blinding
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Blinding of investigators: Yes/No/Not applicable/Not stated
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Blinding of participants: Yes/No/Not applicable/Not stated
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Blinding of outcome assessor: Yes/No/Not applicable/Not stated
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Blinding of data analysis: Yes/No/Not applicable/Not stated
The above are not considered blinded if the treatment group can be identified in >20% of participants because of the side effects of treatment.
Intention‐to‐treat
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Yes ‐ specifically reported by the authors that intention‐to‐treat analysis was undertaken and this was confirmed on study assessment.
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Yes ‐ not stated, but confirmed on study assessment.
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No ‐ not reported and lack of intention‐to‐treat analysis confirmed on study assessment (patients who were randomised were not included in the analysis because they did not receive the study intervention, they withdrew from the study, or were not included because of protocol violation).
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No ‐ stated but not confirmed upon study assessment.
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Not stated.
Completeness of follow‐up
Per cent of patients excluded or lost to follow‐up.
Data analysis
For dichotomous outcomes the results will be expressed as relative risk (RR) with 95% confidence intervals (CI). Data will be pooled using the random effects model but the fixed effect model will also be analysed to ensure robustness of the models chosen and susceptibility to outliers. Where continuous scales of measurement are used to assess the effects of treatment, the weighted mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used. Heterogeneity will be analysed using a chi‐squared test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance, and with the I2 test.
Subgroup analysis
We plan to explore the following.
1) Adults (>18 years old) versus children.
2) Target temperature reduction (35 to 36.5ºC versus placebo and 36.5 to 37.5ºC versus placebo).
3) Achieved temperature reduction (35 to 36.5ºC versus placebo and 36.5 to 37.5ºC versus placebo).
4) Duration of temperature reduction.
5) Time from injury to intervention.
Subgroup analysis will be used to explore possible sources of heterogeneity. Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various interventions being assessed. Where possible, the risk difference with 95% CI will be calculated for each adverse event, compared to no treatment.
Assessment of reporting bias
We will investigate the presence of reporting (publication) bias using funnel plots.
