Hyperbaric oxygen therapy for the adjunctive treatment of traumatic brain injury
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The aim of this review is to assess the evidence for the benefit of adjunctive HBOT in the treatment of acute TBI. We will compare intensive treatment regimens including adjunctive HBOT against similar regimens excluding HBOT. Where regimens differ significantly between studies, this will be clearly stated and the implications discussed.
Background
Traumatic brain injury is a significant cause of premature death and disability. Each year, there are at least 10 million new head injuries worldwide and these account for a high proportion of deaths in young adults (Thurman 1999; Alexander 1992). In the US there are more than 50,000 deaths due to traumatic brain injury each year. The major causes are motor vehicle crashes, falls, and violence (including suicide). Prevention strategies, including restraints for vehicle occupants, are now legally enforced in many countries. However, while road death rates are falling in most industrialised countries, they are rising in many rapidly motorising countries, particularly in Asia. For example, road death rates per head in China are already similar to those in the United States (Roberts 1995). Head injuries are associated with long‐term disability in many patients. In the US, for example, 2% of the population (5.3 million citizens) are living with disability as a result of TBI (Thurman 1999) and this places considerable medical, social and financial burden on both families and health systems (Fearnside 1997).
The pathophysiology of brain injury has a primary and secondary component. At the time of impact there is a variable degree of irreversible damage to the neurological tissue (primary injury). Following this, a chain of events occurs in which there is ongoing injury to the brain through oedema, hypoxia and ischaemia secondary to raised tissue or intracranial pressure, release of excitotoxic levels of excitatory neurotransmitters (e.g. glutamate), and impaired calcium homeostasis (Tymianski 1996; Fiskum 2000) (secondary injury).
Therapy focuses on prevention and/or minimisation of secondary injury by ensuring adequate oxygenation, haemodynamics, control of intracranial hypertension, and strategies to reduce cellular injury. A number of therapies, including barbiturates, calcium channel antagonists, steroids, hyperventilation, mannitol, hypothermia and anticonvulsants have been the topic of previous Cochrane reviews, though none has shown unequivocal efficacy in reducing poor outcome (Schierhout 2003; Roberts 2003a; Langham 2003; Alderson 2003; Roberts 2003b).
Hyperbaric oxygen therapy (HBOT) is a further adjunctive therapy that has been proposed to improve outcome in acute brain injury. HBOT is the therapeutic administration of 100% oxygen at environmental pressures greater than 1 atmosphere absolute (ATA). Administration involves placing the patient in an airtight vessel, increasing the pressure within that vessel, and administering 100% oxygen for respiration. In this way, it is possible to deliver a greatly increased partial pressure of oxygen to the tissues. Typically, treatments involve pressurisation to between 1.5 and 3.0 ATA for periods between 60 and 120 minutes once or more daily.
Since the 1960s, there have been reports that HBOT improves the outcome following brain trauma (Fasano 1964). Administration of HBOT is based on the observation that hypoxia following closed head trauma is an integral part of the secondary injury described above. Hypoxic neurons performing anaerobic metabolism result in acidosis and an unsustainable reduction in cellular metabolic reserve (Muizelaar 1989). As the hypoxic situation persists, the neurons lose their ability to maintain ionic homeostasis, and free oxygen radicals accumulate and degrade cell membranes (Ikeda 1990; Siesjo 1989). Eventually, irreversible changes result in unavoidable cell death. When ischaemia is severe enough, these changes occur rapidly, but there is some evidence that these effects can occur over a period of days (Robertson 1989). This gives some basis to the assertion that a therapy designed to increase oxygen availability in the early period following TBI may improve long‐term outcome. HBOT is also thought to reduce tissue oedema by an osmotic effect (Hills 1999), and any agent that has a positive effect on brain swelling following trauma might also contribute to improved outcomes. On the other hand, oxygen in high doses is potentially toxic to normally perfused tissue, and the brain is particularly at risk (Clark 1982). For this reason, it is appropriate to postulate that in some TBI patients, HBOT may do more harm through the action of increased free oxygen radical damage, than good through the restoration of aerobic metabolism.
Despite 40 years of interest in the delivery of HBOT in these patients, little clinical evidence of effectiveness exists. HBOT has been shown to reduce both intracranial pressure (ICP) and cerebrospinal fluid pressure (CSFP) in brain‐injured patients (Suckoff 1982; Hayakawa 1971), improve grey matter metabolic activity on SPECT scan (Neubauer 1994), and improve glucose metabolism (Holbach 1977). Some studies suggest that any effect of HBOT may not be uniform across all brain‐injured patients. For example, Hayakawa demonstrated that CSFP rebounded to higher levels following HBOT than at pre‐treatment estimation in some patients, while others showed persistent reductions (Hayakawa 1971). It is possible that HBOT has a positive effect in a sub‐group of patients with moderate injury, but not in those with extensive cerebral injury. Furthermore, repeated exposure to hyperbaric oxygen may be required to attain consistent changes (Artru 1976). Clinical reports have attributed a wide range of improvements to HBOT including cognitive and motor skills, improved attention span and increased verbalisation (Suckoff 1982; Neubauer 1994). These improvements are, however, difficult to ascribe to any single treatment modality because HBOT was most often applied in conjunction with intensive supportive and rehabilitative therapies.
HBOT is associated with some risk of adverse effects, including damage to the ears, sinuses and lungs from the effects of pressure, temporary worsening of short‐sightedness, claustrophobia and oxygen poisoning. Although serious adverse events are rare, HBOT cannot be regarded as an entirely benign intervention. For a number of reasons, therefore, the administration of HBOT for TBI patients remains controversial.
Objectives
The aim of this review is to assess the evidence for the benefit of adjunctive HBOT in the treatment of acute TBI. We will compare intensive treatment regimens including adjunctive HBOT against similar regimens excluding HBOT. Where regimens differ significantly between studies, this will be clearly stated and the implications discussed.
Methods
Criteria for considering studies for this review
Types of studies
Randomised and quasi‐randomised controlled trials that compare the effect of treatment for acute TBI where HBOT administration is included, with the effect of similar treatment in the absence of HBOT.
Types of participants
Any person admitted to an intensive care or intensive neurosurgical facility with an acute TBI following blunt trauma.
Types of interventions
HBOT administered in a compression chamber between pressures of 1.5ATA and 3.5ATA and treatment times between 30 minutes and 120 minutes at least once, will be eligible. The comparator group is likely to be somewhat diverse. We will accept any standard treatment regimen designed to maximise brain protection and promote recovery from TBI. We will not include studies where comparator interventions are not undertaken in a specialised acute care setting.
Types of outcome measures
Studies will be eligible for inclusion if they report any of the following outcome measures at any time.
Primary outcomes
1. Functional outcome. Assessment by Glasgow outcome scale or similar.
2. Mortality. We will use data as reported. Where there are multiple times recorded, we will choose the final follow‐up.
Secondary outcomes
1. Activities of daily living (AODL).
2. Intracranial pressure (ICP).
3. MRI or CT evidence of lesion resolution or size of persistent defect.
4. Progress of Glasgow coma score.
5. Adverse events of HBOT.
The timing of outcome evaluations may very between studies. In general, our aim is to group outcomes into three stages for analysis‐ early (immediately after treatment course), medium term (four to eight weeks after treatment) and longer‐term (six months or longer).
Search methods for identification of studies
It is our intention to capture both published and unpublished studies.
Electronic searches
We will search: the Cochrane Controlled Trials Register (CENTRAL Issue 3, 2003), MEDLINE (Ovid), CINAHL, EMBASE and an additional database developed in our hyperbaric facility (the Database of Randomised Trials in Hyperbaric Medicine, Bennett 2002). All databases will be searched from inception to late 2003. The search strategy will be broad and the keywords in the following strategies will be adapted as appropriate. The EMBASE and MEDLINE (OVID) strategies are given in Table 1.
| EMBASE | MEDLINE (OVID) |
| 1. exp head injury/ | 1. exp head injuries‐penetrating |
In addition we will make a systematic search for relevant controlled trials in specific hyperbaric literature sources as follows.
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Experts in the field and leading hyperbaric therapy centres (as identified by personal communication and searching the Internet) will be contacted and asked for additional relevant data in terms of published or unpublished randomised trials.
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Handsearch of relevant hyperbaric textbooks (Kindwall, Jain, Marroni, Bakker, Bennett and Elliot), journals (Undersea and Hyperbaric Medicine, Hyperbaric Medicine Review, South Pacific Underwater Medicine Society (SPUMS) Journal, European Journal of Hyperbaric Medicine and Aviation, Space and Environmental Medicine Journal) and conference proceedings (Undersea and Hyperbaric Medical Society, SPUMS, European Undersea and Baromedical Society, International Congress of Hyperbaric Medicine) published since 1980.
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Contact authors of relevant studies to request details of unpublished or ongoing investigations.
All languages will be considered. Authors will be contacted if there is any ambiguity about the published data.
Data collection and analysis
Data retrieval and management
One reviewer (MB) will be responsible for handsearching and identification of appropriate studies for consideration. Two reviewers (MB and BJ) will examine the electronic search results and identify studies that may be relevant and these studies will be entered into a bibliographic software package (Review Manager) whether one or both reviewers consider this appropriate. All comparative clinical trials identified will be retrieved in full and reviewed independently by three reviewers, two with content expertise with HBOT, one with content expertise in treating acute TBI. In addition, one of the reviewers (MB) has expertise in clinical epidemiology. Reviewers will record data using the data extraction form developed for this review.
Data extraction
Using the data extraction form developed for this review, each reviewer will extract relevant data, grade the studies for methodological quality using the method of Jadad (Jadad 1996), and make a recommendation for inclusion or exclusion from the review. The method of Jadad scores trials on three criteria (randomisation, double‐blinding and description of withdrawals), each of which, if present, is given a score of 1. Further points are available for description of a reliable randomisation method and use of a placebo (modified for our analysis to include a sham HBOT session). The scores are totalled as an estimate of overall quality and we will require a score of at least 2 for inclusion in the review. Any differences will be settled by consensus. In addition, we will indicate for each study selected for inclusion: the method of allocation, adequacy of concealment of allocation, blinding status of participants and outcome observers, and how patient attrition was handled. These factors will be considered for possible sensitivity analysis. All data extracted will reflect original allocation group where possible, to allow an intention to treat analysis. Dropouts will be identified where this information is given.
Analyses
All comparisons will be made using an intention‐to‐treat analysis where possible and reflect efficacy in the context of randomised trialling, rather than true effectiveness in any particular clinical context. For proportions (dichotomous outcomes), relative risk (RR) will be used. We propose to use a fixed‐effect model where there is no evidence of significant heterogeneity between studies (see below), and will employ a random effects model when such heterogeneity is likely.
Primary outcomes
1) Proportion of subjects with good functional outcome (e.g. Glasgow outcome score) will be dichotomised. Subjects with a good recovery or moderate disability will be included in the 'good' group, while those who are severely disabled, remain in a vegetative state or die will be included in the 'bad' group.) The RR for good outcome with HBOT will be established using the intention‐to‐treat data of the HBOT, versus the control group. Analyses will be performed with RevMan 4.2 software. As an estimate of the statistical significance of a difference between experimental interventions and control interventions, we will calculate RR for benefit using HBOT with 95% confidence intervals (CIs). A statistically significant difference between experimental intervention and control intervention will be assumed if the 95% CI of the RR does not include the value 1.0. As an estimate of the clinical relevance of any difference between experimental intervention and control intervention, we will calculate the number‐needed‐to‐treat (NNT) and number‐needed‐to‐harm (NNH) with 95% CI as appropriate.
2) Proportion of those surviving. The RR for death with and without HBOT will be calculated using the methods described in (1) above.
Secondary outcomes
3) Activities of daily living (AODL).The weighted mean differences (WMD) in AODL between HBOT and control groups will be compared using RevMan 4.2. A statistically significant difference will be defined as existing if the 95% CI does not include a zero WMD. The statistical method employed may depend on the nature of the data presented in the relevant papers.
4) Intracranial pressure. The WMD in ICP between the HBOT and control groups will be calculated in a way analogous to (3) above.
5) Dichotomous data will be considered for adverse events (number of patients with adverse events versus number of patients without them in both groups) in the HBOT groups of the included studies.
Sensitivity analyses
We intend to perform sensitivity analyses for missing data and study quality.
Missing data
We will employ sensitivity analyses using different approaches to imputing missing data. The best‐case scenario will assume that none of the originally enrolled patients missing from the primary analysis in the treatment group had the negative outcome of interest whilst all those missing from the control group did. The worst‐case scenario will be the reverse.
Study quality
If appropriate, we will also conduct a sensitivity analysis by study quality based on the presence or absence of a reliable random allocation method, concealment of allocation, and blinding of participants or outcome assessors.
Subgroups
Where appropriate data exists, we will consider subgroup analysis based on:
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age ‐ adults versus children
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dose of oxygen received (pressure, time and length of treatment course)
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nature of the comparative treatment modalities
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severity of injury
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nature of injury on CT scan.
Heterogeneity will be explored and subgroup analyses will be performed if appropriate. Statistical heterogeneity will be assessed using the I2 statistic and consideration will be given to the appropriateness of pooling and meta‐analysis.
| EMBASE | MEDLINE (OVID) |
| 1. exp head injury/ | 1. exp head injuries‐penetrating |
