Hyperbaric oxygen therapy for acute surgical and traumatic wounds
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To summarise the evidence for the effects of HBOT in people with acute surgical and traumatic wounds.
Background
Local and systemic treatment of wounds is characterised by a wide range of therapeutic strategies and large variations in clinical opinion and practice. One of those systemic strategies is hyperbaric oxygen therapy (HBOT).
The roots of hyperbaric oxygen can be traced to 1662, when Henshaw used compressed air to treat multiple diseases. In more recent times Boerema began to study the possible applications of HBOT to surgery, in particular as an aid in open heart surgery (Boerema 1964; Boerema 1965). Since then, interest in this therapy has increased with the result that several centres throughout the world have built high‐pressure chambers (Boerema 1965).
Description of the condition
‘Acute’ wounds are defined as skin injuries that occur as a result of a trauma or surgical procedure and proceed normally along the healing pathway with at least external manifestations of healing and without complications (Lazarus 1994). Lazarus suggested acute wounds proceed through to healing “in an orderly and timely reparative process”. Orderliness refers to the healing sequence of inflammation, angiogenesis, matrix deposition, wound contraction, epithelialisation, and scar remodelling. Timeliness is subjective, but refers to a healing time that could be reasonably expected (Jull 2008).
Acute wounds are more numerous than chronic wounds and costs increase when complications occur. (Franz 2007). Surgical incisions usually heal by primary intention, assisted by sutures, clips etc. Healing by secondary intention occurs when an open wound heals from the base upwards by deposition of new tissue (Vermeulen 2004). This kind of wound healing may occur if there is a tissue deficit and the edges of the wound cannot be brought together and where wounds are compromised by a poor local blood supply (e.g. ischaemic wounds, skin grafts and flaps), infection (e.g. gas gangrene), and/or damage to the vasculature (e.g. lacerations, crush, stab, and biopsy wounds) (MacFarlane 2001). Whilst these wounds are acute in origin they may prove difficult to heal and additional treatments such as HBOT have been promoted as assisting the wound healing process.
Description of the intervention
We define HBOT as the use of 100% oxygen at pressures above 1 atmosphere in order to improve or correct conditions (Bennett 2008). There are two kinds of HBOT chamber:
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a monoplace chamber which is pressurised with oxygen and accommodates a single patient who directly breathes pure oxygen (Niinikoski 2003);
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a multiplace chamber which is pressurised with air and can accommodate several people and/or health care personnel. The patient breathes oxygen through a mask or head tent (Boerema 1964; Villanueva 2004; Wang 2003).
The application of HBOT involves bathing all fluids, tissues and cells of the body in oxygen. HBOT enhances the transportation of oxygen by increasing the oxygen saturation of the blood (mainly as oxyhaemoglobin). Through HBOT oxygen is administered at environmental pressures greater than 1 atmosphere absolute (ATA) to increase the blood oxygen content. This involves placing the patient in an airtight chamber, increasing the oxygen pressure within that chamber, and usually administering 100% oxygen for respiration. Thus, it is possible to deliver a significantly increased partial pressure of oxygen to the tissues. Treatment involves pressurisation up to 1.5 to 3.0 ATA, for a time frame of between 60 to 120 minutes at least once or more than once daily. However, oxygen in high doses is toxic to normally perfused tissue, particularly in the brain and lungs. Therefore regular HBOT sessions should not last longer than one to two hours (Kranke 2004). The period of treatment may range from less than one week to several months, the average being two to four weeks. A typical course might involve 15 to 30 such treatments (Kranke 2004).
Using clinical assessment and investigations (e.g. transcutaneous oxygen measurements) designed to confirm significant peri‐wound hypoxia, hyperbaric practitioners attempt to select wounds in which a response to HBOT is considered likely (Kranke 2004; Hess 2003).
Adverse effects
Oxygen in high doses can be toxic, particularly in richly perfused tissue such as the brain (acute cerebral oxygen toxicity) and lungs (chronic pulmonary oxygen toxicity). Acute cerebral toxicity occurs in approximately 1 in 2000 exposures and does not appear to result in any permanent injury, while the pulmonary changes are dose‐related and reversible at doses used therapeutically. Other potential risks associated with HBOT include damage to the ears, sinuses and lungs from the effect of pressure (barotrauma) and the psychological effect of confinement (Roeckl‐Wiedmann 2005). Whilst serious adverse events are rare, HBOT cannot be regarded as benign (Bennett 2005b).
Indications for hyperbaric oxygen therapy
Today, HBOT is mainly applied to treat gas gangrene, decompression sickness, and carbon monoxide (CO) poisoning. There are several systematic reviews describing the effectiveness of HBOT, one of which is on patients with early presentation of idiopathic sudden sensorineural hearing loss. The application of HBOT improved hearing loss significantly in these cases, but the clinical relevance of the level of improvement is not clear (Bennett 2007). HBOT may also improve local tumour control and reduce mortality for cancers of the head and neck (Bennett 2005a) and may improve radiation injuries of the head, neck, and bowel (Bennett 2005b).
HBOT also appears to be appropriate for poorly healing wounds, exceptional blood loss anaemia, necrotising soft‐tissue infections, refractory osteomyelitis, radio‐necrosis and intracranial abscesses (MacFarlane 2001). HBOT has been used for treating acute and chronic wounds, including surgical wounds, penetrating wounds, lacerations, burns, skin transplantation, open fractures, gas gangrene and diabetic foot ulcers. (Kranke 2004; Villanueva 2004; Bouachour 1996).
The potential value of HBOT for chronic wounds has been investigated in a systematic review by Kranke 2004 which found that in patients with diabetic foot ulcers, HBOT significantly reduced the risk of major amputation and improved the chance of healing at one year. Patients receiving HBOT are one‐third as likely to require such an amputation in comparison to controls and it is estimated that only four patients with HBOT need to be treated to avoid one major amputation (Roeckl‐Wiedmann 2005).
How the intervention might work
HBOT has been proposed as a useful adjunct in the treatment of problematic wounds. HBOT has been shown to cause hyper‐oxygenation of normal tissue and of tissue with poor blood perfusion. Arterial oxygen tensions of greater than 1000 mmHg are routinely achieved during HBOT and such tensions in plasma cause up‐regulation of growth factors, down‐regulation of inflammatory cytokines, increased fibroblast activation, angiogenesis, antibacterial effects and enhanced antibiotic action (Roeckl‐Wiedmann 2005).
Why it is important to do this review
Many claims have been made regarding the effectiveness of HBOT as an adjunctive or primary treatment in the healing of wounds by secondary intention and it is important to test these claims by summarising all the evidence in a systematic review. Some studies have demonstrated the use of HBOT in the management of severe limb trauma (Bouachour 1996), and in the management of thermal burns (Villanueva 2004). HBOT has also been used in the treatment of ischaemic wounds before skin grafting and to support the take of ischaemic flaps (Friedman 2006). Surgical removal (excision or debridement) of the damaged skin is followed by skin grafting. Skin grafts and compromised skin flaps represent a classical problem involving insufficient oxygen supply to tissue. The presence of oxygen is necessary for normal wound healing. Oxygen has been given as a therapeutic modality to assist and speed wound healing (Rodriguez 2008). HBOT is also said to improve the chances that a graft will take. There have been claims that skin grafts and flaps take more completely and rapidly (Kindwall 1991).
Most acute wounds heal without difficulty, however some are subject to factors that can impede healing, like poor local blood supply, infection, or damage to the vasculature. Acute wounds which present even one of these factors have the potential to become acute problem‐wounds. The effectiveness of HBOT for treating these acute wounds has not yet been justified by high‐level evidence and it is timely to undertake a systematic review of the available evidence.
Objectives
To summarise the evidence for the effects of HBOT in people with acute surgical and traumatic wounds.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs).
Types of participants
People with acute surgical and traumatic wounds (e.g. surgical wounds, penetrating wounds, lacerations, skin grafts, animal bites and traumatic wounds) receiving HBOT. We will exclude patients with open fractures and burns, because both have already been the subject of other Cochrane reviews (Villanueva 2004; Bennett 2005c).
Types of interventions
HBOT for acute wounds. Treatment in a single or multiplace chamber with HBO above atmosphere pressure.
Likely comparisons will be:
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HBOT compared with any other intervention;
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HBOT compared with sham‐HBOT;
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comparisons of different intensities of HBOT (ATA);
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comparisons of different numbers of treatment applications.
Types of outcome measures
Primary outcomes
Objective measures of wound healing, such as:
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time to complete healing (days);
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number of wounds completely healed (proportion);
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adverse effects (for example visual disturbance, barotrauma, oxygen toxicity, infection).
Secondary outcomes
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survival of flap, graft, or split skin graft (percentage);
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mortality;
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pain scores (VAS);
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quality of life (QoL);
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patient satisfaction;
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activities daily living (e.g. BAI, Barthel's Index of Activities of Daily Living);
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TcpO2 increase (transcutaneous oxygen tension measurements (Ubbink 1997);
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major and minor amputations;
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length of hospital stay;
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costs.
Search methods for identification of studies
Electronic searches
The following electronic databases will be searched:
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Cochrane Wounds Group Specialised Register
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The Cochrane Central Register of Controlled Trials (CENTRAL) ‐ The Cochrane Library (latest issue)
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Ovid MEDLINE ‐ 1950 to current
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Ovid EMBASE ‐ 1980 to current
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EBSCO CINAHL ‐ 1982 to current
The following search string is proposed for use the Cochrane Central Register of Controlled Trials (CENTRAL):
#1 MeSH descriptor Acute Disease explode all trees
#2 MeSH descriptor Wounds and Injuries explode all trees
#3 (#1 AND #2)
#4 MeSH descriptor Surgical Wound Infection explode all trees
#5 MeSH descriptor Surgical Wound Dehiscence explode all trees
#6 MeSH descriptor Wounds, Penetrating explode all trees
#7 MeSH descriptor Lacerations explode all trees
#8 MeSH descriptor Burns explode all trees
#9 MeSH descriptor Bites and Stings explode all trees
#10 MeSH descriptor Skin Transplantation explode all trees
#11 MeSH descriptor Fractures, Open explode all trees
#12 MeSH descriptor Gas Gangrene explode all trees
#13 ((surgical NEXT wound*) or (incised NEXT wound*)):ti,ab,kw
#14 (laceration* or gunshot or (gun NEXT shot) or stab or stabbing or
stabbed or bite* or bitten):ti,ab,kw
#15 ((traumatic NEXT wound*) or (acute NEXT wound*)):ti,ab,kw
#16 ((mechanical NEXT trauma) or polytrauma):ti,ab,kw
#17 ((thermal or blast or crush or avulsion) NEXT injur*):ti,ab,kw
#18 ("burn" or "burns" or burned or scald*):ti,ab,kw
#19 acute NEXT wound*:ti,ab,kw
#20 acute NEXT ulcer*:ti,ab,kw
#21 ((donor NEXT site*) or (skin NEXT graft*)):ti,ab,kw
#22 ((open NEXT fracture*) or (compound NEXT fracture*)):ti,ab,kw
#23 "gas gangrene":ti,ab,kw
#24 experimental NEXT wound*:ti,ab,kw
#25 "skin infarction":ti,ab,kw
#26 skin NEXT flap*:ti,ab,kw
#27 (#3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR
#13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR
#23 OR #24 OR #25 OR #26)
#28 MeSH descriptor Hyperbaric Oxygenation explode all trees
#29 (hyperbaric* NEXT oxygen*):ti,ab,kw
#30 (HBO or HBOT):ti,ab,kw
#31 (high NEXT pressure NEXT oxygen*):ti,ab,kw
#32 (#28 OR #29 OR #30 OR #31)
#33 (#27 AND #32)
This strategy will be adapted where necessary to search Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL. The MEDLINE search will be combined with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity‐ and precision‐maximising version (2008 revision) (Lefebvre 2008). The EMBASE and CINAHL searches will be combined with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2009). There will be no restrictions on the basis of date or language of publication. We will contact the Trials Search Coordinator of the Cochrane Wounds Group, to assist with the development of the various search strategies.
Searching other resources
We will contact authors and experts in the field for any information about unpublished studies, and we will retrieve the reference sections of all potentially relevant studies to be searched for additional studies. Where possible non‐English language papers will be translated with the assistance of a native speaker and included if eligible.
Data collection and analysis
Selection of studies
Two review authors (AE and HV) will independently select potentially relevant trials based on the titles and abstracts of the articles retrieved by the search. We will obtain full text versions of articles after this initial assessment if they match the inclusion criteria or if further scrutiny is needed to make a decision with regards to inclusion / exclusion. The same review authors will independently make the final selection of trials to be included. A third review author (DU) will arbitrate any discrepancies.
Data extraction and management
Two review authors (AE and HV) will independently extract data from the included trials using a data extraction sheet. If data are missing from reports, or clarification is needed, we will contact the trial authors in an effort to obtain missing information. Data from trials published in duplicate will be included only once.
We will extract the following data:
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characteristics of the trial (method of randomisation, allocation concealment, blinding, intention‐to‐treat, follow‐up, dropouts, setting, location of care, country, source of funding);
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participants (number, age, sex, type of wound, wound size, duration of wound, length of follow up, concurrent illnesses);
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intervention (intensities, frequency);
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comparison intervention;
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results of all relevant outcomes in all groups (intervention and control).
Assessment of risk of bias in included studies
Two review authors (AE and HV) will independently assess each included study using the Cochrane Collaboration tool for assessing risk of bias (Higgins 2008). This tool addresses six specific domains, namely sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other issues (e.g. baseline imbalance, financial support) (see Appendix 1 for details of criteria on which the judgment will be based). Blinding and completeness of outcome data will be assessed for each outcome separately. We will complete a risk of bias table for each eligible study. We will discuss any disagreement amongst all authors to achieve a consensus.
We will present assessment of risk of bias using a 'risk of bias summary figure', which presents all of the judgments in a cross‐tabulation of study by entry. This display of internal validity indicates the weight that the reader may give the results of each study.
Measures of treatment effect
We will calculate summary estimates of treatment effect (with 95% CI) for every comparison. For continuous outcomes, the mean differences (MD) will be presented. For dichotomous outcomes, the absolute risk reduction, i.e. risk difference (RD), will be presented, which is an absolute effect measure that expresses the difference between the experimental and the control event rates and allows calculation of the number needed to treat (NNT). Time to event data will be analysed using hazard ratios or will be dichotomised (e.g. number of wounds healed over a specified time period) in which case it will be analysed as risk ratios.
Assessment of heterogeneity
A logistic model based on the PICO framework will be used to assess the clinical heterogeneity (Ioannidis 2008).Two review authors will independently assess the (dis)similarity of the interventions, outcomes, designs, participants characteristics and settings. Statistical heterogeneity will be identified by visual inspection of graphs and assessment of the value of I2. Data will be pooled, depending on their heterogeneity (Higgins 2003). Heterogeneity will be assessed using values of I2. If the I2 value is 30% or less, a fixed effect model will be used, if I2 is between 30% and 60% a random effects model will be used, and no pooling will be performed if I2 is 60% or higher.
Data synthesis
One review author (AE) will enter data, and analyse it, using Cochrane RevMan software (RevMan 5.0), and another review author (HV) will check it. Methods of synthesising the studies will depend on the quality, design and heterogeneity of the studies identified. If it is appropriate to pool studies, dichotomous outcomes will be presented as risk ratio (95% CI) as the risk difference is affected by the underlying baseline risk of the patients in the study.
Subgroup analysis and investigation of heterogeneity
We will conduct subgroup analyses for each wound type (e.g. surgical wounds).
