Burns 32 (2006) 650–652 www.elsevier.com/locate/burns
Hyperbaric oxygen as adjuvant therapy in the management of burns: Can evidence guide clinical practice? Jason Wasiak a,*, Mike Bennett b, Heather J. Cleland a b
a The Alfred Hospital, Victorian Adult Burns Unit, Commercial Road, Prahran, Melbourne 3183, Australia Prince of Wales Hospital, Department of Diving and Hyperbaric Medicine, Barker Street, Randwick, New South Wales 2031, Australia
In 2006, therapy for burns is based on aggressive and appropriate fluid resuscitation; topical agents, including skin substitutes for pain relief, antisepsis and scar reduction; and early debridement of devitalised tissue and surgical wound closure; all measures designed to promote healing and minimise scar formation. Developments over the last two decades have significantly improved outcomes, but burn remains an ongoing source of mortality and long-term morbidity [1]. An active search therefore continues for interventions that will further improve outcomes. Hyperbaric oxygen therapy (HBOT) may be one such intervention. It was first suggested for the treatment of thermal burns more than 40 years ago when Wada et al. [2] serendipitously observed more rapid healing of seconddegree burns in a group of coal miners who were being treated with HBOT for carbon monoxide poisoning In 1969, Gruber et al. [3] demonstrated that the area sub-adjacent to a full-thickness injury was hypoxic and could be raised to normal or supra-normal levels through the administration of oxygen under pressure and this was followed by a series of animal experiments that demonstrated a significant reduction of oedema, improved microcirculation, reduced inflammatory responses, faster epithelialisation, and improved wound healing with HBOT [4,5]. The apparent effectiveness of HBOT in these animal models is attributed to the grossly increased partial pressure of oxygen in the arterial blood, and a consequent modest increase in the ability of HBOT to deliver a greatly increased partial pressure of oxygen in the tissues. HBOT can achieve improvements in tissue oxygenation, even in the face of significant ischaemia, because very high arterial oxygen tensions (PaO2) can be achieved by oxygen breathing at increased pressure. While the PaO2 of a normal individual * Corresponding author. Tel.: +61 3 9276 2499; fax: +61 3 9276 6568. E-mail address:
[email protected] (J. Wasiak). 0305-4179/$30.00 # 2006 Elsevier Ltd and ISBI. All rights reserved. doi:10.1016/j.burns.2006.04.006
breathing air will be approximately 100 mmHg, breathing oxygen at 2 ATA produces a PaO2 of about 1400 mmHg. Such high arterial partial pressures produce steep gradients down which oxygen diffuses into hypoxic tissues. Normalisation of tissue oxygen tensions in hypoxic wounds by this mechanism is achieved in hyperbaric facilities to produce clinically important benefits for those with diabetic foot ulcers and radiation tissue injury [6,7]. Why should high arterial oxygen tensions and improving tissue oxygenation result in such benefits? Two main potential mechanisms have been demonstrated. First, gross hyperoxia directly inhibits microvascular obstruction through a profound inhibition of the leucocyte activation that is the feature of endothelial injury [8]. This effect is mediated through inhibition of beta two-integrin activation of intracellular adhesion molecule one (ICAM-1) [9] and enables tissues to maintain microvascular flow in areas otherwise subject to the well-described ‘secondary injury’ following a significant thermal burn [10]. This effect persists for some hours at least, and has been demonstrated recently by both Ueno et al. [11] and Miljkovic-Lolic et al. [12] among others. Another direct effect of gross intravascular hyperoxia may be enhanced resolution of oedema through an oxygen osmotic effect [13] because the intravascular tension remains much higher than the tissue tension, there is a constant steep concentration gradient promoting movement of water out of the tissues into the vascular space. Second, the modest increase in tissue oxygen tension enables a raft of immune and healing functions in the hypoxic tissue. For example, the process of phagocytosis involves consumption of oxygen in an ’oxidative burst’ and although such processes are possible at remarkably low tissue oxygen tensions, improving oxygenation to within or above the physiologic range dramatically improves the efficiency of such activity. Allen et al. [14] has shown that oxygen tensions between 40 and 80 mmHg are required to
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maintain activity at 50% of maximum in the NADPH-linked oxygenase responsible for this respiratory burst. For it to work at 90% of maximum, oxygen tension of 400 mmHg may be required [14]. While these putative mechanisms remain under investigation, none of them constitutes proof that HBOT is an effective clinical adjuvant. A recent Cochrane systematic review critically examined the strength of clinical evidence for and against the use of HBOT in this setting [15]. There were surprisingly little reliable clinical data. Twelve studies were retrieved from the published literature, of which four were randomised controlled trials (RCTs) [16– 19]. The four RCTs involved a modest total of only 195 patients, of which 125 were included in the Brannen 1997 [19] trial. Of these four trials, one examined the effect of HBOT on a small experimental burn in a volunteer population; the other looked at serum markers. Although these trials did suggest that HBOT has some effect on the pathology of burns, their relevance to significant clinical burns was undetermined [17,18]. Neither of the two other RCTs could reliably show a benefit of HBOT over control for length of stay, mortality or number of surgical procedures required [16,19]. They were particularly constrained by a lack of power to detect useful clinical differences, and the finding that HBOT was no more effective than placebo may have been erroneous for this reason alone. The sample sizes of these studies may have precluded any definitive statement on safety or frequency of adverse events. The method of randomisation and allocation concealment was not described in the four studies and as a result, the potential for selection bias was considered high and particularly so considering entry into one trial was dependent on the availability of HBO facilities at the time of presentation [19]. In contrast, non-randomised comparative studies and case series have demonstrated some improvements in outcome. In an analysis of a series of 191 patients treated at their facility (138 with HBOT), Hart et al. [16] reported that the overall death rate for those treated with HBOT was 9%, significantly less than the 18% predicted by the American Burn Association Tables. In other series, Grossman and Grossman [20] reported improved healing, reduced length of hospital stay, and reduced mortality, while Niu et al. [21] found that in patients with 35–75% TBSA, 6.8% of the 117 patients given HBOT died versus 14.8% death in the controls ( p = 0.028). The controls were contemporary patients under the care of those burns surgeons who did not refer patients for HBOT during the study period. Niu et al. [21] also noted that fluid resuscitation could be achieved more rapidly, naso-gastric feeding could be initiated within 24 h and there was an acceleration of re-epithelialisation. The average hospital length of stay in the HBOT group was 47 days and 59 days in the control. However, this difference was not statistically significant ( p > 0.05). Cianci et al. [22] also suggested a significant reduction in length of stay in a group of patients given HBOT, compared to a group treated
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when HBOT was not available from 33 to 20.8 days ( p = 0.012) with an average cost per saving per patient of US$ 10,850. Other series supported the case for a significant effect from the addition of HBOT to an acute burns care protocol [23–25]. Even in the matched control and only negative study, by Waisbern et al. [25], in which HBOT failed to reveal either a deleterious or salutary effect on mortality, grafting was reduced by 75% in the HBOT group ( p < 0.001). The authors in that paper suggested renal toxicity was a problem with HBOT, but it was noted that many of the patients at the time were receiving nephrotoxic antibiotics, and renal toxicity is not a recognised complication of HBOT. In general, these results lend support to the concept of HBOT as a potentially useful adjunctive therapy for acute burns. However, they must be observed with caution. We have little high-level clinical data on which to base important decisions regarding the type of burn, if any, for which HBOT is suitable therapy, nor the appropriate oxygen dose. This lack of data is not only compounded by poorly defined comparator therapies, but also a result of a number of methodological shortcomings including poor study design, small sample sizes lacking the power to find important differences and poor randomisation and allocation concealment techniques. The Cochrane review [15] concluded that more reliable clinical data from large randomised trials was required before HBOT could be recommended for the routine treatment of thermal burns. Such trials are likely to require enrolment from multiple burn treatment centres. Future trials would need to consider in particular: appropriate sample sizes with power to detect expected differences, careful definition and selection of target patients, appropriate range of oxygen doses per treatment session (pressure and time) as well as total number of treatments, appropriate and carefully defined comparator therapies and the use of an effective sham. Blinding, while problematic, is not impossible within an HBOT trial and should also be employed. Finally, accurate data on the cost of providing therapy should also be sought. In summary, while there is in our opinion insufficient evidence to recommend routine HBOT in the care of thermal burns, we do believe there is a case for appropriate clinical investigation of this interesting treatment modality.
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