Osteomyelitis is an infection of bone or bone marrow, usually caused by pyogenic bacteria or mycobacteria. Refractory osteomyelitis is defined as a chronic osteomyelitis that persists or recurs after appropriate interventions have been performed or where acute osteomyelitis has not responded to accepted management techniques.
To date, no randomised clinical trials examining the effects of HBO2 therapy on refractory osteomyelitis exist. However, the substantial majority of available animal data, human case series and non-randomised prospective trials suggest that the addition of Hyperbaric Oxygen (HBO2) therapy to routine surgical and antibiotic management in previously refractory osteomyelitis is safe and improves the ultimate rate of infection resolution. Consequently, HBO2 therapy should be considered an American Heart Association (AHA) Class II recommendation in the management of refractory osteomyelitis. More specifically, in uncomplicated extremity osteomyelitis or cases where significant patient morbidity or mortality is not likely to occur, HBO2 therapy can be considered an AHA Class IIb treatment. For patients with more severe Cierny-Mader Class 3B or 4B disease, adjunctive HBO2 therapy should be considered an AHA Class IIa intervention. Additional consideration must also be given to patients with osteomyelitis involving the spine, skull, sternum or other bony structures associated with a risk for high morbidity or mortality. In these patients, HBO2 therapy may be considered an AHA Class IIa intervention prior to undergoing extensive surgical debridement. Finally, for osteomyelitis in the subset of patients with associated Wagner Grade 3 or 4 diabetic ulcers, adjunctive HBO2 should be regarded as an AHA Class I intervention.
In most cases, the best clinical results are obtained when HBO2 therapy is administered in conjunction with culture-directed antibiotics and scheduled to begin soon after thorough surgical debridement. HBO2 therapy is ordinarily delivered on a daily basis for 90–120 minutes using 2.0-3.0 atmospheres of absolute pressure (ATA). Recommendation of a specific treatment pressure is not supported by data. Where clinical improvement is seen, the present regimen of antibiotic and HBO2 therapy should be continued for approximately four to six weeks.
Typically, 20-40 postoperative HBO2 sessions will be required to achieve sustained therapeutic benefit. In cases where extensive surgical debridement or removal of fixation hardware may be relatively contraindicated (e.g. cranial, spinal, sternal or paediatric osteomyelitis), a trial of limited debridement, culture-directed antibiotics and HBO2 therapy prior to more radical surgical intervention provides a reasonable chance for osteomyelitis cure. Again, a course of four to six weeks of combined HBO2 and antibiotic therapy should be sufficient to achieve the desired clinical results. In contrast, if prompt clinical response is not noted or osteomyelitis recurs after this initial treatment period, then continuation of the existing antibiotic and HBO2 treatment regimen is unlikely to be effective. Instead, clinical management strategies should be reassessed and additional surgical debridement and/or modification of antibiotic therapy implemented without delay. Subsequently, re-institution of HBO2 therapy will help maximise the overall chances for treatment success.
Initial evidence for a beneficial therapeutic effect of HBO2 in managing osteomyelitis stemmed from reports collected during the 1960’s. In vitro and in vivo studies have subsequently uncovered specific mechanisms of action. Common to each of these mechanisms is the restoration of normal to elevated oxygen tensions in the infected bone. Mader and Niinikoski demonstrated that the decreased oxygen tensions typically associated with bony infections can be returned to normal or above normal levels while breathing 100% oxygen in a hyperbaric chamber. Achieving such elevations has important consequences for the hypoxic milieu of osteomyelitic tissues.
Neutrophils require tissue oxygen tensions of 30-40 mmHg to destroy bacteria by oxidative killing mechanisms. Leukocyte mediated killing of aerobic Gram-negative and Gram-positive organisms, including Staphylococcus aureus, is restored when the low oxygen tensions intrinsic to osteomyelitic bone are increased to physiologic or supra-physiologic levels. Mader et al. confirmed this finding in an animal model of S. aureus osteomyelitis, demonstrating that phagocytic killing markedly decreased at a PO2 of 23 mmHg, improved at 45 and109 mmHg, but was most effective at 150 mmHg. In this study, animals exposed to air achieved a mean PO2 of 21 mmHg and 45 mmHg in infected and uninfected bone, respectively. When the same animals were exposed to 100% oxygen at 2 ATA, mean PO2 levels of 104 and 321 mmHg in infected and non-infected bone were respectively achieved. Subsequent animal studies by Esterhai confirmed these infection and PO2 dependent results, measuring mean oxygen tensions in infected bone of 16±3.8 mmHg in sea level air, 17.5±2.7 mmHg in sea level oxygen, 198.4±19.7 mmHg in 2 ATA oxygen and 234.1±116.3 mmHg at 3 ATA oxygen, respectively; with the corresponding values for non-infected bone being 31±4.6 mmHg in sea level air, 98.8±22.0 mmHg in sea level oxygen, 191.5±47.9 mmHg in 2 ATA oxygen and 309.3±29.6 mmHg at 3 ATA oxygen. Additionally, HBO2 therapy has been noted to exert a direct suppressive effect on anaerobic infections. This effect can be clinically important, as anaerobes make up approximately 15% of the isolates in chronic, non-haematogenous osteomyelitis.
In addition to enhanced leukocyte activity, HBO2 helps to augment the transport of certain antibiotics across bacterial cell walls. Aminoglycoside transport across the bacterial cell wall is both oxygen-dependent and impaired in a hypoxic environment. More specifically, active transport of antibiotics (e.g. gentamicin, tobramycin, amikacin) across bacterial cell walls does not occur if tissue oxygen tensions are below 20 to 30 mmHg. Therefore, HBO2 exposures can enhance the transport and augment the efficacy of antibiotic action. This synergistic effect has also been shown for the cephalosporin class of antibiotics, where the combination of cefazolin and HBO2 therapy produced a 100-fold greater reduction in bacterial counts than either antibiotics or HBO2 therapy alone. Comparable effects are also seen with HBO2 in mitigating localised soft tissue infections. Sugihara et al. demonstrated a 46% reduction in infection resolution time from a mean of 13 to only 6 days when HBO2 therapy was added to antibiotics in the management of soft tissue infections. As infected soft tissues often act as conduits for initiating and sustaining cortical bone infections, HBO2 therapy's parallel benefit in ameliorating soft tissue infections may be critical to its overall efficacy in refractory osteomyelitis.
There is evidence that HBO2 enhances osteogenesis. Animal data suggests that bone mineralization and healing can be accelerated by intermittent exposure to HBO2. Remodelling of bone by osteoclasts is an oxygen-dependent function. Consequently, inadequate oxygen tensions inhibit microscopic debridement of dead, infected bone by osteoclasts. As previously noted, HBO2 can restore physiologic or provide supra-physiologic oxygen tension in hypoxic bone environments, thus osteoclast function in infected bone can be improved. HBO2 therapy's stimulatory effect on osteoclasts has been confirmed in animal models. Furthermore, as demarcation between healthy and necrotic bone is not always clear at the time of surgery, osteoclast enhancement may improve the overall quality of bony debridement and reduce the chances that local infections will recur.
The pathophysiology of chronic osteomyelitis is characterised by both acute and chronic sources of ischaemia. HBO2 therapy has been shown to be effective in acutely reducing tissue oedema, lowering intra-compartmental pressures and ameliorating the detrimental effects of inflammatory reactions. Over the longer term, HBO2 can be used to promote new collagen formation and capillary angiogenesis in both hypoxic bone and surrounding tissues. This neovascularisation works to counter the less easily reversible consequences of osteomyelitis, such as surgical trauma, tissue scarring and nutrient blood vessel occlusion. By creating a sustained increase in the arterial perfusion of previously hypoxic bone and soft tissues, HBO2 can reduce the susceptibility of these tissues to recurrent infection and necrosis.