Pathophysiology and Hyperbaric Effects
Osteomyelitis represents an inflammatory process with a bacterial infection involving bone. The disease involves ischemia as well as infection, and it may be acute, subacute, or chronic. The term “refractory osteomyelitis” refers to failure to heal despite adequate surgical and antibiotic therapy.
Osteomyelitis is currently classified by Waldvogel, et al., into hematogenous osteomyelitis, contiguous focus osteomyelitis, osteomyelitis associated with vascular disease, and chronic osteomyelitis. Clinicians use hyperbaric oxygen therapy (HBOT) for the treatment of refractory, acute, or chronic osteomyelitis. Osteomyelitis also may be classified by the Cierny-Mader classification as medullary, superficial, localized, and diffuse. The patients are also classified according to factors that may compromise their healing, such as “A,” or normal host, or “B,” compromised host.
Whatever staging system is used, HBOT is purely adjunctive and must be used with appropriate parenteral antibiotics (best determined by bone culture), surgical debridement, nutritional support, and reconstructive surgery.
In clinical practice, choosing the best treatment for osteomyelitis presents physicians with enormous challenges. Major therapies include antibiotics, surgery, and adjunctive therapies, such as HBOT. Historically, comparative clinical studies were used to evaluate the efficacies of different therapies. The multiple clinical variables involved in osteomyelitis make comparative clinical studies difficult to design and evaluate. Significant variables include different infected bones, differing organisms, and different treatment antibiotics. Additional variables include the routes of antibiotic administration, duration of antibiotic treatment, amount of bone penetration by the antibiotic, types of surgery, adequacy of debridement, dead space management, timing of surgery, and the status of adjacent soft tissues. Because osteomyelitis may relapse even years after apparently successful therapy, a minimum of two to five years of follow-up evaluation is recommended. Currently, the most valid osteomyelitis data come from animal model studies in which variables can be tightly controlled.
The results of several open clinical trials indicate that adjunctive hyperbaric oxygen therapy is useful in the treatment of chronic osteomyelitis. Slack reported on five patients with refractory chronic osteomyelitis who showed clinical improvement after treatment with hyperbaric oxygen at two absolute atmospheres. Perrins reported on 24 patients with chronic, recurrent osteomyelitis and cutaneous sinus tracts, in whom previous sequestrectomy, antibiotics, or marsupialization had been unsuccessful. A combination of HBOT and antibiotic therapy resulted in healing of 17 of Perrins’ 24 cases. In four of the non-healed cases, drainage from the sinus tract diminished. In the remaining three cases, the sinus tracts were not influenced by the treatment. Depenbusch reported on 50 patients who had not responded to adequate antibiotic and surgical therapy. Thirty five of these patients (71 percent) had not healed completely after HBOT. The other 15 patients reported some improvement.
Two studies in which the patients served as their own controls were reported by Morrey and Davis. Morrey’s patients met the following criteria: the infection persisted for longer than one month; at least one surgical debridement had been performed; at least two weeks of parenteral antibiotics had been administered; and the patients had been followed for at least one year after surgery. After HBOT therapy, appropriate surgery, and treatment with antibiotics, 34 patients (85 percent) remained clinically free of disease and six experienced recurrence of their osteomyelitis. Davis reported on 38 patients with chronic osteomyelitis who had failed to respond to a previous course of antibiotic and surgical therapy under the same criteria used by Morrey. Thirty four of these 38 patients (89 percent) treated with adjunctive hyperbaric oxygen, antibiotics, and surgery experienced an arrest of disease.
Esterhai performed the only randomized clinical study on adjunctive HBOT. Although his study represents a good attempt at evaluating adjunctive HBOT for osteomyelitis, it falls short of being definitive. The study involved a small number of patients and suffered from methodological problems. There was one failure in 14 patients in the non-HBOT group (93 percent) and three failures of 14 patients in the HBOT group (78 percent). However, three of the four HBOT treatment failures refused further necessary debridement surgery. The fourth patient had such extensive osteomyelitis the authors stated he required an ablative procedure that the patient refused. Thus, all four treatment “failures” were doomed by lack of cooperation, regardless of whether or not the patient received adjunctive HBOT.
To avoid the many variables of clinical osteomyelitis and to objectively evaluate the effect of HBOT in the laboratory, Mader used the Staphylococcus aureus osteomyelitis rabbit model developed by Norden. All animals treated developed stage 4A osteomyelitis in the Cierny-Mader classification system. The results of 28 days of treatment with either HBOT, antibiotic (cephalothin), or a combination of both, or no treatment (control) were compared. HBOT was administered for a total of 20 treatments. At the end of the study, cultures of bone were positive for S. aureus in 91 percent of the control animals, 36 percent of the animals treated with HBOT, 47 percent of the animals treated with cephalothin, and 40 percent of the animals treated with cephalothin and HBOT. All three treatment groups differed significantly (p<0.01) from the control group, but there were no significant differences among the treatment groups. Hyperbaric oxygen alone was as effective as cephalothin in the treatment of experimental S. aureus osteomyelitis.
To establish the mechanism of this effectiveness of hyperbaric oxygen in osteomyelitis, further studies were done. In vitro growth and cephalothin kill curves of this S. aureus strain were conducted after two hour exposure to HBOT. The studies revealed no change from parallel control studies in ambient air. Thus, the beneficial effect of HBOT was not due to the direct killing of the S. aureus.
Argon washouts (perfusion) and oxygen tensions were measured by intramedullary mass spectrometer probes placed in the metaphysis of infected and uninfected tibias. Mean tibial oxygen tensions under ambient room air were 21 mm Hg (infected) and 45 mm Hg (uninfected). During hyperbaric exposure, perfusion in the osteomyelitic bone decreased noticeably compared to normal bone. In vitro phagocytic kills of the S. aureus using a monolayer technique were performed in the tibias in these bones under ambient and HBOT conditions. Oxygen tensions measured 104 mm Hg (infected) and 321 mm Hg. In addition, studies were performed at oxygen tensions of 150 (ambient conditions) 760 mm Hg (100 percent oxygen) and 1500 mm Hg (1 ATA at 100 percent oxygen). Phagocytic killing of this S. Aureus strain decreased markedly at 23 mm Hg of oxygen; significantly improved at 45, 109, 150, 760 mm Hg; and was most effective at 1500 mm Hg.
These studies provided evidence for the following conclusions: hyperbaric oxygen, when administered under standard treatment conditions, was as effective as cephalothin in the eradication of S. aureus from infected bone; osteomyelitic bone in the experimental model has decreased blood flow and a greatly decreased partial pressure of oxygen; HBOT does not directly affect this strain of S. aureus; and HBOT can restore intramedullary oxygen tensions to physiologic or supraphysiologic levels, but this short exposure does not acutely increase blood flow in osteomyelitic bone. One mechanism for HBOT’s effectiveness in S. aureus osteomyelitis may be the increase of intramedullary oxygen to tensions that maximize the efficiency of kill by phagocytes.
Increasing the oxygen tension produces a direct lethal effect on strict anaerobic organisms, and on some micro-aerophilic aerobic organisms. During hyperbaric oxygen therapy, an increase in oxygen tension leads to the increased concentration of superoxide, both intracellularly and extracellularly. Increased superoxide levels predispose to increased hydrogen peroxide production (as well as higher output of other toxic oxygen radicals). Anaerobic organisms are extremely sensitive to these proliferating oxygen radicals because most lack the superoxide-degrading enzyme, superoxide dismutase, and the hydrogen peroxide-degrading enzyme, catalase.
Thus, an increase in the oxygen tension with subsequent oxygen radical formation proves lethal or bacteriostatic for anaerobic organisms. Anaerobic organisms make up approximately 25 percent of the isolates in non-hematogenous osteomyelitis. In LeFrock’s 1988 series focusing on long bone osteomyelitis at the University of Texas, Galveston, anaerobes made up 36 percent of the bone culture isolates.
Hyperbaric oxygen augments the bactericidal action of the aminoglycoside class of antibiotics. The major antibiotics in this drug class include gentamicin, tobramycin, amikacin, and netilmicin. The aminoglycosides lack good antibacterial activity under low oxygen tensions. Low oxygen tensions are found in osteomyelitic bone, and adjunctive hyperbaric oxygen increases tissue oxygen tensions in infected tissue, which allows the aminoglycosides to kill more effectively. Growth and killing studies of Pseudomonas aeruginosa were done aerobically, anaerobically, and under conditions which reproduce the hypoxic levels of infected bone, with reduction of the killing ofPseudomonas aeruginosa by tobramycin under hypoxic conditions.
The effect of tobramycin, of hyperbaric oxygen, and of hyperbaric oxygen plus tobramycin was next studied in thePs. aeruginosa rabbit model of osteomyelitis. In this study, the presence of adjunctive hyperbaric oxygen enhanced the activity of tobramycin in the eradication of Ps. aeruginosa from infected bone. Adjunctive hyperbaric oxygen may also potentiate the bactericidal effect of vancomycin. Under low oxygen tensions, vancomycin, like the aminoglycosides, does not kill micro-organisms as well as under as under normal oxygen levels.
Oxygen is also important in wound healing. When the environment of the fibroblast has an oxygen tension of less than 10 mm Hg, the cell can divide, but it can no longer synthesize collagen. It also cannot migrate to where it is needed for healing. When the oxygen tension is increased, the fibroblast can again carry out these wound healing functions. The collagen produced by these cells forms a protective fibrous matrix, and new capillaries grow into this matrix. Wound healing is a dynamic process, and an adequate oxygen tension is mandatory for this process to proceed to a successful conclusion. HBOT provides oxygen to promote collagen production, angiogenesis, and ultimately wound healing in the ischemic or infected wound. Adequate wound healing is vital in the treatment of osteomyelitis.
Once the bone and soft tissue have been divided, whether by surgery or by infection, the bone and wound must be protected by healing tissues. Bone and soft tissue that fail to heal, or that heal slowly, are susceptible to bacterial reinfection or nosocomial infections. In patients with hypoxic and or/infected wounds, HBOT provides sufficient oxygen to promote collagen production, angiogenesis, and ultimately, wound healing. HBOT is generally unnecessary in a non-compromised patient with a wound, unless there is either surgical hardware in the wound, or the infection occurs in a critical bony structure, such as the skull or sternum.
Refractory osteomyelitis is chronic osteomyelitis which has persisted or recurred after appropriate interventions have been performed, or acute osteomyelitis which has not responded to accepted management techniques. Most patients with refractory osteomyelitis are compromised hosts, and they generally have either systemic or local Cierny-Mader factors, which reduce their ability to heal. Cierny-Mader systemic factors include renal, immune, or liver failure, malnutrition, diabetes, hypoxia, malignancy, extremes of age, and tobacco abuse. Others encompass local factors, including edema, stasis, vascular compromise, scarring, fibrosis, and hypesthesia. Furthermore, studies by Niinikoski and Hunt have shown osteomyelitic bone to be profoundly hypoxic, with oxygen levels of 20 mm Hg or less. Hyperbaric oxygen therapy, HBOT, reverses the hypoxia, and modifies many of the Cierny-Mader factors. HBOT reduces edema, and causes the in-growth of new capillaries into fibrotic or scarred areas, as shown by Hunt et al. HBOT improves the ability of the host to fight infection by directly killing anaerobic bacteria (which comprise 15 percent of all isolates from chronic osteomyelitis); enhancing neutrophil functioning for the destruction of aerobic organisms (Hohn); and improving the transport of commonly used antibiotics, such as the aminoglycosides, across the bacterial cell wall, as shown by Mader et al., and by Morrissey.
Animal and human studies support the use of HBOT in chronic refractory osteomyelitis. Numerous human studies support the animal findings. Strauss found adjunctive hyperbaric oxygen to be the most cost-effective treatment for chronic refractory osteomyelitis. Davis et al., studied a unique group of osteomyelitic patients, those with malignant otitis externa, a progressive and potentially fatal Pseudomonas osteomyelitis of the ear canal and base of the skull. They found that all eight patients with Stage I disease (infection localized to the canal) treated with adjunctive HBOT survived, as did the Stage II patients (infection spread to the base of the skull). Their three HBOT patients with Stage III disease (intracranial extension) represented the first survivors with this severity of malignant otitis externa.
Based upon the extensive data submitted supporting the use of adjunctive hyperbaric oxygen therapy for chronic refractory osteomyelitis, and its subset, malignant otitis externa, we believe adjunctive HBOT to be both clinically effective and cost effective, and it is an appropriate use.
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