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Effectiveness of Hyperbaric Oxygen Therapy for the Management of Chronic Osteomyelitis: A Systematic Review of the Literature

Olga D. Savvidou, MD, PhD; Angelos Kaspiris, MD, PhD; Ioanna K. Bolia, MD; George D. Chloros, MD; Stavros D. Goumenos, MD; Panayiotis J. Papagelopoulos, MD, DSc, FACS; Sotirios Tsiodras, MD, MSc, PhD

Abstract

Hyperbaric oxygen has been used as an adjunctive measure in the treatment of chronic osteomyelitis. The aim of this systematic literature review was to analyze the outcome and the complications of hyperbaric oxygen for chronic osteomyelitis. Forty-five of 96 studies reporting the use of hyper-baric oxygen for 460 patients with chronic osteomyelitis met the inclusion criteria and were analyzed qualitatively. All patients previously received antibiotics and surgical debridement. Mixed bacterial flora was detected in most of the studies. Staphylococcus aureus was the isolated pathogen in 12 (60%) of the 20 cohort and in 4 (20%) of the 20 case studies. Adjuvant hyperbaric oxygen was effective in 16 (80%) of the 20 cohort and 19 (95%) of the 20 case studies. Overall, 308 (73.5%) of 419 patients with complete data had a successful outcome and no reported relapse. Available evidence supports a potentially beneficial role of adjunctive hyperbaric oxygen, especially in refractory cases of chronic osteomyelitis. [Orthopedics. 2018; 41(4):193–199.]

Abstract

Hyperbaric oxygen has been used as an adjunctive measure in the treatment of chronic osteomyelitis. The aim of this systematic literature review was to analyze the outcome and the complications of hyperbaric oxygen for chronic osteomyelitis. Forty-five of 96 studies reporting the use of hyper-baric oxygen for 460 patients with chronic osteomyelitis met the inclusion criteria and were analyzed qualitatively. All patients previously received antibiotics and surgical debridement. Mixed bacterial flora was detected in most of the studies. Staphylococcus aureus was the isolated pathogen in 12 (60%) of the 20 cohort and in 4 (20%) of the 20 case studies. Adjuvant hyperbaric oxygen was effective in 16 (80%) of the 20 cohort and 19 (95%) of the 20 case studies. Overall, 308 (73.5%) of 419 patients with complete data had a successful outcome and no reported relapse. Available evidence supports a potentially beneficial role of adjunctive hyperbaric oxygen, especially in refractory cases of chronic osteomyelitis. [Orthopedics. 2018; 41(4):193–199.]

Chronic osteomyelitis is considered one of the most difficult orthopedic conditions to treat, despite significant progress being made with surgery and antibiotic therapy in the past decade.1 Successful management of chronic osteomyelitis usually requires a combination of multiple surgical interventions at the affected bone site coupled with stabilization through a variety of methods, closure of dead space, soft tissue flap coverage, and bone reconstruction followed by the administration of antibiotics either locally or systemically.2 Susceptibility testing of the microorganisms cultured from the infected site guides antibiotic administration.3 Because efficient concentrations at the site of infection may be obtained for only a short period, antibiotic therapy may not always lead to long-term arrest of the disease.4 Delivery at the local level via various vehicles has been effective in the management of refractory cases.5,6 Nevertheless, failure of an antibiotic treatment is not uncommon.7,8

Intermittent hyperbaric oxygen has been proposed as an adjuvant treatment option for chronic osteomyelitis. The European Society of Clinical Microbiology and Infectious Diseases Study Group on Biofilms currently investigates the benefits of hyperbaric oxygen in the management of biofilm infections.9

Hyperbaric oxygen therapy is defined as the inhalation of 100% oxygen at pressures above the normobaric pressure of 101.3 kPa measured at sea level.10 This leads to a significant increase in the tissue partial oxygen pressure and in the arterial blood oxygen pressure.10 Hyperbaric oxygen counteracts the hypoxia-related inhibition of angiogenesis by inducing neovascularization; it promotes the mobilization of vasculogenic and progenitor cells from bone marrow in either healthy human subjects or diabetic patients and in those treated with radiation.11–13 Furthermore, hyperbaric oxygen reduces tissue edema by suppressing the expression of pro-inflammatory cytokines,14 activates macrophage chemotaxis, increases the bactericidal activity of leukocytes,15 and inhibits toxin production.16 Finally, hyperbaric oxygen prevents tissue reperfusion injuries by inhibiting the neutrophil ß2-integrin adhesion without an adverse effect on the antibacterial function of the neutrophils.14

Hyperbaric oxygen has been widely used in the treatment of chronic osteomyelitis during the past few decades. However, a clear appraisal of its effectiveness is lacking. The aim of this study was to systematically review and evaluate published studies on the overall efficacy and possible complications of hyperbaric oxygen for the treatment of chronic osteomyelitis.

Materials and Methods

A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.17,18 The following databases were thoroughly searched: Medline (via PubMed), Web of Science, the Cochrane Library, Embase, Ovid, Google Scholar, and the World Health Organization International Clinical Trials Registry. The search methodology was performed using the following combination of terms: “chronic osteomyelitis [all fields],” “hyperbaric oxygen [all fields],” and “treatment [all fields].” The titles and the abstracts of the studies were identified and reviewed independently by 2 of the authors (O.D.S., A.K.), who used predefined criteria to select the relevant publications. Inclusion criteria were as follows for the human studies: (1) an appropriate description of the etiology and pathogenesis of the disease; (2) reporting of the pathogen associated with chronic osteomyelitis development; (3) description of the treatment and follow-up protocol used; and (4) reporting of the final outcome of the therapeutic approach (ie, success vs failure). Case reports were reviewed and are reported separately from other types of studies. All articles in English published in peer-reviewed journals were considered. Articles in languages other than English, literature reviews, technical notes, and letters to the editor or expert opinion publications were excluded. Articles with insufficient details regarding type of infection, therapeutic procedure, follow-up, and clinical outcome were also excluded.

The Cochrane Collaboration's tool was used to assess the quality of the studies to ascertain the risk of bias in nonrandomized studies. For each study, patient selection, methodology, follow-up, data, and other issues that could be characterized as having a risk for bias were evaluated. These were defined as low risk, moderate risk, high risk, or unclear risk.1,19

For further minimization of selection bias, all articles were reviewed a third time and then assessed and discussed by all of the authors. If a disagreement occurred regarding the inclusion and exclusion criteria, the senior author (S.T.) made the final decision. Data extraction was performed and data were recorded independently by all of the researchers. Study design, demographic characteristics, surgical intervention, causative microorganism, disease severity, and treatment effectiveness and safety were recorded. Animal studies were examined separately from human studies.

Results

The literature search and cross-referencing resulted in a total of 96 references. On evaluation, 51 articles were excluded and 45 articles were retained. These consisted of 14 retrospective and 6 prospective cohort studies (Table A, available in the online version of the article),20–39 20 case reports (Table B, available in the online version of the article),40–59 and 5 animal studies (Table C, available in the online version of the article).60–64 The included studies were published between 1971 and 2017.

Overview of the causative agents, classification, interventions, follow-up and outcome of the included cohort studiesOverview of the causative agents, classification, interventions, follow-up and outcome of the included cohort studiesOverview of the causative agents, classification, interventions, follow-up and outcome of the included cohort studiesOverview of the causative agents, classification, interventions, follow-up and outcome of the included cohort studiesOverview of the causative agents, classification, interventions, follow-up and outcome of the included cohort studiesOverview of the causative agents, classification, interventions, follow-up and outcome of the included cohort studiesOverview of the causative agents, classification, interventions, follow-up and outcome of the included cohort studiesOverview of the causative agents, classification, interventions, follow-up and outcome of the included cohort studies

Table A:

Overview of the causative agents, classification, interventions, follow-up and outcome of the included cohort studies

Overview of the causative agents, classification, interventions, follow-up and outcome of the included case studies.Overview of the causative agents, classification, interventions, follow-up and outcome of the included case studies.Overview of the causative agents, classification, interventions, follow-up and outcome of the included case studies.Overview of the causative agents, classification, interventions, follow-up and outcome of the included case studies.Overview of the causative agents, classification, interventions, follow-up and outcome of the included case studies.

Table B:

Overview of the causative agents, classification, interventions, follow-up and outcome of the included case studies.

Overview of the causative agents, interventions and outcomes of the included animal studiesOverview of the causative agents, interventions and outcomes of the included animal studies

Table C:

Overview of the causative agents, interventions and outcomes of the included animal studies

Experimental Models

Five studies examined the use of hyperbaric oxygen in an experimental model of chronic osteomyelitis (Table C). All studies examined Staphylococcus aureus–associated chronic osteomyelitis.60–64 One study additionally examined the effectiveness of hyperbaric oxygen for implant-associated chronic osteomyelitis caused by the gram-negative pathogens Klebsiella species and Pseudomonas species known to be implicated in biofilm formation.61 In 4 animal experiments, the effectiveness of hyperbaric oxygen was increased when it was used in combination with systemic antibiotics.60,62,63 Hyperbaric oxygen for implant-associated chronic osteomyelitis led to contradictory results.60,62 Regarding surrogate laboratory parameters evaluating inflammation, 1 animal study reported that hyperbaric oxygen therapy led to a reduction of oxidative stress and inflammatory indices, revealing a potential pathophysiologic explanation for the positive effect of hyperbaric oxygen.60

Human Data

Twenty cohort studies and 20 case studies examined the effectiveness of hyperbaric oxygen for chronic osteomyelitis. A total of 460 patients treated with hyperbaric oxygen were identified. Overall, 308 (73.5%) of 419 patients with complete data had a successful outcome and no reported relapse.

Only 4 studies reported the grade of chronic osteomyelitis according to the Cierny Mader system, classifying 3 patients as having grade II, 26 patients as having grade III, and 30 patients as having grade IV. In addition, only 1 study described the severity of the concurrent pedal ulcers with the calcaneal chronic osteomyelitis in diabetic patients based on the Wagner classification, with 11 patients having grade II and 12 having grade III.

The follow-up period was reported in 27 studies, being a mean of 28.3 months (range, 1–108 months).

The anatomic locations of chronic osteomyelitis, in order of frequency, were as follows: (1) the mandible (62 patients); (2) the tibia/fibula (58 patients); (3) the spine (32 patients); (4) the jaw (30 patients); (5) the hip joint (28 patients); (6) the femur and the calcaneus (23 patients each); (7) the sternum (16 patients); (8) the elbow (14 patients); (9) the pelvis (6 patients); (10) the chest and the humerus (5 patients each); (11) the foot and the ankle (3 patients); (12) the sinus and the temporal bone (3 patients); and (13) the knee joint (2 patients). In 2 studies, the exact location was not clarified. In 3 patients, chronic osteomyelitis developed in more than 1 site (Tables AB).

Staphylococcus aureus was the predominant pathogen associated with chronic osteomyelitis in the studies reviewed (Tables AB). Other implicated pathogens included streptococci species, Pseudomonas aeruginosa, Proteus species, enterococci, Escherichia coli, and other microorganisms (gram-positive cocci [eg, Staphylococcus epidermidis, Propionibacterium acnes]; gram-negative pathogens [eg, Klebsiella species, Serratia species]; anaerobes [eg, clostridia species]; and fungi-like Candida species, Saccharomyces cerevisiae, and Rhizopus species). Mixed flora was also isolated. In 3 studies, the infective organism was not reported.22,32,33

Sixteen cohort studies2,21–23,27–31,33–39 and 19 case studies40–43,45–48,50–59 reported increased rates of successful treatment when combining hyperbaric oxygen with intravenous antibiotics and surgical debridement. Three studies reported the resolution of chronic osteomyelitis with hyperbaric oxygen plus surgical intervention20 or hyperbaric oxygen plus antibiotic administration.26,32 Two studies reported that the extra hyperbaric oxygen application did not improve the results of surgical and antibiotic treatment.24,49 In 1 case study, where no surgical intervention was undertaken, hyperbaric oxygen did not lead to any clinical improvement.44 In 29 (6.3%) of 458 patients, failure of the hyperbaric oxygen treatment was reported.20,22,24,25,27,28,34,37,49 In 20 (4.4%) of 458 patients, recurrence of chronic osteomyelitis was observed.

Failure of hyperbaric oxygen treatment was reported in 7 cases of Staphylococcus aureus–associated chronic osteomyelitis,25,28,37 6 cases with Pseudomonas aeruginosa,20,25,31,34 5 cases with mixed bacterial flora,20,24,27,28,31 and 1 case each with isolation of Escherichia coli34 and Serratia marcescens.37 Finally, in 9 patients for whom hyperbaric oxygen failed, culture did not reveal any bacteria.22,31,37,49

Few occurrences of adverse events were noted. Middle ear barotrauma and ear or sinus pain were most commonly reported,36,38 followed by changes in visual acuity in 2 patients34 and cataract development in 1 patient.65 In 1 case, hyperbaric oxygen was discontinued due to the development of convulsions.39

All of the studies were either prospective or retrospective case series or case reports. Compared with randomized clinical trials, these study designs are prone to selection bias. Only 1 study used a control group.23 No study tested the outcome statistically. The mean quality assessment score of the studies was low, indicating that their quality was fair. The weakness of the methodology quality and the low assessment score indicated increased risk of bias. There were not significant differences between the mean values of the scores estimated by the 2 examiners. The summary of the potential biases is presented in Table D, available in the online version of the article.

Overview of the risk of bias of the included studies

Table D:

Overview of the risk of bias of the included studies

Discussion

To the best of the authors' knowledge, this is the first systematic review focusing on the impact of hyperbaric oxygen in the treatment of chronic osteomyelitis. Despite the fact that the design of the studies included in this review was not optimal to identify the efficacy of hyperbaric oxygen for chronic osteomyelitis, it appeared that the combination of hyperbaric oxygen, intravenous antibiotics, and surgical debridement led to remarkable improvement in clinical and laboratory findings in both animal models and human studies.

Experimental models evaluated in this study used Staphylococcus aureus as the implicated pathogen (ie, the main pathogen evaluated in most human studies). Staphylococcus aureus is known to be a significant pathogen in chronic osteomyelitis. In animal models, hyperbaric oxygen was always used in combination with antibiotics61,64 or ozone.61 Effects on local and systemic inflammation were highlighted in some of these experiments as mediating the therapeutic effect of hyperbaric oxygen. Hyperbaric oxygen not only reduced the histopathological score and the bacterial count of chronic osteomyelitis but also decreased the oxidative (malondialdehyde, superoxidase dismutase, and glutathione peroxidase) and inflammatory (interleukin-1ß, interleukin-10, and tumor necrosis factor-α) indices.61 However, these effects could work both ways; in some reports, hyperbaric oxygen was associated with either a delayed improvement of outcome with antibiotic treatment60 or bacterial growth stimulation62 in implant-associated chronic osteomyelitis. Nevertheless, in implant infections, surgical debridement probably has the primary therapeutic role.

In human subjects, the results of this systematic review indicated that hyperbaric oxygen had at least a moderate beneficial effect on the management of posttraumatic and postoperative chronic osteomyelitis. In spinal,21 tibial,31 or femoral27 chronic osteomyelitis caused by either gram-positive or gram-negative bacteria, adjuvant hyperbaric oxygen often resulted in eradication of the infection, even after the failure of antibiotics.21 Hyperbaric oxygen therapy was additionally moderately effective in patients who developed chronic osteomyelitis after closed and open fractures34 or trauma of various etiologies (eg, war) or after orthopedic operations such as hip arthroplasty.37 Adjuvant hyperbaric oxygen resulted in complete healing of not only the patients with lower extremity chronic osteomyelitis but also the patients with chest, sinus, and mandible chronic osteomyelitis.33,35,38,39,43,48,53,58,59 This beneficial effect may be attributed to either neovascularization of the ischemic tissues or the hyperoxygenation that results in the direct suppression of anaerobic bacteria and stimulation of leukocytes.66

Sternal infection and osteomyelitis in patients undergoing cardiothoracic surgery increases the mortality rate.67 Hyperbaric oxygen is considered a safe adjuvant treatment for sternal chronic osteomyelitis of gram-positive, gram-negative, or mycobacterial etiology, minimizing the intensive care unit stay.23,47,52,54,57

In diabetic patients, vascular insufficiency is the major reason for secondary chronic osteomyelitis infection. This is due to severe ulcers of the lower extremities, which lead to amputation. The combination of hyperbaric oxygen, surgical debridement of the necrotic tissues, and intravenous antibiotics may prevent amputation in difficult cases of Pseudomonas aeruginosa–associated chronic osteomyelitis20 or in the absence of an effective antibiotic regimen.42

In immunocompromised patients and in children, chronic osteomyelitis is usually caused by hematogenous spread. Hemodialysis-dependent patients have high rates of chronic osteomyelitis because of phagocyte dysfunction.68 Although the use of hyperbaric oxygen in these populations is controversial,24 the reviewed reports indicated that adjuvant hyperbaric oxygen can lead to remarkable clinical improvement25 or complete recovery.29

The effectiveness of hyperbaric oxygen therapy has also been studied in osteopetrosis, which is a rare genetic disease caused by metabolic imbalances and complicated by chronic osteomyelitis in approximately 10% of patients.40,41 The combination of surgical debridement40 or endoscopic lavage41 of the necrotic tissue and hyperbaric oxygen has been associated with increased success rates, even in the absence of high doses of antibiotics.41 Nevertheless, in such difficult cases, when a combination of surgical and antibiotic treatment fails, hyperbaric oxygen is controversial.49

In addition to adjuvant hyperbaric oxygen, other factors, such as the secure immobilization of the infected area27,28 and the removal of the infected implants, may contribute to a successful outcome in difficult cases of chronic osteomyelitis. The combination of hyperbaric oxygen, antibiotics, and debridement35 with full or partial removal of internal35,48,53 or external20 fixation devices and hardware23,30,37,47,50,52,54,57 was correlated with increased clinical improvement. The exact contribution of hyperbaric oxygen in such cases, which are almost always complicated by biofilm development, is difficult to elucidate. In vitro studies have shown that hyperbaric oxygen can be used as an adjuvant to ciprofloxacin on biofilms caused by Pseudomonas aeruginosa, enhancing the bactericidal activity of ciprofloxacin.69,70 Although there is an increasing acceptance of the advantages of hyperbaric oxygen on biofilm infections, its use remains controversial.

In this study, hyperbaric oxygen therapy was found to be generally safe and well tolerated; most of the side effects reviewed were mild and reversible. Awareness is necessary because, in a few of the cases, potentially severe side effects (eg, barotrauma, seizures, congestive heart failure and pulmonary edema, and infantile purpura fulminans and pulmonary toxicity) were reported. Some additional minor adverse events were found with the use of hyperbaric oxygen, including transient vision changes, occasional earache and sinus pain in patients with colds or allergies that resolved after their symptomatic treatment with decongestants38 or application of tympanostomy tubes,34 and cataract development.39 Minor symptoms improved shortly after the interruption of hyperbaric oxygen.32

The most serious contraindication to using hyperbaric oxygen is the suspicion of an untreated or undiagnosed pneumothorax. Relative contraindications include any febrile illness that may potentially cause reduction of the central nervous system seizure threshold, poorly controlled seizure disorder, hyperthyroidism, congestive cardiac failure, chronic obstructive pulmonary disease, and claustrophobia.71 Concurrent administration of hyperbaric oxygen with chemotherapeutic agents such as doxorubicin, bleomycin, or cisplatin should be avoided because of their interference in mechanisms of free oxygen radical scavenging. On the other hand, malignancy is not a contraindication for hyperbaric oxygen use, as hyperbaric oxygen is not implicated in the induction of tumor growth or cancer pathogenesis.72 It was reported that hyperbaric oxygen use in patients with a malignancy was not associated with cancer expansion or recurrence.46

Cost-effectiveness issues may counteract the beneficial effect of adjuvant hyperbaric oxygen for chronic osteomyelitis identified in this review; no studies exist regarding this. Compared with standard of care treatment, adjuvant hyperbaric oxygen therapy was cost-effective in studies of its therapeutic use for diabetic ulcers.73,74 In these studies, hyperbaric oxygen therapy correlated with an increased quality-adjusted life years index and a lower proportion of major amputation. When considering financial gains for a relatively expensive therapy, direct and indirect medical costs need to be addressed, such as savings in wound dressing materials, hospital admissions, travel, and rehabilitation. These have been favorably affected in diabetic ulcer and chronic wound studies.75 Treatment for diabetic ulcers and treatment for chronic osteomyelitis have many similarities.

The major limitation of this review was the heterogeneity of the included studies, which made their accurate comparison difficult. More specifically, great variability in treatment protocols, selection criteria, and follow-up periods and missing classification of disease severity and statistical analysis of the outcomes and recovery rates were observed. Other limitations of this review included the large number of case reports, the low level of evidence, and the small number of patients in the included surveys. Finally, a significant amount of the data were derived from studies before 2000. Thus, considerable information about the current treatment protocols is lacking.

Conclusion

Hyperbaric oxygen appears to be a safe and potentially useful adjunctive intervention for the management of chronic osteomyelitis of various etiologies. Hyperbaric oxygen combined with other important therapeutic interventions, such as antibiotics and/or surgical debridement, was associated with high recovery rates of chronic osteomyelitis, especially when followed by a secure stabilization of the bone and removal of the infected implant. Nevertheless, quality data regarding this finding are scarce. Randomized controlled trials should be conducted to investigate the efficacy of hyperbaric oxygen for chronic osteomyelitis.

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Overview of the causative agents, classification, interventions, follow-up and outcome of the included cohort studies

Author, year, locationType of studyParticipantsMicroorganismClassification systemInterventionFollow – upSummary outcome
Akkurt et al 2017, Turkey [20]RetrospectiveChronic calcaneal osteomyelitis in diabetic patients with severe pedal ulcer (n=23)Staphylococcus aureusKlebsiella pneumoniaeEscherichia ColiPseudomonas aeruginosa11 pts with grade II and 12 pts with grade III Wagner classificationSurgical debridement Application of ILIZAROV external fixation No antibiotics administration HBOTNot reportedComplete clinical cure in 18 pts (78%) with painless and functional foot Partial recovery in 3 pts Failure in 2 pts - amputation
Onen et al 2015, Turkey [21]RetrospectiveSpinal osteomyelitis not improved by antibiotic therapy (n=19) Cervical:1 Thoracic:4 Lumbar:14Gram negative MRSAEnterococcus spp. Pseudomonas aeruginosaAcinetobacter sppNot reportedAntibiotics administration (IV Cefazoline) HBOT (in cases that were intractable to 3 weeks of antibiotic therapy)23 monthsThe combination of antibiotics and HBOT led all cases to a successful outcome. No recurrence and no signs of infection
Skeik et al 2015, USA [22]RetrospectiveChronic refractory osteomyelitis (n=23)Not reportedNot reportedSurgical debridement Antibacterial therapy HBOTNot reported19 (82.6%) of the patients showed a successful out come 4 (17.4%) failed to demonstrate any improvement
Yu et al 2011, Taiwan [23]RetrospectiveOsteomyelitis of the sternum after sternotomy and cardiothoracic surgery (n=12)MRSAStaphylococcus aureusKlebsiella pneumoniaeEscherichia ColiAcinetobacter baumanniiMycobacterium tuberculosisNot reportedSurgical debridement Empiric antibiotic administration HBOT (in six patients)Not reportedThe group on adjuvant HBOT (n=6) appeared to have ↓ length stay in ICU, ↓ duration of positive non-invasive pressure ventilation, ↓ duration of invasive mechanical ventilation No hospital death was noticed (compared with 3 deaths in the non-HBOT group)
Saarinen et al 2011, Finland [24]RetrospectiveChronic mandibular osteomyelitis mimicking recurrent parotitis (n=6)Streptococcus viridansStreptococcus anginosusActinomycesFysobacteriumCandida albicansEnterococcus faecalisNot reportedSurgical debridement Antibiotic administration(based on the antibiogram) HBOT (in two patients)60 monthsNo significant clinical difference in clinical outcome compared to no HBOT group
Chen et al 2008, Taiwan [25]ProspectiveChronic diffuse osteomyelitis of the tibia (n=7) and humerus (n=3) in hemodialysis patientsStaphylococcus aureusPseudomonas aeruginosaNot reportedSurgical debridement Parental antibiotic administration HBOTNot reportedIn 8 pts arrest of the disease was observed In 2 pts failure of the treatment was observed that led to amputation
Lentrodt et al 2007, Germany [26]Retrospective cases studyChronic recurrent mandibular osteomyelitis in childhood (n=3)No microbiological investigation was taken due to lack of pus or abscessesNot reportedNo surgical debridement Antibiotic therapy (teicoplanin, clindamycin, penicillin G) HBOT41 monthsAll patients free of symptoms
Chen et al 2004, Taiwan [27]ProspectiveChronic refractory osteomyelitis of the femur (n=13)Staphylococcus aureus Escherichia coli (most common)Klebsiella pneumoniaePseudomonas aeruginosaEnterococcus spp Morganella morganniEnterobacter cloacaeCitrobacter freudiiGrade IIIA: 2pts,IVA: 9 pts, IVB: 2pts according to Cierney Mader classificationSurgical debridement Cancellous bone grafting Antibiotic therapy (Vancomycin, Gentamycin, Cefamezide, Piperacillin, Ampicillin) HBOT22 monthsGood wound healing No discharge No recurrence or infection
Chen et al 2004, Taiwan [28]ProspectiveChronic refractory osteomyelitis of the tibia (n=14) due to close (n=5) and open II, IIIB, IIIC open fractures (n=9)Staphylococcus aureus (most common)Escherichia coliPseudomonas aeruginosaEnterococcus spp Serratia mercescensAeromonas sobriaGrade IIIA: 2 pts, IIIB:3 pts IVA: 3 pts, IVB: 6 pts according to Cierney Mader classification15 monthsNo recurrence in 11 (78.6) patients Extra HBOT sessions in 2 patients 1 patient with mixed flora after open IIIB fracture received above knee amputation
Baltenspenger et al, 2004, Switzerland [29]RetrospectiveChronic osteomyelitis of the jaw (n=30)Staphylococcus coagulase (−)Enterococci spp Klebsiella spp Actinomyces spp Neisseria spp Haemophilus spp FusobacteriumPropionibacteriumNo bacterial growth in 3 culturesNot reportedSurgical debridement-decortication, partial resection Antibiotic therapy (Clindamycin+Trimethoprim-sulfamethoxazole, amoxicillin, doxycycline) HBOT48 to 56 months11(36.7%) patients completely free of symptoms Moderate effect in 14 (46.6%) patients Recurrence in 5 (16.7%) patients
Aitasalo et al, 1998, Finland [30]RetrospectiveChronic osteomyelitis of the mandible/maxilla (n=33)Staphylococci spp Streptococcus viridansStreptococcus spp Enterococci spp Actinomyces spp Klebsiella spp Bacteroides spp Peptostreptococcus sppNot reportedSurgical debridement Decortication with periosteal grafting Antibiotic therapy HBOTOver than 10 monthsSuccess in 26 (79%) patients No signs for oxygen toxicity
Maynor et al, 1998, USA [31]RetrospectiveChronic osteomyelitis of the tibia (n=34)Staphylococcus aureusStaphylococcus coagulase (−)Escherichia coliPseudomonas spp Serratia marcescensEnterobacter spp Bacteroides spp Clostridia spp YeastGrade IIB: 3pts, IIIB: 17 pts, IVB: 14 pts according to Cierney Mader classificationIV Antibiotics based on the antibiogram Tobramycin beads Microsurgical muscle transplantation in 20 pts HBOT24 to 84 months21/26 (81%) at 24 months were drain free
Dan Waisman et al, 1998, Israel [32]RetrospectiveChronic osteomyelitis of femur/toe in children (n=5) suffering from familiar dysautonomia (n=2), septic arthritis of the hip(n=1), open wound (n=1) and paraplegia (n=1)Not reportedNot reportedAntibiotic therapy (Aminoglycosides) HBOTNot reported5/5 (100%) patients recovered without surgical intervention
Berg et al 1989, USA [33]Retrospective cases studyCase 1: chronic osteomyelitis of the tibia after IIIB open fracture Not reportedNot reportedOpen debridement and curettage Antibiotic administration HBOT18 monthsDrain free
Case 2: chronic osteomyelitis of the great toe in a patient with Diabetes Mellitus type IAmputation at the first metatarsal/skin graftAntibiotic administrationHBOT12 monthsDrain free
Davis et al, 1986 USA [34]ProspectiveChronic non-hematogenous osteomyelitis (n=38) after open fractures(n=2), closed fractures treated with open reduction and internal fixation(n=8) and abscess or infection at the side of a prosthesis (n=10)Staphylococcus aureusPseudomonas aeruginosaProteus mirabilisEscherichia coliStaphylococcus epidermidisSerratia marcescensEnterobacter cloacaeNot reportedSurgical debridement Parenteral antibiotic administration based on the antibiogram HBOT34 months34 pts remained clinically free of infection The treatment of 3 pts with Ps. aeruginosa infection and one patient with E. coli, failed
Seftel et al 1985, USA [35]Retrospective cases studyCase 1: chronic osteomyelitis of the tibia and humerus after open fracture in a patient with chronic malnutritionMRSAProteus mirabilisStage IIIB according to Cierney Mader classificationSurgical debridement Antibiotic administration (Vancomycin+Tobramycin) HBOT14 monthsWithout clinical symptoms
Case 2: chronic osteomyelitis of the acetabulum and proximal femur after osteotomies due to osteonecrosisMRSAEscherichia coliPseudomonas aeruginosaEnterococcus sp.Stage IVA according to Cierney Mader classificationSurgical debridement Antibiotic administration (Vancomycin+Tobramycin) HBOT32 monthsWithout clinical symptoms sedimentation rate <10mm/h
Case 3: chronic osteomyelitis of the femur after external fixationMRSAStaphylococcus epidermidisPseudomonas aeruginosaStage IIIA according to Cierney Mader classificationSurgical debridement/bone graft Antibiotic administration (Vancomycin+Tobramycin) HBOT35 monthsWithout clinical symptoms sedimentation rate<5mm/h
Case 4: chronic osteomyelitis of the femur after open reduction and internal fixation revision surgery for non-union fractureMRSAStage IVA according to Cierney Mader classificationSurgical debridement with hardware removal and intramedullary pinning Antibiotic administration (Vancomycin) HBOT23 monthsunion of the fracture site sedimentation rate<5mm/h
Case 5: chronic osteomyelitis of the ankle after open fracture pinningMRSAStreptococcus pyogenesStreptococcus morbillorumPseudomonas aeruginosaEnterococcus spp Bacteroides fragilisStage IVA according to Cierney Mader classificationSurgical debridement Antibiotic administration (Vancomycin + Tobramycin + Clindamycin) HBOT2 monthsNo clinical or laboratory osteomyelitis signs
Eltorai et al 1984, USA [36]RetrospectiveChronic osteomyelitis of the hip (n=28) Pelvis (n=6), lumbar spine (n=3), sacrum (n=5), knee joint(n=2), tibia (n=2), elbow(n=14) in patients with paraplegia (n=30) and tetraplegia (n=14) after spinal cord injuryStaphylococcus aureusStreptococcus spp Escherichia coliPseudomonas aeruginosaEnterococcus spp Klebsiella spp Serratia sppNot reportedSurgical debridement, osteotomies, muscle grafts Antibiotic administration based on antibiogram HBOT6 to 108 monthsNo side effects of the treatment 30 pts considered cure Recurrence in 5 patients Amputation in 5 patients
Morrey et al 1979, USA [37]ProspectiveChronic refractory osteomyelitis of the femur, tibia, spine, and foot (n=53, 40 patients treated with adjuvant HBOT)Staphylococcus aureusEscherichia coliPseudomonas aeruginosaSerratia spp Proteus sppNot reportedSurgical debridement, sequestrectomy, autologous bone graft, soft tissue procedures Antibiotic administration based on antibiogram HBOT23 months33 patients: clinical free 7 patients recurrence of osteomyelitis
Depenbusch et al, 1972, USA [38]ProspectiveChronic refractory osteomyelitis of the extremities (n=25), Spine-pelvis(n=4), Chest wall (n=5), Frontal sinus(n=2) Mandible (n=13) (Total n=59)Staphylococcus aureusEscherichia coliPseudomonas aeruginosaProteusKlebsiellaEnterobacter sppNot reportedSurgical debridement, sequestrectomies, Antibiotic administration based on antibiogram HBOTExcellent results-healing in 35 patients In 24 patients decreased drainage and pain reduction No side effects
Hamblen, 1971, UK [39]Retrospective cases studyCase 1: chronic osteomyelitis of the tibia after open comminuted fracture and extensive soft-tissue damage after a military missile traumaStaphylococcus pyogenesPseudomonas pyocyaneaNot reportedSurgical debridement, sequestrectomies, skin graft, bone graft Antibiotic administration (Penicillin, lincomycin, fucidic acid) HBOTThe HBOT treatment was discontinued after 6 days due to convulsions Complete healing
Case 2: patient with lasting 47 years chronic osteomyelitis of the femurStreptococcus faecalisProteus sppNot reportedSurgical debridement Antibiotic administration (Ampicillin) HBOTThe osteomyelitis sinus was not healed Rapidly decrease of the drainage and the sedimentation rate Amputation was not avoid
Case 3: chronic osteomyelitis of the fibula following surgical treatment of an ankle fracture-dislocationNot reportedNot reportedSurgical debridement, sequestrectomies, Antibiotic administration (cloxacillin) HBOTThe sinus of the osteomyelitis was healed within 10 days Healthy surrounding tissues, No clinical or laboratory findings of the infection

Overview of the causative agents, classification, interventions, follow-up and outcome of the included case studies.

Author, year, locationType of studyParticipantsMicroorganismInterventionFollow – upSummary outcome
Sun et al 2016, China [40]Case studyPatient with osteopetrosis complicated with chronic mandibular osteomyelitis (n=1)Negative cultureSurgical debridement Antibiotics administration (Cefuroxim + ornidazole) HBOT6 monthsComplete healing without recurrence
Liu et al 2016, China [41]Case studyPatient with osteopetrosis complicated with chronic maxillary osteomyelitis (n=1)Not reportedSurgical lavage Low-doses antibiotics administration (cefazolin 1 gr every 8hs) HBOT2 monthsComplete healing without recurrence
Goerger et al 2016, France [42]Case studyPatient with Diabetes Mellitus type II, complicated with skin infection and osteomyelitis of the midfoot (n=1)Klebsiella pneumoniaeSurgical debridement Daily wound cleaning HBOT No antibiotics administration1 monthNegative bacteriological cultures of the wounds
Seng et al 2016, France [43]Case studyChronic osteomyelitis after a distal humeral fracture (n=1)Saccharomyces cerevisiaeAntifungal therapy (:voriconazole) Antibacterial therapy (Imipenem-cilastin and oral ciprofloxacin) HBOT1.5 months (6 weeks)The external fixation of the primary treatment was removed after 6 weeks No signs of infection
Singh et al 2015, Canada [44]Case studyChronic sclerosing osteomyelitis of the mandible (n=1)Staphylococcus aureusStaphylococcus ludgenencisStreptococcus viridansAntibiotics administration (Ceftriaxone IV and oral Metronidazole) HBOTNo improvement from the conservative therapy Hemimandibulectomy and fibular free flap reconstruction
Lu et al 2015, Taiwan [45]Case studyOsteomyelitis of posterior mandibular due to arsenic exposure (n=1)Not reportedSurgical debridement and trimming Antibacterial therapy (Ampicillin) HBOT48 monthsNo signs of inflammation and normal bone structure
Ueki et al 2014, Japan [46]Case studyOsteomyelitis in Cervical spine and epidural abscess on C4–C7 after chemotherapy for hypo pharyngeal carcinoma (n=1)No microorganism identified in the pharyngeal culturesNo surgical treatment applied Antibiotics administration (Meropenem) HBOTNo recurrence was noted
De Nadai et al 2013, Brazil [47]Case studyChronic osteomyelitis of the sternum (n=1)Staphylococcus aureusSurgical debridement Antibiotics administration (Metronidazole and Cefotaxime) HBOT1 monthChest CT and bone sintigram showed bone remodeling and absence of osteomyelitis
Delasotta et al 2013, USA [48]Case studyChronic post-traumatic osteomyelitis due to subtrochanderic fracture (n=1)MRSASurgical debridement Antibiotics administration (vancomycin) HBOT10 monthsRapid improvement after adjunctive HBOT Without any symptoms during the follow-up period
García CM et al 2013, Spain [49]Case studyChronic osteomyelitis of the mandible in a patient with osteopetrosis (n=1)Not reportedSurgical debridement, sequestrum, drainage of the abscess Long term antibiotic administration (clindamicyn) HBOT12 monthsUnresolved COM
Grecchi et al 2012, Italy [50]Case studyChronic osteomyelitis of the mandible complicated with osteonecrosis due to periimplant infectionActinomyces sppSurgical debridement-sequestrectomy Antibiotic administration p.os HBOTComplete healing
Leahy and Sader, 2011, Australia [51]Case studyChronic osteomyelitis of the skull base with the involvement of the petrous temporal bone (n=1)Pseudomonas aeruginosaAntibiotic administration (meropenem+ teicoplanin) plus fluconazole p.os HBOT2 monthsComplete resolution of the infection
Shields et al 2010, USA [52]Case studyChronic refractory osteomyelitis of the sternum after median sternotomy (n=1)Escherichia ColiMultiple surgical debridements Long term antibiotic administration HBOT16 monthsThe HBOT was applied due to surgical debridement and antibiotic therapies failure The HBOT resulted in pain relief, healing of the infection and improvement of the laboratory indexes No recurrence during the follow-up period
Wilkins et al 2009, USA [53]Case studyChronic post-operative osteomyelitis of the distal femur after anterior cruciate ligament repair (n=1)Rhizopus speciesSurgical debridement Antifungal therapy (IV Amphotericin B) HBOT36 monthsNo evidence of recurrent infection Application of distal femoral endoprosthesis Musculoskeletal functional score: 50%
Sun et al, 2008, Taiwan [54]Case studyChronic osteomyelitis of the sternum after coronary artery grafting by-passNo bacterial growth in culturesSurgical debridement Antibiotic administration (Vancomycin) Topical antimicrobial dressing HBOT10 monthsClinical asymptomatic patient C-reactive protein: normalized
Murray and Lieberman 2002, USA [55]Case studyChronic anaerobic osteomyelitis of proximal tibia in a child with sickle cell disease (n=1)Fusobacterium nucleatumSurgical debridement Antibiotic therapy (Clindamycin IV) HBOTThe infection was cured and the patient resumed full activities
Roldan et al, 2001, Germany [56]Case studyChronic recurrent multifocal osteomyelitis of the mandible in a patient (n=1) with SAPHO syndrome (Synovitis, Acne, Pustulosis palmoplantaris, Hyperostosis and OsteitisPropionibacterium acnesStaphylococcus epidermidisDecortications of the mandible with application of PMMA beads Immunostimulatory treatment with allogenic blood Antibiotic administration (tetracycline and amoxicillin-clavunate) HBOT18 monthsFree of pain The clinical and scintigraphic findings indicate healing.
Petzold et al, 1999, Germany [57]Case studyChronic osteomyelitis of the sternum after orthotopic heart transplantation (n=1)Staphylococcus aureusLocal debridement Partial sternal wire removal Open antiseptic irrigation HBOTOver than 60 monthsThe patient was asymptomatic
Goodhart 1993, USA [58]Case studyChronic osteomyelitis of the proximal humerus after IIIC open fracture (n=1)Mycobacterium fortuitumDrainage of the soft tissue abscess Limited debridement of the proximal humerus shaft Oral Antibiotic administration (ciprofloxacin) HBOT24 monthsNo side effects No recurrence of osteomyelitis
Neimkin and Jupiter, 1985, USA [59]Case studyChronic metastatic osteomyelitis of the left distal radius and septic necrosis of the left lunateClostridium septicumSurgical debridement and application of external fixation for joint fusion IV-antibiotic administration (Penicillin and cephalothin) HBOT19 monthsNo recurrence of the osteomyelitis Painless pseudarthrosis of the wrist

Overview of the causative agents, interventions and outcomes of the included animal studies

Author, year, locationType of studyAnimal model/speciesMicroorganismInterventionSummary outcome
Jorgensen et al 2017, Denmark [60]Experimental animal studyImplant – associated osteomyelitis of the tibia in C57BL6/j mice (n=80)Staphylococcus aureusSubcutaneous antibiotics administration (Daptomycin and rifampicin) for 14 days HBOTHBOT treatment lead to an initial 3–4% body mass reduction of the animalsHBOT treatment increased the animals' bone turnoverHBOT reduced the number of animals with abscesses signs HBOT treatment did not improve the outcome of antibiotic treatment measured through the bacterial load on implants and bones
Oguz et al 2011, Turkey [61]Experimental animal studyOsteomyelitis of the femur in Sprague-Dawley rats (n=48)Methicillin resistantStaphylococcus aureus (MRSA)Intraperitoneal administration of VancomycinO3HBOTHBOT treatment was effective in decreasing the oxidative stress indices and the inflammatory cytokine levels of osteomyelitis The histopathological score of osteomyelitis in the HBOT plus Vancomycin group was lower thanthe control group The bacterial counts in the Vancomycin plus HBOT and Vancomycin plus HBOT and O3 groups were significantly lower than the control group
Shandley et al 2011, USA [62]Experimental animal studyImplant – associated osteomyelitis of the tibia in C57BL6/j miceMethicillin resistantStaphylococcus aureus (MRSA)Klebsiella pneumoniae Pseudomonas aeruginosaProphylactic HBOT treatment Post infection HBOT treatment No antibiotics administrationHBOT does not appeared to be an efficient treatment of an implant-associated osteomyelitis
Mendel et al, 1999, Germany [63]Experimental animal studyOsteomyelitis of the tibia in Wistar rats (n=104)Staphylococcus aureusAntibiotics administration (Cefazolin) HBOTHBOT treatment alone reduce the colony-forming units of S. aureus Cefazolin alone reduce the colony-forming units of S. aureus The effectiveness of the treatment was more pronounced with the combination of HBOT and Cefazolin
Mader et al 1978, USA [64]Experimental animal studyOsteomyelitis of the tibia in New Zealand white rabbits (n=66)Staphylococcus aureusAntibiotics administration (Cephalothin) HBOTThe animal mortality rates, the gross severity of osteomyelitis and the killing curves of S. aureus were similar in all treatment groups HBOT is as effective as the antibiotic therapy

Overview of the risk of bias of the included studies

StudyPatient selectionQuality of methodologyFollow-upData reportOther issuesTotal
Akkurt et al 2017, [20]+/−+/−?+/−+/−4.5
Onen et al 2015, [21]+/−+/−+++/−3.0
Skeik et al 2015, [22]+/−?7.5
Yu et al 2011, [23]+/−+/−?+/−+/−4.5
Saarinen et al 2011, [24]+/−+/−++/−+/−4.0
Chen et al 2008, [25]+/−+/−?+/−+/−4.0
Lentrodt et al 2007, [26]+/−+/−++/−+/−4.0
Chen et al 2004, [27]+++/−++1.0
Chen et al 2004, [28]+++/−++1.0
Baltenspeng er et al, 2004, [29]+/−+/−++/−+/−4.0
Aitasalo et al, 1998, [30]+/−+/−+/−+/−+/−5.0
Maynor et al, 1998,[31]+/−++++/−2.0
Dan Waisman et al, 1998, [32]+/−?7.5
Berg et al 1989, [33]+/−9.0
Davis et al, 1986[34]++/−+++1.0
Seftel et al 1985, [35]+/−++/−++/−3.0
Eltorai et al 1984, [36]+/−+/−+/−++/−4.0
Morrey et al 1979, [37]++/−+/−+/−+/−4.0
Depenbusch et al, 1972, [38]++/−?+/−+/−3.5
Hamblen, 1971, [39]+/−+/−?+/−+/−4.5
Authors

The authors are from the First Department of Orthopedic Surgery (ODS, IKB, GDC, SDG, PJP) and the Fourth Department of Internal Medicine (ST), National and Kapodistrian University of Athens, School of Medicine, “ATTIKON” University General Hospital, Athens; and the Laboratory of Molecular Pharmacology (AK), School of Health Sciences, University of Patras, Patras, Greece.

Dr Papagelopoulos is a previous Blue Ribbon Article Award recipient (Orthopedics, May/June 2018.)

Drs Savvidou and Kaspiris have contributed equally to this work and should be considered as equal first authors.

The authors have no relevant financial relationships to disclose.

Correspondence should be addressed to: Olga D. Savvidou, MD, PhD, First Department of Orthopedic Surgery, National and Kapodistrian University of Athens, School of Medicine, “ATTIKON” University General Hospital, 1 Rimini St, 12462 Chaidari, Athens, Greece ( olgasavvidou@gmail.com).

10.3928/01477447-20180628-02

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