Hyperbaric Oxygen Applications in Infection Disease

Emerg Med Clin N Am

Hyperbaric Oxygen: Applicationsin Infectious Disease

Colin G. Kaide, MD, FACEP, FAAEM*,Sorabh Khandelwal, MD

Department of Emergency Medicine, The Ohio State University Medical Center,

0136 Means Hall, 1654 Upham Drive, Columbus, OH 43240, USA

The first hyperbaric chamber was built in 1662 by a British clergymannamed Nathaniel Henshaw. It was compressed manually with a bellows us-ing room air and likely did not reach pressures that had any clinical signif-icance. From that time until 1955 various hyperbaric apparatus have beenused with varying (limited) success to treat certain conditions. There was lit-tle if any science or understanding behind the application of hyperbaricsduring this period. In 1955, Churchill-Davidson and colleagues used hyper-baric oxygen (HBO) to try to augment the effects of radiation therapy forpatients who had cancer, which began the era of the scientific use of HBOin clinical medicine.

Over its long history, HBO has been used for many purposes, rangingfrom ‘‘anti-aging treatments’’ and boosting the athletic ability of competi-tors to treatment of chronic neurologic conditions. For many of these appli-cations, the scientific foundations were weak and the research backing theiruse was questionable.

The Undersea and Hyperbaric Medicine Society (UHMS) was founded in1967 (originally as the Undersea Medical Society) to help promote the ex-change of data and research within the commercial and military dive med-icine communities. Later, the clinical practice of hyperbaric medicine cameunder the auspices of the UHMS. It now acts as the primary scientific bodyfor hyperbaric medicine. In 1976 the UHMS developed the multispecialtyHyperbaric Oxygen Therapy Committee to oversee the development of anevidence-guided list of indications for the use of HBO. There are currently

26 (2008) 571–595

* Corresponding author.

E-mail address: [email protected] (C.G. Kaide).

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572 KAIDE & KHANDELWAL

13 indications for HBO for which there is in vitro and in vivo evidence to sup-port its use (Box 1) [1]. Some of these conditions involve infectious processes.

In this article we discuss the use of HBO as an adjunct to aggressive med-ical and surgical management of infectious processes.

Hyperbaric physiology

HBO therapy is the application of pressures greater than 1 atmosphereabsolute (ATA) to an environment of 100% oxygen, which results in the in-crease in the partial pressure of oxygen, proportional to the increase in pres-sure. When a patient is placed into a hyperbaric chamber, the oxygen isdelivered by the lungs to the entire body. This systemic delivery of oxygenshould not be confused with topical oxygen therapy, in which a specificbody part is subjected to oxygen under pressure with the oxygen deliveredlocally to an open wound.

Under normobaric conditions, we live at 1 ATA of pressure measured atsea level. That is to say that a person at sea level has downward pressureexerted on his body equal to the weight of the atmosphere above him. In me-dial applications, it is customary to measure atmospheric pressure in milli-meters of mercury (mm Hg). A pressure of 760 mm Hg is equal to 1ATA, 14.7 psi, 760 torr, or 33 ft of seawater.

At the depth of 33 ft of seawater, a diver is exposed to 2 ATA: 1 ATAfrom the atmosphere above the water and 1 ATA from the pressure exertedby the 33 ft (10 m) of seawater. Henry’s law specifies that the partial pressure

Box 1. Indications for hyperbaric oxygen therapy

Air/gas embolismDecompression sicknessCarbon monoxide poisoningCrush injury, compartment syndrome, and other acute ischemiasExceptional blood loss anemiaDelayed radiation injury (osteo and soft tissue)Skin grafts and flapsThermal burnsEnhancement of healing in selected problem woundsNecrotizing soft tissue infectionsClostridial myositis and myonecrosis (gas gangrene)Osteomyelitis (refractory), includes malignant otitis externaIntracranial abscesses

Data from Feldmeier JJ, editor. Hyperbaric oxygen 2003: indications andresults: the Hyperbaric Oxygen Therapy Committee Report. Kensington (MD): Un-dersea and Hyperbaric Medical Society; 2003.

573HYPERBARIC OXYGEN

of a gas dissolved in a liquid is proportional to the pressure exerted on thatgas. At 2 ATA a diver breathing 21% oxygen would develop a PO2 of 320mm Hg, twice the PO2 at 1 ATA. Although the percentage of oxygen at 2ATA is still 21%, the diver is breathing in twice as many molecules of oxy-gen per breath, which is equivalent to breathing 42% oxygen at 1 ATA.Conversely, if that individual were to travel to a higher elevation, such as8000 ft (2440 m), the pressure exerted by the atmosphere would be equalto 75% of the pressure at sea level. The PO2 would be 120 (0.75 � 160)and the resultant effective fraction of inspired oxygen would be 15.75%.

There are two gas laws that explain the effects of HBO: Boyle’s law andHenry’s law. Boyle’s law describes the change in volume of a gas as a func-tion of pressure and Henry’s law states that the concentration of a gas dis-solved in a liquid is proportional to the partial pressure of that gas above thesolution. HBO capitalizes on Henry’s law by significantly increasing the am-bient PO2 causing a dramatic increase in the amount of dissolved oxygen car-ried by the blood. As the partial pressure of oxygen reaches 100 mm Hg,hemoglobin becomes fully saturated. Under normobaric conditions, the dis-solved oxygen is negligible, representing only 0.3 mL of oxygen per 100 mLof blood (called volume percentdvol%), compared with 20 vol% carried byhemoglobin. Under hyperbaric conditions, however, the PaO2 at 2.5 ATA (atypical HBO treatment pressure) approaches 2000 mm Hg. This pressure ishigh enough to generate 5.4 vol% of dissolved oxygen, which can sustainbasal metabolic functions in the complete absence of any hemoglobin. Hy-peroxygenated plasma can transport oxygen to areas that are inaccessible tored cells, delivering oxygen to relatively hypoxic tissues in proportion to theoxygen tension of the plasma (Box 2).

Mechanisms of antimicrobial effect of hyperbaric oxygen therapy

As the result of the hyperoxic environment generated by HBO, somephysiologic and biochemical changes occur, which promote an additionalantimicrobial effect that can enhance or modulate standard therapy. Someeffects of the hyperoxic environment as they pertain to infectious diseasesinclude the following:

Suppression of clostridial alpha toxin production in gas gangrene (dis-cussed later in this article) [2].

Box 2. Oxygen content calculation

The oxygen content of the blood is determined by thecombination of the oxygen carried by hemoglobin plus theoxygen dissolved in the blood.

Oxygen Content = 1.34 (HgB) (% Saturation) + PO2 (.003)


Enhancement of leukocyte-killing activity. Granulocytes kill microorgan-isms by oxygen-independent and oxygen-dependent mechanisms. Theoxygen-independent system alone is inadequate to eradicate all of thewound pathogens, as evidenced by a decrease in microorganism killingin hypoxic environments [3,4]. The oxygen-dependent system consumeslarge amounts of molecular oxygen to produce an ‘‘oxidative burst’’ af-ter phagocytosis of offending pathogens. The burst consists of oxygenradicals, such as hydroxyl radicals, peroxides, and superoxide. Theproduction of these substances increases in a fashion directly propor-tional to the amount of available oxygen [5]. Further, it has beenshown that this process is significantly retarded in a hypoxicenvironment.

Bacterial growth suppression in hyperoxic tissues. Healthy normoxicwounds with adequate perfusion are highly resistant to infection [6].In multiple animal models, it has been clearly demonstrated that bac-terial growth in hypoxic, poorly perfused tissues increases. In tissueswhere the oxygen tension fell below 30 mm Hg, an established bacterialinfection quickly destroyed the tissue. In a controlled environment, theelevation of oxygen tension in inoculated tissue caused a resistance toinfection that was slightly better than in the comparison group that re-ceived antibiotics alone. Moreover, there seemed to be a synergistic ef-fect between a hyperoxic environment plus antibiotics [7].

Enhancement of antibiotic effects. Certain antibiotics show improvedefficacy when delivered in a hyperoxic environment. The activity ofaminoglycosides and the antimetabolite agents trimethoprim, sulfame-thoxazole, and sulfasoxazole all show an increase in effectiveness inhigh oxygen tensions [8,9]. Additionally, agents such as vancomycinand the fluoroquinolones show decreased activity in a hypoxic milieu[10,11]. The effectiveness of these agents returns to normal whennormoxia is restored.

Improvement in tissue repair. Poorly vascularized, ischemic tissue showsa significantly decreased healing response and increased susceptibilityto infection [12]. The presence of necrotic tissue and infection in theopen wound further slows the healing process. When exposed toHBO following standard treatment protocols, clearing of the infectionand wound closure are significantly improved. HBO has little effect onwound closure in adequately vascularized, normoxic tissues. Enhance-ment of osteoclastic and osteoblastic activity also occurs, which en-hances the clearing of bone infections and promotes healing inosteomyelitis.

Effects on anaerobic bacteria. Anaerobic bacteria lack the ability to de-fend adequately against free radicals and other toxic oxygen species.The enhancement of production of these endogenous antimicrobialagents by granulocytes is the primary mechanism by which HBO canbe bacteriocidal to anaerobic organisms.


Necrotizing soft tissue infections

Necrotizing fasciitis (NF) is a rapidly progressive, life-threatening, deep-seated soft tissue infection that causes necrosis of the fascia and subcutane-ous tissues. Bacterial endotoxins, exotoxins, and protease enzymes degradefat and the extracellular matrix, resulting in rapid and extensive tissue dam-age and severe systemic toxicity [13]. Although NF is a relatively uncommoninfection with 500 to 1500 cases reported in the United States annually, itincurs a mortality of 20% to 40% [14,15]. Those who survive NF usuallyhave significant morbidity, frequently undergoing multiple surgical debride-ments and possibly even amputation.

NF can occur in two distinct populations of patients. Type I NF occurs inindividuals who have a history of peripheral vascular disease, immune com-promise, diabetes, or surgery, and is a polymicrobial disease. Typically, theinciting factor is a wound (eg, trauma to the skin, a decubitus ulcer, postop-erative wound, animal or insect bite, or insulin injection site). Type I NFflora can be composed of both aerobic and anaerobic bacteria with commonisolates including Staphylococcus aureus, Escherichia coli, Bacteroides fragi-lis, and various species of Streptococci, Enterococci, Peptostreptococcus, Pre-votella, Porphyromonas, and Clostridium [16]. A particular form of NFcalled Fournier gangrene is also a polymicrobial infection, usually com-posed of enteric organisms. It attacks the perineal region and anterior ab-dominal wall. In males, the penis and scrotum are also affected.

Type II NF accounts for about 10% to 15% of cases [15,17]. It is themonomicrobial form and is caused by Group A Streptococcus (Streptococ-cus pyogenes). Recently, however, cases caused by community-associated,methicillin-resistant S aureus (MRSA) as the sole organism have been re-ported [18]. Type II NF can develop spontaneously in apparently healthypeople who have minimal or no prior trauma and in the absence of a knowncausative factor or portal of entry for bacteria [19,20]. In some patients, pre-disposing factors, such as skin trauma and blunt injury, can sometimes befound.

Rationale and evidence for hyperbaric oxygen therapy

The primary modalities for treatment of NF are aggressive, early surgicaldebridement along with broad-spectrum antibiotic therapy directed at pre-sumed causative agents. Surgical treatment includes the excision of necroticfascia, compromised skin, and subcutaneous tissue. Frequently, multiple de-bridements are necessary within the first 24-hour period [21]. Although an-tibiotic therapy is essential in the treatment of NF, it is secondary inimportance to surgical debridement [21]. The use of HBO in NF plays a com-plimentary and adjunctive role and should never substitute for the primaryinterventions [14,22]. Although there are no large randomized controlledstudies that clearly demonstrate the effectiveness of HBO in NF, clinical


experience and multiple small clinical reports suggest that HBO can playa valuable role in the overall management plan for many patients sufferingfrom this devastating disease [21].

Of the clinical series supporting the use of HBO in NF, the most compel-ling were published by Mader (1988), Riseman (1990), and Escobar (2005)[23–25]. Mader [24] reported on 22 patients who had NF involving the scro-tum and perineum (Fournier gangrene). He noted a reduction in mortalityfrom 67% to 25% when HBO was added to standard treatment.

Riseman and colleagues [25] reported on 17 patients who had NF whoreceived HBO plus standard therapy compared with 12 patients who re-ceived standard therapy alone. The HBO group was described as more seri-ously ill on admission. The reduction in mortality from 66% to 23% in theHBO group, along with a decrease in the number of necessary debridements,prompted the authors to strongly advocate that HBO be added to standardtherapy in institutions where it is available. The authors went as far as to saythat withholding HBO will cause unnecessary deaths and is thereforeunethical.

The most recent study by Escobar and colleagues (2005) [23] retrospec-tively evaluated 42 patients who had NF in various body locations. Thesepatients had significant comorbidities, including diabetes mellitus, chronicrenal failure, intravenous drug abuse, peripheral vascular disease, and ma-lignancy. They used a standard regimen for HBO, which was added to ag-gressive surgical debridement, antibiotic therapy, and critical care. Theirpatient population incurred a mortality of 11.9%, compared with the na-tional average mortality rate of 34%. There were no amputations in theHBO-treated group compared with the reported rate of 50% nationally.Their study further refuted two common criticisms of HBO: delaying surgi-cal intervention and creation of HBO-induced complications. They demon-strated no delays to operative intervention or interference in standard care.There were no clinically relevant complications related to the HBO.

To date there has only been one study that suggested a potential harmassociated with HBO in NF. In 1977, Tehrani and Ledingham [26] re-ported an 88% mortality in 14 patients who received HBO along withconservative surgical treatment. In this study, however, the first 8 patientsreceived HBO plus only incision and drainage as the primary surgical in-tervention as opposed to aggressive surgical debridement. Seven of the pa-tients died. In the final 6 patients, a more aggressive surgical debridementalong with HBO lead to a 33% mortality. This outcome argues moreagainst the dangers of conservative surgical intervention than it does re-garding the adjunctive HBO. See Table 1 for a summary of studies ofHBO in NF.

Management with hyperbaric oxygen

Box 3 outlines the treatment protocol for necrotizing fasciitis.

Table 1

Summary of studies on hyperbaric oxygen treatment in necrotizing fasciitis

Author Year Study conclusions

Tehrani et al [26] 1977 Conservative surgery combined with HBO therapy

was associated with high mortality (88%)

Eltorai et al [98] 1986 100% survival

Gozal et al [99] 1986 Mortality rate of 12.5%

Riseman et al [25] 1990 Significant decrease in mortality and the number of

debridements in the HBO-treated group

Brown et al [100] 1994 A nonsignificant decrease in mortality with HBO

therapy; no difference in length of hospitalization

or number of debridements

Shupak et al [101] 1995 No significant difference in mortality or number of

debridements

Korhonen et al [102] 1998 Mortality rate of 9% in patients who had Fournier

gangrene

Escobar et al [23] 2005 11.9% mortality in HBO group with no

amputations; 34% mortality in historical controls

with 50% amputation rate


Summary for necrotizing fasciitis

Based on data accumulated from the trials done to date, it is reasonableto recommend HBO as adjunctive to aggressive surgical debridement. Thereseems to be a decrease in mortality and number of debridements required inpatients who receive HBO. It is important to understand that HBO cannever substitute for aggressive debridement and definitive operative man-agement of NF should not be delayed awaiting HBO treatment. If a substan-tial time delay in going to the operating room (OR) is encountered, HBO

Box 3. Hyperbaric oxygen treatment protocol for necrotizingfasciitis

Pressure: HBO treatments started at 2.0–2.5 ATADuration: 90–120 minutesFrequency: Treatment is initially done twice daily until the

patient’s condition is stabilized; then treatments can bechanged to once daily.

Treatments: Treatments can continue until clinical improvementis maximized.

Use review: The continued use of HBO should be reviewed after30 treatments.

Data from Feldmeier JJ, editor. Hyperbaric oxygen 2003: indications andresults: the Hyperbaric Oxygen Therapy Committee Report. Kensington (MD):Undersea and Hyperbaric Medical Society; 2003.


may be initiated before surgery only if the treatment does not further delaydebridement. When patients are at hospitals that do not have HBO avail-able, surgical management should take precedence and transfer to anHBO center can be done postoperatively after the patient is stabilized if itis clinically indicated.

Gas gangrene

Gas gangrene is a rapidly progressive, invasive clostridial infection of pre-viously healthy muscle tissue. It is also known as clostridial myonecrosis. Itproduces massive local tissue destruction along with severe systemic symp-toms. It is a relatively rare disease with 1000 to 3000 cases per year in theUnited States [27].

Gas gangrene is caused by various species of Clostridium. These areGram-positive, spore-forming, anaerobic rods normally found in soil andthe human and animal gastrointestinal tract. The most common species im-plicated in gas gangrene is Clostridium perfringens (80%–90%) [28]. This or-ganism is the causative agent in traumatic and postsurgical cases. Directinoculation of a traumatic wound with C perfringens in a hypoxic wound en-vironment with a compromised blood supply is the perfect milieu forgrowth. Many traumatic wounds are contaminated with Clostridium spores,but only a small percentage actually develop gas gangrene. It seems thatboth inoculation with the organism and a relatively hypoxic tissue environ-ment are necessary for the clinical disease process to develop. Although it isan anaerobe, C perfringens can grow in a restricted fashion in oxygen ten-sions up to 70 mm Hg.

Clostridium septicum, which is more aerotolerant, is most commonly im-plicated in cases of spontaneous gas gangrene [28]. This infection usually oc-curs when bacteria enter from the gut by way of breaks in the gastric mucosain patients who have colon cancer. Hematogenous spread causes infection inmuscle tissue. Other Clostridia species make up a minority of cases and in-clude bifermentans, fallax, histolyticum, and a few others.

The clinical syndrome of infection with C perfringens begins with pain atthe infection site that seems out of proportion to the size of the woundedarea. Local tissue destruction results in bleb and bullae formation. Rapid ex-tension of the wound almost seems to happen in real time, at rates up to 15cm/h [29]. When present, gas can sometimes be seen on radiographs and feltin the tissue as crepitus [28]. In at least 50% of cases, however, gas is notdemonstrable, either on radiographs or clinically. Owing to variability,the detection of gas should not be used to make or break the diagnosis ofclostridial infection. A ‘‘sickly sweet’’ odor can be detected from the wounddrainage. Systemic symptoms include a low-grade fever, disproportionatetachycardia (140–160), and cognitive symptoms ranging from a flat affectto severe anxiety. Hypotension is a late finding and heralds impending cir-culatory collapse and death.


Clostridium spreads rapidly in the tissue not so much as a function of bac-terial replication but rather by the elaboration of many exotoxins [30]. Thesevarious toxins break down connective tissue, lyse blood components, andcause necrosis of muscle tissue. Systemic effects are also seen, includingshock, myocardial depression, capillary leaking, renal failure, and death.The most clinically important of the toxins seems to be alpha toxin. Alphatoxin is a phospholipase C that acts along with less important toxins to de-grade cell membranes and produce a liquefactive necrosis. Further, it canpromote local vasoconstriction and platelet aggregation leading to occlusionof small vessels. This process can help to create an environment of tissuehypoxia and contribute to the spread of the bacteria. Studies looking atClostridium that contained a mutant, nonfunctional form of alpha toxinshowed that the bacteria lost all virulence and did not produce the charac-teristic muscle necrosis and tissue destruction [31]. Reintroduction of thegene with a normal form of alpha toxin restored the bacteria’s virulenceand destructive properties. Finally, alpha toxin, acting with other toxins(primarily theta toxin) causes a powerful myocardial depressant effect.


Alpha toxin is rapidly cleared from the body within 2 hours of production.For the bacteria to continue to spread, continuous elaboration of alpha toxinis required. At a tissue PO2 of 250 mm Hg, alpha toxin production by Clos-tridium completely ceases [2]. This level of tissue oxygen is easily producedin hyperbaric conditions at 3 ATA. Because dead tissue cannot be salvagedand normal tissue is not yet affected, the target for therapy is to stop the alphatoxin in the infected but salvageable tissue in between. The faster this is ac-complished, the more tissue can be spared; to borrow a concept from theworld of heart attacks, ‘‘time is muscle.’’ Unstable patients who may betoo sick to go to the OR for formal debridement may be made stable enoughhemodynamically to tolerate aggressive OR procedures immediately after thefirst HBO treatment. The authors of this chapter have observed this phenom-enon in at least five patients in the last 5 years (Colin G. Kaide,MD, FACEP,FAAEM and Sorabh Khandelwal, MD, unpublished data, 2002–2007).

In addition to inhibiting the production of alpha toxin, HBO also has ananti-anaerobic organism effect and suppresses the growth of clostridia [32].This effect has been shown in vitro and in vivo. Many subsequent basic sci-ence and animal studies clearly demonstrated inhibition of alpha toxin for-mation, inhibition of the growth of clostridia, and a potential bactericidaleffect of HBO delivered at a pressure of 3 ATA [28].

Since the 1960s, HBO therapy has been used for the treatment of gas gan-grene. Early animal study protocols showed that HBO alone was not suffi-cient to eradicate clostridial infections. When HBO was used in combinationwith antibiotics and aggressive debridement, mortality was significantly im-proved over surgery and antibiotics taken together or separately [33].


To date there have been no randomized controlled trials (RCTs) in hu-mans to compare the addition of HBO to standard therapy for gas gan-grene. Based on a review of results published through 1984, Peirce [34]concluded that HBO should be a standard addition to antibiotics and sur-gical debridement and further stated that an RCT to compare these modal-ities would be unethical. In 1977, Heimbach and colleagues [35] reported onthe substantial decrease in mortality seen with the use of HBO in the cumu-lative series of more than 1200 patients from 117 reports in the world’s lit-erature. Bakker [36] added an additional 600 patients for which HBOdemonstrated a clear reduction in mortality and morbidity when used inconjunction with surgery and antibiotic therapy. A review in the New En-gland Journal of Medicine in 1996 concluded that despite the lack ofRCTs the evidence supports HBO as an adjunctive therapy with the follow-ing benefits: improved demarcation of viable and dead tissue allowing formore judicious debridement, decreased amputation rate, and a substantialimprovement in systemic symptoms [37].

Management with hyperbaric oxygen therapy

Unlike necrotizing fasciitis, HBO should be started before surgical de-bridement when possible, especially in unstable, systemically ill patients.Those who are too sick to tolerate formal operative procedures couldhave initial fasciotomies performed at the bedside, followed by immediateHBO treatment. Definitive operative management should then be performedwith HBO interposed between debridements. Treatment should be contin-ued until definitive improvement is seen. Transfer to an HBO facility is rec-ommended when possible. The conditions of the patient, proximity to anHBO center, and the comfort level of the practitioners should be factoredinto the decision as to whether to transfer a patient immediately or to doso after initial operative management (Box 4).

Box 4. Hyperbaric oxygen treatment protocol for gas gangrene

Pressure: HBO treatments started at 3 ATADuration: 90 minutesFrequency: Treatment is initially done three times in the first 24

hours then twice daily for the next 2–5 days.Treatments: If the patient remains toxic, the treatment profile

needs to be extended.Use review: The continued use of HBO should be reviewed after

10 treatments.



Summary for gas gangrene

Despite the lack of an RCT comparing HBO to standard therapy, thesheer number of published results, which all are consistent in their findings,allow for the strong recommendation that HBO therapy be an integral partof the management of clostridial gas gangrene. Good evidence shows thatHBO acts to halt alpha toxin production, substantially decreases the repro-duction of clostridium, and augments the killing of the organism. Morbidityand mortality are decreased along with the extent of debridements and thenumber of limb amputations required.

Chronic refractory osteomyelitis

Osteomyelitis is an infectious process of the bone accompanied by inflam-matory mediated bony destruction. Osteomyelitis can be further brokendown into acute and chronic subtypes. Acute osteomyelitis develops overdays or weeks, whereas chronic osteomyelitis is defined as a longstanding in-fection that evolves over months or even years. The chronic form is charac-terized by the persistence of microorganisms, low-grade inflammation, andthe presence of necrotic bone and fistulous tracts [38]. Refractory osteomy-elitis is a chronic osteomyelitis that persists or recurs after appropriate inter-ventions have been performed. It is also termed refractory when an acuteosteomyelitis does not respond to accepted management interventions,including antibiotics and surgery [39]. The functional definition mostcommonly applied to hyperbaric candidates includes failure to respond toa 4- to 6-week course of appropriate parenteral antibiotics [40].


There are several mechanisms that may explain the effects of HBO inchronic refractory osteomyelitis. They all stem from the increase in oxygentension that is produced during HBO treatments. Oxygen tension in infectedbone is decreased. Breathing 100% oxygen in hyperbaric conditions cannormalize and even produce supraphysiologic tissue oxygen tensions in in-fected bone [41,42].

When oxygen tensions fall below 30 to 40 mm Hg, leukocyte-mediatedkilling of aerobic Gram-positive and Gram-negative organisms is impaired[43]. Several animal models have demonstrated the benefit of HBO in animalmodels of chronic S aureus and Pseudomonas aeruginosa osteomyelitis [44].By increasing tissue oxygen levels, HBO has also been also shown to havea direct suppressive effect on anaerobic organisms [45,46]. As described ear-lier, HBO augments the efficacy of several classes of antibiotics, such asaminoglycosides and cephalosporins. This effect may be because of enhance-ment of antibiotic transport across bacterial cell walls because transport isoxygen dependent and does not occur if oxygen tensions are less than20 to 30 mm Hg [47]. HBO may also play a role in osteogenesis by


promoting fibroblast activity, which allows for collagen synthesis necessaryfor healing [40], and by enhancing osteoclast activity. An increase in osteo-clastic activity improves the overall quality of debridement and reduced thechances that local infection will recur [44]. Finally, in the acute phase, HBOcombats factors that lower tissue oxygen tension by reducing tissue edema,decreasing elevated compartmental pressures, and limiting the effects of in-flammation. In the long term, HBO promotes new collagen formation andangiogenesis. This neovascularization reduces the likelihood of recurrent in-fection and thus limits further bone destruction [44].

There are no controlled, prospective, randomized trials on the use ofHBO in chronic refractory osteomyelitis. Although this type of trial is pre-ferred, it would be difficult to accomplish, given the relative infrequency ofthe illness and the varied patient and disease characteristics.

Initial evidence for the use of HBO in chronic refractory osteomyelitisfirst appeared in a paper published in the Lancet in 1965 [48]. There havebeen numerous studies since then that have argued in favor of HBO. Morreyfollowed 40 patients for an average of 23 months after HBO for refractorycases of osteomyelitis and noted an 85% remission rate [49]. Davis and col-leagues [50] similarly reported successful results with 38 patients demon-strating an 89% remission rate. Bingham and Hart [51] reported on theirseries of 70 patients treated with HBO and demonstrated improvement inall patients with 63% of them remaining disease free. Depenbusch [52] re-ported on 50 patients who had success rates around 70%. More recentlythere have been several additional articles that have reported the long-termsuccess with HBO. Chen and colleagues [53] demonstrated an 86% remissionrate in 15 patients who had an average follow-up period of 17.2 months.Aitasalo and colleagues [54] demonstrated a 79% remission rate in 33 pa-tients who had a median follow-up period of 34 months. Maynor andcolleagues [55] demonstrated resolution of wound drainage in 86% at a 24-month follow-up, 80% at 60 months, and 63% at 84 months. Only oneretrospective study found no benefit with HBO [56]. After a closer reviewof the data, it seems that treatment failures were attributable to patients’ non-compliance with surgery rather than whether the patient received HBO.


The Cierney-Mader classification system of osteomyelitis is a useful wayof characterizing which patients may benefit from HBO (Fig. 1) [57,58]. TheCierney-Mader classification system stages osteomyelitis by severity and in-corporates systemic and local factors that may have an effect on immunesurveillance, metabolism, and local vascularity. Using this classification, ad-junctive HBO may be useful for the most difficult cases of refractory osteo-myelitis, including those in stage 3 or 4, accompanied by the systemic andlocal factors mentioned previously [59]. Some have proposed includingHBO on any patient who has recurrence of osteomyelitis after appropriate

Cierney-Mader Classification for Osteomyelitis

Anatomic Type

Stage 1 Medullary osteomyelitis

Stage 2 Superficial osteomyelitis

Stage 3 Localized osteomyelitis

Stage 4 Diffuse osteomyelitis

Physiologic Class

A Host

Normal

B Host

Compromised

C Host

Treatment worse than disease

SYSTEMIC COMPROMISE (Bs)

• Malnutrition• Renal liver failure• DM• Chronic hypoxia• Immune deficiency• Malignancy• Extremes of age• Immunosuppression• Tobacco abuse

LOCAL COMPROMISE (Bl)

• Chronic lymphedema• Venous stasis• Major vessel compromise• Arteritis• Extensive scarring• Radiation fibrosis• Small vessel disease• Complete loss of local sensation

Fig. 1. Cierney-Mader classification for osteomyelitis.


surgical and medical management regardless of coexistent compromisingfactors (Box 5).

Summary for osteomyelitis

Successful treatment of chronic refractory osteomyelitis does not dependon HBO alone. It requires a multidisciplinary approach that includes ag-gressive debridement, good local wound care, and appropriate antibioticuse. It is also critical to maximize off-loading if the ulcer is located on a pres-sure point. Additional systemic factors that contribute to successful treat-ment include maximizing nutritional intake (especially protein) andcontrolling serum glucose levels.

The evidence supports the use of HBO in chronic refractory osteomyelitisgiven the ample animal data and in vitro experimental studies along witha large body of clinical experience. Because of the absence of RCTs, HBOreceives a class-II evidence-based indication based on the AHA 1999 Guide-lines [60].

Box 5. Hyperbaric oxygen treatment protocol for chronicrefractory osteomyelitis

Pressure: HBO treatments at 2.0–2.5 ATADuration: 90–120 minutesFrequency: Treatment is done once dailyTreatments: Treatments on average range from 15–40 per

infectious episodeUse review: The continued use of HBO should be reviewed after

40 treatments

More frequent treatments or treatments greater than 3 ATA may actuallyhinder bone repair.



The addition of HBO as an adjunctive therapy significantly increases theupfront cost of treatment. In complicated cases of refractory osteomyelitis,however, the long-term expenses associated with prolonged hospitalization,long courses of antimicrobial therapy, and additional surgery actually offsetthe differences, frequently making HBO cost effective.

Zygomycosis (mucormycosis) fungal disease

Mucormycosis is a term used to define infections caused by molds of theorder Mucorales, under the class Zygomycetes. Zygomycosis is a term usedto describe any invasive infection caused by the class Zygomycetes, whichincludes Mucorales and Entomophthorales. Although both orders are capa-ble of causing significant disease, fungi belonging to the order Mucoralesare angiotropic, cause tissue infarction, and are associated with dissemina-ted and frequently fatal infections, especially when associated with variousimmunosuppressive conditions, such as poorly controlled diabetes mellitus,neutropenia, malignancies, transplants, burns, chronic renal failure, and theuse of immunosuppressive and deferoxamine therapy [61,62]. Mucormycosismost commonly causes rhinocerebral syndromes. Less common presenta-tions include pulmonary, cutaneous, gastrointestinal, and disseminatedinfections. Definitive diagnosis almost always requires histopathologic evi-dence of fungal invasion of tissue. Management traditionally has dependedon timely diagnosis, aggressive surgical debridement, and rapid administra-tion of antifungal therapy.


Most of the clinical series of HBO use in fungal infections involve mucor-mycosis. The rationale for its use most likely lies in augmentation of the


bactericidal action of the polymorphonuclear leukocytes [3,41,63]. Other po-tential mechanisms of action include enhancement of macrophage functionand synergism with amphotericin B through the correction of lactic acidosis[64,65]. Additional contributing factors include fibroblast activation, neo-vascularization, and the increase in oxygen tension in infected tissues to nor-mal or supraphysiologic levels [65].

Although there are no randomized clinical trials on the use of HBO inmucormycosis, the data coming from published reports/series are compel-ling. Price and Stevens [66] reported a successful outcome on a case of ful-minant rhinocerebral mucormycosis using HBO after all other therapyfailed. Ferguson and colleagues [67] retrospectively looked at 12 patientswho had rhinocerebral mucormycosis and found that 4 of 6 not receivingHBO died and only 2 of 6 receiving HBO died, with one of these patientsactually showing improvement in the disease process. Couch and colleagues[68] reported successful outcomes on two cases of rhinocerebral mu-cormycosis with brain tumor abscesses not responding to standard care.Survival with a diagnosis of bilateral cerebro-rhino-orbital mucormycosis isuncommon with surgical and medical management alone. De La Paz andcolleagues [69], however, reported a successful outcome in a case of a66-year-old man who had this disease using adjunctive HBO. Yohai andcolleagues [70] reviewed 145 patients (139 from the literature and 6 from hisown institution) looking at survival factors. They found a favorable effectof HBO on the prognosis of mucormycosis. More recently, Segal and col-leagues [71] looked at 14 patients who had invasive fungal infections by Mu-corales or Aspergillus spp over a 12-year period. These cases showed a 50%survival with a treatment regimen consisting of surgery, antibiotics, andHBO. Simmons and colleagues [72] report a case of a an 8-year-old girl whohad type 1 diabetes who survived rhinocerebral mucormycosis complicatedby internal carotid artery and cavernous sinus thromboses using HBO aspart of her treatment regimen. John and colleagues [62] reviewed 28 cases,many of which are mentioned above, in which zygomycosis was treatedwith HBO, and concluded that HBO is a promising treatment modality butdoes not make any firm conclusions given that most of the evidence is fromcase reports/series.


Box 6 outlines the protocol for treating mucormycosis with hyperbaricoxygen therapy.

Summary for mucormycosis

Given that it is unlikely that any randomized study will be performed onthis disease process, the clinical evidence strongly supports using HBO in themanagement of the highly fatal rhinocerebral mucormycosis.

Box 6. Hyperbaric oxygen treatment protocol for mucormycosis

Pressure: HBO treatments at 2.0–2.5 ATADuration: 90–120 minutesFrequency: Treatment is done one to two times dailyTreatments: Treatments should continue to a minimum of 40

with up to 80 having been used in previous reports



Diabetic foot ulcerations

Although diabetes affects only 3% of the population, foot ulcers in pa-tients who have diabetes contribute to more than half of all lower extremityamputations performed in the United States [73]. Diabetic foot ulcers occurin 1.9% of adults annually [74] resulting in amputation rates of 15% to 20%within 5 years [75]. The physiology behind ulcer development in the diabeticfoot has been reviewed extensively and is beyond the scope of this reading[76]. Universally accepted care for diabetic foot ulcers includes (a) optimizednutritional support and glycemic control; (b) appropriate off-loading; (c) de-bridement of nonviable tissue; (d) provision of a moist, clean environment forsupport of granulation tissue and epithelialization; (e) surgical remedy of vas-cular insufficiency; and (f) infection control [77–79]. Infection, overcoloniza-tion, and osteomyelitis are frequent complications in diabetic foot ulcers.


The rationale for HBO therapy in diabetic foot ulcerations is multifacto-rial [80–82]. Effects stem primarily from optimization of the oxygen concen-tration and the oxygen gradient from wound edge to the hypoxic center,which stimulates neovascularization and fibroblast replication with subse-quent collagen deposition. Phagocyte activity and leukocyte-mediatedkilling are enhanced. Finally, under hyperbaric conditions there is an up-regulation of vascular endothelial growth factor and platelet-derived growthfactor.

There is much debate about whether HBO is effective as an adjunct in thetreatment of diabetic foot ulceration [83,84]. Evidenced-based guidelines(Infectious Disease Society of America, US Public Health Service gradeB-I) favor the use of HBO in ulcers not responsive to conventional therapyand surgery [79]. A systematic review undertaken by Roeckl-Wiedman andcolleagues [85] also found that HBO therapy confers a significant reductionin the risk for major amputation with an number needed to treat of 4.Although there was a trend toward greater ulcer healing, there was no


statistically significant difference in wound area reduction or need for minoramputation.

In 2001 Centers for Medicare & Medicaid Services (CMS), after review-ing a technology assessment report by the New England Medical Center andother reviews, made a positive determination on the use of HBO therapy indiabetic foot ulcers.


Box 7 shows the treatment protocol for diabetic foot ulcers. The CMScriteria [86] for the use of HBO in diabetic foot ulcers are:

Patient has type 1 or 2 diabetes and has a lower extremity wound that isattributable to diabetes

Patient has a wound classified as Wagner grade III or higher (Table 2)[87,88].

Patient has failed an adequate course of standard wound therapy (definedas 30 days of standard treatment, including assessment and correctionof vascular abnormalities, optimization of nutritional status, and glu-cose control, debridement, moist wound healing, off-loading, and in-fection control).

Summary for diabetic foot ulcers

The UHMS Hyperbaric Oxygen Therapy Committee report summarizesindividual studies in this area and concludes that HBO for diabetic foot ulcersmeets the requirements for AHA class I (definitely recommend) based on levelI evidence [1]. The use of HBO not only leads to more expeditious woundhealing but it also results in a decrease in the rate of major amputations.

Intracranial abscess

Intracranial abscess (ICA) encompasses cerebral abscess, subdural empy-ema, and epidural empyema. Although many factors, such as early and

Box 7. Hyperbaric oxygen treatment protocol for diabetic footulcers

Pressure: HBO treatments at 2.0–2.5 ATADuration: 90–120 minutesFrequency: Treatment is done one to two times dailyTreatments: Use review is required each 30 days of treatment.


Table 2

Wagner grading system for diabetic foot ulcers

Grade Clinical description

0 Intact skin

1 Superficial without penetration into deeper layers

2 Deeper, reaching tendon, bone, or joint capsule

3 Deeper, with abscess, osteomyelitis, or tendonitis extending to those

structures

4 Gangrene of some portion of the toe or forefoot

5 Gangrene involving the entire foot or enough of the foot that local

procedures are not an option

Data from Feldmeier JJ, editor. Hyperbaric oxygen 2003: indications and results: the Hyper-

baric Oxygen Therapy Committee Report. Kensington (MD): Undersea and Hyperbaric Med-

ical Society; 2003; with permission.


more accurate diagnosis, better surgical techniques, and more accurate an-tibiotic coverage, have led to decreases in mortality over time, ICA con-tinues to show mortality rates of around 20% [89].


The rationale for using HBO in ICA includes inhibition of anaerobic or-ganisms that make up the flora [45,46], reduction in perifocal brain edema[90–92], and enhancement of leukocyte-mediated killing of bacteria [43]. Ad-ditional benefit is seen in cases with concomitant skull osteomyelitis, whichis frequently present in cases of rhinogenic and otogenic intracranial ab-scesses [93].

Randomized studies of this disease are unlikely and treatment recommen-dations for HBO are based on case reports and case series. These are infre-quent in the literature. Lampl and Frey [93] summarized data availablethrough 1998 (publications, conference proceedings, and unpublished sour-ces) and found a total of 48 patients treated with HBO incurring a 2% mor-tality. Two recent articles addressing adjunctive HBO for intracranial abscesswere also positive. Kutlay and colleagues [94] reported on their experiencesfrom 1999 to 2004 on 13 patients who had bacterial brain abscesses treatedwith stereotactic aspiration combined with HBO and antibiotics. Theyfound that adjunctive HBO can reduce the need for reoperations, durationof antibiotic therapy, and overall costs. Kurschel and colleagues [95] re-ported on the successful use of adjunct HBO therapy in five children treatedbetween 1995 and 2002, stating that adjunct HBO can result in reduction inthe duration of antibiotic use, directly affecting the length of hospitalization.


Although some patients who have ICA may do well with a more conser-vative therapeutic approach, there are certain conditions and complications


that warrant a more aggressive strategy (Box 8). Adjunctive HBO therapyshould be considered if any of the following are present [89]:

Multiple abscessesAbscesses in a deep or dominant locationA compromised hostSituations in which surgery is contraindicatedInadequate or no response to standard surgical and antibiotic treatment

Summary for intracranial abscess

Admittedly, the limited number of patients who have ICA treated withHBO makes it difficult to draw any definitive conclusions, but the low mor-tality seen thus far is encouraging and strongly supports the consideration ofadjunct HBO therapy in this group of illnesses.

Malignant otitis externa

Malignant otitis externa (MOE) is an uncommon but potentially life-threatening infection in immunocompromised patients and elderly peoplewho have diabetes. P aeruginosa is the causative organism in 98% of casesand the remaining 2% are caused by S aureus, Proteus mirabilis, Klebsiellaoxytoca, Pseudomonas cepacia, Staphylococcus epidermidis, and rarely As-pergillus fumigatus [64]. Complications of MOE include osteomyelitis ofthe base of the skull, involvement of the temporomandibular joint, cranialnerve palsies, and central nervous system complications, which are themost common cause of death. These complications include meningitis, intra-cranial abscess, and cerebral venous sinus thrombosis. Management

Box 8. Hyperbaric oxygen treatment protocol for intracranialabscess

Pressure: HBO treatments started at 2.0–2.5 ATADuration: 60–90 minutesFrequency: Daily or twice daily depending on clinical conditionTreatments: The total number of treatments is variable,

depending on clinical response. In the largest series of patientswho had ICA who were treated with HBO, the average numberof treatments was 13.

Use review: The continued use of HBO should be reviewed after20 treatments.



traditionally has relied on aggressive use of antibiotics and surgical debride-ment if possible. HBO should be considered in recurrent cases and in pa-tients who have advanced MOE in whom the disease process seemsrefractory to antibiotics [44]. Rationale for its use stems from its effective-ness in normalizing oxygen tension in infected tissue. This process is neces-sary for leukocyte-mediated killing of bacteria, neovascularization, andaugmentation of osteoclastic and osteoblastic activity. Davis and colleagues[96] reported on 17 patients who had MOE who received adjunctive treat-ment with HBO. All 17 patients responded well to HBO, as defined by90% or greater return of cranial nerve function and an infection-free inter-val of 1 year. More importantly, 9 patients who had advanced disease failingantibiotics and surgery responded to HBO. Narozny and colleagues [97] re-ported on their experiences using adjunctive HBO for MOE and believedthat it was a valuable and beneficial modality. Similar to chronic refractoryosteomyelitis, HBO treatments should be performed at 2 to 2.5 ATA for 90to 120 minutes per treatment.

Contraindications to and side effects of hyperbaric oxygen therapy

There are only two absolute contraindications to HBO treatment. Un-treated pneumothorax presents a problem in that transfer or diffusion of ad-ditional oxygen into the space outside of the lung subsequently expands ona decrease in the pressure as the patient returns to the normobaric state,with the potential to cause tension physiology. The concurrent use of cis-platin and HBO can delay wound healing. Concurrent use of bleomycinor a history of bleomycin use at any time in the past along with HBO hasbeen associated with significant lung injury from interstitial pneumonitis.HBO seems to enhance the cardiac toxicity of doxorubicin and is contrain-dicated until well after the doxorubicin is stopped.

Relative contraindications and their potential problems are listed inTable 3. Side effects of HBO include middle ear and sinus barotrauma,

Table 3

Relative contraindications to hyperbaric oxygen therapy

Upper respiratory infections These problems contribute to difficulty

equalizing the pressure in the middle earChronic sinusitis

Stapes implant

Chronic obstructive pulmonary disease

with CO2 retention

Theoretically, high levels of oxygen may

interfere with hypoxic drive in CO2

Seizure disorder High levels of oxygen can cause oxygen

toxicity seizures in approximately 1 in

4000 patients. Fever slightly increases

the risk for seizurea

High fever

History of thoracic surgery Increases the risk for pneumothorax

History of spontaneous pneumothorax

Pulmonary lesions on chest radiograph

a Seizures are usually self-limited and of little clinical consequence.


claustrophobia, oxygen-induced seizure, tension pneumothorax, maturationof existing cataracts, and progressive myopia that resolves within a fewweeks after treatments stop.

Summary

HBO is clearly not a panacea. It has some specific, generally accepted ap-plications in infectious diseases that are often additive or adjunctive to reg-ular medical therapy. Admittedly, there is a paucity of RCTs for HBO. Withthe low incidence of the diseases discussed above, however, the randomiza-tion of patients would be difficult. In our opinion, withholding HBO be-cause of the lack of randomized trials in the face of a huge body ofclinical experience and in vitro studies, especially in these devastating diseaseprocesses, would be bordering on unethical.

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Hyperbaric Oxygen Applications in Infection Disease

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