1

5 Hyperbaric Oxygen Therapy in Treatment of Hypoxic Wounds

8 Chenchen Wang, MD, MS

9 Joseph Lau, MD

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11

12

13

14 September 24, 2001

15 Contract No. 270-97-0019

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17

18 New England Medical Center EPC

19 Boston, MA
 Hyperbaric oxygen

1 Background

2 Hyperbaric oxygen (HBO) therapy is achieved by having the patient

3 breathe 100% oxygen at greater than normal atmospheric (sea level)

4 pressure. Wounds are often hypoxic and hypoxia impairs leukocyte

5 bacteriocidal activities and wound healing. The benefit of HBO is based on

6 the premise that raising tissue oxygen level will therefore enhance the

7 wound healing ability. Adjunctive HBO therapy is used extensively in the

8 management of a variety of disorders ranging from refractory wounds to

9 standard medical and surgical care. The clinical effects of HBO therapy

10 differ for the varying conditions treated.

11 Potential risks for patients undergoing therapy with HBO include

12 myopia, barotraumatic otitis, pneumothorax, and seizures. Some patients

13 may experience claustrophobia due to the confined space of the treatment

14 chambers. Most adverse events are self-limiting and resolve after

15 termination of therapy. Some patients with barotraumatic otitis may require

16 the placement of tympanostomy tubes. Serious, life-threatening events are

17 probably rare but not well quantified.

18 The Center for Medicare and Medicaid Services (CMS) requested

19 assistance from the Agency for Healthcare Research and Quality (AHRQ)

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 Hyperbaric oxygen

1 to perform an assessment on the use of hyperbaric oxygen (HBO) for

2 treatment of hypoxic wounds.

3 CMS received a request to evaluate HBO therapy as a treatment for

4 non-diagnostic-specific wounds based on the pathophysiology of wound

5 healing aided by standard wound care and adjunctive HBO therapy. The

6 following nine diagnostic specific wounds (acute and non-acute conditions)

7 are currently covered by existing Medicare policy on the use of HBO as an

8 adjunctive therapy:

9 1. Acute traumatic peripheral ischemia (acute)

10 2. Crush injuries and suturing of severed limbs (acute)

11 3. Acute peripheral arterial insufficiency (acute)

12 4. Compromised skin grafts (acute)

13 5. Osteoradionecrosis

14 6. Soft tissue radionecrosis

15 7. Gas gangrene (acute)

16 8. Progressive necrotizing infections

17 9. Chronic refractory osteomyelitis

18

19 CMS would like to know whether the current literature supports

20 expanding coverage to include the use of HBO therapy in hypoxic wounds.

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 Hyperbaric oxygen

1 CMS also received a request for coverage from Advanced Hyperbaric

2 Technologies, Inc. for the use of topical hyperbaric oxygen (THO) therapy

3 pulsed at 50mmHg intermittent pressure for hypoxic wounds of the

4 extremities and delivered at 22mmHg for the treatment of hypoxic wounds

5 to the torso. At present, Medicare has a Non-Coverage policy for THO.

6 The New England Medical Center (NEMC) Evidence-based Practice

7 Center (EPC) was asked to determine the state of current evidence on the

8 use of HBO as an adjunctive therapy for the treatment of hypoxic wounds.

9 Specific questions that CMS would like to address include:

10

11 1. Is there sufficient objective evidence that the use of HBO, as adjunctive

12 therapy to standard wound care, aids in wound healing?

13 o Chronic refractory wounds

14 o Wound conditions covered current Medicare Policy.

15 2. At what point in treatment should HBO therapy be introduced?

16 3. What other treatment modalities must be employed along with HBO

17 therapy in order to maximize therapeutic benefits?

18 4. Wounds are generally classified based on diagnosis. Could wounds be

19 classified based on a level of “hypoxia” rather than diagnostic specific

20 (such as diabetic)?

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 Hyperbaric oxygen

1 5. Are there useful criteria to determine when an individual is likely to

2 benefit from HBO therapy or when an individual will be non-responsive

3 to HBO therapy?

4 6. Are there are absolute contraindications when considering HBO therapy

5 in mono-place or multi-place chambers?

6 7. Which method of measuring tissue oxygen is most reliable and lends

7 itself to standardization throughout large populations?

9 The NEMC EPC was also asked to summarized the evidence on the

10 use of THO.

11

12

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 Hyperbaric oxygen

1 Methods

2 Literature search

3 We conducted a systematic review of published literature to evaluate

4 the effect of HBO on wound care. The literature consists of technology

5 assessment and original investigation reports. We identified original

6 investigations on this topic from the references of the recently published

7 technology assessment (TA) reports provided by AHRQ and additional

8 systematic reviews we found on this topic. We also conducted a Medline

9 literature search to identify human studies published in English language

10 on HBO for wound care using search terms of “hyperbaric oxygen” and

11 “wound$ or injur$.” This search yielded 159 citations.

12 For THO, we reviewed the material from Advanced Hyperbaric

13 Technologies, Inc. provided to us by AHRQ. We also conducted a literature

14 search in Medline for additional English language articles on the use of

15 THO in human using search terms of “topical”, “hyperbaric”, and “oxygen.”

16 This search yielded 32 citations.

17

18 Study selection

19 In this evidence report, we considered only published articles that

20 reported original data, and published in English language, included at least

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 Hyperbaric oxygen

1 5 human subjects, evaluated the use of HBO or THO for wound care, and

2 reported clinical outcomes. We accepted randomized controlled trials

3 (RCT), non-randomized comparison studies, and case series.

5 Reporting of results

6 We assessed the characteristics of the original research articles, their

7 results, and relevance to CMS questions. We extracted the following data

8 from each original study and summarized this information in evidence

9 tables:

10 • Patient demographics

11 • Description of the conditions, diagnostic criteria, wound duration

12 • Measurements of tissue oxygen level around wound

13 • Study design

14 • Description of hyperbaric oxygen regimen

15 • Side effects of treatment

16 • Major clinical outcomes

17

18 There were several non-randomized prospective controlled trials. In

19 some of these non-randomized trials, patients who refused HBO because

20 of claustrophobia or patients with contraindications served as controls.

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 Hyperbaric oxygen

1 Most studies were retrospective reviews of patient series and compare

2 results of patients treated with HBO and those without HBO. This group of

3 retrospective studies was labeled as “retrospective comparison.” Most

4 studies did not report specific diagnostic criteria for the underlying

5 conditions. For these studies, we entered “clinical” under the “diagnostic

6 criteria” column in the evidence tables.

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 Hyperbaric oxygen

1 RESULTS

2 Summary of Technology Assessment Reports

3 1. Technology Assessment (Blue Cross and Blue Shield Association),

4 August 1999

5 Hyperbaric Oxygen Therapy for Wound Healing- Part 1

6 This TA evaluated the efficacy of HBO therapy in promoting wound

7 healing in: 1) chronic non-healing wounds, 2) compromised skin grafts or

8 flaps, and 3) acute traumatic peripheral ischemia.

9 The evidence on chronic non-healing wounds including diabetic and

10 non-diabetic ulcers consists of two RCTs of 30 and 70 patients (Doctor

11 1992; Faglia 1996), respectively, and two non-randomized controlled trials

12 (Baroni 1987, Zamboni 1997) involving 28 and 10 patients, respectively.

13 Another RCT of 16 patients evaluated the effects of HBO therapy in chronic

14 non-healing non-diabetic wounds (Hammarlund 1994). All of these studies

15 reported beneficial results with the use of HBO.

16 One RCT (Perrins 1967) of 48 patients reported improved survival of

17 split skin grafts when HBO was added to standard surgical management

18 (protocol consisted of HBO at 2 ATA for 2 hours, twice daily for 3 days).

19 There was a 29% increase in graft take in the HBO-treated patients. The

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 Hyperbaric oxygen

1 study suggested that HBO treatment might be valuable when extensive raw

2 areas have to be covered.

3 One well-designed placebo-controlled double-blinded RCT of 36

4 patients reported the results of HBO treatment in severe crush injures of

5 the limb (Bouachour 1996). A favorable effect was found for adjunctive

6 HBO in reducing the number of surgical procedures and improving the

7 incidence of complete wound healing as compared to placebo patients.

8 We did not review acute thermal burn data that was presented in this

9 TA since it is not within the scope of our topics.

10 2. Technology Assessment (Blue Cross and Blue Shield Association),

11 Dec 1999

12 Hyperbaric Oxygen Therapy for Wound Healing- Part II

13 This TA evaluated the evidence of the efficacy of HBO therapy for

14 severe infectious wounds that included chronic refractory osteomyelitis,

15 clostridial myonecrosis (gas gangrene), and necrotizing soft-tissue

16 infections.

17 The evidence on adjunctive HBO and chronic refractory osteomyelitis

18 consists only of one prospective study of 28 patients (Esterhal 1987). HBO

19 was administered at 2 ATA for 2 hours and 6 days per week showed no

20 statistical significant difference in the complete healing rates between HBO-

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1 treated and control patients (79% versus 90%). Among the control group,

2 13 of 14 patients (90%) who did not receive HBO treatment achieved

3 complete healing. In addition, HBO therapy was reported to have no

4 beneficial effect on the healing outcome, the speed of healing, the

5 recurrence of infection, or the length of hospitalization.

6 Four non-randomized comparison studies were identified on the use

7 of HBO therapy for nercotizing soft tissue infections. Two reports (n=29 and

8 n=26) observed a favorable and statistically significant effect on survival

9 when HBO was added to surgical and medical management. Two other

10 studies (n=54 and n=37) found adjunctive HBO treatment did not reduce

11 mortality.

12 This TA found no RCT on clostridial myonecrosis (gas gangrene) and

13 HBO therapy. Seventeen different clinical series enrolled in 903 patients

14 were identified in this report and all patients were treated with a

15 combination of surgical debridement, antibiotic therapy and HBO. The total

16 reported mortality rate across the series was 22%. They also compared five

17 case series of 118 patients treated without HBO and stated the total

18 mortality rate across the series was 51%. However, their averages were

19 not weighted by the study size and may be biased.

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 Hyperbaric oxygen

1 3. Technology Assessment (Blue Cross and Blue Shield Association),

2 Dec 1999

3 Hyperbaric Oxygen Therapy for Wound Healing- Part III

4 Part III of the BCBSA’s TA evaluated acute traumatic brain injury,

5 spinal cord injury, chronic refractory perineal Crohn’s disease, and brown

6 recluse spider bites. We did not review the studies examined in this TA

7 because these topics are not part of the wound categories.

9 4. Hyperbaric Oxygen Therapy (November 2000 Australia)

10 MSAC applications 1018-1020 assessment report

11 The report evaluates the safety and efficacy of HBO for thermal

12 burns, diabetic wounds including diabetic gangrene and diabetic foot

13 ulcers, non-diabetic wounds and decubitus (or pressure) ulcer, soft tissue

14 infections including necrotizing fasciitis, Fournier’s gangrene, and

15 necrotizing arachnidism, actinomycosis, soft tissue radionecrosis,

16 osteomyelitis, osteoradionecrosis, skin graft survival, multiple sclerosis and

17 cerebral palsy, cardiovascular conditions including acute myocardial

18 infarctions, cerebrovascular disease, and peripheral obstructive arterial

19 disease (POAD), soft tissue injuries including acute ankle sprains and

20 crush injuries, facial paralysis (Bell’s palsy), cluster and migraine

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 Hyperbaric oxygen

1 headaches, Legg-Calve-Perthes disease (necrosis of the femoral head,

2 especially prevalent in children), sudden deafness and acoustic trauma,

3 Crohn’s disease, osteoporosis, cancer and carbon monoxide poisoning.

4 Topics in the Australian report that are relevant to our evidence report

5 include the following six conditions: diabetic and non-diabetic wounds,

6 necrotizing soft tissue infections, osteomyelitis, osteoradionecrosis, skin

7 graft survival, soft tissue injuries, and crush injuries.

8 1. Two RCTs and three non-randomized comparative studies were

9 identified for diabetic wounds including diabetic gangrene and diabetic

10 foot ulcers. The Australian report concluded that HBO is effective in

11 promoting wound healing, and reduced the length of hospital stays and

12 the likelihood of major amputations in patients with diabetic wounds.

13 There may also be cost savings associated with these treatment

14 benefits. Only one RCT on non-diabetic wounds recruited 16 patients

15 was identified. It found that HBO was associated with decreases in the

16 area of chronic non-diabetic wounds. However, the study included only a

17 small number of relatively tightly-selected subjects and examined only

18 one outcome measure.

19 2. Six studies on necrotizing soft tissue infections including necrotizing

20 fasciitis and Fournier’s gangrene, and the prevention and treatment of

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1 osteoradionecrosis were identified and there was some indication that

2 HBO improved survival. However, one study reported that the number of

3 operations was increased in the intervention group.

4 3. A single study on osteomyelitis showed that HBO did not produce a

5 statically significant improvement over the comparison therapy in length

6 of hospital stay, clinical outcome and recurrence.

7 4. One study provides some evidence that HBO is more efficacious than

8 penicillin in the prevention of osteoradionecrosis. Another study provided

9 some evidence of the efficacy of HBO in the treatment of

10 osteoradionecrosis.

11 5. Two RCTs on skin graft survival were identified. HBO may well

12 demonstrate a beneficial effect on the survival of split skin grafts and

13 myocutaneous flaps, but the results are difficult to interpret in light of the

14 failure of the studies to adequately describe the patient population and

15 comparison interventions. The outcome measures were also poorly

16 described. A single study found that HBO benefited patients with crush

17 injuries of the lower limbs, although this benefit was mainly reported in

18 terms of decreasing surgical intervention rather than decrease healing

19 time.

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1 Based on the above data, MSAC recommended that public funding

2 for HBO should be provided, in either a multiplace or monoplace chamber,

3 for: diabetic wounds, necrotizing soft tissue infections, and the prevention

4 and treatment of osteoradionecrosis. HBO should not be supported for:

5 non-diabetic wounds, soft tissue radionecrosis, osteomyelitis, skin graft

6 survival and soft tissue injuries including crush injuries.

8 5. Hyperbaric oxygen treatment in Alberta –Technology

9 Assessment Report (April 1998)

10 The Alberta report evaluated evidence of HBO treatment and the

11 potential impact on health care costs of a second HBO facility in the

12 province. Conditions this report evaluated and relevant to our review

13 include gas gangrene, osteoradionecrosis, necrotizing soft tissue

14 infections, lower wound extremities, and compromised skin grafts and

15 flaps. Using systemic review and cost analysis, the report concluded that

16 HBO is efficacious for osteoradionecrosis, diabetic leg ulcers, and gas

17 gangrene. The report also concluded that while some reports suggest a

18 possible use of HBO for soft tissue radiation injuries and necrotizing soft

19 tissue infections, the available evidence appears insufficient to support its

20 routine use in treatment of these conditions. The available evidence does

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1 not support the routine use of HBO for refractory osteomyelitis,

2 compromised skin grafts/flaps, and ischemic traumatic peripheral injuries

3 (e.g. crush injury, compartment syndrome).

5 6. Hyperbaric Oxygen Therapy in the management of Carbon

6 Monoxide Poisoning, Osteoradionecrosis, Burns, Skin Grafts and

7 Crush Injury Birmingham, April 2000

8 This review focused on five conditions and identified 13 RCTs, six on

9 carbon monoxide poisoning, two on osteoradionecrosis, three on burn, one

10 on skin grafts and one on crush injury. Only four RCTs met our purpose in

11 this evaluation. There were two RCTs on osteoradionecrosis, one double-

12 blinded study that recruited 12 patients reported a significant reduction in

13 healing time in the HBO group, and the other study reported no effect. One

14 RCT on skin grafts and flaps was identified. In patients with major soft-

15 tissue surgery this study found significant improvements in would

16 dehiscence, infection and healing time in the HBO group. One RCT on

17 crush injury was identified which reported a significant effect on wound

18 healing particularly in patients over 40 years old.

19 Overall, they concluded that there is no convincing evidence that

20 HBO is of benefit for the treatment of osteoradionecrosis, burns, skin grafts

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 Hyperbaric oxygen

1 or crush injury. However, there may be a physiological rationale for HBO to

2 be efficacious for conditions involving hypoxia such as osteoradionecrosis

3 and wound healing.

5 7. A systematic review of foot ulcer in patients with Type 2 diabetes

6 mellitus. II: treatment

7 This systematic review assessed the value of HBO for foot ulcers in

8 patients with Type 2 diabetes mellitus. Two RCTs were identified. The first

9 RCT included 70 patients with severe infected diabetic foot ulcers and

10 compared usual care versus usual care plus daily 90-minute sessions of

11 HBO at 2.2-2.5 atmospheres. Participants either had full thickness

12 gangrene or abscess or a large infected ulcer that had not healed after 30

13 days. After 10 weeks, rates of major amputation were significantly lower in

14 the intervention group. In another RCT of 30 patients with chronic infected

15 foot ulcers compared usual treatment versus usual treatment plus four

16 treatments of HBO over 2 weeks. The risk of major amputation was lower

17 in the intervention group but not significantly.

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 Hyperbaric oxygen

1 Summary of studies with original data

2 For completeness, we evaluated one more condition, chronic non-

3 healing (diabetic and non-diabetic wounds). For the following ten

4 conditions, we found a total of 8 RCTs, 16 non-randomized comparison

5 studies, and 18 case series.

7 1. Acute traumatic peripheral ischemia

8 We found no study on this topic.

10 2. Crush injuries and suturing of severed limbs

11 Only one study, a RCT on crush injury (Bouachour 1996) including 36

12 patients (18 HBO and 18 control) was found. HBO treatments were

13 typically given at 2.5 ATA for 90 minutes, twice daily for six days in a

14 mutiplace chamber. Wound healing, major surgery, time of healing and

15 length of stay in the hospital were evaluated. Tissue oxygen level around

16 the wound was measured in the study but this was not used as inclusion

17 criteria for HBO treatment. The study concluded that HBO improved

18 complete healing rates and reducing wound infection and wound

19 dehiscence in crush injury. Adverse effect due to HBO was no mentioned.

20

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1 3. Acute peripheral arterial insufficiency

2 We found no study on this topic.

4 4. Compromised skin grafts

5 Two studies, both RCT (Marx 1995, Perrins 1967) on skin grafts,

6 were found. HBO treatments were typically given either for a total of 20

7 sessions or twice daily for three days. The number of wound infections,

8 dehiscence, and delayed wound healing as well as survival of patch grafts

9 and sheet grafts, were measured.

10 These studies did not provide detailed information about the patients’

11 characteristics such as age, sex, and wound duration, as well as clearly

12 defined diagnostic criteria of the underlying conditions. Tissue oxygen level

13 around the wound was not measured in these studies. They concluded that

14 HBO, improved survival of skin grafts and reducing wound infection and

15 wound dehiscence in crush injury. There was no reporting of adverse

16 effects in either study.

17

18 5. Osteoradionecrosis

19 Two RCTs and one case series on osteoradionecrosis (Marx 1985,

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1 Tobey 1979, McKenzie 1993) were found. HBO treatments were typically

2 given at 2.0 to 2.5 ATA for a total of 20 sessions. Tissue oxygen level

3 around the wound was not measured in these studies.

4 Clinical signs and symptoms, rate of osteoradionecrosis, and X-ray

5 were measured in two trials and persistent mucosal and sutaneous

6 coverage were measured in the case series.

7 Two trials did not provide detailed information about the patients’

8 characteristics such as age, sex. They concluded that HBO treatment

9 reduced the rate of osteoradionecrosis. The RCTs provided no reporting of

10 adverse effect. The case series reported one case of transient minor

11 blurring of vision.

12

13 6. Soft tissue radionecrosis

14 We found no study on this topic.

15

16 7. Gas gangrene

17 Seventeen studies on gas gangrene were identified, 4 retrospective

18 comparison studies and 13 case series. The number of patients in these

19 series varied from 9 to 139 and included both children and adults. None of

20 the studies measured tissue oxygen levels or used hypoxia as criteria for

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 Hyperbaric oxygen

1 wound evaluation. Mortality was used as outcome measures in most of the

2 studies. The rates of clinical improvement, infection controlled and

3 amputation were also evaluated. HBO regimen was used at 2 to 3 ATA and

4 the number of sessions ranged from 4 to 44. Each session usually lasting

5 for 90 minutes.

6 Most authors commented that adjunctive HBO was therapeutically

7 beneficial. However, because of the non-comparative nature of case

8 series, it is difficult to assess the therapeutic effects of HBO reliably. The

9 reported mortality rates of these studies ranged from 11% to 52%.

10 Six case series reported adverse events attributed to HBO. A total of

11 23 patients with seizures attributed to oxygen toxicity were reported in five

12 studies involving 322 patients. One death attributed to seizure was reported

13 in a study of 88 patients (Darke 1977). One case of fatal pneumothorax

14 was reported in one study of 30 patients (Tonjum 1980). Other adverse

15 effects include earaches and barotraumatic otitis.

16

17 8. Progressive necrotizing infections

18 Six non-randomized and three case-series studies that evaluated the

19 use of HBO in nercotizing fasciitis were identified. (Hollabaugh 1998,

20 Shupak 1995, Sawin 1994, Brown 1994, Barzilai 1985, Risenman 1990,

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1 Korhonen 1988, Eltoral 1986, Gozal 1986). HBO was generally given at 2

2 to 3 ATA for 5 to 7 sessions (typical session last for 90 minutes) but two

3 studies did not report the data about how the HBO was given. None of the

4 studies measured tissue oxygen levels or used hypoxia as criteria for

5 wound evaluation.

6 Mortality, length of hospital and ICU stay, duration of antibiotic

7 therapy, healing, and number and type of operations were measured in

8 necrotizing fasciitis.

9 There were inconsistent findings regarding the survival rates in

10 patients with necrotizing fasciitis. Three studies found that there is no

11 significant difference between HBO and control groups, casting doubt on

12 HBO’s effectiveness in reducing patient mortality and morbidity rates

13 (Shupak 1995, Barzilai 1985, Brown 1994). Three other studies found

14 significantly reduced mortality rates in the HBO group (Hollabaugh 1998,

15 Sawin, 1994, Risenman 1990). However, 3 case series found increased

16 recovery rate and reduced mortality.

17 None of the studies reported data on adverse events.

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1 9. Chronic refractory osteomyelitis

2 One non-randomized controlled trial (Esterhai 1987) and one case

3 series (Davis 1986) that evaluated the use of HBO in one on chronic

4 refractory osteomyelitis were identified

5 HBO was generally given at 2 and 2.4 ATA for 2 hours and 6 days

6 per week in one study. None of the studies measured tissue oxygen levels

7 or used hypoxia as criteria for wound evaluation.

8 Recurrence of infection, length of hospital, wound healing, and

9 number and type of operations were measured in necrotizing fasciitis.

10 One non-randomized controlled trials revealed that that HBO had no

11 significant effect on the healing outcomes for patients with chronic

12 refractory osteomyelitis (Esterhal 1987). However, the case series found 34

13 out of 38 patients remained free of clinical signs of osteomyelitis for an

14 average of 34 months. Two patients reported transient vision changes and

15 3 required tympanostomy tubes.

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17

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1 10. Chronic non-healing wounds (diabetic and non-diabetic

2 ulcers)

3 Two RCTs (Faglia 1996, Doctor 1992) and 4 non-randomized studies

4 (Faglia 1998, Zamboni 1997, Baroni 1987, Oriani 1990) on diabetic wounds

5 that evaluated the use of HBO were identified.

6 Tissue oxygen level around the wound was measured in three

7 studies (Faglia, 1998, Zamboni 1997, Faglia, 1996) but this was not used

8 as inclusion criteria for HBO treatment. HBO was generally given at 2 to 2.8

9 ATA for 5 days/week (typical session last for 45 to 90 minutes).

10 Anatomic clinical features of ulceronecrotic lesion, wound surface

11 area, complete healing, rate amputations and hospital stay were used to

12 measure outcomes in diabetic and non-diabetic wounds.

13 The studies concluded that HBO is beneficial in the management of

14 diabetic and non-diabetic wounds. They found that HBO significantly

15 reduced wound size when compare with standard wound care alone and

16 had a higher rate of complete healing as well as a decreased in major

17 amputation rate in diabetic wounds (Baroni 1987, Zamboni 1997, Faglia

18 1998, Oriani 1990).

19 Only one study reported adverse effects due to HBO therapy, a case

20 of barotraumatic otitis (Faglia 1996).

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2 There was one study on non-diabetic wounds (Hammarlund 1994).

3 Tissue oxygen level around the wound was not measured in the study.

4 HBO was generally given at 2.5 ATA for 5 days/week for total of 30

5 treatments in multiplace chamber (typical session last for 90 minutes).

6 The wound area was scanned into a computer and measured in the

7 non-diabetic wounds.

8 The study found that HBO significantly reduced wound surface area

9 decreased at 6-week endpoint when compare with control group and

10 concluded that HBO is beneficial in the management of non-diabetic

11 wounds. There was no reporting of adverse effects.

12 Because of limited data on non-diabetic ulcer, we are not able to

13 conclude whether diabetic and non-diabetic ulcers should be viewed

14 differently.

15

16

17

18

19

20

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2 C. Topical hyperbaric oxygen studies

3 Two RCTs (Leslie 1988, Heng 2001), two non-randomized

4 comparison studies (Lehman 1985, Landau 1998), one prospective cohort

5 (Heng 2000) and seven case series were identified that involved diabetic

6 foot ulcers, necrotic gangrenous wounds, human bite infections, infected

7 meningomyelocele, rheumatoid arthritis ulcers, burns and other infected leg

8 and foot ulcers.

9 THO regimen was used at 1.03-1.04 ATA for most studies, but it

10 differed in session duration. Three studies had treatment sessions lasting

11 90 minutes, other studies had treatment duration of 20 minutes to 12 hours.

12 No studies measured tissue oxygen level as part of the evaluation.

13 Bacterial cultures, wound complete healing, clinical improvement,

14 recurrent ulceration, amputation, length of hospital stay, return to functional

15 status, complications, and costs were used to measure outcomes. Most

16 studies reported that THO enhanced the complete healing rate on wounds

17 (Fischer 1975, Fischer 1969, Diamond 1982, Heng 2000, Ignacio 1985,

18 Olejniczak 1976, Heng 2001, Landau 2001), led to shorten hospitalization

19 and earlier return to functional status (Lehman 1985). They also found that

20 THO is effective in stimulating angiogenesis, granulation and epithelium

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1 formation and marked inhibition of bacterial growth (Heng 2000, Fisher

2 1969). However, two studies found that there is no significant difference

3 between THO and control groups in the treatment of lower extremity ulcers

4 (Landau 1998, Leslie 1998).

5 No adverse effects from the use of THO were noted or reported in the

6 12 studies.

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1 Answers to specific questions

2 • Is there sufficient objective evidence that the use of HBO, as adjunctive

3 therapy to standard wound care, aids in wound healing?

4 o Chronic refractory wounds

5 Most of the TAs that we reviewed concluded that HBO is a beneficial

6 adjunctive therapy to standard wound care in patients with chronic

7 refractory wounds (progressive necrotizing infections, chronic refractory

8 osteomyelitis). Our assessment of the primary studies on this type of

9 wound concurs with their conclusions.

10 o Wound conditions covered under current Medicare Policy.

11 Listed next to each of the conditions is the number of randomized and

12 non-randomized comparative studies (not including case series) evaluated

13 in this rapid response report addressing the topic.

14 1. Acute traumatic peripheral ischemia (no study)

15 2. Crush injuries and suturing of severed limbs (1 RCT)

16 3. Acute peripheral arterial insufficiency (no study)

17 4. Compromised skin grafts (2 RCTs)

18 5. Osteoradionecrosis (2 RCTs, 1 case series)

19 6. Soft tissue radionecrosis (no study)

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1 7. Gas gangrene (4 non-randomized comparison studies, 13

2 case series)

3 8. Progressive necrotizing infections (6 non-randomized

4 studies, 3 case series)

5 9. Chronic refractory osteomyelitis (1 non-randomized study, 1

6 case series)

7 10. Chronic non-healing wounds (diabetic ulcers: 2 RCT, 4

8 non-randomized study; non diabetic ulcers: 1 non-

9 randomized study)

10

11 There is sufficient objective evidence that HBO aids in wound healing

12 for: compromised skin grafts, osteoradionecrosis, gas gangrene,

13 progressive necrotizing infections, and chronic non-healing wounds.

14

15 • At what point in treatment should HBO therapy be introduced?

16 The literature provides no guidance on when HBO therapy should be

17 initiated for chronic non-healing wound. Only two studies that evaluated the

18 effect of HBO on chronic diabetic wounds reported the duration of the

19 wounds prior to treatment, which ranged from at least 6 to 12 months. For

20 acute wounds such as necrotizing faciitis, HBO treatments generally were

29
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1 reported to have begun immediately upon hospitalization or after initial

2 wound debridement.

4 • What other treatment modalities must be employed along with HBO

5 therapy in order to maximize therapeutic benefits?

6 In all studies, HBO was used as adjunctive therapy in addition to the

7 main treatment modalities of wound debridement and antibiotics.

9 • Wounds are generally classified based on diagnosis. Could wounds be

10 classified based on a level of “hypoxia” rather than diagnostic specific

11 (such as diabetic)?

12 There is insufficient evidence to use measured tissue hypoxia as a

13 criteria to determine whether adjunctive HBO treatments might be

14 efficacious in reducing the mortality and morbidities. None of the studies

15 evaluated in this report used measured tissue hypoxia as patient inclusion

16 criteria. Only two RCTs (Faglia 1996, Bouachour 1996) and two non-

17 randomized comparison studies (Faglia 1998, Zamboni 1997) reported

18 measurements of transcutaneous tissue oxygen levels. Mean

19 transcutaneous tissue oxygen levels on admission of these studies were:

20 12mmHg in the HBO group and 35mmHg in the control group (Zamboni

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1 1997), 28mmHg (±13.4) (Faglia 1998), 22mmHg (±10.6) (Faglia 1996), and

2 about 15-19mmHg (Bouachour 1996). These measurements represent

3 averages of the study populations and were not correlated with outcomes

4 of individual patients. Therefore, this information is not useful to guide

5 treatments for individual patients. The large difference in tissue oxygen

6 levels between the HBO group and control group in the Zamboni study also

7 suggests patient selection bias in this non-randomized study that will make

8 interpretation of outcomes difficult.

10 • Are there useful criteria to determine when an individual is likely to

11 benefit from HBO therapy or when an individual will be non-responsive

12 to HBO therapy?

13 No study we analyzed attempted to address this question. All studies

14 reported summary data of patients and did not stratify their results by

15 potential predictors of response.

16

17 • Are there absolute contraindications when considering HBO therapy in

18 mono-place or multi-place chambers?

19 We found no studies that addressed the issues of efficacy or safety

20 differences between mono-place versus multi-place chambers.

31
 Hyperbaric oxygen

1 Examination of the adverse events reporting from all the studies revealed

2 that oxygen toxicity in the form of seizures was observed up to about 10%

3 of the patients in several studies. In one study, a patient died as a result of

4 the seizure. One fatality due to pneumothorax was reported in a case

5 series of 30 patients. The need to provide emergency care during HBO

6 treatment suggests that multi-place chambers may provide a safer

7 treatment modality.

9 • Which method of measuring tissue oxygen is most reliable and lends

10 itself to standardization throughout large populations?

11 This question cannot be answered with the studies we reviewed in

12 this report. Only two RCTs (Faglia 1996, Bouachour 1996) and two non-

13 randomized comparison studies (Faglia 1998, Zamboni 1997) reported

14 transcutaneous measurements of tissue oxygen levels. Three studies

15 evaluated 195 patients with diabetic leg ulcers. The fourth study

16 (Bouachour 1996) involved 36 patients with acute limb injuries and reported

17 that it used the miniature Clarke electrode as the method of transcutaneous

18 measurement. Zamboni (1997) used an instrument from Radiometer

19 America Inc. (TCM3/TINA) and took measurements in noninflamed skin

20 1cm medially away from the wound edge at the midpoint of the ulcer. The

32
 Hyperbaric oxygen

1 other two reports did not provide specific information about the method of

2 tissue oxygen measurement.

33
 Hyperbaric oxygen

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17 colon and rectum. Dis Colon Rectum 1976;19:112-19.
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33 Korhnen K, Hirn M, Niinikoski J. Hyperbaric oxygen in the treatment of
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36 Landau Z, Schattner A. Topical hyperbaric oxygen and low energy laser
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2 application of hyperbaric oxygen. In Kindwall E, ed. Hyperbaric Medicine
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9 Lehman WL et al. Human bite infections of the hand: adjunct treatment with
10 hyperbaric oxygen. Infections in Surgery. June 1985; 460-465.
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12 Marx RE, Johnson RP, Kline SN. Prevention of osteoradionecrosis: a
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14 J Am Dental Assoc 1985;111:49-54.
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16 McKenzie MR, Wong FL, Epstein JB, Lepawsky M. Hyperbaric oxygen and
17 postradiation osteonecrosis of the mandible. Eur J Cancer 1993;29B:201-7.
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22 Olejniczak S. Topical oxygen promotes healing of leg ulcers. Medical
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25 Oriani G, et al. Hyperbaric oxygen therapy in diabetic gangrene. J
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32 Perrins D. Influence of hyperbaric oxygen on the survival of split skin grafts.
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35 Raphael J, Elkharret D,et al. Trial of normabaric and hyperbaric oxygen for
36 acute carbon monoxide intoxication. The Lancet 1989; 2: 414-19.
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38 Riseman JA, Zamboni WA, et al. Hyperbaric oxygen therapy for necrotizing
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2 Roding B, Groeneveld P.H.A, Boerema I. Ten years of experience in the
3 treatment of gas gangrene with hyperbaric oxygen. Surg Gynecol Obstet
4 1972;134:3-9.
5
6 Rudge F.W. The role of hyperbaric oxygenation in the treatment of
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8
9 Sawin, RS, Schaller RT, Tapper D, Morgan A. Early recognition of neonatal
10 abdominal wall necrotizing fasciitis. Am J Surg 1994;67:481-84.
11
12 Schweigel JF, Shim SS. A comparison of the treatment of gas gangrene
13 with and without hyperbaric oxygen. Surg Gynecol Obstet 1973;136:969-
14 70.
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16 Shupak A, Halpern P, Ziser A, Melamed Y. Hyperbaric oxygen therapy for
17 gas gangrene casualties in the Lebanon war, 1982. Israel J Med Sci
18 1984;20:323-26.
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20 Shupak A, Shoshani O, Goldenberg I, Barzilai A, Moskuna R, Bursztein S.
21 Necrotizing fasciitis: An indication for hyperbaric oxygenation therapy?
22 Surgery 1995;118:873-78.
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24 Skiles MS, Covert GK, Fletcher HS. Gas-producing clostridial and
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26 Thom S, Taber R, Mendiguren I, Clark J, Hardy K, Fisher A. Delayed

27 neuropsychologic sequelae after carbon monoxide poisoning: Prevention
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4 prospective study. Undersea & Hyperbaric Medicine 1997; 24: 175-9.

39
 Evidence tables

Table 1. Technology assessment reports examined

Table 2. Original reports

Table 3. Topical hyperbaric oxygen studies

1
Table 1. Technology Assessment Reports Examined
Indications
Name Title

Acute peripheral
Year

Acute traumatic

Other unrelated
healing wound

Crush injuries

Osteomyelitis
Gas gangrene
Organization/

radionecrosis

radionecrosis
Chronic non-

(diabetes and

insufficiency
nondiabetis)

Narcotizing
Skin grafts
Country

Soft tissue

conditions
peripheral

infections
ischemia

Chronic
arterial

Osteo-
BC/BS TEC 1 Hyperbaric Oxygen 3R 1R 1R 2R
August 1999 Therapy for Wound 2N 5N
USA Healing-Part I
+ + _
BC/BS TEC II Hyperbaric Oxygen 4N 4N 1N
August 1999 Therapy for Wound 17 C
USA Healing-Part II
+ +/- _
BC/BS TEC III Hyperbaric Oxygen
August 1999 Therapy for Wound
USA Healing-Part III

MSAC Hyperbaric Oxygen 3R 2R 1R 6N 1N 31 R

applications Therapy 3N 1N 14 N
assessment 1C
report + _ _ +/- _
Nov 2000
Australia

2
Table 1. Technology Assessment Reports Examined (continued)
Indications
Name Title

Acute peripheral
Acute traumatic
Year

healing wound

Other unrelated
Crush injuries

Osteomyelitis
Gas gangrene
radionecrosis

radionecrosis
(diabetes and

insufficiency
nondiabetes)
Organization/

Chronic non

Necrotizing
Skin grafts

Soft tissue

conditions
peripheral

infections
Country

ischemia

Chronic
arterial

Osteo-
Saunders Hyperbaric oxygen 1R 1R 2R 9R
April 2000 therapy in the
USA management of carbon
monoxide poisoning,
osteoradionecrosis, + + +
burns, skin grafts and
crush injury
Mason A systematic review 2R
1999 of foot ulcer in
USA patients with type 2
diabetes mellitus II: +
treatment
Alberta Hyperbaric Oxygen 2R 1R 1R 2N 1N 3N 1N 10 N
April 1998 Treatment in Alberta 2N 1C 2C 3C 1C

Canada + + + + + + +/-
Abbreviation: R = randomized controlled trials
N = non-randomized comparison studies
C = case series
+ = significant effect
- = no effect
+/- = conflicting results

3
 Table 2

1. Acute traumatic peripheral ischemia (no study)

2. Crush injuries and suturing of severed limbs (1 RCT)

3. Acute peripheral arterial insufficiency (no study)

4. Compromised skin grafts (2 RCTs)

5. Osteoradionecrosis (2 RCTs, 1 case series)

6. Soft tissue radionecrosis (no study)

7. Soft tissue gangrene (4 non-randomized comparison, 13 case series)

8. Progressive necrotizing infections (6 non-randomized comparison, 3 case series)

9. Chronic refractory osteomyelitis (1 non-randomized comparison, 1 case series)

10. Chronic non-healing wounds (diabetic ulcers: 2 RCT, 4 non-randomized comparison;

non-diabetic ulcers: 1 non-randomized comparison)

4
1. Acute traumatic peripheral ischemia (no study)

2. Crush injuries and suturing of severed limbs

Part I
Author, N Patient Study design Wound Diagnostic criteria Measured tissue
year of demographics duration PO2
publication,
country (Y/N)
Bouachour 36 Mean age: RCT, Within 6 Type II or III, Gustillo Y
1996 HBO 46y (16 sd) double-blinded, hour of classification
France 18 HBO Control 52y (21 sd) placebo- injury depending on soft- Miniature Clark
18 Control controlled tissue injury. electrode

Part II
Author, HBO regimen Outcome Side effects Major results
year of measures and comments
publication,
country
Bouachour HBO 2.5 ATA, 90 minutes twice Wound healing, ND Complete healing
1996 daily for six days. major surgery, time HBO: 17; Control: 10 p<0.01
France Placebo 1.1 ATA of air. of healing, length New surgical procedures
Multiplace chamber. of stay HBO: 1; Control: 6; p<0.05

3. Acute peripheral arterial insufficiency (no study)

5
4. Compromised skin grafts
Part I
Author, N Patient demographics Study Wound Diagnostic criteria Measured
year of design duration tissue PO2
publication,
country (Y/N)
Marx 160 ND RCT ND Patients requiring tissue N
1995 flaps in tissues radiated to
USA 80 HBO a dose greater than
Unable to 80 Control 6400cGy.
retrieved article
Perrins 48 ND RCT NA Clinical N
1967 (infants excluded)
UK 24 HBO
24 control

Part II
Author, HBO regimen Outcome Side effects Major results
year of measures and comments
publication,
country
Marx Comparison therapy plus HBO for 20 Wound ND Wound infection
1995 sessions prior to surgery, then 10 infection, HBO: 5; Control: 19 P=0.001
USA sessions after surgery. wound Wound dehiscence
Chamber type not reported. dehiscence, HBO: 9; Control: 38 P=0.001
delayed wound Delayed wound healing
healing HBO: 9; Control: 44
Perrins HBO 2 ATA 2 hours on evening of Survival of ND Improved survival of skin grafts
1967 operation and twice daily for three patch and sheet HBO: 84.2%
UK days in a Vicker’s clinical transparent grafts Control: 62.7%; P<0.01
pressure chamber

6
5. Osteoradionecrosis
Part I

Author, N Patient demographics Study Wound Diagnostic criteria Measured

year of design duration tissue PO2
publication,
country (Y/N)
Marx 74 No data on age, gender. RCT, Irradiated bone at Socket wounds which N
1985 Patients with indications for not risk >6 months and had failed to heal after
USA 37 HBO removal of one or more blinded <15 years after tooth removal.
37 penicillin teeth in a segment of the exposure
mandible that had received
>6000 Rads.
Tobey 12 HBO ND RCT, NA Clinical N
1979 unknown double-
USA controls blinded
McKenzie 26 Median age 56y Case ND Strict criteria of Marx N
1993 (28 - 80) series et al.
Canada 19 M, 7 F

7
Part II

Author, HBO regimen Outcome Side effects Major results

year of measures and comments
publication,
country
Marx HBO 2.4 ATA for 90 minutes, 20 Rate of ND Rate of osteoradionecrosis
1985 sessions prior, and ten post tooth osteoradionecrosis HBOT: 5.4%
USA removal, one session daily for five to Control: 30%
six days a week.
Chamber type not reported.
Tobey HBO 2.0 ATA for two hours per day, X-ray, clinical signs ND “Significant improvement in HBO
1979 five days per week for eight weeks. and symptoms. group.” This is a preliminary report,
USA Comparator as above but 1.2 ATA. full analysis of the study apparently
Chamber type not reported. never published.
McKenzie HBO was delivered at 2.5 ATA, with Persistent mucosal 1 case of transient 21 of 26 patients improved following
1993 100% oxygen for 90 min per drive. and cutaneous minor blurring of HBO as part of treatment regime; 13
Canada Multiplace chamber. coverage vision of 26 met strict criteria for resolution
of disease

8
6. Soft tissue radionecrosis (no study)

9
7. Gas gangrene
Retrospective comparison studies: Part I

Authors, N Patient demographics Wound Diagnostic criteria Measured tissue PO2

year of duration
publication, (Y/N)
country
Gibson 46 Age: 16-83y NA Clinical and bacteriologic N
1986 Trauma (n=17)
New 29 HBO Surgical (n=21)
Zealand 12 Control Spontaneous (n=8)
Diabetes (n=11)
Hitchcock 33 Mean age: 52y (15-84) NA Clinical and N
1975 Bacteriologic
USA 19 HBO Gas gangrene infections of
14 Control the small intestine, colon
and rectum
Schweigel 43 Gas gangrene due to: ND Clinical and bacteriologic N
1973 Abd surgeries (n=19)
Canada 7 HBO Compound fracture
36 Control (n=42)
Other surgeries (n=10)
Jackson 24 Posttraumatic =18 NA Clinical and bacteriologic N
1973 Postoperative =6
Canada 15 HBO
9 Control

10
Retrospective comparison studies: Part II

Authors, HBO regimen Outcome Side effects Major results

year of measures and comments
publication,
country
Gibson Average of 4.5 Mortality ND Mortality:
1986 treatments over a two- HBO: 9/29 (31) %
New day period. Control: 7/12 (58%); P<0.05
Zealand Monoplace chamber.
Hitchcock A tight-fitting oronasal Mortality ND Mortality
1975 mask equipped with a HBO: 7/19 (37%)
USA demand valve. The Control: 7/14 (50%)
bottom time is two hours
at 3 ATA
Schweigel ND Mortality ND No quantitative results reported.
1973 “Fewer deaths reported among patients treated
Israel with HBO compared to those with HBO compared
to those not treated with HBO”
Jackson 5 sessions at 90 min Mortality, ND Mortality
1973 each, up to 3.0 atm over a amputation HBO: 4/15 (27%)
Canada 30-hour period Control: 5/9 (56%)
Chamber use did not Amputation (among survivors)
report HBO: 2/11
Control: 3/4

11
Case series: Part I

Authors N Patient demographics Wound Diagnostic criteria

year of duration
publication,
country
Rudge 77 Mean age: 33y NA Clinical and bacteriological
1993 (10d - 81y) Clostridial Myonecrosis
USA
Trivedi 15 13 adults (12 M and 1 F) NA A swab was taken for smear and anaerobic
1990 2 children (both males) culture from the wound after inspection
India
Hirn 32 Mean age: 55y (17–84) NA On the basis of the clinical appearance of the
1988 21 M, 11 F patient and presence of gram-positive rods on a
Finland smear
Unsworth 73 Age 5-85y NA Clinical
1984
Australia
Hart 139 Mean age: 38y (7-84) NA Bacteriologic culture and/or histologic studies of
1983 95 M, 44 F tissues removed
USA
Guidi 21 No age or gender data NA History, clinical evaluation of wound area, X-ray
1981 studies, bacteriological findings
Italy

12
Case series, Part I (continued)

Authors N Patient demographics Wound Diagnostic criteria

year of duration
publication,
country
Tonjum 30 Mean age 51y (13-83) Mean 13 days Patients’ general condition on admission classified into three
1980 23 M, 7 F (13 hours to 8 stages of serverity: Stage I- mild (1); Stage II – toxic (18); Stage
Norway 12 patients with diabetes weeks) III – moribund (11)
Skiles 33 Age: 24-83y NA Clinical history, physical findings and Gram’s stain
1978
USA
Fowler 9 ND NA Clinical
1977
USA
Darke 88 Mean age: ~54y (10-90) Less than 24 Clostridial infection: patients presented with infection and had a
1977 M:F 2.5:1 hours and up positive culture of pathogenic clostridia form the wound or blood.
UK to 28 days Non-clostridial infection: patients with infection, spreading
Diabetes (n=20) 23 % gangrene and usually gas formation demonstrable clinically or
radiologically.
Holland 49 Age: ~10-80y NA Clinical evidence and smears of wound secretions demonstrating
1975 gram-positive rods
UK
Hart 44 Age: 7-73y NA Pathologic examination of debrided tissue and culture of clostridia
1974
USA
Roding 130 ND NA Clinical and bacteriologic
1972
Netherlands

13
Case series: Part II

Author, HBO Regimen Outcome Side effects Major results

year of measures
publication,
country
Rudge All patients treated in USAF Mortality, ND Survival correlated well with site of
1993 hyperbaric chambers.(? multiplace) amputation infection (P=0.004) and time to HBO
USA (p=0.08)
Trivedi 100 % oxygen for 2 hours at Infection control 3 patients had Within 3-5 sittings, all cases were
1990 approximately 2.5 atm. Each one slight earaches found to be devoted of clostridial
India received a minimum of 3 successive during treatments organisms as judged by smear and
sittings. Vockers monoplace chamber. culture methods
Hirn 2.5 ATA for 120 minutes. 3 treatments Mortality 3 patients had Mortality: 9/32 (28%)
1988 first 24 hours; thereafter continued convulsions, 3
Finland twice daily until cure. Vockers patients suffered
monoplace chamber. barotrauma
Unsworth Five sessions were given in the first 48 Mortality, ND Mortality: 15/73 (22%)
1984 hours, each at 2.8 atm for 2 hours, and amputation
Australia its use was continued until clinical clinical
improvement occurred, in a large improvement
walk-in chamber (? Multiplace).
Hart Monoplace chamber. Mortality, 8 patients suffered Mortality: 27/139 (19%)
1983 amputation seizures Amputations: 24/139 (17%)
USA

14
Case series, Part II (continued)

Author, HBO Regimen Outcome Side effects Major results

year of measures
publication,
country
Guidi Each HBO at 2.8 atm lasted for 2 h. Mortality, ND Mortality: 4/21 (19%)
1981 Started within 2-3 h after admission or amputation, Amputations: 7/21 (33%)
Italy immediately after surgical procedures clinical
in a multiplace chamber. improvement
Tonjum HBO 3 ATA for 100 min. During the Mortality, One pneumo- Mortality: 9/30 (30%)
1980 first 24 hours, treatment was given at amputation thorax. Three one death occurred in the patient with
Norway 8 hours intervals, during the following patients developed pneumothorax, another death in
2 days at 12 hours intervals, making a convulsions patient with “oxygen toxicity”
total of 7 periods of treatment in a without sequelae. Amputations: 6/30 (20%)
stationary pressure chamber.
Skiles ND Mortality Treatment Mortality: 17/33 (52%)
1978 terminated in one
USA patient who
developed
convulsion
Fowler HBO at 2.5 to 3 ATA for 90 minutes Mortality, ND Mortality: 1/9 (11%)
1977 and then continued every 8 hours for amputation Amputations: 3/5 lower extremities
USA two days, and then every 12 hours for cases
three days (4-11 treatments) in a
monoplace chamber
Darke HBO 1.5 to 2 hour were given in a Mortality, 8 episodes of Mortality: 28/88 (32%)
1977 monoplace chamber at 2.5ATA, total clinical convulsions
UK exposure of 15-20 hours over 7 days. improvement attributed to HBO,
one death

15
Case series, Part II (continued)

Author, HBO Regimen Outcome Side effects Major results

year of measures
publication,
country
Holland Five to seven 2 hour of 100% oxygen at Mortality and morbidity, ND Mortality 13/49 (27%)
1975 3 ATA. With the first three treatment primary wound closure,
UK being completed during the initial 24 organisms recovered
hours. Chamber type not reported.
Hart 2.5 atm for 90 minutes every 8 hrs for 24 Mortality ND Mortality: 10/44 (23%)
1974 hrs, then twice a day.
USA Multiplace and monoplace chambers.
Roding 3 sessions of 2 hours during the first 24 Mortality ND Mortality: 29/130 (22%)
1972 hours, 2 sessions of 2 hours during the
Netherlands second and third 24 hours. Chamber type
not reported.

16
8. Progressive necrotizing infections
Retrospective comparison studies: Part I

Authors, N Patient demographics Wound Condition(s) Diagnostic Measured

year of duration criteria tissue PO2
publication,
country (Y/N)
Hollabaugh 26 Mean age: 57y (26 - 87) NA Fournier’s gangrene Clinical N
1998 10 pts with diabetes (35 %),
USA 14 HBO 9 pts alcohol abuse,
12 Control 3 pts immunosuppressed
Shupak 37 Mean age NA Necrotizing fasciitis Clinical N
1995 HBO: 53y (15 sd)
Israel 25 HBO 14 M, 11 F
12 Control Control: 57y (16 sd)
9 M, 3 F
Sawin 7 Mean age: 9 days (3-15) NA Neonatal abdominal Clinical N
1994 6 with omphalitis, 1 infected wall
USA 4 HBO circumcision wound necrotizing fasciitis
3 Control
Brown 54 Mean age NA Major truncal Clinical N
1994 HBO: 51y (17 sd) necrotizing infections:
Canada 30 HBO 22 M, 8 F necrotizing fasciitis,
24 Control Controls: 62y (13 sd) gas gangrene,
13 M, 11 F Fournier’s gangrene

17
Retrospective comparison studies: Part I (continued)

Authors, N Patient demographics Wound Condition(s) Diagnostic Measured

year of duration criteria tissue PO2
publication,
country (Y/N)
Risenman 29 Mean age ND Patients with Clinical N
1990 HBO: 60y (14-82); necrotizing fasciitis,
USA 17 HBO 11 M, 6 F gas gangrene, or
(1987-90) Control: 69y (41-88); Fournier’s disease
7 M, 5 F. On admission,
12 Control 1/12 patient in control was
(1980-87) in shock vs 5/17 HBO
patients, 4 patients (33%)
had diabetes mellitus.
Barzilai 11 Mean age NA Necrotizing fasciitis Clinical N
1985 HBO: 48 (13 sd); 3 M
Israel 3 HBO Control: 56 (9 sd);
8 Control 6 M, 2 F

18
Retrospective comparison studies: Part II

Author, HBO Regimen Outcome Side Effects Major results

year of Measures and comments
publication,
country
Hollabaugh 90 minutes at 2.4 atm Mortality ND Mortality
1998 Mean duration of HBO 12 days. HBO: 1/14 (7%);
USA Chamber type not reported Control: 5/12 (42%)
Shupak HBO at 2.5 atm, 2 cycles of 45 Mortality and ND Mortality
1995 min each separated by 5 min of morbidity, and risk HBO: 9/25 (36%);
Israel air breathing, until improvement. factors for grave Control: 3/12 (25%); p=N.S.
INMI’s walk-in chamber. prognosis Length of hospital stay
HBO: 16d ± 6.4;
Controls: 20d ±13.8; p=N.S.
Sawin ND Mortality ND Mortality
1994 HBO: 2/4;
USA Control: 0/3
Brown HBO administered at 2.5-3 atm Mortality, length of ND Mortality
1994 90 min per session, hospital and ICU HBO: 9/30 (30%);
Canada HBO followed each debridement stay, duration of Control: 10/24 (42%); P=NS
until no evidence of necrosis, antibiotic therapy
80% of patients received < 5 and number and No significant differences in duration of
sessions; 20% of patients received type of operations hospital or ICU stay, or duration of
5-7 sessions. antibiotic therapy.
Chamber type not reported.

19
Retrospective comparison studies: Part II (continued)

Author, HBO Regimen Outcome Side Effects Major results

year of Measures and comments
publication,
country
Risenman 90 minutes at 2.5 ATA every 8 Mortality, ND Mortality
1990 hours first day, then twice debridements HBO: 4/17 (23%)
USA daily for total of 10 treatments. Control:8/12 (67%); P<0.025
Monoplace chamber Mean debridements/patients:
HBO: 1.2 per case
Control: 3.3 per case; P<0.03
Barzilai ND Mortality ND Mortality
1985 HBO: 2/3 (66%)
Israel Control: 5/8 (62%)

20
Case series: Part I

Authors N Patient demographics Wound Condition(s) Diagnostic criteria

year of duration
publication,
country
Korhonen 33 Mean age: 51y (24–84) 2-7 days Fournier’s Identification of multiple pathogenic
1988 31 M, 2 F Gangrene organisms in the primary Gram stain or
Finland 7 diabetes, 4 alcoholism, culture, and systemic toxicity.
2 immunosuppressed
Eltorai 9 Age: 44-65y NA Fournier’s gangrene Clinical and bacteriologic
1986
USA 1 patient with diabetes
Gozal 16 Mean age: 51.9y (20-84) ND Necrotizing Clinical
1986 Fasciitis
Israel 5 patient with diabetes

Case series: Part II

Author, HBO Regimen Outcome Side effects Major results

year of measures
publication,
country
Korhonen 2.5 ATA for 120 min. 3 treatments during the first 24 hours; Mortality, ND Mortality: 3/33 (9%)
1988 then continued twice daily until clearing of toxic symptoms amputation
Finland of clostridial infection. Both Vockers monoplace chamber
and multiplace chamber.
Eltorai Four to 12 (one patient needed 40) sessions of HBO at 2 to Recovery ND All patients recovered
1986 2.5 ATA.
USA Chamber type not reported.
Gozal Three HBO session in the first 24 hours and two sessions per Mortality ND Mortality: rate of 12.5%
1986 day thereafter. Each session consists of 100% oxygen at 2.8
Israel to 3 ATA for 90 min in a multiple hyperbaric chamber.

21
9. Chronic refractory osteomyelitis
Part I
Author, N Patient Study Wound Condition(s) Diagnostic criteria Measured
year of demographics design duration tissue PO2
publication,
country (Y/N)
Esterhal 28 matched by Non- Mean 70 Uncomplicated Osteomyelitis staging N
1987 staging system randomized months chronic refractory system per Cierny,
USA 14 HBO and general health controlled (8-628) osteomyelitis Mader, and Penninck
14 control status trial (data verified)
mean age: 40y
(15-74)
19 M, 9 F
Davis 38 Mean age: 40y Case series Average 8.9 y Non-hematogenous Clinical and N
1986 (16-76) (6-15) osteomyelitis had bacteriological
USA 24 M, 14 F been present for at
least 6 months

Part II
Authors, HBO regimen Outcome Side effects Major results and comments
year of measures
publication,
country
Esterhal Daily administration for time to wound healing, ND Treatment failures:
1987 2 hours at 2 ATA, 6 initial clinical outcome, HBO: 3/14
USA days per week length of Control: 1/14
Chamber type not hospitalization, .
reported. recurrence of infection
Davis HBO 2.4 ATA. Clinical sign of 3 patients required 34 of 38 patients remained free of
1986 Chamber type not osteomyelitis tympanotomy tubes; 2 clinical signs of osteomyelitis for an
USA reported. Free of infection patients reported average of 34 months
transient vision changes

22
10. Chronic non-healing wounds
Part I
Author, N Patient demographics Study Wound Condition(s) Diagnostic criteria Measured
year of design duration tissue PO2
publication,
country (Y/N)
Faglia 70 Mean age RCT ND Severe infected Lesions were Y
1996 HBO: 62y (10.4 sd); diabetic foot classified according
Italy 35 HBO Control: 54y (7.8 sd) ulcers to Wagner grading TcPO2 on
33 Control 84 M, 31 F method admission
Doctor 30 Mean age: RCT ND Diabetic patients Clinical N
1992 Number of HBO: 56y (45-70) with chronic foot
India subjects in study M:F=3:1 lesions
arms can not be Control: 60y (48-70) hospitalized
determined M:F=2:1

Part II
Author, HBO regimen Outcome Side effects Major results
year of measures and comments
publication,
country
Faglia 100% oxygen at 2.5 ATA In 1st Vascular procedures, 2 subjects with Major amputations
1996 phase, 2.2 - 2.4 ATA in 2nd phase. amputation rates barotraumatic otitis HBO: 3/35 (8.6%)
Italy 90 min daily in 1st phase 5d/wk in (did not interrupt Control: 11/33 (33.3%)
2nd phase. Multiplace chamber. treatment) Risk ratio: 0.26 (0.08-0.84); P=0.016
Doctor 4 sessions of HBO over 2 weeks Wound cultures, ND Above ankle amputations
1992 at 3 ATA for 45 min each. assessment of local HBO: 2/15, Control: 7/15; P<0.05
India Monoplace chamber wound daily, skin Minor (others) amputations
flaps, hospital stay, HBO: 4/15, Control: 2/15; P=NS
need for amputation, Number of positive cultures decreased
level of amputation from baseline of 19 to 3 in HBO; 16 to 12
in control, P<0.05

23
Non-randomized comparative studies

Part I
Authors, N Patient demographics Study design Wound Condition(s) Diagnostic criteria Measured
year of duration tissue PO2
publication,
country (Y/N)
Faglia 115 Mean age: 63y (10 sd) Comparative ND Diabetic Clinical (lesions were Y
1998 51 HBO 84 M, 31 F study wounds classified according to (not used
Italy 64 Control Wagner) as criteria)
Zamboni 10 Mean age Controlled >6 Chronic lower Clinical Y
1997 HBO: 84y (8.9); 4 M, 1 F trial months extremity (not used
USA 5 HBO Control: 54y (7.8); diabetic as criteria)
5 Control 4 M, 1 F Patients who wounds
Outpatient setting. There refused HBO (TCM3/
is a trend that the wound treatment TINA,
size and TcPO2 is worse served as Radiometer
in HBO group but not controls American
statistically significant. Inc)
Baroni 28 HBO: Controlled ND Ulceronecrotic Clinical and N
1987 mean age 58y (41-72) trial diabetic foot Bacteriological
Italy 18 HBO 11 M, 7 F lesions
10 Control Control: control group
mean age 59y (46-75) subjects
6M, 4F refused
HBOT for
psychological
reason

24
Non-randomized comparative studies: Part I (continued)

Authors, N Patient Study design Wound Condition(s) Diagnostic Measured

year of demographics duration criteria tissue PO2
publication,
country (Y/N)
Oriani 80 Mean age Retrospective ND Diabetic patients Clinical N
1990 HBO: 53y (12 sd) comparison. with ulceronecrotic
Italy 62 HBO Control: 58y (8 sd) Controls consist of lesions
18 Control patients who refused
HBO or
contraindication

25
Non-randomized comparative studies: Part II

Authors, HBO regimen Outcome Side effects Major results and comments
year of measures
publication,
country
Faglia In the first phase: HBOT Major amputations ND Major amputations:
1998 at 2.5 ATA, HBO: 7/51
Italy A daily session (90 min Control: 20/64 P=0.012
for each session).
In the second phase:
2.4-2.2 ATA.
Chamber type not
reported.
Zamboni 30 HBO treatments at 2 Wound surface area, ND HBO in conjunction with standard wound care
1997 ATA 2 hr/day, 5 day/wk complete healing, significantly reduced wound size when compare
USA for 7 weeks amputations with standard wound care alone (P<0.05).
Chamber type not At 4 to 6 month follow-up, the HBO treated
reported. patients had a higher rate of compete healing (4/5
versus 1/5), no amputation in either group
Baroni 100 % oxygen at 2.8 Amputation, anatomic ND Healing
1987 ATA 90 min daily. clinical features of HBO: 16/18 (89%); Control: 1/10 (10%) P=0.001
Italy Multiplace chamber ulceronecrotic lesions Amputation
HBO: 2/18; Control: 4/10
Oriani Initial HBO at 2.8 ATA, “Recovery”, ND “Recovery”
1990 then at 2.5 ATA 6 days amputation HBO: 59/62 (96%)
Italy a week until beginning Control: 12/18 (67%)
granulation and then 5 Amputation
days a week until HBO: 3/62 (5%)
recovery. Chamber type Control: 6/18 (33%) P<0.001
not reported.

26
2) Non-diabetic ulcers

Part I
Author, N Patient demographics Study Wound Condition(s) Diagnostic criteria Measured
year of design duration tissue PO2
publication,
country (Y/N)
Hammarlund 16 Median age: 67y (42-75); RCT, More than Non-diabetic leg Clinical N
1994 9 M, 7 F double- one year ulcers. No signs
Sweden 8 HBO No large vessel disease blinded, of healing the
8 Control as measured by placebo- prior 2 months.
ultrasound Doppler. controlled

Part II
Author, HBO regimen Outcome Side effects Major results
year of measures and comments
publication,
country
Hammarlund HBO: 100 % oxygen at 2.5 ATA, The wound area ND Mean wound surface area decreased
1994 90 min, 5 days/wk for total of 30 was scanned into a at 6 week endpoint
Sweden treatments. computer and HBO: 35.7 % (±17%)
Multiplace chamber. measured. Control: 2.7 % (±11%)
P < 0.001.

27
Table 3. Topical hyperbaric oxygen studies

28
Table 3. Topical hyperbaric oxygen studies – Part I

Author, N Patient demographics Study design Wound Condition(s) Diagnostic criteria Measured
year of duration tissue pO2
publication,
country (Y/N)
Leslie 28 Mean age 49 y (32-71) RCT Mean 6.3 Diabetic A well-demarcated N
1988 16 M, 12 F wk wounds foot ulcer, diagnosis
USA 12 HBO Both groups were (1-32) of diabetes mellitus,
16 Control similar in age, clinical absence of gangrene
characteristics at
baseline
Heng 2001 40 THO age 73.8 RCT ND Necroticlgangr Clinical N
USA (SD=6.4) enous wounds
29 THO 13 M
50 Control
Control age 75.5
26 M, 1F
Lehman 43 ND Prospective ND Human bite Clinical and N
1985 comparison infections bacteriologic
USA 16 HBO study
27 Control (claims to be
randomized,
but not true)
Landau 50 Age: 59 ± 11y Non 9 ± 6.6 Chronic Clinical N
1998 Range 38-88 randomized month, diabetic foot
Israel 15 THO M=28; F=22 comparison range 2-70 ulcers
35 Control

29
Table 3. Topical hyperbaric oxygen studies – Part I (continued)

Author, N Patient Study design Wound Condition(s) Diagnostic criteria Measured

year of demograph duration tissue PO2
publication, ics
country (Y/N)
Heng 15 Mean age: Prospective ND Necrotic gangrenous Unchanged or N
2000 76y (56-92) cohort wounds worsened for 6 or
USA 8 M, 7 F more weeks before
11 diabetes THO treatment
Fischer 52 Age: 9-84y Case series, Months to Lesions of the lower Clinical N
1969 years extremities
USA 2 diabetes 6 cases used
self control
Fischer 8 Age: 1 to 14 Case series NA Infected meningomyelocele Clinical N
1969 days
USA

Fischer 30 Age: 8-95y Case series 15 days to Burns, pressure sores, Clinical N
1975 6 years venous stasis ulcers,
USA infected surgical wounds,
rheumatoid arthritis ulcers
Olejniczak 174 93 M, 81 F Case series ND Leg Ulcers due to various Clinical N
1976 etiologies
USA
Diamond 11 Age: 25-85y Case series ND Lower extremity Clinical N
1982 Ulcerations
USA 1 diabetes

30
Table 3. Topical hyperbaric oxygen studies – Part I (continued)

Author, N Patient Study Wound Condition(s) Diagnostic criteria Measured

year of demographics design duration tissue PO2
publication,
country (Y/N)
Ignacio 15 12 diabetes Case series ND Extensive leg and foot Clinical N
1985 ulcers
USA

Landau 100 ND Case series 7±5 Diabetic foot ulcers Clinical N

2001 months
Israel

31
Table 3. Topical hyperbaric oxygen studies – Part II
.
Author, THBO regimen Outcome Side effects Major results
year of measures and comments
publication,
country
Leslie THBO 90 min twice daily with a Bacterial cultures, ND Ulcer area and changes in ulcer depth
1988 topical hyperbaric bed chamber which measurements of the revealed no statistically significant
USA provided humidified 100% oxygen at ulcers differences between treatment groups
pressures cycling between 0 and 30
mmHg every 20 secs.
Heng THBO at 1.04 ATA Wound measurements ND Wound healing:
2001 Histological assessment THO: 90%
USA Cost analysis Control: 22%
The size of ulcers (at 4 weeks)
THO: significantly smaller
Control: larger
Lehman 50 mmHg 100% oxygen is cycled Hospital stay, return to ND Shorter hospitalization and earlier
1985 every 30 seconds for 90 minutes twice functional status return to functional status was found
USA daily. complications in the severe infection subgroup
treated with THBO
Landau Oxygen 100% was pumped into the Clinical improvement No side There was no significant clinical
1998 bag and the pressure in the chamber effect difference between the topical
Israel was kept to between 20 and 30 hyperbolic oxygen alone or combined
mmHg(1.02-1.03 ATM) with a low power laser. Both methods
should be considered in the treatment
of chronic diabetic foot ulcers.

32
Table 3. Topical hyperbaric oxygen studies – Part II (continued)

Author, THBO regimen Outcome Side effects Major results

year of measures and comments
publication,
country
Heng Oxygen flow into the bag at the Wound healing ND 22 of 24 ulcers (13 of 15 patients) were
2000 rate of 15 L/min. Pressures at least (Ulcer size, severity healed by 12 weeks.
USA 10 mm below capillary filling grading of wounds)
pressures. 4h/day, 4 consecutive Costs
days each week, over a 4-week
period.
Fischer A constant 22 mmHg (1.03 ATA) Healing of lesions ND 6 failures out of 52 patients
1969 of pure oxygen at a flow-rate of 2-
USA 8 L/min continuously for 4-12
hr/day
Fischer A constant 22 mmHg (1.03 ATA) Cessation of ND Cerebrospinal fluids leakage is stopped as
1969 of pure oxygen at a flow-rate of 1- cerebrospinal fluid soon as pressurized oxygen was applied.
USA 4 L/min for a total of 10 hr/day leakage, Marked inhibition of bacterial growth
bacterial growth Granulation and epithelium formation are
stimulated
Fischer Oxygen at 4L/min at pressure not Healing of lesions ND Completed healing of all lesions
1975 exceeding 22 mmHg (1.03 ATA)
USA twice daily, each session 2-3
hours.
Olejniczak 3.4 liters per minute oxygen flow is Complete healing ND Compete healing:
1976 applied twice a day for 20 min, with 33/33 (100%) posttraumatic ulcers
USA pressure in each bag from 0 to 5 11/11 (100%) varicose veins
mmHg 87/91 (96%) phlebitis
10/33 (30%) arteriosclerosis ulcers
Diamond 22 mmHg at a flow rate of 4 Clinical ND Total healing in all 11 patients who were
1982 L/min. All treatments were 90 improvement, refractory to outpatient management.
USA min, twice a day. bacterial cultures

33
Table 3. Topical hyperbaric oxygen studies – Part II (continued)

Author, THBO regimen Outcome Side effects Major results

year of measures and comments
publication,
country
Ignacio 16 to 20 mmHG pressure for Assessment of the ND Complete healing in 11 of 15 patients (73%).
1985 45 min each session using a vascular integrity, and
USA disposable, inflatable, vinyl complete pictorial
sleeve applied twice a day. documentation of the
size of the ulcers and the
progress of response
Landau THO was administered by Total cured No side Cure: 81/100 (81%)
2001 pumping 100% humidified effect Recurrent ulceration: 3/81 (4%)
Israel oxygen Recurrent ulceration Amputations: 19
Into a hyperbaric chamber,
150 min x 2 to 3/week, up to Amputations THO therapy may be a safe, simple, and
1.4 atm inexpensive early adjunctive treatment for
patients with chronic diabetic foot ulcers.

34