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HBOT: What The Studies Show

In a thorough review of the literature on the use of hyperbaric oxygen therapy in the lower extremity, this author offers a closer look at the research on HBOT for diabetic foot ulcers as well as a variety of other conditions ranging from refractory osteomyelitis and soft tissue infection to crush injuries and compromised grafts and flaps.

Hyperbaric oxygen therapy (HBOT) has served as a primary or adjunctive therapy for many medical conditions since the 19th century. The literature concerning the efficacy of HBOT is extensive and varies dramatically in overall quality, opinions and results. For almost every aspect of HBOT, further investigation and more studies would be helpful in making HBOT part of the medical community’s accepted standard of care.
There are currently 14 different conditions/indications for HBOT that have the approval of the Undersea and Hyperbaric Medical Society.1 These conditions/indications include:   
1. Air or gas embolism
2. Carbon monoxide poisoning
3. Clostridial myositis and myonecrosis (gas gangrene)
4. Crush injury, compartment syndrome and other acute traumatic ischemias
5. Decompression sickness
6. Arterial insufficiencies
7. Severe anemia
8. Intracranial abscess
9. Necrotizing soft tissue infections
10. Osteomyelitis (refractory)
11. Delayed radiation injury (soft tissue and bony necrosis)
12. Compromised grafts and flaps
13. Acute thermal burn injury
14. Idiopathic sudden sensorineural hearing loss
Physicians most commonly use HBOT to treat decompression sickness, gas embolism or conditions of tissue hypoxia.

What Are The Contraindications And Possible Complications Of HBOT?
Untreated pneumothorax is the only absolute contraindication to HBOT. Other relative contraindications include claustrophobia, obstructive lung disease, upper respiratory infections, sinus infections, recent ear or thoracic surgery, pulmonary blebs or bullae on chest X-rays, and uncontrolled fever.2 Exercise caution with people who have a history of seizure disorders and when there is concomitant use of bleomycin or doxorubicin (Doxil, Janssen Pharmaceuticals).3-5

Physicians generally regard HBOT as being safe and well tolerated. The most common complication is middle ear barotrauma with an approximate incidence ranging between 0.34 and 2 percent.6-8 Other less common adverse side effects include sinus barotrauma, reversible myopia, pulmonary barotrauma, pulmonary oxygen toxicity, seizures, hypoglycemia and decompression sickness.3,7,9

A Guide To Technique And Clinical Benefits
Most patients receiving HBOT do so in airtight chambers made of metal and acrylic material filled with 100 percent oxygen that is pressurized from 2.0 to 3.0 ATA (atmospheric pressure absolute). Multiplace chambers allow better monitoring of critically ill patients while single occupancy chambers are more appropriate for stable patients receiving treatment for chronic medical conditions. Acute therapy may only require a few treatments whereas chronic conditions may require 30 or more HBOT sessions to be effective. Treatment times vary from 45 minutes to 300 minutes depending on the indication of the therapy.6,9,10 Topical oxygen therapy, however, does not have any strong clinical evidence and Medicare does not reimburse for it at this time.6

With regard to tissue hypoxia and wound healing, HBOT can facilitate fibroblast proliferation and angiogenesis, decrease inflammation, increase the flexibility of red blood cells, increase growth factors, mobilize stem cells within bone marrow, augment neutrophil bactericidal activity, limit clostridial exotoxins and spore production, kill certain anaerobes, and inhibit the growth of several other bacterial pathogens.3,6,11-19

What The Research Says About Diabetic Foot Ulcers And HBOT
Physicians have promoted HBOT as an effective treatment for diabetic foot ulcers with the first controlled trial coming in 1987.20 Unfortunately, since that trial was published, there have been more systematic reviews of the HBOT and diabetic foot ulcer literature than there have been new randomized controlled trials.21 A review of the literature concerning the efficacy of HBOT in treating diabetic foot ulcers reveals a vast array of conflicting information.

According to the 2015 UHM Clinical Practice Guideline for HBO2 to Treat Diabetic Foot Ulcers, there are currently nine randomized controlled trials, more than 20 observational studies and nearly a dozen review articles that investigate the use of HBOT in the treatment of diabetic foot ulcers.21 However, the inconsistent treatment protocols, small sample sizes and questionable methodology used in these studies contribute to the continued debate about what role HBOT should have in the treatment of diabetic foot ulcers.21

After doing a systematic review of the literature, the Undersea and Hyperbaric Medical Society was able to rate the quality of evidence and generate the following 2015 practice recommendations for the treatment of diabetic foot ulcers with HBOT.21  

1. In patients with Wagner Grade 2 or lower diabetic foot ulcers, do not use HBOT.
2. In patients with Wagner Grade 3 or higher diabetic foot ulcers that have not shown significant improvement after 30 days of treatment, add HBOT to the standard of care to help reduce the risk of major amputation and incomplete healing.
3. In patients with Wagner Grade 3 or higher diabetic foot ulcers who have just had surgical debridement of an infected foot (e.g., partial toe or ray amputation, debridement of ulcer with underlying bursa, cicatrix or bone; foot amputation; incision and drainage of deep space abscess; or necrotizing soft tissue infection), add acute postoperative HBOT to the standard of care to reduce the risk of major amputation and incomplete healing.

The aforementioned Undersea and Hyperbaric Medical Society HBOT treatment protocols are all based on the assumption that the practitioner has aggressively addressed revascularization of the ischemic foot, debrided any devitalized tissue, offloaded a neuropathic foot lesion, and used appropriate anti-infective therapies prior to utilizing adjunctive HBOT.21

What Studies Reveal About HBOT For Other Lower Extremity Wounds And Conditions
Refractory osteomyelitis. In 2009, Goldman found through a systematic review that there is a moderate level of evidence that HBOT can promote remission of refractory osteomyelitis if one combines hyperbaric oxygen with a comprehensive program of surgery and antibiotics.22 However, the results are controversial as there were no randomized controlled trials to help determine the strength of the association and the literature primarily focused on younger patients (mean age of 40) who developed osteomyelitis after a complex fracture or trauma.22

According to Mader and colleagues, HBOT is useful for the treatment of osteomyelitis as it increases the oxygen tension in infected bone tissue.23 An adequate oxygen tension is necessary for oxygen-dependent killing of organisms by the polymorphonuclear leukocytes and fibroblast activity leading to angiogenesis and wound healing. Based on cohort and case-controlled studies, the Undersea and Hyperbaric Medical Society Oxygen Therapy Committee Report in 2003 indicated that HBOT is an American Heart Association (AHA) level II-b treatment for osteomyelitis.10 However, further studies, specifically a randomized control trial, would be of benefit to solidify the approved usage of HBOT for osteomyelitis treatment.

Soft tissue infection. In cases of aggressive soft tissue infection such as gas gangrene and necrotizing fasciitis, primary treatment includes aggressive debridement and antibiotic therapy. Wilkinson did a retrospective cohort study on 44 patients who had a necrotizing soft tissue infection. The use of adjunctive HBOT lead to an almost ninefold increase in the patient’s rate of survival and significantly reduced the incidence of amputation.24 With acute soft tissue infections, one should use HBOT early with two to three daily 90-minute sessions at 3 atm. The higher pressure helps maintain the oxygen tension above 300 mmHg, which is sufficient to inhibit clostridial spores and exotoxin production.3

Crush injuries and compartment syndrome. Trauma resulting in crush injuries and/or compartment syndrome is often devastating. Acute limb compartment syndrome is a surgical emergency as it can lead to increased tissue pressure that reduces capillary perfusion below a level necessary for tissue viability. Delayed treatment is associated with significant morbidity due to irreversible ischemic necrosis of the muscles and nerves in the compartment.25

Bouachour and coworkers evaluated the efficacy of HBOT in the treatment of crush injuries in 36 patients in a randomized, double-blind, placebo-controlled clinical trial.26 The patients in the study received either a 90-minute twice-daily HBOT treatment or a 90-minute twice-daily sham treatment. Both groups started within 24 hours and received a total of six days of treatment. The HBOT-treated group had fewer amputations (one versus six) and required fewer skin flaps, grafts and vascular surgery. The HBOT-treated group also had higher rates of complete healing (17 patients versus 10 patients in the sham treatment group). The study proved HBOT to be a useful adjunct in the management of severe (grade III) crush injuries of the limbs in patients more than 40 years old.

Acute thermal burn injury. The efficacy of HBOT in the treatment of burns is not clear at this time. There is conflicting information within the literature. An economic analysis by Cianci and colleagues evaluated patients with 19 to 50 percent total body surface area burns.27 Over a five-year period, the study examined the length of stay, the number of surgical procedures and the total cost of care. Half of the patients received HBOT while the other half did not. The HBOT-treated group had a decreased length of stay, reduction of surgical procedures and decreased overall cost.

In contrast, a larger randomized prospective trial evaluating the use of HBOT in burn patients did not show any benefit in mortality, the length of stay or the extent of autograft use.28 Therefore, the authors of this study concluded that there is insufficient evidence to support the use of HBOT for acute burns.28 A systematic review of the literature by Villaneuva and colleagues in 2004 also confirmed there was no evidence to support the use of HBOT for acute burns.29 Further studies are needed in this area as the data available is too limited at this time.

Compromised grafts and flaps. Researchers published a comprehensive review study evaluating the use of HBOT for compromised grafts and flaps in 2006.30 It showed that if one utilizes HBOT prior to and three days following skin grafting, there was a 29 percent increase in graft survival. Most of the support for HBOT in preventing graft/flap failure comes from a large number of animal studies.17,30

However, a recent 2008 retrospective cohort human study evaluated the use of HBOT after patients underwent reconstructive surgery for Gustilo type III A, B, and C war wounds to the extremities.31 Flap necrosis occurred in 51 percent of patients who did not receive HBOT versus only 15 percent in those who did receive HBOT. Skin graft lysis occurred in 52 percent of patients who were not treated with HBOT versus only 23 percent in those who were treated with HBOT. Since the amount of literature is limited, further studies are needed at this time.

Arterial insufficiency ulcers. In 2007, the Wound Healing Society released clinical practice guidelines for arterial insufficiency ulcers.32 The guidelines state that one should consider HBOT an adjuvant therapy in patients whose ulcers are not healing despite revascularization or in patients with non-reconstructable anatomy. Additional criteria include the ability of the hypoxia to be reversed by hyperbaric oxygenation.6,33-35 In 2001 Grolman and colleagues conducted a retrospective case series on the use of HBOT to treat arterial insufficiency ulcers in 36 patients, who were non-bypass candidates.36 Seventy percent of patients with periwound TCOM >10 mmHg healed their wounds versus 11 percent of those with TCOM <10 mmHg. Authors considered the level of evidence to be moderate.22,36

Calciphylaxis. Calciphylaxis often presents as aggressive expanding gangrene of the skin in patients who usually (75 percent) have end-stage renal disease. There is no current standard of care and treatments can include extensive debridement, use of phosphate binders, parathyroidectomy and increase in dialysis.22,37 Calciphylaxis has a mortality rate of 80 percent due to sepsis and organ failure.37

Basile and colleagues conducted a retrospective case series about patients who were treated with HBOT for calciphylaxis.38 The study has a small sample size with nine patients completing the study. However, the results of the study were encouraging, given the usually poor prognosis associated with survival and/or limb preservation. Of the nine patients, eight completely healed. This led to 75 percent healing for those who completed the study with a tissue diagnosis. In addition, the nine patients survived in the one-year follow-up. A large RCT would possibly yield further insight in treating this rare but potentially fatal condition.

Could HBOT Have An Impact For Other Conditions In The Future?
There are a myriad of potential uses of HBOT that are currently under further investigation. These conditions include myocardial infarction, traumatic brain injury, spinal cord injury, sickle cell crisis, fibromyalgia, acute stroke, neonatal hypoxic-ischemic brain damage, increasing insulin sensitivity, cerebral palsy-related brain perfusion, radiation-induced neurotoxicity, posttraumatic stress disorder, depression, generalized anxiety disorder and acute pancreatitis. Obviously, further investigation is needed prior to broad utilization of HBOT for any of these conditions.

In Conclusion
Hyperbaric oxygen therapy has proven to be a useful adjunctive therapy for multiple conditions. The level of evidence is moderate for the use of HBOT for diabetic foot ulcers, crush injuries and soft tissue infections. Further investigation and clinical trials are needed to examine the use of HBOT for the treatment of chronic osteomyelitis, burns, compromised grafts/flaps, arterial insufficiency ulcers and calciphylaxis.

Dr. Swain is a board certified wound specialist physician (CWSP) of the American Board of Wound Management and a Diplomate of the American Board of Podiatric Medicine. He is a consultant with MiMedx and is in private practice in Jacksonville, FL.

References

  1.     Undersea & Hyperbaric Medical Society. Available at www.uhms.org . Accessed on May 31, 2015.
  2.     Tokly AS, Korpinar S, Erelel M, et al. Are pulmonary bled and bullae a contraindication for hyperbaric oxygen treatment? Respir Med. 2008; 102(8):1145-7.
  3.     Roth RN, Weiss LD. Hyperbaric oxygen and wound healing. Clin Dermatol. 1994; 12(1):141-56.
  4.     Torp KD. Carraway MS. Ott MC, et al. Safe administration of hyperbaric oxygen after bleomycin: a case series of 15 patients. Undersea Hyperb Med. 2012; 39(5):873-9.
  5.     Karagoz, B, Suleymanoglu S, Uzun G, et al. Hyperbaric oxygen therapy does note potentiate doxorubicin-induced cardiotoxicity in rats. Basic Clin Pharmacol Toxical. 2008; 102(3):287-92.
  6.     Suzuki K. A guide to hyperbaric oxygen therapy for diabetic foot wounds. Podiatry Today. 2007; 20(12):18-22.
  7.     Camporesi EM, Bosco G. Mechanisms of action of hyperbaric oxygen therapy. Undersea Hyperb Med. 2014; 41(3):247-52.
  8.     Beard T, Warriner R, Fife C et al. Hyperbaric oxygen therapy adverse events in relation to treatment depth, a retrospective analysis from 48 centers. Presented at Session C, Annual Undersea and Hyperbaric Medical Society 40th meeting, Maui, HI, June 2007.
  9.     Leach RM, Rees PJ, Wilmhurst P. Hyperbaric oxygen therapy. Br Med J. 1998; 317(7166):1140-3.
  10.     Feldmeier JJ. Hyperbaric oxygen 2003, Indications and results: UHMS Hyperbaric oxygen therapy committee report. Undersea and Hyperbaric Medical Society, Kensington, MD, 2003.
  11.     Wattel F, Mathieu D, Neviere R, Bocquillon N. Acute peripheral ischaemia and compartment syndromes: a role for hyperbaric oxygenation. Anaesthesia. 1998; 53(Suppl 2):63-5.    
  12. Marx RE, Ehler WJ, Tayapongsak P, Pierce LW. Relationship of oxygen dose to angiogenesis induction in irradiated tissue. Am J Surg. 1990; 160(5):519-24.
  13.     Kaye D. Effect of hyperbaric oxygen on Clostridia in vitro and in vivo. Proc Soc Exp Bio Med. 1967. 124(2):360-6.
  14.     Hill GB, Osterhout S. Experimental effects of hyperbaric oxygen on selected clostridial species. In-vitro studies. J Infect Dis. 1972; 125(1):17-25.
  15.     Mader JT, Brown GL, Guckian JC, et al. A mechanism for the amelioration by hyperbaric oxygen of experimental staphylococcal osteomyelitis in rabbits. J Infect Dis. 1980; 142(6):915-22.
  16.     Lee CC, Chen SC, Tsai SC, et al. Hyperbaric oxygen induces VEGF expression through ERK, JNK and C-JUN/AP-1 activation in human umbilical vein endothelial cells. J Biomed Sci. 2006; 13(1):143-56
  17.     Friedman HI, Fitzmaurice M, Lefaivre JF, et al. An evidence-based appraisal of the use of hyperbaric oxygen on flaps and grafts. Plastic Recon Surg. 2006; 117(Suppl 7):175S-190S.
  18.     Calhoun JH, Cobos JA, Mader JT. Does hyperbaric oxygen have a place in the treatment of osteomyelitis? Orthop Clin N Am. 1991; 22(3):467-471.
  19.     Thom SR, Bhopale VM, Velazquez OC, et al. Stem cell mobilization by hyperbaric oxygen. Am J Physciol Heart Circ Physiol. 2006; 290(4):H1378-H1386.
  20.     Baroni G, Porro T, Faglia E, Pizzi G, Mastropasqua A, Oriani G, Pedesini G, Favales F. Hyperbaric oxygen in diabetic gangrene treatment. Diabetes Care. 1987; 10(1):81–86.
  21.     Huang ET, Mansouri J, Murad MH, et al. A clinical practice guideline for the use of hyperbaric oxygen therapy in the treatment of diabetic foot ulcers. Undersea Hyperbaric Med. 2015; 42(3):205-247.
  22.     Goldman RJ. Hyperbaric oxygen therapy for wound healing and limb salvage: a systematic review. PM R. 2009; 1(5):471–489.
  23.     Mader JT, Adams KR, Wallace WR, Calhoun JH. Hyperbaric oxygen as adjunctive therapy for osteomyelitis. Infect Dis Clin North Am. 1990;4(3):433–440.
  24.     Wilkinson D, Doolette D. Hyperbaric oxygen treatment and survival from necrotizing soft tissue infection. Arch Surg. 2004; 139(12):1339-45.
  25.     Pearse MF, Harry L, Nanchahal J. Acute compartment syndrome of the leg : Fasciotomies must be performed early, but good surgical technique is important. Br Med J. 2002; 325(7364):557-558.
  26.     Bouachour G, Cronier p, Goello JP, et al. Hyperbaric oxygen therapy in the management of crush injuries: a randomized double-blinded placebo-controlled clinical trial. J Trauma. 1996; 41(2):333-9.
  27.     Cianci P, Williams C, Leuders H, et al. Adjunctive hyperbaric oxygen in the treatment of thermal burns: an economic analysis. J Burn Care Rehab. 1990; 11(2):140-3..
  28.     Brannen AL, Still J, Haynes, MS, et al. A randomized prospective trial of hyperbaric oxygen in a referral burn center population. Am Surg. 1997; 63(3):205-8.
  29.     Villanueva E, Bennett MH, Wasiak J, Lehm JP. Hyperbaric oxygen therapy for thermal burns. Cochrane Database Syst Rev. 204:CD004727
  30.     Thom SR. Hyperbaric oxygen: its mechanisms and efficacy. Plast Reconstr Surg. 2011; 127(Suppl 1):131S–141S.
  31.     Roje Z, Roje Z, Eterovic D, et al. Influence of adjuvant hyperbaric oxygen therapy on short-term complications during surgical reconstruction of upper and lower extremity war injuries: retrospective cohort study. Croat Med J. 2008; 49(2):224-32.
  32.     Hopf H, Ueno C, Aslam R, et al. Guidelines for the treatment of arterial insufficiency ulcers. Wound Rep Regen. 2007; 14(6):693-710.
  33.     Gesell LB, ed. Hyperbaric Oxygen Therapy Indications, 12th Edition. Undersea and Hyperbaric Medical Society, Durham, NC, 2008.
  34.     Hopf H, West J. Arterial subcommittee: should hyperbaric oxygen therapy be utilized in the control arm of clinical research studies for arterial (ischemic) wounds? provisional guidelines for chronic wound care: arterial, diabetic, pressure and venous. Presented at Wound, Ostomy and Continence Nurses Society and Wound Healing Society, June 21, 1999.
  35.     Shah J. Hyperbaric oxygen therapy. J Am Col Cerif Wound Spec. 2010; 2(1):9-13.
  36.     Grolman RE, Wilkerson DK, Taylor J, et al. Transcutaneous oxygen measurements predict a beneficial response to hyperbaric oxygen therapy in patients with nonhealing wounds and critical limb ischemia. Am Surg. 2001;67(11):1072-1079
  37.     Wollina U. Update of cutaneous calciphylaxis. Indian J Dermatol. 2013; 58(2):87-92.
  38.     Basile C, Montanaro A, Masi M, et al. Hyperbaric oxygen therapy for calcific uremic arteriolopathy: a case series. Jf Nephrol. 2002;15(6):676-680.

For further reading, see “Point-Counterpoint: HBOT: Is It Worthwhile For DFUs?” in the March 2014 issue of Podiatry Today.

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David Swain, DPM, CWSP
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