Last month, Medicare began reimbursing for hyperbaric oxygen (HBO) treatment as an adjunctive therapy for diabetic foot ulcers. After an exhaustive review of the literature, the Centers for Medicare and Medicaid (CMS) concluded that “HBO therapy is clinically effective and, thus, reasonable and necessary in the treatment of certain patients with limb-threatening diabetic wounds of the lower extremity.” According to the CMS, patients must meet each of the following three criteria: • the patient has type I or type II diabetes and has a lower extremity wound that is due to diabetes; • the patient has a wound classified as Wagner grade III or higher; and • the patient has failed an adequate course of standard wound therapy. The policy also requires that patients show no measurable signs of healing with standard therapy for at least 30 days prior to initiation of HBO.1,2 Medicare based this decision on an analysis of two randomized clinical trials, especially the report by Faglia, one combined randomized/non-randomized trial, seven case series, two abstracts and several technology assessments.3 Technology assessments by the BlueCross BlueShield Association, the Medical Services Advisory Committee in Australia, the British Journal of Medicine Clinical Evidence Report and the Agency for Healthcare Research and Quality concluded that HBO significantly reduces wound size when compared with standard wound care alone. They also concluded that HBO supports a higher rate of complete healing and decreased major amputation rates in diabetic wounds.4-7 The American Diabetes Association 1999 Consensus Development Conference on Diabetic Foot Wound Care recommended that, “It is reasonable, however, to use this costly modality to treat severe and limb- or life-threatening wounds that have not responded to other treatments, particularly if ischemia that cannot be corrected by vascular procedures is present.”8 While an exhaustive review of this literature is beyond the scope of this paper, let’s take a closer look at how HBO can enhance healing in diabetic lower extremity wounds and key considerations in proper patient selection. Understanding The Causal Factors Behind Impaired Wound Healing Diabetes mellitus is the classic example of a systemic disease that directly and indirectly impacts wound healing. While peripheral sensory and motor neuropathy predispose to injury and ulceration of the foot, other factors predispose to wound healing complications. Collagen accumulates at a slower rate and breaking strength is diminished in incisional wounds. Both collagen synthesis and vascular ingrowth are decreased. There is also impairment of the phagocytic function of granulocytes and decreased granulocyte chemotaxis. There is atherosclerosis, which may have a more peripheral distribution in diabetics than in non-diabetics, along with increased thickening and decreased permeability of capillary basement membranes. These vascular changes may limit blood flow and compound local tissue hypoxia in foot ulcers. Not surprisingly, diabetic ulceration and impaired wound healing continue to contribute to high rates of lower extremity amputation in spite of recent advances in distal arterial bypass and angioplasty. Pecoraro concluded that periwound cutaneous perfusion is the critical physiological determining factor of diabetic ulcer healing, indicating a 39-fold increased risk of early healing failure when the average periwound TcPO2 is <20mmHg.9 This finding was independent of segmental Doppler arterial blood pressure at the dorsalis pedis artery level, specifically suggesting hypoxia as a primary determining factor in ulcer healing failure. Although revascularization remains the mainstay of increasing distal blood flow and optimizing periwound perfusion in the diabetic foot ulcer patient, limb salvage and amputation reduction has plateaued with revascularization alone. How HBO Can Facilitate Wound Healing HBO consists of a patient breathing 100 percent oxygen while his or her entire body is enclosed in a pressure chamber. The topical application of oxygen is not recognized by the FDA as hyperbaric therapy and is not reimbursed by Medicare. Oxygen is transported two ways in that it is chemically bound to the hemoglobin and physically dissolved in the plasma. When the patient breathes air at sea level, the hemoglobin is already fully saturated so increasing the amount of respired oxygen can affect only the plasma-dissolved oxygen. Breathing oxygen at an elevated atmospheric pressure produces an increase in the plasma-dissolved oxygen fraction, which is proportional to the atmospheric pressure of the respired gas. Monoplace hyperbaric chambers are usually compressed with oxygen whereas multiplace chambers are compressed with air while the patient breathes 100 percent oxygen using a hood or aviator’s face mask. Typical treatments involve 90 minutes of oxygen breathing at 2.0 to 2.5 atmospheres absolute (ATA) with air breaks administered at 20- to 30-minute intervals in order to reduce the risk of central nervous system oxygen toxicity. (While HBO treatment is remarkably safe, be aware that otologic and pulmonary barotrauma and central nervous system, pulmonary and ocular oxygen toxicity can occur. Central nervous system oxygen toxicity is rare, but it can manifest as seizures. Seizures are less likely to occur if there are brief periods of air breathing.) Arterial PO2 elevations of 1500 mmHg or greater are achieved when the body is exposed to pressures of 2 to 2.5 ATA. Soft tissue and muscle PO2 levels can be elevated to about 300 mmHg. Oxygen diffusion varies in a direct linear relationship to the increased partial pressure of oxygen present in the circulating plasma caused by HBO. At pressures of 3 ATA, the diffusion radius of oxygen into the extravascular compartment is estimated to increase from 64 micons to about 247 micons at the pre-capillary arteriole. This significant level of hyperoxygenation allows for the reversal of localized tissue hypoxia, which may be secondary to ischemia or to other local factors within the compromised tissue. Hypoxia is a biochemical barrier to normal wound healing. In the hypoxic wound, HBO treatment allows an acute correction of the pathophysiology related to oxygen deficiency and impaired wound healing. Using HBO increases oxygen levels within the marginally vascularized periwound compartment, enhancing leukocyte bacteriocidal function. It may also potentiate some antibiotic effects. There are direct toxic effects on anaerobic bacteria and suppression of exotoxin production. It also enhances collagen synthesis and cross-linking, and other matrix deposition. What The Clinical Evidence Reveals Additionally, recent evidence suggests that HBO may induce specific growth factor receptors (PDGF) and stimulate growth factor (VEGF) release. There is also evidence that employing HBO may ameliorate or prevent leukocyte-mediated ischemia reperfusion injury.10-13 There have been 13 published peer-reviewed studies (including seven randomized, controlled trials) of HBO in diabetic foot wounds. A total of 606 diabetic patients received HBO with a 71 percent bipedal limb salvage rate, compared to 463 control patients who had a 53 percent bipedal limb salvage rate. All diabetic wounds were Wagner III-IV. It is interesting to compare this to the becaplermin clinical trials that involved Wager II ulcers. Control patients had healing rates of 25 percent while those receiving becaplermin had healing rates of 43 percent. A large retrospective series of 1,144 diabetic foot ulcer patients demonstrated the effectiveness of using adjunctive HBO in modified Wagner III, IV and V (equivalent to Wagner grade II, III and V) ulcers, based on ulcer/wound improvement, healing and salvage of bipedal ambulation (see “The Impact Of HBO: What One Study Shows” above).14 Currently, CMS policy reimburses only for treatment of Wagner III and greater ulcers. Final Thoughts On Appropriate Patient Selection The justification for using HBO adjunctively for a specific problem wound rests upon the clinical presentation of the wound and whether there is evidence of malperfusion or persistent or progressive local infection. Measuring transcutaneous PO2 (TcPO2) in tissue adjacent to the wound can be useful in discriminating those patients without significant hypoxia who do not require HBO from those who do. In general, TcPO2 values below 40 mmHg indicate microcirculatory impairment. Impairment in healing increases as the value decreases below this threshold. Obtaining TcPO2 values during HBO treatment may offer the best prediction of who will respond favorably to adjunctive HBO.14 The best way to use TcPO2 is in a step-wise manner. A low baseline TcPO2 confirms that spontaneous healing will probably not occur. You should then proceed to revascularization if possible. If TcPO2 still remains low, then you should check the in-chamber TcPO2. If that value is greater than 200 mmHg, the likelihood of benefit from HBO is high and a course of HBO may be appropriate, assuming other criteria have been met. You must regularly re-evaluate patients undergoing HBO for evidence of benefit. One should evaluate patients for functional outcome. You should remove necrotic toes or other material prior to initiating HBO. In many cases, a transmetatarsal amputation is an acceptable outcome. HBO cannot be used to “resurrect” necrotic material. When HBO is used adjunctively in a setting of multidisciplinary wound care, it has the potential to significantly improve diabetic foot ulcer outcome and limb salvage in this challenging group of patients. Dr. Warriner is the Medical Director of the Southeast Texas Center for Wound Care and Hyperbaric Medicine at the Conroe Regional Medical Center Hospital in Conroe, Tx. He is a Fellow of the American College of Hyperbaric Medicine, is a Certified Wound Specialist and is certified by the American Board of Anesthesiology. Dr. Fife is the Medical Director of the Memorial Hermann Center for Wound Healing and Hyperbaric Medicine in Houston, Tx. She is a Clinical Associate Professor within the Department of Anesthesiology at the University of Texas Health Science Center. Dr. Steinberg (pictured) is an Assistant Professor in the Department of Orthopaedics/Podiatry Service at the University of Texas Health Science Center.
References 1. Shuren J, Dei Cas R, Kucken L, Tilman K (Coverage and Analysis Group). CMS CAG-00060N, Hyperbaric Oxygen Therapy (HBO) in the Treatment of Hypoxic Wounds and Diabetic Wounds of the Lower Extremities. CMS August 30, 2002. 2. CMS Program Memorandum to Intermediaries/Carriers Transmittal AB-02-183 December 7, 2002 Coverage of hyperbaric oxygen (HBO) therapy for the treatment of diabetic wounds of the lower extremities and Medicare Coverage Issues Manual Transmittal 164 December 27, 2002 Section 35-10 Hyperbaric oxygen therapy (revised). 3. Faglia E, et al. Adjunctive systemic hyperbaric oxygen therapy in the treatment of diabetic foot ulcer. A randomized study. Diabetes Care 1996;19:1338-43. 4. BlueCross BlueShield Association Assessment Program. Hyperbaric Oxygen Therapy for Wound Healing—Parts I, II, III. 1999; 14(2, 15, 16). Blue Cross Blue Shield Association Technology Evaluation Center. 5. Medical Services Advisory Committee (MSAC), Department of Health and Aged Care, Australia. Hyperbaric Oxygen Therapy, November 2000; MSAC applications 1018-1020 Assessment Report. 6. British Journal of Medicine, Clinical Evidence. Diabetic foot ulcer. June, 2001 Issue 5. 7. Agency for Healthcare Research and Quality Contract No. 270-97-0019, September 24, 2001, Hyperbaric Oxygen Therapy in Treatment of Hypoxic Wounds. 8. American Diabetes Association (April 7-8, 1999) Consensus Development Conference on Diabetic Foot Wound Care. Diabetes Care 1999; 22(8) 1354-1360. 9. Pecoraro RE, Ahroni JH, Boydo EG, Stensel VL. Chronology and determinants of tissue repair in diabetic lower extremity ulcers. Diabetes 1991; 40:1305-1312. 10. Hampson NB (ed). Hyperbaric Oxygen Therapy: A Committee Report. Undersea and Hyperbaric Med Soc, Kensington, MD, 1999, 82pp. 11. Thom SR. Hyperbaric oxygen therapy. J Intensive Care Med 1989; 4:58-74. 12. Tiabbles PM, Edelsberg JS. Medical progress: Hyperbaric oxygen therapy. N Engl J Med 1996; 334:1642-1648. 13. Boykin JV. Hyperbaric oxygen therapy: A physiological approach to selected problem wound healing. Wounds 1996; 8(6): 183-198. 14. Fife CE, Buyukcakir C, Otto GH, Sheffield P, Warriner RA, Love TL , Mader J. The predictive value of transcutaneous oxygen tension measurement in diabetic lower extremity ulcers treated with hyperbaric oxygen therapy: A retrospective analysis of 1144 patients. Wound Rep Reg 2002; 10: 198-207.