Is There A Role For HBO In Limb Salvage?
There are 15 million people in the United States with diabetes mellitus, half of whom are undiagnosed. Diabetic foot ulcers (DFUs) occur in 12 percent of these individuals, accounting for 60 percent of lower extremity amputations and costing more than $1 billion annually.1 Diabetic foot ulcers have various mechanisms including: • microneurovascular dysfunction with loss of the nociceptive reflex and an exacerbated inflammatory response; • vasomotor dysfunction with arteriovenous shunting; • capillary basement membrane thickening with altered capillary exchange; • foot deformities increasing the likelihood of pressure points; • diminished sensation; and • ischemia due to tibial peroneal occlusive disease. In addition to neuropathy, patients with diabetes suffer from impaired resistance to infection. This has been partly explained by an impaired “respiratory burst.”2 There is also impaired microvascular perfusion due to changes in platelet aggregation and increased rigidity of red cells. Diabetic foot ulcers are hard to heal. Margolis has demonstrated that even with adequate arterial inflow, diabetic foot ulcers have a 24 percent closure rate at 12 weeks and a 31 percent closure rate at 20 weeks.3 Other researchers have demonstrated that adherence to standardized protocols based on clinical guidelines reduces the amputation rate.4 For example, Margolis, et al., demonstrated a 68 percent healing rate at 20 weeks in lower complexity DFUs managed by protocol within a multicenter wound care network in comparison to a 44 percent healing rate prior to the standardization of care.5
Understanding The Impact Of Tissue Hypoxia
While it is possible that strict care protocols can overcome some impediments to healing, the final common denominator among most non-healing wounds is tissue hypoxia. It is well known that hypoxia inhibits healing. More than 30 articles since 1984 have demonstrated that tissues below 40 mmHg signify impaired healing.6 If the transcutaneous oximetry (TcPO2) value is less than 20 mmHg, then the risk of amputation is 161 times greater than in patients whose TcPO2 is at least 40 mmHg. Furthermore, if the Doppler ankle-brachial index (ABI) is less than 0.45, the risk of amputation is 55 times greater than if the ABI is 0.7.7 Among chronic limb ischemia patients undergoing bypass for ischemic tissue loss, 63 percent required more than three months for complete healing with the mean time to healing being 86 days. Greater than 7 percent of these patients never healed.8 These data suggest there is significant room for improvement in the outcome of DFU healing in general and ischemic foot ulcers in particular. The focus of that effort should be on the correction of hypoxia and, clearly, current revascularization techniques are not the final answer.
A Closer Look At The Effects Of HBO
Hyperbaric oxygen (HBO) is a treatment in which the patient breathes oxygen intermittently while inside a chamber at a pressure greater than 1.4 ATA (atmospheres absolute), usually 2.0 to 2.4 ATA. Treatments usually last for 90 minutes per day and patients usually undergo between 20 and 60 treatments.9 While the oxygen carrying capacity of hemoglobin is fixed due to the structure of the molecule, an increase in atmospheric pressure allows additional oxygen to dissolve in the blood plasma. An additional 2 volumes percent of oxygen dissolve into the blood plasma for each additional atmosphere of pressure to which the body is exposed. In addition to the correction of hypoxia, HBO reportedly facilitates upregulation of growth factors and the activation of growth factor receptors, control of excess inflammation, better control of infection and increased angiogenesis. Hyperbaric oxygen therapy clearly increases wound oxygen concentration, even in ischemic wounds, as long as there is some arterial inflow.10,11 Although correction of hypoxia is one mechanism by which HBO improves wound healing, a growing body of research makes it clear that, at the supraphysiologic tissue levels attained under hyperbaric conditions, HBO therapy acts like a drug with multiple effects that continue after the treatment ends. Wound oxygen tension decreases rapidly at the end of a treatment although levels may not completely return to baseline for several hours.12 The brief period of wound hyperoxia initiates a cascade of events that continue between treatments. For example, recent studies in a murine model and in cultured cells demonstrate the existence of a feed forward mechanism for HIF-1 alpha activation. Chronic intermittent hypoxia (CIH) induced reactive oxygen species (ROS) activate HIF-1 alpha, which subsequently promotes persistent oxidative stress. This may further amplify HIF-1 activation and result in an increase in gene expression.13 This increase in hypoxia-inducible factor (HIF) leads to an increase in VEGF and promotes neovascularization. It is possible that the cycling of hypoxia and hyperoxia actually contributes to the acceleration of healing one sees with HBO. Research has shown that HBO increases resistance to infection, fibroblast replication and collagen deposition, neovascularization and epithelialization, particularly in hypoxic wounds.14-17 There is likely a direct effect related to the increased availability of oxygen in the wound for these processes. However, it appears likely that the pharmacologic effects of hyperoxia predominate and that increased angiogenesis — and a resulting decrease in wound hypoxia between treatments — is the major determinant of efficacy. Resistance to infection appears to relate more directly to the increase in oxygen in the wound during the treatment period. Increased oxygen clearly increases the bacterial killing capacity of neutrophils.18 Hyperbaric oxygen also directly potentiates antibiotics, particularly aminoglycosides, and suppresses toxin synthesis.19 Hyperbaric oxygen therapy has a number of pharmacologic effects, one of which is the induction of growth factors and growth factor receptors. It also upregulates PDGF receptors.20 These mechanisms may relate to nitric oxide (NO). Researchers have recently shown that HBO upregulates basic fibroblast growth factor (bFGF) and the hepatocyte growth factor in acutely ischemic hind limbs in a murine model. The interaction of neutrophil surface beta-integrins with intercellular adhesion molecules (ICAMs) on the endothelial surface causes neutrophil adhesion. This may be beneficial in allowing neutrophil migration to the wound but may also cause pathological endothelial dysfunction as in ischemia reperfusion injury. Hyperbaric oxygen inhibits neutrophil beta-2 integrin function by a localized effect on membrane guanylate cyclase, an effect that appears to be mediated by NO.21 Other effects include the mobilization of endothelial stem cells from the bone marrow. The combination of the direct effects of wound hypoxia correction and the pharmacologic effects of hyperoxia lead to a number of clinically observed benefits. These benefits include: • more rapid and effective control of infection; • reduction of ischemia reperfusion injury; • reduction of pathologic inflammation; • reduction of edema; • increased neovascularization and collagen deposition, which together result in increased granulation tissue; • increased epithelialization; and • increased osteogenesis. In regard to the reduction of edema, this effect has widely been attributed to hyperoxia-induced vasoconstriction. However, it seems more likely to result from a reduction in inflammation. Edema is generally caused by “leaky” vessels and venous hypertension as opposed to excess arterial flow. Vasoconstriction would reduce arterial inflow. A reduction in inflammation would likely restore integrity to the vessels and thereby reduce edema.
What Does The Clinical Data Reveal About HBO?
While the biochemical data of HBO is compelling, does the clinical data support its use? In his randomized, prospective trial of Wagner II, III and IV diabetic foot ulcers, Faglia noted that 8.6 percent of patients in the HBO group had major amputations in comparison to 33.3 percent of those in the control group.22 The 68 patients were similar in terms of age, duration of diabetes, diabetic control, years of insulin, Wagner grade, renal disease, infection and vascular disease. Researchers randomized patients to HBO or standard care only with both groups receiving aggressive debridement, moist wound care, antibiotics and revascularization if indicated. A blinded surgeon made amputation decisions. Hyperbaric oxygen therapy significantly decreased major amputations. Furthermore, Faglia was also able to show that a course of HBO improved baseline transcutaneous values to a statistically significant degree, inferring an improvement in the vascular supply to the area. Abida et al., evaluated 18 patients with ischemic diabetic foot ulcers with one group receiving 100 percent oxygen at 2.4 ATA air and one group receiving air at 2.4 ATA. The patients received treatment for 90 minutes at a time for a total of 30 treatments. When researchers assessed healing at one year, 5 of 8 HBO patients were healed in comparison to 1 of 9 controls.23 From 1987 to 1996, six studies involved 435 patients who underwent HBO with an 80 percent success rate. A retrospective study of the outcome of 1,144 diabetic foot ulcer patients receiving HBO showed a 76 percent overall success rate of HBO, including a 42 percent benefit rate among patients with foot gangrene.10 A careful review of the wound healing literature from 1996 to 2006 yielded over 1,000 articles. These included trials of familiar products now in common use such as platelet derived growth factors and semisynthetic human skin. Without exception, all RCTs in the area of wound healing excluded patients with diabetic foot ulcers whose Wagner grades were higher than II or those who had any symptoms of ischemia. Since 1996, the only wound healing trials that involved Wagner III or IV wounds, or included patients with known ischemia have been hyperbaric medicine studies. This observation raises significant concern regarding the applicability of RCT trial design among patients with threatened limbs.
Is HBO Cost-Effective?
We have established that the physiological rationale of HBO is sound and that randomized, controlled trials support the benefit of this modality. The next question is one of cost benefit. The Cochrane collaboration performed a review of HBO and DFU. The study evaluated three RCTs, including a total of 118 patients, for which the relative risk for major amputation was 0.31. The study concluded that it is necessary to treat four patients with HBO in order to avert one major amputation.24 Guo, et al., subsequently performed a study to evaluate the cost benefit of HBO.25 The study population was a hypothetical cohort of 1,000 patients who were 60 years of age and had severe DFU. Researchers constructed a decision tree model to estimate the cost effectiveness of HBO in the treatment of DFU at one, five and 12 years. In this theoretical cohort, the HBO group had 45 more minor amputations. However, 155 cases of major lower extremity amputation would be averted while patients gain approximately 50, 265 and 608 quality-adjusted life years (QALY) at one, five and 12 years respectively. This exercise suggests that the benefits of HBO accrue over time, in part due to savings from averted major amputations.
What You Should Know About HBO And Medicare
As a result of the data to support its benefit, hyperbaric oxygen therapy has garnered recommendations from seven independent evidence-based reviews: Blue Cross Blue Shield (1999), the American Diabetic Association Foot Council (1999), the Wound Healing Society (2006), the British Journal of Medicine (2001-2002), the Agency for Healthcare Research and Quality (AHRQ) report to CMS (2001), the Medical Services Advisory Committee of Australia (2000) and the Centers For Medicare and Medicaid Services (CMS) Coverage Decision for HBOT in Diabetic Foot Wounds (2002). The CMS coverage memorandum, which was issued December 27, 2002, states that the evidence is adequate to conclude that HBO is clinically effective. Accordingly, the CMS maintains that HBO is reasonable and necessary in the treatment of certain patients with limb-threatening diabetic wounds of the lower extremity. The criteria are that the patient must have diabetes and a lower extremity wound, classified as a Wagner 3 or worse, with no measurable signs of healing for at least 30 days despite standard wound therapy. It is unfortunate that the coverage criteria for HBO are limited to diabetic foot ulcerations since limb salvage is often required among non-diabetic patients. However, the CMS limited its coverage decision to randomized, blinded trial data. These trials, in turn, have historically been limited to well-defined clinical disease models such as diabetic foot ulcers. The “ischemic limb” represents an ill-defined category from a clinical standpoint for which randomized, controlled trials are difficult to design. Although it is likely that the salutary effects of HBO extend to non-diabetic ischemic leg ulcers, Medicare coverage policy does not.
Assessing The Role Of HBO In The Limb Salvage Armamentarium
Hyperbaric oxygen therapy is not a substitute for revascularization when revascularization is possible. However, data confirm that even after revascularization, wounds may remain hypoxic and that these hypoxic wounds benefit from elevating tissue PO2. Patients for whom revascularization is not possible will not heal unless physicians correct tissue hypoxia. We recommend a stepwise approach to limb salvage. The first step is to assess whether wounds are likely to heal spontaneously. Baseline transcutaneous or skin perfusion pressure values of 30 mmHg or less suggest that spontaneous healing is not likely. The physician must then consider appropriate referral for revascularization options. After vascular status has been optimized, one can then repeat transcutaneous oximetry or skin perfusion testing. Data suggest transcutaneous oximetry values will increase by at least 30 mmHg after successful revascularization procedures.26 If revascularization does not achieve such a response, healing is not likely without further intervention. One can then reassess transcutaneous oximetry (TcPO2) while the patient is inside the hyperbaric chamber. Researchers have noted that values of 200 mmHg or better while patients with diabetes are in an HBO chamber are associated with benefits from HBO.10 However, a trial of HBO may still be appropriate even in patients with low in-chamber values since the predictive value of TcPO2 is less than 70 percent. Take all available clinical data into consideration when making clinical decisions. This stepwise approach can facilitate the cost effective use of HBO in patients with limb threatening ulcerations. Optimizing healing in patients with ischemic ulcers requires a multidisciplinary approach that must include glycemic control, debridement, pressure relief, smoking cessation, wound care and revascularization. This usually requires a “team approach” to care. Hyperbaric oxygen therapy is not a substitute for multidisciplinary care. However, these data suggest that HBO works in combination with a comprehensive plan of care for limb salvage. Dr. Hopf is a Professor in the Department of Anesthesiology at the University of Utah School of Medicine. She is the Medical Director of IHC Urban Central Region Wound Care Services in Salt Lake City. Dr. Fife is an Associate Professor in the Department of Anesthesiology at the University of Texas Health Science Center in Houston. She is the Director of Clinical Research at Memorial Hermann Center for Wound Healing and Hyperbaric Medicine.
1. Faries PL, Teodorescu VJ, Morrissey NJ, Hollier LH, Marin ML. The role of surgical revascularization in the management of diabetic foot wounds. Am J Surg. 187(5A):34S-37S Review, May 2004.
2. Qvist eta al, Shah et al, Tan, Sima et al. Diminished production of thromboxane B2 and prostaglandin E by stimulated polymorphonuclear leukocytes from insulin-treated diabetic subjects. Diabetes 32(7):622-6, July 1983.
3. Margolis DJ, Kantor J, Berlin JA, Healing of diabetic neuropathic foot ulcers receiving standard treatment. A meta-analysis. Diabetes Care 22(5):692-5, May 1999.
4. Driver VR, Madsen J, Goodman RA. Can reducing amputation rates in patients with diabetes at a military medical center? The limb preservation service model. Diabetes Care 28(2): 248-253, 2005.
5. Margolis DJ, Allen-Taylor L, Hoffstad O, Berlin JA, Healing diabetic neuropathic foot ulcers: are we getting better? Diabet Med 22(2):172-6, Feb. 2005.
6. Hopf HW, Ueno C, Alslam R, Burnand K, et al. Guidelines for the treatment of arterial insufficiency ulcers. WWR, 14(6):693–710.
7. Reiber GE, Pecoraro RE, Koepsell TD, Risk factors for amputation in patients with diabetes mellitus. A case-control study. Ann Intern Med. 15;117(2):97-105, July 1992.
8. Goshima, et al, A new look at outcomes after infrainguinal bypass surgery: Traditional reporting standards systematically underestimate the expenditure of effort required to attain limb salvage. J Vasc Surg 39;330-5, 2004.
9. Feldmeier JJ. Hyperbaric Oxygen 2003: Indications and Results: The Hyperbaric Oxygen Therapy Committee Report. Kensington, MD: Undersea and Hyperbaric Medical Society, 2003.
10. Fife CE, Buyukcakir C, Otto GH, Sheffield PJ, 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 1,144 patients. Wound Repair Regen 10: 198-207, 2002.
11. Rollins MD, Gibson JJ, Hunt TK, Hopf HW. Wound oxygen levels during hyperbaric oxygen treatment in healing wounds. Undersea Hyperb Med 33: 17-25, 2006.
12. Sheffield PJ. Measuring tissue oxygen tension: a review. Undersea Hyperb Med 25: 179-88, 1998.
13. Semenza GL, Prabhakar NR. HIF-1-dependent respiratory, cardiovascular, and redox responses to chronic intermittent hypoxia. Antioxid Redox Signal 9: 1391-6, 2007.
14. Mader JT. Phagocytic killing and hyperbaric oxygen: Antibacterial mechanisms. HBO Reviews 2:37-49, 1981.
15. Hunt TK, Pai MP. The effect of varying ambient oxygen tensions on wound metabolism and collagen synthesis. Surg Gynecol Obstet 135: 561-7, 1972.
16. Hopf HW, Gibson JJ, Angeles AP, Constant JS, Feng JJ, Rollins MD, Zamirul Hussain M, Hunt TK. Hyperoxia and angiogenesis. Wound Repair Regen 13: 558-64, 2005.
17. Zhao LL, Davidson JD, Wee SC, Roth SE, Mustoe TA. Effect of hyperbaric oxygen and growth factors on rabbit ear ischemic ulcers. Arch Surg 129: 1043-1049, 1994.
18. Allen DB, Maguire JJ, Mahdavian M, Wicke C, Marcocci L, Scheuenstuhl H, Chang M, Le AX, Hopf HW, Hunt TK. Wound hypoxia and acidosis limit neutrophil bacterial killing mechanisms. Archives of Surgery 132: 991-6, 1997.
19. Korhonen K, Klossner J, Hirn M, Niinikoski J. Management of clostridial gas gangrene and the role of hyperbaric oxygen. Ann Chir Gynaecol 88: 139-42, 1999.
20. Bonomo SR, Davidson JD, Yu Y, Xia Y, Lin X, Mustoe TA. Hyperbaric oxygen as a signal transducer: upregulation of platelet derived growth factor-beta receptor in the presence of HBO2 and PDGF. Undersea Hyperb Med 25: 211-6, 1998.
21. Thom SR: Effects of hyperoxia on neutrophil adhesion. Undersea Hyperb Med 31: 123-31, 2004.
22. Faglia E, et al. Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcers. Diabetes Care 19(12): 1338-1343, 1996.
23. Abidia A, Laden G, Kuhan G, Johnson BF, Wilkinson AR, Renwick PM, Masson EA, McCollum PT. The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial. European Journal of Vascular Surgery 25:513-518, 2003.
24. Kranke P, Bennett M, Roeckl-Wiedmann I, Debus S. Hyperbaric oxygen therapy for chronic wounds (Cochrane Review). In: The Cochrane Library, Issue 2, Chichester, UK: John Wiley & Sons, Ltd, 2004.
25. Guo S, et al. Cost-effectiveness of adjunctive hyperbaric oxygen in the treatment of diabetic ulcers. Int J Technol Assess Health 19(4):731-737, 2003.
26. Hanna GP, Fujise K, Kjellgren O, et al. Infrapopliteal transcatheter interventions for limb salvage in diabetic patients: importance of aggressive interventional approach and role of transcutaneous oximetry. J Am Coll Cardiol 30:664-669, 2003.