Pathophysiology and Hyperbaric Effects
Diabetic wounds present a major problem for modern health care. The foot is the most common site of infection in the diabetic. For diabetic patients, foot problems remain the number one reason for hospital admission. The annual cost of foot care exceeds $15 billion. An estimated 25 percent of the 11 million Americans with diabetes develop foot problems, and one in 15 require a limb amputation during their lifetime.
The incidence of amputation in diabetics remains unacceptably high: six per 1000 patients. Diabetics account for 50 to 70 percent of all amputations performed each year in the U.S. In 1986, 152,000 amputations were done in America. Ten percent of those surgeries resulted in the loss of a foot, 35 percent involved the loss of a lower leg, and 30 percent resulted in the loss of the knee joint. Ipsilateral or higher amputation occurs in 24 percent of cases. One complication often goes unrecognized: contralateral amputation, which occurs at a rate of 10 percent per year.
Diabetic amputees also experience other difficulties. Among other things, only 50 percent of the patients survive more than three years after the amputation. Although many individuals who lose limbs traumatically can expect to be rehabilitated to full activity, only 40 to 50 percent of elderly amputees can expect to enjoy such a successful outcome.
Diabetic wounds are extraordinarily expensive to treat, yet some payors allow insufficient reimbursement for the intensive treatment required. Diagnosis related group (DRG) reimbursement policies permitted only 10 days of hospitalization for diabetic foot complications in 1985. Payment amounted to $731 per day, for a total hospital reimbursement of $3,748. Unfortunately, the duration of hospitalization for treatment of diabetic foot infections averaged 22 to 36 days.
Costs averaged from $5,000 to $7,000, and outliers vastly exceeded such averages. Such expenses did not include outpatient expenditures.
Amputation offers a poor solution. Patients pay high personal costs when limbs are lost. Economic costs for one primary amputation reportedly amount to more than $40,000. Yet, Medicare reimbursement for primary amputation totals only $12,500. When an amputation occurs, patients generally remain hospitalized for 40 days, and to maximize walking ability or potential, patients may need an additional six to nine months of rehabilitation. For elderly patients, such rehabilitation may not prove successful. Many elderly diabetic amputees remain bound to wheelchairs for the rest of their lives because they lack sufficient energy, balance, and strength to walk. Their sedentary existences lead to other health problems. Within two years, for example, most amputees must undergo stump modification or proximal reamputation. Although the direct costs of amputation exceed $1.5 billion a year in the U.S., other medical costs add another half billion a year to the figure.
Then there are the social costs of amputation to consider. Many amputees fail to maintain productive lives because they can no longer sustain gainful employment. Many require public assistance, at substantial cost. But personal costs perhaps loom the largest. Due to the medical, personal, and social costs of amputation, policy makers increasingly ponder methods for improving salvage. A multidisciplinary team approach offers promise in saving limbs and reducing costs.
Three factors predispose a diabetic to develop wound problems: neuropathy, angiopathy, and immunopathy. Neuropathies involving both peripheral (motor and sensory fibers) and autonomic innervation are common complications of long-standing diabetes mellitus. Such pathology often involves a combination of these fibers. Among the most commonly recognized neuropathies is sensory neuropathy, perhaps because of its clear pathophysiology and the ease in evaluating the condition. This neuropathy contributes to the possibilities of patients becoming infected. When patients fail to feel pain and proprioceptive sensation, they injure themselves more easily and often fail to rapidly recognize tissue damage and infection. Patients experiencing such problems can also repeatedly traumatize the joints and tissue of the foot, creating increasingly serious problems.
Motor neuropathy causes weakness of various muscle groups, ultimately resulting in foot deformities. Typically, weakness of the intrinsic muscles leads to protrusion of the metatarsophalangeal joints. Such a condition eventually causes hammer toes and pes cavus because the weight bearing surfaces are structurally overloaded. Destruction of callus, skin breakdown, and trophic ulcerations may also develop.
Such events open the first line of defense against infection and offer a fertile breeding ground for invasive bacteria. Autonomic dysfunction leads to decreased sweating. Resulting dryness may predispose the patient to more scaling, cracking, and fissuring of the skin of the foot. With each crack, further tissue breakdown and infection can occur.
Angiopathy, or the presence of peripheral vascular disease affecting the foot, contributes to the possibility of infection. Two disease processes may be involved, although the mechanisms are not yet clear. Microangiopathy and chronic macroangiopathic occlusive arterial disease contribute to vascular problems. The recent medical literature challenges the importance of microvascular versus macrovascular changes. Now researchers suspect microangiopathy may relate to inhibition of diapedesis of leukocytes and exchange of immune substance through thickened capillary basement membranes. Similarly, oxygen diffusion through thick membranes is reduced. Prospective controlled studies have substantiated the thickening of capillary basement membranes, a microvascular change clinicians had postulated.
But perhaps more importantly, diabetics experience the effects of macroscopic obstructive arterial disease. Such disease can lead to diminished flow through major arterial systems. The development of collateral circulation may maintain an adequate blood supply at ambient temperatures. Vascular reserve is often diminished, however. One prospective study identified vascular impairment as one of three factors significantly more common in diabetics with foot lesions (p<0.001). Doppler studies were used to assess the impairment.
Another important pathophysiologic factor involves changes in the immune system of the diabetic patient, when hyperglycemia occurs. Migration of polymorphonuclear leukocytes, phagocytosis, and cell-mediated immune response are all impaired in the poorly-controlled diabetic.
Once an infection occurs, most tight glucose control is lost. Data analyzed in two recent reviews suggest that patients with diabetes mellitus are predisposed to more frequent and severe infections. They are also less capable of fighting those infections.
HBOT offers physiological benefits for such patients. They include: improved oxygenation of threatened margins of wounds, generation of granulation tissue, enhanced phagocytosis and killing of select organisms. Still other benefits are enhanced penetration of some organisms by antibiotics whose transmembrane transport is oxygen dependent, and improved wound healing with an increased rate of fibroblast collagen production to support capillary angiogenesis. Recent studies by Sapico, LeFrock, Wheat, and others described the diabetic foot infection as polymicrobial, with a high incidence of anaerobes. HBOT offers a beneficial direct bacteriostatic effect on anaerobic micro-organisms.
Such observations were corroborated by clinical studies by Batoni, et al., and Hart, Strauss, Perrins, and Barr. Baroni, et al., performed a prospective, double-blinded, randomized, controlled clinical trial of inpatients with diabetic foot infections and partial foot gangrene. That study showed the wounds of 16 of 18 patients treated with HBOT healed, compared with one of the 10 control patients. HBOT produced wound healing in 89 percent of patients, while the wound of only one control healed, 10 percent (p< 0.001).
Studies Investigating the Efficacy of HBO
Numerous retrospective studies have shown the efficacy of HBO. Davis reviewed a clinical series of 168 patients with compromised refractory diabetic foot wounds treated over a seven-year period. Utilizing the parameter of limb salvage, a success rate of 70 percent was obtained. Thirty percent of the individuals failed to respond and required amputation above or below the knee. Failures were most common in older patients without palpable pedal pulses and with large vessel occlusion at or above the ankle, as diagnosed by angiography. In 1988, Cianci treated 19 patients with diabetes in a subset of 39 lower extremity lesions, with a salvage rate of 89 percent. Forty-two percent of these patients had undergone successful revascularization and were referred because of persistent infection or non-healing wounds. Salvage was defined as: bipedal ambulation, if two limbs were originally present; and intact wound coverage remaining for at least one year. HBO costs were $12,668 and were reflected in total hospital charges of $34,370, with an average length of stay of 35 days.
More recently, data on another series of 41 patients with diabetes, who averaged 63 years in age, was analyzed. Thirty-nine patients (97 percent) were suffering limb-threatening lesions. Fifty-five percent of the patients had undergone revascularization. An average Wagner score of 4, indicating gangrene of the toes or forefoot, was obtained. (A Wagner score is a diagnostic indicator, as discussed later in this protocol.) Thirty-one patients (78 percent) experienced successful salvage of their lower extremities. HBO charges in this series were $15,900, total hospital charges were $32,000, and the average length of stay was 27 days. These figures compare favorably with the cost of primary amputation and the hospitalization required.
Avoiding rehabilitation costs and the additional savings involved in preventing re-amputation or stump revision was an additional benefit. The follow-up of these patients over one to six years (average of 30 months) has shown a 92 percent durability. That is, patients were able to ambulate without further lesions or problems. Two of the patients have suffered below-the-knee amputations.
In 1992, Oriani reported a 10-year experience that showed 80 percent salvage in a group that received HBO, versus 40 percent in controls (p< 0.001). Initial treatment with 15 HBO sessions and re-evaluation was recommended, because significant improvement in wound healing should be apparent at that time. If improvement was noted, treatment was continued for an additional 10 sessions. If absent, HBO was discontinued. Gismondi has noted the importance of careful, aggressive debridement and meticulous wound care in reducing hospital stay, the number of HBO treatments, and ultimately, cost of care.
In 1993 and 1994, a pilot study was undertaken by Stone, et al., to examine the results of hyperbaric oxygen therapy in patients with diabetes. Data were collected in a retrospective manner utilizing 1,633 consecutive patients who were treated in Dallas clinics over a 33-month period (March 1992 through November 1994). Five hundred and one patients (31 percent) presenting with diabetes and ischemic wounds were identified by diagnosis codes and confirmed by chart review. Patients were grouped by treatment modality: hyperbaric oxygen therapy (n=119) versus conservative treatment alone (n=382), which was administered according to the clinical judgment of the treating physician. Limb salvage (defined as bipedal ambulation if two limbs were present) was used as the endpoint for the study.
Hyperbaric treatment consisted of oxygen therapy delivered at an individualized rate, duration, and ATA for each patient. Complete follow-up was available for 73 percent (87 of 119) of the patients receiving hyperbaric oxygen. Some patients were referred from outside centers, and, therefore, their records were unavailable for review (n = 32).
Conservative treatment was based on the standard of care and individualized to include, the following, if necessary: revascularization, dietary modification, smoking cessation, antibiotics, behavioral modification, wound debridement, glycemic control, and offloading. Patients referred for HBO had larger wounds (mean ± SE area: 2533 ± 987 vs. 1199 ± 61 mm3, p=0.18), more wounds per patient (3.8 vs. 2.4, p< 0.0001), and a greater percentage of these people were recommended for amputation (31 percent vs. 19 percent, p=0.002). Despite having the more serious wounds, the limb salvage rate was greater in the HBO patients (72 percent vs. 53 percent, p<0.002).
The results of multiple other retrospective studies involving approximately 500 patients have been consistent and indicate a 70 to 90 percent success rate in patients who had been refractory to other modes of therapy, with success defined as the avoidance of amputation and, in many cases, complete wound healing.
Baroni and associates prospectively treated 28 patients, 18 of whom received HBO. Unfortunately, the patients were not randomized. They were placed in the control group if they had claustrophobia, ischemic heart disease, paresthesia, or were felt to be unmotivated. All patients received daily debridement of ulcers including removal of necrotic tissue. Physicians performing the debridements were blinded to group assignment. Sixteen of the 18 patients (89 percent) in the treatment group completely healed and remained healed at a follow-up of 1–36 months (13.5 ± 10.1). Only one (10 percent) of the patients in the control group healed. The amputation rate was 12.5 percent in the treated group versus 40 percent in the control group (p<0.001). The HBO patients were sufficiently improved to be discharged in 62 days, and 16 completely healed. Nine of ten of the control group had not healed 82 days later.
In a follow-up study in 1990, 62 of 80 patients (78 percent) received a course of HBO. Ninety-six percent of the HBO patients went on to heal versus 66 percent of the control group. The amputation rate in the HBO group was 4.8 percent versus 33 percent in the control group (p<0.001). The incidence of amputation in the untreated group was essentially unchanged from a group of patients treated nearly 10 years earlier without the benefit of adjunctive HBO. There were no statistical differences in any of the groups relating to age, glycemic control, or complications of diabetes.
In a recently reported study, individuals with diabetes with non-healing foot ulcers were consecutively admitted to a hospital for treatment. They were randomly assigned to an HBO group or a control group. Two individuals, one in each group, did not complete the protocol and were excluded from analyses. A total of 35 individuals received HBO. Three (8.6 percent) of them underwent major amputation (the outcome variable) versus eleven (33.3 percent) in the non-HBO group (p=0.016). The relative risk for the treated group was 0.26 (95 percent CI 0.08-0.84). Multivariate analysis confirmed the protective role of HBO (odds ratio 0.084, p=0.033, 95 percent CI 0.008-0.821) and indicated as negative prognostic determinants low ankle-brachial index values (odds ratio 1.715, p = 0.013, 95 percent CI 1.121-2.626) and high Wagner grade (odds ratio 11.199, p=0.022, 95 percent CI 1.406-89.146).
Arenson OJ, Sherwood CE, Wilson RC: Neuropathic angiopathy and sepsis in the diabetic foot, Part 2. Angiopathy. JAMA 1981;71:661-665.
Baroni G, Porro T, Fagilia, et al.: Hyperbaric oxygen in diabetic gangrene treatment. Diabetes Care 1987;10:81-86.
Bouhanick B, Verret JL: Necrobiosis lipoidica: treatment by hyperbaric oxygen and local corticosteroids. Diabetes Metab 1998;24(2):156-159.
Cianci P: Adjunctive hyperbaric oxygen therapy in the treatment of the diabetic foot. J Am Podiatr Med Assoc 1994;84(9):448-455.
Cianci P, Petrone G, Drager S, et al.: Salvage of the difficult wound/potential amputation in the diabetic patient. In: Hyperbaric Medicine: Proceedings of the Joint Meeting, Second Swiss Symposium on Hyperbaric Medicine and Second European Conference on Hyperbaric Medicine. Basel, Switzerland: Foundation for Hyperbaric Medicine; 1990:177-87.
Cianci P, Petrone G, Green B: Adjunctive hyperbaric oxygen in the salvage of the diabetic foot. Undersea Baromed Res 1991;18(Suppl):108.
Cianci P, Petrone G, Drager S, Leuders H, Lee H, Shapiro R: Salvage of the problem wound and potential amputation with wound care and adjunctive hyperbaric oxygen therapy: an economic analysis. J Hyperbaric Med 1988;3(3)127-141.
Davis JC: The use of adjuvant hyperbaric oxygen in the treatment of the diabetic foot. Clin Podiatr Med Surg 1987;4(2):429-437.
Davis JC, Buckley CJ, Barr P: Compromised soft tissue wounds: correction of wound hypoxia. In: Problem Wounds: The Role of Oxygen. Davis, JC and Hunt, TK, eds: New York, NY: Elsevier Science Publishing Co.; 1988:143-152.
Dean SM, Werman H: Calciphylaxis: a favorable outcome with hyperbaric oxygen. Vasc Med 1998;3(2):115-120.
Ebskov G, Josephsen P: Incidence of reamputation and death after gangrene of the lower extremity. Prosthet Orthotics Inter 1980;4:77-80.
Faglia E, Favales F, Aldeghi A, Calia P, Quarantiello A, Oriani G, Michael M, Campagnoli P, Morabito A: Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer: a randomized study. Diabetes Care 1996;19:1338-1343.
Fierer J, Daniel N, Davis C: The fetid foot: lower extremity infection in patients with diabetes mellitus. Rev Infec Dis 1979;1:210-217.
Fisher, BH: Treatment of ulcers on the legs with hyperbaric oxygen. J Dermatol Surg 1975;1:55.
Gismondi A, Caione R, Sturda G: The “V Fazzi Hospital” diabetic foot wound care protocol: a cost-benefit evaluation. In: Schmutz J, Wendling J, eds: Proceedings of the Joint Meeting on Diving and Hyperbaric Medicine. Basel, Switzerland: Foundation for Hyperbaric Medicine; 1992:182-184.
Hammarlund C, Sundberg T: Hyperbaric oxygen reduced size of chronic leg ulcers: a randomized double-blind study. Plast Reconstr Surg 1994; 93(4):829-833.
Heat JL, Allen SN, Henry M, et al.: Diabetic foot infections. Bacteriologic analysis. Arch Intern Med 1986;46:1925-1940.
Hughes CD, Johnson CC, Bamberge NM, et al.: Treatment and long term follow-up of diabetic or ischemic foot infection a randomized prospective double-blind trial of cefoxitin vs. ceftizoxmine. Clin Ther 1987;10 S:36-49.
Hunt TK: The physiology of wound healing. Ann of Emer Med 1988;17 (12):1265-1273.
Hunt, TK, Pai MP: The effect of varying ambient oxygen tensions on wound metabolism and collagen synthesis. Surg Gynecol Obstetr 1972;125:561-567.
Joseph WS, LeFrock JL: The pathogenesis of diabetic foot infections. Immunopathy, Angiopathy, and Neuropathy. J of Foot Surg 1987;26:7-11.
Kihn RB, Warren R, Beebe GW: The geriatric amputee. Ann Surg 1972;176 (3):305-314.
Knighton DR, Flylling CP, Fiegel VD, Cerra F: Amputation prevention in an independently reviewed at risk diabetic population using a comprehensive wound care protocol. Am J Surg 1990;160:466-472.
Kozak GP: Management of Diabetic Foot Problems. Philadelphia, PA: W.B. Saunders Co.; 1984.
LeFrock JL, Blais F, Schell RF, et al.: Cefoxitin in the treatment of diabetic patients with lower extremities infections. Infec Surg 1983;2:361-374.
LeFrock JL, Johnson ES, Smith LG, et al.: Non-comparative trial of ticarcillin plus clavulanic acid in skin and soft tissue infections in diabetics: Am J Med 1985;79(S) 122-124.
LeFrock JL, Joseph WS: Lower extremity infections in diabetics. Infec Surg 1986;5:135-145.
LeFrock JL, Joseph WS: A team approach to infections of the lower extremity in the diabetic patient. J of Foot Surg 1987;26:1-2.
LeFrock JL, Molavi A: Foot infections in diabetic patients. Mediguide to Infectious Disease 1983;3(1):1-4.
LeFrock JL, Molavi A: Necrotizing skin and subcutaneous infections. J Antimicrob Chemother 1982;9(A):183-192.
LeFrock JL, Smith BR: The penicillins and bone penetration of antibiotics. J of Foot Surg 1987;26:34-41.
Levin ME: Prevention and treatment of diabetic foot wounds. J Wound Ostomy Continence Nurs 1998;25(3):129-146.
Levin ME, O’Neal LW: The Diabetic Foot. CV Mosby, St. Louis, MO; 1988.
Lipsky BA, Pecoraro RE, Wheat LJ: The diabetic foot, soft tissue and bone infection. Infectious Disease Clinics NA 1990;4:409-432.
LoGerfo FW, Coffman JD: Vascular and microvascular disease of the foot in diabetes. NEJM 1984;311: 1615-1619.
LoGerfo FW, Misare BD: Current management of the diabetic foot. Adv Surg 1996;30:417-426.
Louie TJ, Bartlett JG, Tally FP, et al.: Aerobic and anaerobic bacteriology in diabetic foot ulcers. Ann Inter Med 1976;85:461-463.
McDermott JE, Zell G: The role of hyperbaric oxygen in the management of diabetic ulcer. Presented at: 1989, AOFAS Annual Meeting, Sun Valley, ID.
Mackey WC, McCullough JL, Conlon TP: The cost of surgery for limb-threatening ischemia. Surgery 1986;99(1):26-35.
Mader JT, Adam KR, Sutton TE: Infectious Diseases: Pathophysiology and mechanisms of hyperbaric oxygen. J Hyperbaric Med 1987;2:133-140.
Mader JT: Mixed anaerobic and aerobic soft tissue infection. In: Davis JC, Hunt TK, eds: Problem Wounds: The Role of Oxygen.New York, NY: Elsevier; 1988:173-186.
Marx RE, Johnson RP, Kline, SN: Prevention of osteoradionecrosis: a randomized prospective clinical trial of hyperbaric oxygen versus penicillin. Jour Am Dent Assn 1985;11:49-54.
O’Hare, JA, Ferriss JB, Twomey B, O’Sullivan GJ: Poor metabolic control, hypertension and microangiopathy independently increase the transcapillary escape rate of albumin in diabetics. Diabetologia 1983;25:260-263.
Oriani G: Diabetic foot and hyperbaric oxygen therapy: a ten-year experience. J Hyperbar Med 1992;7:213-21.
Oriani G, Meazza D, Favales F, Pizzi G, Aldeghi A, Faglia E: Hyperbaric oxygen therapy in diabetic gangrene. J Hyperbar Med 1990;5(3):171-175.
Oriani G, Sala C, Campagnoli P, Sacchi C, Meazza DT, Ronzio A, Montino O: Oxygen therapy and diabetic gangrene: a review of 10 years experience. In: Schmutz J, Wendling J, eds: Proceedings of the Joint Meeting on Diving and Hyperbaric Medicine. Basel, Switzerland: Foundation for Hyperbaric Medicine; 1992:178-81.
Peterson LR, Lissach LM, Canter K, et al.: Therapy of lower extremity infections with ciproflaxacin in patients with diabetes mellitus, peripheral vascular disease or both. Am J Med 1989;86:801-808.
Riseman JA, Zamboni WA, Curtis A, Graham DR, Konrad HR, Ross DS: Hyperbaric oxygen therapy for necrotizing fasciitis reduces mortality and the need for debridements. Surgery 1990;108 (5)847-850.
Sapico FL, Bessman, AN, Canawati HH: Bacteremia in diabetic patients with infected local extremities. Diabetes Care 1982;5:101-104.
Sapico FL, Canawati HN, Witt JL, et al.: Quantitative aerobic and anaerobic microbiology of infected diabetic feet. J Clin Microbiol 1980;12:413-420.
Sapico Fl, Witte JL, Caneweti HN, et al.: The infected foot of the diabetic patient: quantitative microbiology and analysis of clinical features. Rev Infect Dis 1984;(65) 171-179.
Stone JA, Scott RG, Brill LR, Levine BD: The role of hyperbaric oxygen therapy in the treatment of the diabetic foot. Diabetes 1995;44(Suppl 1):71A.
Strauss MB, Villavicencio PR, Hart GB, Benge CA: Salvaging the difficult wound through a combined management program. In: Kindwall EP, ed: Proceedings of the (1984) VIII International Congress on Hyperbaric Medicine. San Pedro, CA: Best Publishing Company; 1987:207-212.
Undersea and Hyperbaric Medical Society. Hyperbaric Oxygen Therapy: A Committee Report. Undersea Hyperbaric Medical Society, Publ No. 30 CR(HBO). Bethesda, MD: Undersea and Hyperbaric Medical Society; 1989.
Unger HD, Lucca M: The role of hyperbaric oxygen therapy in the treatment of diabetic foot ulcers and refractory osteomyelitis. Clinics in Podiatr Med and Surg 1990;7:483-492.
Wagner FW Jr: A classification and treatment program for diabetic neuropathic and dysvascular foot problems. In: American Academy of Orthopedic Surgeons: Instructional Course Lecture. St. Louis, MO: CV Mosby; 1979 Vol. 28:1-47.
Wattel F, Mathieu D, Coget, JM: Prediction of final outcome with transcutaneous oxygen measurements of problem wounds treated with hyperbaric oxygen. In: Hyperbaric Medicine: Proceedings of the Joint Meeting, Second Swiss Symposium on Hyperbaric Medicine and Second European Conference on Hyperbaric Medicine. Basel, Switzerland: Foundation for Hyperbaric Medicine; 1990:221-223.
Wattel FE, Mathieu DM, Fossati P, Neviere RR, Coget JM: Hyperbaric oxygen in the treatment of diabetic foot lesions: search for healing predictive factors. J Hyperbar Med 1991;6:263-68.
Weisz G, Ramon Y: Treatment of necrobiosis lipoidica diabeticorum by hyperbaric oxygen. Acta Derm Venereol 1993;73(6):447-448.
Williams RL: Hyperbaric oxygen therapy and the diabetic foot. J Am Podiatr Med Assoc 1997;87(6):279-292.
Zamboni WA, Stephenson T: Evaluation of hyperbaric oxygen for diabetic wounds: a prospective study. Undersea Hyperbar Med 195;22(Suppl):11.
Zatz A, Brenner BM: Pathogenesis of diabetic microangiopathy: the hemodynamic view. Ann J M 1986;80:443-453.
Zamboni WA, Wong HP: Evaluation of hyperbaric oxygen for diabetic wounds: a prospective study. Undersea Hyperb Med 1997;24(3):175-179.