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Treatment of diabetic foot infection with hyperbaric oxygen therapy
Foot and Ankle Surgery 16 (2010) 91–95
Contents lists available at ScienceDirect
Foot and Ankle Surgery journal homepage: www.elsevier.com/locate/fas
Treatment of diabetic foot infection with hyperbaric oxygen therapy Chin-En Chen MDa,*, Jih-Yang Ko MDb, Chin-Yeng Fong MDb, Rei-Jahn Juhn MDa a b
Department of Orthopedic Surgery, Golden Hospital, 12-2, Minsheng E. Rd., Pingtung City 900, Taiwan, ROC Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC
A R T I C L E I N F O
A B S T R A C T
Article history: Received 10 January 2009 Received in revised form 19 May 2009 Accepted 18 June 2009
Background: This study was performed to evaluate the effectiveness of hyperbaric oxygen therapy (HBOT) in the treatment of the infected diabetic foot. Methods: Forty-two patients with 44 infected diabetic feet receiving HBOT were divided into two groups. One group of 21 patients with 21 feet received <10 sessions of HBOT. The other 21 patients with 23 feet received >10 sessions of HBOT. Results: In patients who received <10 sessions of HBOT, seven patients achieved satisfactory wound healing. Feet were preserved in 33.3%. In patients with >10 sessions of HBOT, 16 patients with 18 feet achieved good wound healing. Of these patients, 78.3% preserved their feet. This group of patients received an average of 22.8 HBOT treatments. Conclusions: Adjunctive HBOT has a positive effect on wound healing in diabetic foot with infection. The effect of HBOT seems dose dependent because the amputation rate is decreased in patients who receive adequate HBOT. ß 2009 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.
Keywords: Hyperbaric oxygen therapy Diabetic foot ulcer Diabetes mellitus Infection Amputation
1. Introduction Foot lesions in patients with diabetic mellitus are a major health problem with significant morbidity and mortality. At least one study estimated that 20–25% of all hospital admissions of patients with diabetes are due to foot lesions [1]. About 2.5% of patients with diabetes will develop a foot ulcer each year [2,3]. For those patients with diabetes who develop ulcers, excess care costs are substantial compared with diabetic patients without foot ulcers [3,4]. Ulceration of the foot is the main predisposing factor leading to amputation in patients with diabetes mellitus. The rate of lower extremity amputation among patients with diabetes mellitus is 15–40 times greater than the rate in patients without diabetes mellitus [5]. Adjunctive hyperbaric oxygen therapy (HBOT) together with surgical debridement, local wound care, and appropriate antibiotic treatment collectively treat diabetic foot with infection [6–9]. Hyperbaric oxygen therapy is a safe treatment modality with few side effects [10,11]. Patients with diabetic foot ulcer comprise the largest group of wound-healing problems, and diabetic foot ulcer is the most common wound referred for HBOT. Only a few controlled prospective studies have evaluated the efficacy of HBOT in wound healing [1,11]. In a respective study of 1506 cases treated with HBO, D’Angostino Dias et al. found several sessions of HBOT were
* Corresponding author. Tel.: +886 8 7223000; fax: +886 8 7216032. E-mail address: [email protected] (C.-E. Chen).
necessary for chronic injury as compared with acute injury [12]. The indication for HBO therapy in clinical applications is not performed in every major teaching hospital in Taiwan. The purpose of this study was to retrospectively evaluate the clinical results of HBOT in patients with diabetic foot ulcer, and to assess the dose relationship of HBOT. 2. Materials and methods From January 2006 through December 2007, 42 patients with 44 diabetic feet who received treatment with HBO were included in this retrospective study. Twenty females and 22 males with an average age of 67 years (range, 45–85 years) were enrolled. The severity of the diabetic ulcer was classified using Wagner classification [13]. Only those patients with grade III lesions (deep ulcer with infection, osteomyelitis, or septic arthritis) and grade IV lesions (deep ulcer and gangrene of a portion of foot) were included. Cases with superficial ulcers or foot gangrene that warranted amputation were excluded from this study. The common infecting microorganisms were Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus and mixed infection (Table 1). The initial evaluation of each patient included a complete medial history, the results of bacterial culture, the use of antibiotic treatment, and history of surgical treatment. Laboratory data included leukocyte count, total lymphocyte count, hemoglobin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), glucosylated hemoglobin (HbA1c), and albumin. Other studies
1268-7731/$ – see front matter ß 2009 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.fas.2009.06.002
C.-E. Chen et al. / Foot and Ankle Surgery 16 (2010) 91–95
92
Table 1 Comparison of pathogens in diabetic foot ulcer wounds in patients with successful and failed hyperbaric oxygen therapy. Bacterial cultures Aerobic Enterococcus species Pseudomonas aeruginosa Escherichia coli Staphylococcus aureus Klebsiella pneumonia Staphylococcus epidermidis Acinetobacter baumannii b-Streptococcus, group B Corynebacterium species Citrobacter freundii Serratia marcescens Morganella morganii Proteus mirabilis Proteus vulgaris Streptococcus species Citrobacter brakii Enterobacter cloacae Anaerobic Bacteroid fragilis Prevotella bivia Peptostreptococcus Clostridium species Fungus Yeast-like
Successful HBOT (25 diabetic feet)
Failed HBOT (19 diabetic feet)
6 6 4 9 3 2 1 2 2 2 1 1
3 5 2 1
1
3 2
1 1 1 2 1 1
1 1
using a mask system with 2.5 atmospheres absolute (ATA) for a 2-h duration with an intermittent schedule of 25 min of 100% oxygen breathing and 5 min of air breathing for one dive per day, 5 days per week, and intermittent schedule during the 2 days on the weekend. However, some patients abandoned the treatment against the advice too early because there was no significant improvement of the ulcer in the early stage. A few patients had early withdrawal from the treatment by himself due to the personal problem, including intolerance of treatment pressure after several times trials, or poor compliance to the treatment course. Therefore, patients could be divided arbitrarily into two groups according to the number of HBOT greater or less than 10 sessions. Patients in group 1 received <10 sessions of HBOT, and patients in group 2 received >10 sessions HBOT. The success of treatment was defined as the presence of a healed wound and with preservation of the affected foot for at least 6 months after the completion of HBOT. Failure was defined by amputation of the foot (below or above knee level) or having a persistent foot ulcer with no significant improvement for 6 months after the completion of HBOT.
4 1 1 1
3
1
2.1. Statistical analysis The data of both groups was compared statistically with the Mann–Whitney analysis test. The difference was considered statistically significant if P < 0.05. 3. Results
included peripheral vascular circulation and ankle-brachial index (ABI) with Doppler ultrasound. The treatment protocol consisted of a combination of medical and surgical treatments. Medical treatments included antibiotic treatment and adequate metabolic control, while surgical treatment included debridement and wound care. The choice of antibiotics was determined according to the results of a culture and sensitivity test. An endocrinologist and a clinical nutritionist were responsible for metabolic control. The wound was surgically debrided, and cared for with normal saline wet dressing initially. Repeat surgical debridement was performed as needed depending upon the wound appearance. Soft tissue reconstruction was performed for large soft tissue defect in which wound healing without secondary intervention was impossible. All patients received HBOT in a diving chamber (Haux-Starmed 2000 Hyperbaric Chamber, Haux-Life-Support GmbH, Karlsbad [Ittersbach], Germany) except for medical treatment and surgical intervention. Ten sessions of HBOT were required as a treatment unit. In the compression chamber, 100% oxygen was delivered
The severity of the ulcer was graded according to Wagner classification [13], and included 10 grade III lesions and 11 grade IV lesions in group 1. In group 2, there were 7 grade III lesions, and 16 grade IV lesions. In group 1, there were 10 females and 11 males with an average age of 68 years old (range, 46–83 years). The average duration of diabetes history was 11.5 years (range, 1–40 years). The average duration of infection was 7 weeks (range, 1 week to 1 year). The average number of HBOT treatments was 3.5 sessions (range, 1–7), and the average follow-up duration was 13.3 months (range, 6–29 months). In group 2, there were 21 patients with 23 feet including 10 females and 11 males with an average age of 66 years old (range, 45–85 years). The average duration of diabetes history was 13.2 years (range, 4–30 years). The average duration of infection before HBOT was 14 weeks (range, 2 weeks to 1 year). The average number of HBOT sessions was 22.8 (range, 10–47), and the average follow-up was 14.8 months (range, 6–30 months). In group 1, 7
Fig. 1. A 60-year-old female with a diabetic foot ulcer of 3 months is shown. (A) The wound condition is revealed before hyperbaric oxygen therapy (HBOT). (B) Good granulation tissue formation is shown after 20 sessions of HBOT.
C.-E. Chen et al. / Foot and Ankle Surgery 16 (2010) 91–95
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Fig. 2. A 65-year-old male with left diabetic foot ulcer of 2 months duration is shown. (A and B) The soft tissue defect is noted before HBOT. (C and D) The patient’s wound healed after 20 sessions of HBOT.
patients of the 21 patients had healed wounds, and 33.3% successfully preserved their feet. Fourteen patients failed HBOT and underwent subsequent treatment, including surgery in 10 patients (below-knee amputation in 9 and above-knee amputation in 1) and further medical treatment of persistent ulcer. However, in the latter group of patients who received medical treatment, no improvement was observed at the time of last follow-up in four patients. In group 2, 16 patients with 18 feet had healed wounds, with preservation of the feet in 78.3% (Figs. 1 and 2). Five patients who failed treatment underwent surgery in four patients (including below-knee amputation in two and above-knee amputation in two) and medical treatment of persistent ulcer in one. Table 2 Comparison of demographic and laboratory data between study groups of patients with hyperbaric oxygen therapy of diabetic foot ulcer. <10 sessions (21 diabetic feet)
>10 sessions (23 diabetic feet)
68 11 11.48 10.11
66 21 13.22 7.55
0.45 0.39
11360.00 5532.24
10378.2 3563.06
0.79 0.07
Age (year) Duration of DM (years) Leukocyte count (count/cc) Total lymphocyte (count/cc) Hemoglobin (gm/ml) ESR (mm/min) CRP (mg/l) HbA1c (%) Albumin (g) Ankle-brachial index Operation times HBO (sessions)
1388.53 534.86
1701.39 552.75
10.18 1.47 43.22 30.52 129.77 88.17 9.23 2.91 2.83 0.59 0.71 0.31 3.68 3.18 3.48 1.94
10.91 1.36 66.80 32.16 59.02 60.36 9.8 1.92 3.33 0.58 0.76 0.30 4.61 3.04 22.78 9.775
Results Success Failure
7 14
18 5
P
0.11 0.23 0.07 0.41 0.12 0.81 0.20 <0.05
The comparison data of both groups are summarized in Table 2. No statistically significant difference was noted for age, duration of diabetes mellitus, albumin, ESR, CRP, and ABI. However, the number of sessions of HBOT was positively correlated with the success rate of treatment. Patients receiving more than 10 sessions of HBOT showed a significantly higher rate of success than patients receiving less than 10 treatment sessions (P < 0.05). The data of patients who underwent successful and failed HBOT treatment are summarized in Table 3. The average number of HBOT sessions was 18.4 times in patients who experienced a successful outcome, and 7.2 times in patients who experienced failure. This difference was statistically significant (P < 0.05). There was no statistically significant difference in age, duration of diabetes mellitus, albumin, ESR, CRP, and ABI.
Table 3 Comparison of demographic and laboratory data between study groups of patients with hyperbaric oxygen therapy of diabetic foot ulcer. Success (25 diabetic feet) Age (year) Duration of DM (years) Leukocyte count (count/cc) Total lymphocyte (count/cc) Hemoglobin (gm/ml) ESR (mm/min) CRP (mg/l) HbA1c (%) Albumin (gm) Ankle-brachial index HBO sessions Surgeries (no.)
Failure (19 diabetic feet)
P
65 11 12.68 7.12
68 11 12.00 10.83
0.33 0.39
10783.33 3819.25
10900.00 5454.25
0.77
1585.50 591.19
1501.33 529.54
0.58
10.94 1.38 52.04 33.75 64.23 64.99 9.33 1.93 3.15 0.41 0.79 0.28 18.44 12.55 4.48 3.07
10.11 1.42 59.00 33.41 171.10 72.15 9.59 3.19 2.93 0.82 0.68 0.32 7.16 1.86 3.76 3.19
0.08 0.76 0.04 0.91 0.38 0.38 <0.05 0.26
94
C.-E. Chen et al. / Foot and Ankle Surgery 16 (2010) 91–95
4. Discussion The incidence of foot ulcer in patients with diabetes mellitus is nearly 2.5% per year [2]. For those who develop diabetic foot, morbidity, mortality, and health care costs are substantial compared with those patients without foot ulcers. The presence of peripheral neuropathy, peripheral vascular disease, and poor sugar control in conjunction with minor trauma of the foot increases the incidence of diabetic foot ulcer [14]. Diabetic ulcer often progresses to infection of the surrounding tissue resulting in osteomyelitis, and amputation may be indicated. To avoid the tragedy of amputation, the development of foot ulcers in diabetic patients must be prevented. If a foot ulcer already has developed, the promotion of wound healing and prevention of amputation are critical. Many factors may affect wound healing in patients with diabetes, including impairment of fibroblastic function, collagen production, cell-mediated immunity, and phagocytosis [1]. Many studies show the strongest risk factor is impaired cutaneous oxygenation resulting in amputation [14–17]. Low oxygen tension and cellular hypoxia adversely affect the function of neutrophils, macrophages, and fibroblasts during inflammation and repair. The rationale for HBOT is its beneficial effect on the microenvironment of the wound. Although HBO cannot significantly increase the oxygen saturation of hemoglobin, it can significantly increase the fraction of oxygen physically dissolved in the plasma [18]. Under hyperbaric conditions, wound tissue oxygen tension can be increased 10- to 15-fold [19]. Elevation of oxygen tension in hypoxic wound stimulates fibroblast proliferation, collagen production, neovascularization, and epithelialization [20,21]. In addition, oxygen has a direct lethal effect on anaerobes and indirect activity against aerobic bacteria [22,23]. Despite the potential benefits and favorable clinical reports [6,24], HBOT is not used as a standard treatment for infected diabetic foot in Taiwan. Lee et al. reported an 81% success rate in treating Wagner III and IV diabetic foot lesions with adjunctive HBOT [6]. The treatment course of HBOT in their series, however, is broadly variable with a range from 5 to 83 times with a mean of 35.3 treatments. Doctor et al. reported a 46.7% amputation rate in patients who did not receive HBOT, and only 13.3% of patients who receive HBOT required amputation [7]. In our series, patients receiving <10 sessions of HBOT had a success rate of 33.3% and amputation was necessary in 47.7%. Comparatively, patients who received >10 sessions of HBOT had a success rate of 78.3% and an amputation rate of 17.4%. The difference between the two groups was statistically significant (P < 0.05). The data of this study show that HBOT appears to be dose dependent. In patients who receive <10 sessions of HBOT, one can only expect some improvement in leukocyte bacterial killing efficiency and relief of. Connective tissue regeneration, bone healing, and capillary proliferation processes might require more sessions of HBOT. The amputation rate in our series was similar to Doctor et al. [7], and the amputation rate decreased in those patients who received >10 sessions of HBOT. Many prognostic factors were reported for HBOT treatment of infected diabetic foot. Lee et al. reported that leukocyte count and ABI were significantly different between the success and failure groups [6]. The researchers suggested that a consultation for vascular bypass surgery was mandatory if ABI was below 0.45 in a diabetic patient. Faglia et al. also found that the patients with low ABI and high Wagner grades had a poor prognosis [25]. In our series, no statistical correlation was found in ESR, CRP, albumin, ABI, and leukocytosis. Although the success of HBOT in diabetic ulcers may depend on the ischemic level of the tissue, patients with critical ischemia often have deceptively high ABI due to arterial arthrosclerosis. Therefore, ABI should not be viewed alone.
Nevertheless, there was a statistical correlation between the number of HBOT treatments and the rate of success or failure. The importance of the types of the infecting microorganisms in the diabetic patients with foot ulcer has been discussed in the literature [6,24]. In a study by Calhoun et al., the most common organism was S. aureus and nearly three fourths were polymicrobial infection [24]. The most common infectious microorganism in our series was P. aeruginosa. Other common organisms included S. aureus and Enterococcus. Although a high percentage of mixed infection was noted, the bacterial distributions were similar in patients who had undergone successful and failed HBOT treatment. Wounds infected with S. aureus and anaerobic infection usually had a better clinical response to surgical debridement and HBOT. The limitations of this study include the small sample size, which precluded comparative evaluation of potentially important variables such as treatment methods for diabetes mellitus, and the presence of other comorbidities, such as diabetic renal and neuropathic complications. The duration of follow-up is relatively short in our study patients. Therefore, the long-term effect of HBOT is unknown. Prospective study may elucidate the number of sessions necessary for the treatment of different grades of severity of diabetic foot infection. Nonetheless, the results in this study seem to indicate that fewer than 10 sessions of HBOT for diabetic foot infection is considered inadequate. In conclusion, adjunctive HBOT has a positive effect on wound healing in conjunction with medical and surgical treatments in patients with infected diabetic foot ulcers. The effect of HBOT seems dose dependent because the amputation rate is decreased in patients who received adequate sessions of treatment. Conflict of interest No benefits or funds were received in support of this study. Acknowledgement We thank Han-Hsiang Chen, MD, for his assistance in the statistical analysis of the data in this report. References [1] Zamboni WA, Wong HP, Stephenson LL, Pfeifer MA. Evaluation of hyperbaric oxygen for diabetic wounds: a prospective study. Undersea Hyperb Med 1997;24:175–9. [2] Moss SE, Klein R, Klein BE. The prevalence and incidence of lower extremity amputation in a diabetic population. Arch Intern Med 1992;152:610–6. [3] Ramsey SD, Newton K, Blough D, McCulloch DK, Sandhu N, Reiber GE, et al. Incidence, outcomes, and cost of foot ulcers in patients with diabetes. Diabetes Care 1999;22:382–7. [4] Chuck AW, Hailey D, Jacobs P, Perry DC. Cost-effectiveness and budget impact of adjunctive hyperbaric oxygen therapy for diabetic foot ulcers. Int J Technol Assess Health Care 2008;24:178–83. [5] Most RS, Sinnock P. The epidemiology of lower extremity amputations in diabetic individuals. Diabetes Care 1983;6:87–91. [6] Lee SS, Chen CY, Chan YS, Yen CY, Chao EK, Ueng WN. Hyperbaric oxygen in the treatment of diabetic foot infection. Chang Gung Med J 1997;20:17–22. [7] Doctor N, Pandya S, Supe A. Hyperbaric oxygen therapy in diabetic foot. J Postgrad Med 1992;38:112–4. [8] Baroni G, Porro T, Faglia E, Pizzi G, Mastropasqua A, Oriani G, et al. Hyperbaric oxygen in diabetic gangrene treatment. Diabetes care 1987;10:81–6. [9] Zgonis T, Garbalosa JC, Burns P, Vidt L, Lowery C. A retrospective study of patients with diabetes mellitus after partial foot amputation and hyperbaric oxygen treatment. J Foot Ankle Surg 2005;44:276–80. [10] Bakker DJ. Hyperbaric oxygen therapy and diabetic foot. Diabetes Metab Res Rev 2000;16(Suppl. 1):s55–8. [11] Brakora MJ, Sheffield PJ. Hyperbaric oxygen therapy for diabetic wounds. Clin Podiatr Med Surg 1995;12:105–17. [12] D’Angostino Dias M, Fontes B, Poggetti RS, Birolini D. Hyperbaric oxygen therapy: type of injury and number of sessions—a review of 1506 cases. Undersea Hyperb Med 2008;35:53–60. [13] Wagner Jr FW. The dysvascular foot: a system for diagnosis and treatment. Foot Ankle 1981;2:64–122.
C.-E. Chen et al. / Foot and Ankle Surgery 16 (2010) 91–95 [14] Reiber GE, Pecoraro RE, Koepsell TD. Risk factors for amputation in patients with diabetes mellitus: a case-control study. Ann Intern Med 1992;117: 97–105. [15] McNeely MJ, Boyko EJ, Ahroni JH, Stensel VL, Reiber GE, Smith DG, et al. The independent contributions of diabetic neuropathy and vasculopathy in foot ulceration. How great are the risks? Diabetes Care 1995;18:216–9. [16] Pecoraro RE, Ahroni JH, Boyko EJ, Stensel VL. Chronology and determinants of tissue repair in diabetic lower-extremity ulcers. Diabetes 1991;40: 1305–13. [17] Levin ME. Preventing amputation in the patient with diabetes. Diabetes Care 1995;18:1383–94. [18] Unger HD, Lucca M. The role of hyperbaric oxygen therapy in the treatment of diabetic foot ulcers and refractory osteomyelitis. Clin Podiatr Med Surg 1990;7:483–92. [19] Ackerman NB, Brinkley FB. Oxygen tensions in normal and ischemic tissues during hyperbaric therapy: studies in rabbits. JAMA 1966;198:1280–3.
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[20] LaVan FB, Hunt TK. Oxygen and wound healing. Clin Plast Surg 1990;17:463– 72. [21] Roeckl-Wiedmann I, Bennett M, Kranke P. Systemic review of hyperbaric oxygen in the management of chronic wounds. Br J Surg 2005;92:24–32. [22] Knighton DR, Holliday B, Hunt TK. Oxygen as an antibiotic: a comparison of the effects of inspired oxygen concentration and antibiotic administration on in vivo bacterial clearance. Arch Surg 1986;121:191–5. [23] Mader JT, Brown GL, Guckian JC, Wells CH, Reinarz JA. A mechanism for the amelioration by hyperbaric oxygen of experimental staphylococcal osteomyelitis in rabbits. J Infect Dis 1980;142:915–22. [24] Calhoun JH, Cantrell J, Cobos J, Lacy J, Valdez RR, Hokanson J, et al. Treatment of diabetic foot infections: Wagner classification, therapy, and outcome. Foot Ankle 1988;9:101–6. [25] Faglia E, Favales F, Aldeghi A, Calia P, Quarantiello A, Oriani G, et al. Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer: a randomized study. Diabetes Care 1996;19:1338–43.
Contents lists available at ScienceDirect
Foot and Ankle Surgery journal homepage: www.elsevier.com/locate/fas
Treatment of diabetic foot infection with hyperbaric oxygen therapy Chin-En Chen MDa,*, Jih-Yang Ko MDb, Chin-Yeng Fong MDb, Rei-Jahn Juhn MDa a b
Department of Orthopedic Surgery, Golden Hospital, 12-2, Minsheng E. Rd., Pingtung City 900, Taiwan, ROC Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC
A R T I C L E I N F O
A B S T R A C T
Article history: Received 10 January 2009 Received in revised form 19 May 2009 Accepted 18 June 2009
Background: This study was performed to evaluate the effectiveness of hyperbaric oxygen therapy (HBOT) in the treatment of the infected diabetic foot. Methods: Forty-two patients with 44 infected diabetic feet receiving HBOT were divided into two groups. One group of 21 patients with 21 feet received <10 sessions of HBOT. The other 21 patients with 23 feet received >10 sessions of HBOT. Results: In patients who received <10 sessions of HBOT, seven patients achieved satisfactory wound healing. Feet were preserved in 33.3%. In patients with >10 sessions of HBOT, 16 patients with 18 feet achieved good wound healing. Of these patients, 78.3% preserved their feet. This group of patients received an average of 22.8 HBOT treatments. Conclusions: Adjunctive HBOT has a positive effect on wound healing in diabetic foot with infection. The effect of HBOT seems dose dependent because the amputation rate is decreased in patients who receive adequate HBOT. ß 2009 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.
Keywords: Hyperbaric oxygen therapy Diabetic foot ulcer Diabetes mellitus Infection Amputation
1. Introduction Foot lesions in patients with diabetic mellitus are a major health problem with significant morbidity and mortality. At least one study estimated that 20–25% of all hospital admissions of patients with diabetes are due to foot lesions [1]. About 2.5% of patients with diabetes will develop a foot ulcer each year [2,3]. For those patients with diabetes who develop ulcers, excess care costs are substantial compared with diabetic patients without foot ulcers [3,4]. Ulceration of the foot is the main predisposing factor leading to amputation in patients with diabetes mellitus. The rate of lower extremity amputation among patients with diabetes mellitus is 15–40 times greater than the rate in patients without diabetes mellitus [5]. Adjunctive hyperbaric oxygen therapy (HBOT) together with surgical debridement, local wound care, and appropriate antibiotic treatment collectively treat diabetic foot with infection [6–9]. Hyperbaric oxygen therapy is a safe treatment modality with few side effects [10,11]. Patients with diabetic foot ulcer comprise the largest group of wound-healing problems, and diabetic foot ulcer is the most common wound referred for HBOT. Only a few controlled prospective studies have evaluated the efficacy of HBOT in wound healing [1,11]. In a respective study of 1506 cases treated with HBO, D’Angostino Dias et al. found several sessions of HBOT were
* Corresponding author. Tel.: +886 8 7223000; fax: +886 8 7216032. E-mail address: [email protected] (C.-E. Chen).
necessary for chronic injury as compared with acute injury [12]. The indication for HBO therapy in clinical applications is not performed in every major teaching hospital in Taiwan. The purpose of this study was to retrospectively evaluate the clinical results of HBOT in patients with diabetic foot ulcer, and to assess the dose relationship of HBOT. 2. Materials and methods From January 2006 through December 2007, 42 patients with 44 diabetic feet who received treatment with HBO were included in this retrospective study. Twenty females and 22 males with an average age of 67 years (range, 45–85 years) were enrolled. The severity of the diabetic ulcer was classified using Wagner classification [13]. Only those patients with grade III lesions (deep ulcer with infection, osteomyelitis, or septic arthritis) and grade IV lesions (deep ulcer and gangrene of a portion of foot) were included. Cases with superficial ulcers or foot gangrene that warranted amputation were excluded from this study. The common infecting microorganisms were Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus and mixed infection (Table 1). The initial evaluation of each patient included a complete medial history, the results of bacterial culture, the use of antibiotic treatment, and history of surgical treatment. Laboratory data included leukocyte count, total lymphocyte count, hemoglobin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), glucosylated hemoglobin (HbA1c), and albumin. Other studies
1268-7731/$ – see front matter ß 2009 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.fas.2009.06.002
C.-E. Chen et al. / Foot and Ankle Surgery 16 (2010) 91–95
92
Table 1 Comparison of pathogens in diabetic foot ulcer wounds in patients with successful and failed hyperbaric oxygen therapy. Bacterial cultures Aerobic Enterococcus species Pseudomonas aeruginosa Escherichia coli Staphylococcus aureus Klebsiella pneumonia Staphylococcus epidermidis Acinetobacter baumannii b-Streptococcus, group B Corynebacterium species Citrobacter freundii Serratia marcescens Morganella morganii Proteus mirabilis Proteus vulgaris Streptococcus species Citrobacter brakii Enterobacter cloacae Anaerobic Bacteroid fragilis Prevotella bivia Peptostreptococcus Clostridium species Fungus Yeast-like
Successful HBOT (25 diabetic feet)
Failed HBOT (19 diabetic feet)
6 6 4 9 3 2 1 2 2 2 1 1
3 5 2 1
1
3 2
1 1 1 2 1 1
1 1
using a mask system with 2.5 atmospheres absolute (ATA) for a 2-h duration with an intermittent schedule of 25 min of 100% oxygen breathing and 5 min of air breathing for one dive per day, 5 days per week, and intermittent schedule during the 2 days on the weekend. However, some patients abandoned the treatment against the advice too early because there was no significant improvement of the ulcer in the early stage. A few patients had early withdrawal from the treatment by himself due to the personal problem, including intolerance of treatment pressure after several times trials, or poor compliance to the treatment course. Therefore, patients could be divided arbitrarily into two groups according to the number of HBOT greater or less than 10 sessions. Patients in group 1 received <10 sessions of HBOT, and patients in group 2 received >10 sessions HBOT. The success of treatment was defined as the presence of a healed wound and with preservation of the affected foot for at least 6 months after the completion of HBOT. Failure was defined by amputation of the foot (below or above knee level) or having a persistent foot ulcer with no significant improvement for 6 months after the completion of HBOT.
4 1 1 1
3
1
2.1. Statistical analysis The data of both groups was compared statistically with the Mann–Whitney analysis test. The difference was considered statistically significant if P < 0.05. 3. Results
included peripheral vascular circulation and ankle-brachial index (ABI) with Doppler ultrasound. The treatment protocol consisted of a combination of medical and surgical treatments. Medical treatments included antibiotic treatment and adequate metabolic control, while surgical treatment included debridement and wound care. The choice of antibiotics was determined according to the results of a culture and sensitivity test. An endocrinologist and a clinical nutritionist were responsible for metabolic control. The wound was surgically debrided, and cared for with normal saline wet dressing initially. Repeat surgical debridement was performed as needed depending upon the wound appearance. Soft tissue reconstruction was performed for large soft tissue defect in which wound healing without secondary intervention was impossible. All patients received HBOT in a diving chamber (Haux-Starmed 2000 Hyperbaric Chamber, Haux-Life-Support GmbH, Karlsbad [Ittersbach], Germany) except for medical treatment and surgical intervention. Ten sessions of HBOT were required as a treatment unit. In the compression chamber, 100% oxygen was delivered
The severity of the ulcer was graded according to Wagner classification [13], and included 10 grade III lesions and 11 grade IV lesions in group 1. In group 2, there were 7 grade III lesions, and 16 grade IV lesions. In group 1, there were 10 females and 11 males with an average age of 68 years old (range, 46–83 years). The average duration of diabetes history was 11.5 years (range, 1–40 years). The average duration of infection was 7 weeks (range, 1 week to 1 year). The average number of HBOT treatments was 3.5 sessions (range, 1–7), and the average follow-up duration was 13.3 months (range, 6–29 months). In group 2, there were 21 patients with 23 feet including 10 females and 11 males with an average age of 66 years old (range, 45–85 years). The average duration of diabetes history was 13.2 years (range, 4–30 years). The average duration of infection before HBOT was 14 weeks (range, 2 weeks to 1 year). The average number of HBOT sessions was 22.8 (range, 10–47), and the average follow-up was 14.8 months (range, 6–30 months). In group 1, 7
Fig. 1. A 60-year-old female with a diabetic foot ulcer of 3 months is shown. (A) The wound condition is revealed before hyperbaric oxygen therapy (HBOT). (B) Good granulation tissue formation is shown after 20 sessions of HBOT.
C.-E. Chen et al. / Foot and Ankle Surgery 16 (2010) 91–95
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Fig. 2. A 65-year-old male with left diabetic foot ulcer of 2 months duration is shown. (A and B) The soft tissue defect is noted before HBOT. (C and D) The patient’s wound healed after 20 sessions of HBOT.
patients of the 21 patients had healed wounds, and 33.3% successfully preserved their feet. Fourteen patients failed HBOT and underwent subsequent treatment, including surgery in 10 patients (below-knee amputation in 9 and above-knee amputation in 1) and further medical treatment of persistent ulcer. However, in the latter group of patients who received medical treatment, no improvement was observed at the time of last follow-up in four patients. In group 2, 16 patients with 18 feet had healed wounds, with preservation of the feet in 78.3% (Figs. 1 and 2). Five patients who failed treatment underwent surgery in four patients (including below-knee amputation in two and above-knee amputation in two) and medical treatment of persistent ulcer in one. Table 2 Comparison of demographic and laboratory data between study groups of patients with hyperbaric oxygen therapy of diabetic foot ulcer. <10 sessions (21 diabetic feet)
>10 sessions (23 diabetic feet)
68 11 11.48 10.11
66 21 13.22 7.55
0.45 0.39
11360.00 5532.24
10378.2 3563.06
0.79 0.07
Age (year) Duration of DM (years) Leukocyte count (count/cc) Total lymphocyte (count/cc) Hemoglobin (gm/ml) ESR (mm/min) CRP (mg/l) HbA1c (%) Albumin (g) Ankle-brachial index Operation times HBO (sessions)
1388.53 534.86
1701.39 552.75
10.18 1.47 43.22 30.52 129.77 88.17 9.23 2.91 2.83 0.59 0.71 0.31 3.68 3.18 3.48 1.94
10.91 1.36 66.80 32.16 59.02 60.36 9.8 1.92 3.33 0.58 0.76 0.30 4.61 3.04 22.78 9.775
Results Success Failure
7 14
18 5
P
0.11 0.23 0.07 0.41 0.12 0.81 0.20 <0.05
The comparison data of both groups are summarized in Table 2. No statistically significant difference was noted for age, duration of diabetes mellitus, albumin, ESR, CRP, and ABI. However, the number of sessions of HBOT was positively correlated with the success rate of treatment. Patients receiving more than 10 sessions of HBOT showed a significantly higher rate of success than patients receiving less than 10 treatment sessions (P < 0.05). The data of patients who underwent successful and failed HBOT treatment are summarized in Table 3. The average number of HBOT sessions was 18.4 times in patients who experienced a successful outcome, and 7.2 times in patients who experienced failure. This difference was statistically significant (P < 0.05). There was no statistically significant difference in age, duration of diabetes mellitus, albumin, ESR, CRP, and ABI.
Table 3 Comparison of demographic and laboratory data between study groups of patients with hyperbaric oxygen therapy of diabetic foot ulcer. Success (25 diabetic feet) Age (year) Duration of DM (years) Leukocyte count (count/cc) Total lymphocyte (count/cc) Hemoglobin (gm/ml) ESR (mm/min) CRP (mg/l) HbA1c (%) Albumin (gm) Ankle-brachial index HBO sessions Surgeries (no.)
Failure (19 diabetic feet)
P
65 11 12.68 7.12
68 11 12.00 10.83
0.33 0.39
10783.33 3819.25
10900.00 5454.25
0.77
1585.50 591.19
1501.33 529.54
0.58
10.94 1.38 52.04 33.75 64.23 64.99 9.33 1.93 3.15 0.41 0.79 0.28 18.44 12.55 4.48 3.07
10.11 1.42 59.00 33.41 171.10 72.15 9.59 3.19 2.93 0.82 0.68 0.32 7.16 1.86 3.76 3.19
0.08 0.76 0.04 0.91 0.38 0.38 <0.05 0.26
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4. Discussion The incidence of foot ulcer in patients with diabetes mellitus is nearly 2.5% per year [2]. For those who develop diabetic foot, morbidity, mortality, and health care costs are substantial compared with those patients without foot ulcers. The presence of peripheral neuropathy, peripheral vascular disease, and poor sugar control in conjunction with minor trauma of the foot increases the incidence of diabetic foot ulcer [14]. Diabetic ulcer often progresses to infection of the surrounding tissue resulting in osteomyelitis, and amputation may be indicated. To avoid the tragedy of amputation, the development of foot ulcers in diabetic patients must be prevented. If a foot ulcer already has developed, the promotion of wound healing and prevention of amputation are critical. Many factors may affect wound healing in patients with diabetes, including impairment of fibroblastic function, collagen production, cell-mediated immunity, and phagocytosis [1]. Many studies show the strongest risk factor is impaired cutaneous oxygenation resulting in amputation [14–17]. Low oxygen tension and cellular hypoxia adversely affect the function of neutrophils, macrophages, and fibroblasts during inflammation and repair. The rationale for HBOT is its beneficial effect on the microenvironment of the wound. Although HBO cannot significantly increase the oxygen saturation of hemoglobin, it can significantly increase the fraction of oxygen physically dissolved in the plasma [18]. Under hyperbaric conditions, wound tissue oxygen tension can be increased 10- to 15-fold [19]. Elevation of oxygen tension in hypoxic wound stimulates fibroblast proliferation, collagen production, neovascularization, and epithelialization [20,21]. In addition, oxygen has a direct lethal effect on anaerobes and indirect activity against aerobic bacteria [22,23]. Despite the potential benefits and favorable clinical reports [6,24], HBOT is not used as a standard treatment for infected diabetic foot in Taiwan. Lee et al. reported an 81% success rate in treating Wagner III and IV diabetic foot lesions with adjunctive HBOT [6]. The treatment course of HBOT in their series, however, is broadly variable with a range from 5 to 83 times with a mean of 35.3 treatments. Doctor et al. reported a 46.7% amputation rate in patients who did not receive HBOT, and only 13.3% of patients who receive HBOT required amputation [7]. In our series, patients receiving <10 sessions of HBOT had a success rate of 33.3% and amputation was necessary in 47.7%. Comparatively, patients who received >10 sessions of HBOT had a success rate of 78.3% and an amputation rate of 17.4%. The difference between the two groups was statistically significant (P < 0.05). The data of this study show that HBOT appears to be dose dependent. In patients who receive <10 sessions of HBOT, one can only expect some improvement in leukocyte bacterial killing efficiency and relief of. Connective tissue regeneration, bone healing, and capillary proliferation processes might require more sessions of HBOT. The amputation rate in our series was similar to Doctor et al. [7], and the amputation rate decreased in those patients who received >10 sessions of HBOT. Many prognostic factors were reported for HBOT treatment of infected diabetic foot. Lee et al. reported that leukocyte count and ABI were significantly different between the success and failure groups [6]. The researchers suggested that a consultation for vascular bypass surgery was mandatory if ABI was below 0.45 in a diabetic patient. Faglia et al. also found that the patients with low ABI and high Wagner grades had a poor prognosis [25]. In our series, no statistical correlation was found in ESR, CRP, albumin, ABI, and leukocytosis. Although the success of HBOT in diabetic ulcers may depend on the ischemic level of the tissue, patients with critical ischemia often have deceptively high ABI due to arterial arthrosclerosis. Therefore, ABI should not be viewed alone.
Nevertheless, there was a statistical correlation between the number of HBOT treatments and the rate of success or failure. The importance of the types of the infecting microorganisms in the diabetic patients with foot ulcer has been discussed in the literature [6,24]. In a study by Calhoun et al., the most common organism was S. aureus and nearly three fourths were polymicrobial infection [24]. The most common infectious microorganism in our series was P. aeruginosa. Other common organisms included S. aureus and Enterococcus. Although a high percentage of mixed infection was noted, the bacterial distributions were similar in patients who had undergone successful and failed HBOT treatment. Wounds infected with S. aureus and anaerobic infection usually had a better clinical response to surgical debridement and HBOT. The limitations of this study include the small sample size, which precluded comparative evaluation of potentially important variables such as treatment methods for diabetes mellitus, and the presence of other comorbidities, such as diabetic renal and neuropathic complications. The duration of follow-up is relatively short in our study patients. Therefore, the long-term effect of HBOT is unknown. Prospective study may elucidate the number of sessions necessary for the treatment of different grades of severity of diabetic foot infection. Nonetheless, the results in this study seem to indicate that fewer than 10 sessions of HBOT for diabetic foot infection is considered inadequate. In conclusion, adjunctive HBOT has a positive effect on wound healing in conjunction with medical and surgical treatments in patients with infected diabetic foot ulcers. The effect of HBOT seems dose dependent because the amputation rate is decreased in patients who received adequate sessions of treatment. Conflict of interest No benefits or funds were received in support of this study. Acknowledgement We thank Han-Hsiang Chen, MD, for his assistance in the statistical analysis of the data in this report. References [1] Zamboni WA, Wong HP, Stephenson LL, Pfeifer MA. Evaluation of hyperbaric oxygen for diabetic wounds: a prospective study. Undersea Hyperb Med 1997;24:175–9. [2] Moss SE, Klein R, Klein BE. The prevalence and incidence of lower extremity amputation in a diabetic population. Arch Intern Med 1992;152:610–6. [3] Ramsey SD, Newton K, Blough D, McCulloch DK, Sandhu N, Reiber GE, et al. Incidence, outcomes, and cost of foot ulcers in patients with diabetes. Diabetes Care 1999;22:382–7. [4] Chuck AW, Hailey D, Jacobs P, Perry DC. Cost-effectiveness and budget impact of adjunctive hyperbaric oxygen therapy for diabetic foot ulcers. Int J Technol Assess Health Care 2008;24:178–83. [5] Most RS, Sinnock P. The epidemiology of lower extremity amputations in diabetic individuals. Diabetes Care 1983;6:87–91. [6] Lee SS, Chen CY, Chan YS, Yen CY, Chao EK, Ueng WN. Hyperbaric oxygen in the treatment of diabetic foot infection. Chang Gung Med J 1997;20:17–22. [7] Doctor N, Pandya S, Supe A. Hyperbaric oxygen therapy in diabetic foot. J Postgrad Med 1992;38:112–4. [8] Baroni G, Porro T, Faglia E, Pizzi G, Mastropasqua A, Oriani G, et al. Hyperbaric oxygen in diabetic gangrene treatment. Diabetes care 1987;10:81–6. [9] Zgonis T, Garbalosa JC, Burns P, Vidt L, Lowery C. A retrospective study of patients with diabetes mellitus after partial foot amputation and hyperbaric oxygen treatment. J Foot Ankle Surg 2005;44:276–80. [10] Bakker DJ. Hyperbaric oxygen therapy and diabetic foot. Diabetes Metab Res Rev 2000;16(Suppl. 1):s55–8. [11] Brakora MJ, Sheffield PJ. Hyperbaric oxygen therapy for diabetic wounds. Clin Podiatr Med Surg 1995;12:105–17. [12] D’Angostino Dias M, Fontes B, Poggetti RS, Birolini D. Hyperbaric oxygen therapy: type of injury and number of sessions—a review of 1506 cases. Undersea Hyperb Med 2008;35:53–60. [13] Wagner Jr FW. The dysvascular foot: a system for diagnosis and treatment. Foot Ankle 1981;2:64–122.
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