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Doi:10.1053/j.jfas.2008.08.002Effect of Hyperbaric Oxygen Therapy on
Healing of Diabetic Foot Ulcers
Arife Polat Duzgun, MD,1 Hakan Ziya Satır, MD,2 Omer Ozozan, MD,1 Barıs Saylam, MD,1
Bahadır Kulah, MD, MS, FACS,3 and Faruk Coskun, MD4
Hyperbaric oxygen therapy can be used as an adjunct to standard wound care in the treatment ofdiabetic patients with foot ulcers. We undertook a prospective, randomized investigation of the use ofhyperbaric oxygen therapy versus standard therapy for the treatment of foot ulcers in diabetic patients.
A number of demographic variables were analyzed in regard to wound healing. We noted that foot ulcersin patients in the hyperbaric oxygen therapy group were more likely to heal, and were more likely toundergo amputation distal to the metatarsophalangeal joint compared with those patients receivingstandard therapy without hyperbaric oxygen. We feel that hyperbaric oxygen therapy should beconsidered a useful adjunct in the management of foot ulcers in diabetic patients. Level of ClinicalEvidence: 2 ( The Journal of Foot & Ankle Surgery 47(6):515–519, 2008) Key Words: amputation, diabetic foot ulcer, hyperbaric oxygen therapy, wound healing major amputation in diabetic patients with foot ulceration urrently, standard therapy (ST) for lower extremity In a review of 6 studies, HBOT was observed wounds in diabetic patients entails wound debridement, to decrease the risk of major lower extremity amputations in off-loading, systemic antibiotic therapy, and supportive 118 patients In yet another investigation, involving 55 medical therapy in an effort to heal wounds within a rea- patients with diabetic foot ulcers that extended deep to the sonable period of time, generally considered to be up to 4 to deep fascia, it was noted that the use of HBOT decreased the 5 months. Another current option for the treatment of dia- betic patients with lower extremity ulceration is hyperbaric HBOT has been shown to promote healing in diabetic oxygen therapy (HBOT). HBOT is a systemic treatment wounds by means of its anti-edema, antibacterial, and neo- option, wherein the patient breathes 100% oxygen for a vascularization effects Because of its apparently specified period of time in a pressurized chamber. In the beneficial effect on wound healing, there is a trend toward 1970s, the clinical use of HBOT in patients with diabetic resorting to the use of HBOT in cases of problematic foot wounds was initiated by the positive treatment results wounds such as diabetic foot ulcers, particularly when reported in a number of case reports and series there is a concern for neovascularization The Faglia et al prospectively reported on 70 diabetic pa- primary aim of this prospective randomized controlled tients who received HBOT, and observed a decreased rate of trial was to evaluate the effects of HBOT on diabetic foot major amputations (transtibial or more proximal) in com- ulcers, and to compare this form of therapy to standard parison with standard therapy. Similarly, several other stud- ies also demonstrated that HBOT decreased the risk of Patients and Methods
Address correspondence to: Faruk Coskun, MD, Sehit Adem Yavuz Sokak No: 7/11, 06100-Kizilay, Ankara, Turkey. E-mail: After receiving approval from the Ethical Committee of Ankara Numune Teaching and Research Hospital, Turkey, General Surgeon, Ankara Numune Teaching and Research Hospital, Department of 3rd Surgery, Ankara, Turkey.
consecutive patients who were admitted to the Emergency 2General Surgeon, Ankara Numune Teaching and Research Hospital, Surgical Department between January 2002 and December 2003 for the treatment of infected diabetic foot ulceration Associate Professor of Surgery, Ankara Numune Teaching and Re- search Hospital, Department of 3rd Surgery, Ankara, Turkey.
were evaluated for potential inclusion in the investigation.
4Associate Professor of Surgery, Director of 3rd Surgery Department, In addition to receiving standard medical assessment, each Ankara Numune Teaching and Research Hospital, Department of 3rd patient was evaluated to determine whether HBOT was Financial Disclosure: None reported.
contraindicated Diabetic patients were con- Conflict of Interest: None reported.
sidered eligible if they were at least 18 years of age, and if Copyright 2008 by the American College of Foot and Ankle Surgeons they had a foot wound that had been present for at least 4 1067-2516/08/4706-0005$34.00/0doi:10.1053/j.jfas.2008.08.002 weeks despite appropriate local and systemic wound care.
VOLUME 47, NUMBER 6, NOVEMBER/DECEMBER 2008 Contraindications to hyperbaric oxygen therapy*
A number of independent variables were measured and recorded, including age, gender, duration of diabetes, hy- pertension, lipid-lipoprotein levels (triglyceride, choles- Obstructive pulmonary diseaseHistory of otic surgery terol, high-density lipoprotein, low-density lipoprotein, and very low density lipoprotein), obesity, smoking habits, and Febrile state (since fever decreases seizure threshold) glycosylated hemoglobin (HbA1c). Patients with a body mass index (BMI) of 30 or greater were defined as obese.
Smokers were defined as either current (active smokers or Current corticosteroid, amphetamine, catecholamine, or thyroid those who had quit within 2 months of presentation), ornonsmokers. High lipid-lipoprotein levels were defined as follows: triglyceride 180 mg/dL or higher, cholesterol 200mg/dl or higher, and low-density lipoprotein 160 mg/dL or The Wagner* classification of diabetic foot
higher. Outcome variables were defined as total closure ulceration
of the wound without the need for surgical intervention in the operating room (complete cure with bedside debride-ment); graft or flap closure required; amputation distal to the metatarsophalangeal joints (MTPJ) (distal am- Superficial ulcer with subcutaneous involvement Deep ulcer with tendon or joint involvement putation) required to achieve closure; amputation prox- imal to the metatarsophalangeal joints (proximal amputa- Wet or dry gangrene (forefoot), without cellulitis tion) required to achieve closure; no change (defined as no sign of healing during the course of treatment); and operative surgical debridement (in the operating room) ofthe wound was all that was required to achieve closure.
The foot wounds were categorized according to a modifi- Statistical analyses were performed using a personal cation of the Wagner classification and the computer running SPSS 11.0 (SPSS, Inc. Chicago, IL) for diagnosis of osteomyelitis was made based on bone biopsy Windows 98 (Microsoft, Inc., Redmond, WA). Two-tailed at the time of surgical intervention. Moreover, photographic unpaired Student t tests were used to analyze continuous images were obtained before and after the therapy. All of numeric data, including age, duration of diabetes, and the patients were further evaluated in an effort to determine HbA1c measurements, whereas the Mann Whitney U (Wil- whether or not they would be suitable candidates to undergo coxon rank sum) test was used to analyze categorical data, HBOT. After confirming eligibility, the patients were ran- including gender, hypertension, obesity, lipid-lipoprotein domly assigned to the standard treatment group or the levels, smoking status, insulin dependence, and ulcer grade.
standard therapy plus HBOT group, using a random number Statistical significance was defined at the 5% (P Յ .05) table and allocating patients to the treatment groups accord- ing to a predetermined sequence wherein consecutivelyenrolled patients corresponding to an even random numberreceived ST, and those corresponding to an odd random number received ST ϩ HBOT. We continued this processuntil we had 50 participants in each treatment group.
A total of 100 patients were determined to be eligible for ST entailed daily wound care, including dressing changes participation in the investigation and, in accordance with the and local debridement at bedside or in the operating room, random allocation protocol, 50 of these were allocated ST as well as amputation when indicated. Infection controls and the other 50 to ST combined with HBOT. The overall were carried out by clinical follow-up, and by performing mean duration of follow-up was 92 Ϯ 12 weeks. The culture-antibiograms of surgically obtained specimens to baseline characteristics of the treatment groups are de- determine appropriate antibiotic therapy. In the HBOT picted in In the ST group there were 50 patients, group, standard therapy was supplemented by hyperbaric and the female-to-male ratio was 23:27, their mean age was oxygen treatments administered at a maximum working 63.00 Ϯ 9.15 years, and their mean duration of diabetes was pressure of 20 atmospheres absolute (ATA), using a 15.88 Ϯ 5.56 years. In the HBOT group, there were 50 unichamber pressure room (Patterson Companies, Inc., St.
patients, and the female-to-male ratio was 13:37, their mean Paul, MN) employing a volume of 10 m3 at 2 to 3 ATA for age was 58.1 Ϯ 11.03 years, and their mean duration of 90 minutes. Treatment was administered as 2 sessions per diabetes was 16.90 Ϯ 6.24 years. There were no statistically day, followed by 1 session on the following day, alternating significant differences between the groups in regard to age, throughout the course of therapy, which typically extended duration of diabetes, the type and treatment of their diabe- tes, hypertension, lipid-lipoprotein levels, and ulcer grade.
Baseline characteristics of the cohort by treatment
HBOT displayed this outcome over the course of the ob- groups (N ؍ 100)*
servation period. Although all of these findings were statis-tically significant when nonparametric null hypothesis tests were calculated, the association with the risk factor vari-ables changed considerably (Ͼ10%) when univariate and multiple variable logistic regression equations were com- puted for ulcer grade and HBOT, indicating confounding between these variables (results not shown).
It is generally understood that tissue hypoxia can be a significant factor in the etiology of nonhealing foot ulcers in diabetic patients. Through its correction of peripheral isch- emia, HBOT may be useful in promoting healing when promotes healing in a variety of ways. First, the oxygen gradient that is produced by HBOT promotes the formationof new vessels required for wound healing, and increases Abbreviations: ST, standard therapy; HBOT, hyperbaric oxygen
fibroblast proliferation and collagen production therapy.
*Results presented as either mean Ϯ SD for continuous numeric In addition, HBOT has bactericidal and bacteriostatic ef- data, or count and percent for categorical data.
fects on both aerobic and anaerobic bacteria through the †Probability of the null hypothesis calculated using 2-tailed, un- action of the super oxide enzyme, which acts more rapidly paired Student t test for continuous numeric data and the Mann at high oxygen tensions (Ն30 to 40 mm Hg) HBOT Whitney U (Wilcoxon rank sum) test for categorical data.
has also been shown to have synergistic effects with ami- ‡Current smokers ϭ active smokers or those who had quit within 2months of presentation.
noglycosides, trimethoprim, nitrofurantoin, and sulfisox- §High lipid-lipoprotein levels ϭ triglyceride Ն 180 mg/dL, choles- azole Furthermore, hyperoxic vasoconstriction that terol Ն 200 mg/dL, and low-density lipoprotein Ն 160 mg/dL.
takes place during HBOT reduces capillary pressure and increases vascular permeability. The resulting decrease intranscapillary fluid transfer increases extravascular fluid re- Statistically significant differences were identified between sorption, which reduces lower extremity edema the proportion of males, obese patients, and smokers, all of In animal studies, Niinikoski has demonstrated that which were more prevalent in the HBOT group wound healing was an oxygen dependent process by mea- When we compared the result of ST to ST ϩ HBOT, a suring transcutaneous oxygen pressure TcP0 (13, 14). By number of statistically significant findings were made employing the same technique, Sheffield demonstrated Specifically, there were zero (0%) patients in the ST that chronic tissue hypoxia could be corrected by HBOT.
group who healed without surgery performed in the oper- Guidelines based on transcutaneous oximetry and ulcer ating room, versus 33 (66%) of the patients in the group grade classification can be used to aid the clinician in receiving HBOT healed without going to the operating determining which patients are suitable candidates for room. To achieve wound coverage and healing, 50 (100%) of those in the ST group required either operative debride- clinicians used transcutaneous oximetry only for follow-up, ment in the operating room, an amputation, or the use of a after initially basing their decision on wound grade and flap or skin graft; whereas 8 (16%) of those in the group other factors. The Wagner classification is commonly receiving HBOT required these forms of surgical manage- used to grade severity of diabetic foot ulcers, although the ment. In regard to distal (distal to the MTPJ level) versus system can be criticized for lacking sensitivity and speci- proximal (proximal to the MTPJ level) amputation, 24 ficity, and for not taking into consideration differences (48%) of those in the ST group underwent distal amputation between neuropathic and vasculopathic diabetic foot ulcers.
whereas 17 (34%) of them required proximal amputation. In Wyss et al have demonstrated that wound healing can the group receiving HBOT, 4 (8%) underwent distal ampu- be hindered in conditions involving decreasing transcutane- tation, and zero (0%) required proximal amputation. In ous oxygen levels. Despite efforts to provide guidelines regard to observing no change in wound healing, zero (0%) regarding the use of HBOT, many clinicians still rely on patients in the ST group and 9 (18%) in the group receiving clinical acumen rather than transcutaneous oxygen measure- VOLUME 47, NUMBER 6, NOVEMBER/DECEMBER 2008 Outcomes by intervention and ulcer grade (N ؍ 100)*
Abbreviations: ST, standard therapy; HBOT, hyperbaric oxygen therapy.
*Results presented as count and percentage.
†Outcomes: Healed ϭ complete closure without debridement in the operating room, Graft or flap ϭ graft or flap closure required, Distal
amputation ϭ amputation distal to metatarsophalangeal joints, Proximal amputation ϭ amputation proximal to the metatarsophalangeal
joints, Debridement ϭ standard therapy wound debridement, Debridement ϭ operative surgical debridement (in the operating room) of the
wound was all that was required to achieve closure, No change ϭ failure to heal during the course of treatment.
‡Probability of the null hypothesis calculated using the Mann Whitney U (Wilcoxon rank sum) test.
§No matching, n ϭ 0, in this subcategory.
ments to determine when a patient could benefit from the the amputations were localized proximal to the MTPJs.
Moreover, HBOT appears to reduce the need for costly and In our study, ulcers were categorized in accordance with technically more involved surgical interventions, such as Wagner’s classification. Importantly, and likely due to ran- skin flaps and grafts, as well as amputations and debride- domization, a statistically significant difference in the base- ments that require the operating room. We believe that line severity of the ulcers was not observed between the HBOT is a useful adjunct in the treatment of nonhealing treatment groups Interestingly, however, there diabetic foot ulcers, and that the cost of HBOT itself will be was a higher prevalence of males, obese patients, and smok- reduced as it becomes more widely available in the clinical ers in the HBOT group and, despite these traditionally setting, and as further knowledge of its other advantages, harmful risk factor variables (in regard to wound healing), such as limited side effects and relative safety, become more those in the HBOT group fared more favorably than did those in the ST group This supports the idea thatHBOT has a strong beneficial effect on wound healing indiabetic patients since, even in the presence of risk factors References
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High Efficiency Cloning of Drug Resistance Genes Via Safe Vector Host Systems High Efficiency Cloning of Drug Resistance Genes Via Safe Vector Host Shahrzad S. Connolly1,2 & Stephen N. Connolly2 1Department of Microbial Diseases, St John’s Institute of Dermatology, Guy’s, Kings College & St Thomas’s Hospitals, University of London, 2School of Science & Technology, Univ