hyperbaric oxygen therapy as treatment of diabetic 1

Hyperbaric oxygen therapy as treatment of diabeticfoot ulcers

Magnus Löndahl1,2*

1Department of Clinical Sciences inLund, Lund University, Lund, Sweden2Department of Endocrinology, SkåneUniversity Hospital, Lund, Sweden

*Correspondence to: MagnusLöndahl, Department ofEndocrinology, Skåne UniversityHospital, SE-221 85 Lund, Sweden.E-mail: [email protected]

Summary

Hyperbaric oxygen therapy (HBO) could be described as a short-term, high-dose oxygen inhalation and diffusion therapy, delivered systemically throughairways and blood, achieved by having the patient breathing concentratedoxygen at a pressure higher than 1 absolute atmosphere. In clinical practice,monoplace or multiplace hyperbaric chambers are used to achieve this. Treat-ment is usually given as daily 90- to 120-min-long HBO sessions at pressuresbetween 2.0 and 2.5 absolute atmosphere, aiming for 30–40 treatmentsessions.The use of HBO as treatment of diabetic foot ulcers has been founded on weakscientific ground, although the outcomes from previous studies are in concertwith the conclusions from preclinical studies and supports the theoreticalframework of HBO reversing hypoxia-induced pathology. Two well-designedrandomized double-blind trials have put HBO on firmer ground and may jus-tify adjunctive HBO treatment to a selected group of patients with nonhealingdiabetic foot ulcers.Some health economic studies suggest potential cost effectiveness, but thesestudies are limited by deficient primary clinical data and should be interpretedwith caution.Several issues remain to be addressed, such as developing robust criteria toimprove treatment protocols, determining which patients are likely to bene-fit, and when to start and stop treatment. Copyright © 2012 John Wiley &Sons, Ltd.

Keywords diabetes; foot ulcer; hyperbaric oxygen; hyperbaric oxygen therapy;healing; review

Introduction

Although hyperbaric oxygen therapy (HBO) has been in the armamentarium ofdiabetic foot management for almost 50 years [1], the acceptance of HBOamong clinicians treating patients with diabetic foot ulcers has been poor.Inevitably, HBO has been used by charlatans unscrupulously promoting cureof almost any disease, and evidence supporting the usefulness of HBO in dia-betic foot ulcer healing has been limited, although not inferior to many othermore commonly used treatment modalities in the field of the diabetic foot[2,3]. In recent years, two double-blind randomized controlled trials (RCTs)have shown beneficial effect of HBO in terms of ulcer healing and healthre-lated quality of life [4–6].

In this review, the rational and clinical setting of HBO and the present clin-ical evidence for the use of HBO in the armamentarium of the diabetic footare discussed.

Received: 19 July 2011Revised: 6 October 2011Accepted: 7 October 2011

REVIEW ARTICLE

Copyright © 2012 John Wiley & Sons, Ltd.

DIABETES/METABOLISM RESEARCH AND REVIEWSDiabetes Metab Res Rev 2012; 28(Suppl 1): 78–84.Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2256

Definition

From a pharmacological point of view, HBO could bedescribed as a short-term, high-dose oxygen inhalationand diffusion therapy, delivered systemically through air-ways and blood, achieved by having the patient breathingconcentrated oxygen at a pressure higher than 1 absoluteatmosphere (ATA) [7]. In clinical practice, hyperbaricchambers are used to achieve this. Breathing high-doseconcentrations of oxygen at surface levels and topicalexposure of limbs to high-dose concentrations of oxygenare not included in the definition of HBO.

Mechanisms of action

Hyperbaric oxygen therapy exerts its therapeutic effect byfour mechanisms: mechanical effects, bacteriostatic effects,hyperoxygenation for treatment of monoxide and cyanidepoisoning, and finally, treatment aiming for restorationfrom hypoxia [8].

The principles for the use of HBO are based on applica-tion of the basic physical laws in effort to correct abnormaltissue oxygen tension. Boyle’s law states that at constanttemperature, the volume of a gas is inversely proportionalto its pressure; Dalton’s law states that the total pressureexerted by a gaseous mixture equalizes the sum of the par-tial pressures of each individual gas in the mixture; andfinally, Henry’s law states that the concentration of gas ina solution is determined by its partial pressure and by itssolubility coefficient.

Under normal perfusion conditions, resting tissues ex-tract about 50 mL of oxygen per litre of blood, most ofwhich is delivered by haemoglobin. During air breathingat normobaric pressure, haemoglobin is saturated to about97% when leaving the pulmonary circulation, and only asmall fraction of oxygen is dissolved in the blood, about3 mL of oxygen per litre of blood. If 100% oxygen is admin-istrated, the volume of dissolved oxygen increases to 15 mLper litre of blood, and duringHBO at 2.5 ATA, almost 60mLof oxygen is dissolved in each litre of blood [9].

After transportation to the capillary bed, oxygen isdependent on diffusion to reach cells and intracellularspaces. The rate of oxygen delivery is inversely propor-tional to the square distance and directly proportional topO2 at the initial point at the capillary [10].

The intercapillary distances vary between different tis-sues. A major denominator of capillary density is meta-bolic rate; that is, distances between capillaries are shortin muscle and other highly oxygen-consuming tissues butconsiderably longer in slow-healing tissues with lowermetabolic rates, such as tendon, fascia, and subcutis. In di-abetic microvascular disease, capillary function is declinedand distances between capillaries are increased. To avoidhypoxia in the presence of microvascular disease, oxygenneeds to diffuse longer distances, thus requiring higherpO2 levels at the edge of the capillaries. The increment inpO2 at therapeutic hyperbaric conditions creates a poten-tial threefold augmentation in diffusion distance [11].

Rational of HBO in ulcer healing

Hyperbaric oxygen therapy has been shown to improveleukocyte function, stimulate vascularization, and en-hance formation of granulation tissue [12–14].

In wounds, the single most bactericidal mechanism isoxidant production, and pO2 is one of the most importantfactors for bactericidal production in human leucocytes[15]. HBO facilitates the oxygen-dependent peroxidasesystem in leucocytes, increases generation of oxygen freeradicals and thereby enhances oxidation of proteins andmembrane lipids, and inhibits bacterial metabolic func-tion [16,17]. In ischemic tissue, restoration of tissue pO2

re-establishes the phagocytic function of macrophages[18–20]. HBO improves oxygen-dependent transport ofcertain antibiotics across bacterial cell walls [21,22]. Also,environment becomes less suitable for anaerobic bacteriaas pO2 increases in the tissue.

Neovascularization occurs through two mechanisms,angiogenesis and vasculogenesis. The former is stimu-lated by regional factors and the latter by recruitmentand differentiation of circulating stem/progenitor cells(SPCs) [23,24]. HBO enhances these processes, that is,by increasing production of growth factors such as vascu-lar endothelial growth factor, which is the most specificgrowth factor for neovascularization [25,26]. Oxidativestress at sites of neovascularization stimulates growth fac-tor synthesis by augmenting synthesis and stabilization ofhypoxia-inducible factor 1, a process further enhanced byHBO [27–30]. HBO also enhances extracellular matrixformation, an O2-dependent process closely linked to neo-vascularization [31,32].

Nitric oxide synthase 3 activity is required for SPC mobili-zation from the bone marrow. SPC mobilization is impairedin patients with diabetes, probably because of reduced nitricoxide synthase activity caused by hyperglycaemia andinsulin resistance [33,34]. HBO mobilizes SPC in peoplewith and without diabetes by stimulating NO synthesisin bone marrow [28,35]. HBO reduces tissue oedemaby mechanisms of vasoconstriction in nonischemictissue [36].

High lactate concentrations in wounds stimulate pro-collagen synthesis [13]. The enzymatic steps in whichprocollagen is converted to collagen and cross-linked tocollagen matrix are oxygen dependent [37]. In animalexperiments, collagen deposition in hyperoxic environ-ment has been shown to be three times that in a hypoxicenvironment. Correction of both vasoconstriction andhypoxemia might increase collagen deposition tenfold[38]. Furthermore, fibroblast replication is most optimalat tissue pO2 levels of 40–60 mmHg [10].

Clinical setting of HBO

There are two different kinds of hyperbaric chambers,monoplace and multiplace chambers. A monoplace hyper-baric chamber is generally made of acrylic material topermit direct patient observation. The cylinder is usually

HBO as Treatment of Diabetic Foot Ulcers 79

Copyright © 2012 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2012; 28(Suppl 1): 78–84.DOI: 10.1002/dmrr

pressurized entirely with oxygen. Multiplace chambersare typically steel constructions in which two or morepatients are pressurized. For safety reasons (fire hazards),the ambient gas is pressurized with air and patientsbreathe oxygen via hoods or masks.

Robust evidence is lacking for selection of treatmentregimen leading to optimal therapeutic benefit (i.e. hyper-baric pressure level, duration of treatment sessions, num-ber of HBO sessions, and not least timing of HBO). Patientswith diabetic foot ulcers are usually treated once daily atpressures of 2.0–2.5 ATA [39]. During a treatment ses-sion, patients usually breathe oxygen for 80–90 min.Another 5 to 10 min per session is generally requiredfor compression and decompression. To minimize therisk of oxygen toxicity – a rare but severe complicationof HBO – we may separate periods of breathing 100%oxygen by one or two 5-min-long intervals of air breath-ing. A typical treatment protocol consists of 30–40 treat-ment sessions [39].

Contraindications

The only absolute contraindications for HBO are un-treated pneumothorax, ongoing treatment with somechemotherapeutic agents, and any history of treatmentwith bleomycin. Relative contraindications are sinusitis,severe chronic obstructive pulmonary disease, historyof pneumothorax or thoracic surgery, uncontrolled highfever, claustrophobia, upper respiratory infection, andinability to equalize pressure in the middle ear. Many ofthese contraindications are related to known complica-tions of HBO, such as barotrauma, which can be exacer-bated by emphysema or inability to equalize middle earpressure, and seizures for which an uncontrolled fevercan be a predisposing factor.

Evidence of clinical usefulness

The first study presenting data on diabetic foot ulcer out-come after HBO was published in 1979 by Hart et al., thefirst controlled study in 1987 by Baroni et al., and the firstRCT 5 years later by Doctor et al. [48–50]. Another fiveRCTs evaluating the effect of HBO in patients withdiabetic foot ulcers have been published as well as severalcase series and nonrandomized controlled studies(Table 1).

Although case series and nonrandomized studies con-stitute a limited source of evidence, the consistency inoutcome between these studies is notable, although publi-cation or patient selection bias or other confounding fac-tors could be involved.

Previous reviews of RCTs evaluating the effect of HBOhave identified several limitations in study design andmethodology, including lack of blinding, limited informa-tion on randomization, study procedures, wound classifi-cation, and specified use of sham therapy [3,51–55]. Onlytwo studies score all 5 points on the Jaded scale (Table 2).

Altogether, in published controlled trials with follow-uptimes between 3 months and 3 years, ulcer healing hasbeen evaluated in 108 patients in double-blind RCTs andin 208 patients in nonrandomized controlled studies.Healing rates are significantly higher in patients treatedwith adjunctive HBO as compared with placebo or multi-disciplinary wound care alone in RCTs (54% versus 24%)as wells as in nonrandomized controlled studies (77%versus 25%) [4,5,49,59–61]. Major amputation rates arereported in four of these RCTs and three of these con-trolled but nonrandomized trials [4,5,49,50,56,61]. Majoramputations has been performed in 5% (n=61) of HBO-treated patients and 24% (n=57) of non-HBO-treatedpatients in the non-RCTs compared with 8% (n=107)and 19% (n=104) in the RCTs [4,5,49,50,56,61]. How-ever, amputation rates in the control groups of these stud-ies were considerably higher in the earlier nonblindedRCTs (36% versus 4%) [4,5,50,56]. This might mirror achange in indications for major amputation, because non-healing of a chronic ulcer could be an indication of majoramputation in the setting of the earlier but not in the laterstudies. The study by Duzgun et al. [58] is not included inthis analysis because major and minor amputations weredifferently defined.

Several studies, including the two double-blind RCTs,show improved health-related quality of life in patients re-ceiving HBO [4,5,62].

Complications

Although HBO has several potential side effects, com-pared with many other medical therapies, it may be con-sidered as a rather safe treatment modality. Among themost commonly reported complications are barotraumas.Barotrauma may occur at any tissue and gas interfacewithin the body. In clinical practice, middle ear barotrau-mas dominate, but the most important organ that may beaffected is the lung. In a case series of 11 376 treatmentsessions, 17% of all patients reported ear pain or discom-fort during compression [40]. However, persistent injuriesvisible in ear microscopy are less common, with reportedincidences between 0.5% and 3.8% [5,40,41]. However,because barotrauma might lead to persistent hear loss orvertigo, tympanostomy with tube placement ought to beconsidered when patients have problems to equalizepressures.

During decompression, the intrapulmonary gas volumeincreases, and if this additional gas volume cannot bebreathed out, lungs may tear from an overpressure, caus-ing pneumothorax, emphysema, or in worst-case sce-nario, an air embolus. Pulmonary barotraumas arerare, with an incidence of 1 in 50 000 to 60 000 treat-ments [42,43].

Reversible myopia, due to oxygen toxicity of the lens,is a common side effect affecting up to every fifth pa-tient [44]. Cataract is not a clinical problem duringnormal treatment series but seems to be persistentand highly frequent after prolonged treatment series

80 M. Löndahl


(>150 treatment sessions) [45]. Such exposures aretherefore no longer recommended.

Patients with diabetes mellitus, especially those on in-sulin therapy, are at increased risk of hypoglycaemia, usu-ally occurring within 2 to 6 h of the HBO session [5,46].

Oxygen seizure is a rare and self-limiting complicationwithout any long-term implications [40].

Prolonged exposures for oxygen may cause pneumoni-tis and alveolitis, but these consequences of pulmonaryoxygen toxicity are not a problem in clinical use of HBO.

Table 1. Description of wound characteristics, study design, and outcome of studies evaluating the effect of hyperbaric oxygen

Reference and year Wound description No. of patients Outcome and comments

Hart and Strauss, 1979 [48] Chronic nonhealing diabeticfoot ulcers

11 Healing rate, 10/11 (91%)

Matos, 1983 [66] Nonhealing diabetic foot ulcers 70 Healing or significant improvementwas seen in 60% of all patientsIschemia, infection, or neuropathy present

Baroni et al., 1986 [49] Wagner grade 3 and 4 I: 18 Healing: I: 16/18; C: 1/16Matched control group C: 16 Amputation: I: 2/18; C: 4/16Surgeons blinded Amputation rates at the centre, 40%

Perrins and Barr, 1986 [67] Unknown 26 Healing rate, 67%Amputation was avoided in 18%

Davies, 1987 [68] Wagner grade 3 and 4 168 Healing rate, 70%Daily HBO for 30–60 days

Wattel et al., 1990 [69] Ulcers, 11 diabetic and 9 arteriosclerotic 20 Healing was seen in 15 patientsTcPO2 was a predictive factorfor ulcer healing

HBO, 2.5 ATATwo sessions of 90 min per dayMedian, 46 (15–108) sessions

Oriani et al., 1990 [59] Controls were selected for,but refused, HBO

I: 62 Healing: I: 66%; C: 33%

Group extension of Baroni’s study? C: 18Cianci et al., 1991[70] Wagner grade 4 41 Limbs were salvaged in 78%

Limb-threatening infection in 97%Revascularization in 55%

Doctor et al., 1992 [50] Chronic ulcers RCT Amputation: I: 2/15; C: 7/15, p<0.05Randomization after necessary debridementand 3 days of antibiotic treatment in hospital.

I: 15C: 15

Four HBO sessions, 45 min, 3.0 ATAWeisz et al., 1993 [71] Ulcer duration >3 months 14 Healing was seen in 11 patients

All palpable foot pulsesHBO, 2.5 ATAMedian, 56�10 sessions

Ciaravino et al., 1996 [72] Nonhealing wounds 54 Some improvement, 11%Diabetes, 17/54 patients No improvement, 80%Mean, 30 HBO sessions Inconclusive, 9%

Complications in 63% (barotraumas, 43%)Faglia et al., 1996 [56] Wagner grade 2–4 RCT Amputation: I: 8.6%; C: 33.3%, p<0.02

Duration >3 months I: 36HBO, 90 min, 2.2–2.5 ATA C: 34

Lee et al., 1997 [73] Infected foot ulcers 31 Major amputation, 6HBO, 35�22 sessions Healing, 25

Zambroni et al., 1997 [74] HBO, 2.0 ATA, 30 sessions I: 5 Healing at 4–6 months of follow-up:C: 5 I: 80%; C: 20%

Kalani et al., 2002 [61] Basal TcPO2 <40 mmHgand >100 mmHg breathing O2

I: 17 Three-year follow-up:C: 21 Healing: I: 76%; C: 48%

Amputation: I: 12%; C: 33%HBO, 2.5 ATA, 40–60 sessionsKessler et al., 2003 [57] Wagner grade 1–3 RCT Ulcer area reduction:

Duration >3 months I: 14 Week 2: I: 42%; C: 22%, p<0.04Neuropathy present C: 13 Week 4: I: 48%; C: 42%, NS2 sessions/day, 10 days90 min, 2.5 ATA

Abidia et al., 2003 [4] Ulcer duration ≥6 weeks RCT One-year follow-up:Diameter, 1–10 cm2. I: 9 Ulcer healing: I: 63%; C: 0/8, p<0.03ABI <0.8 or TBI <0.7 C: 9 Amputation: I: 13%; C: 13%HbA1c <8.5% Drop out: I: 1; C:1HBO, 30 sessions, 90 min, 2.4 ATA

Duzgun et al., 2008 [58] Ulcer duration ≥4 weeks RCT Ulcer healing without debridementin the operating room: I: 33; C: 0HBO, 30–45 sessions, 90 min, 2.5 ATA I: 50

C: 50Löndahl et al., 2010 [5] Ulcer duration >3 months RCT One-year follow-up

No need for or possibility ofvascular surgery

I: 49 ITT analysis

HBO, 40 sessions, 90 min, 2.5 ATA C: 45Ulcer healing: I: 52%; C: 29%, p=0.03Amputation: I: 7%; C: 3%Per protocol analysisUlcer healing: I: 61%; C: 27%, p<0.01Amputation: I: 3%; C: 3%

HBO, hyperbaric oxygen therapy; ATA, absolute atmosphere; RCT, randomized controlled trial. I, Intervention; C, Control; ABI, anklebrachial index; TBP, toe blood pressure; ITT, intention to treat;



The most common fatal complication is associated withfire in the chamber. At least 88 human fatalities in 36 sep-arate hyperbaric chamber fires have been reported [47].Increased fire risk applies especially to chambers pressur-ized with oxygen.

Health economics

Cost-effectiveness is important in treatment selection.Only a few health economic analyses evaluating thecost-effectiveness of HBO in diabetic foot ulcer treatmenthave been published, and they are limited by deficient pri-mary clinical data [4,63–65]. Still, these studies suggest apotential cost-effectiveness of HBO, for example, a crudeanalysis of the double-blind RCT by Abidia et al. [4] – onlytaking HBO and dressing costs into account – suggestsa saving of £2960 per patient during the first year offollow-up.

The cost of a full-course HBO treatment for diabeticfoot ulcer varies from one place to another, and severalfactors including set-up costs, ongoing costs, reimburse-ment systems, and numbers of patients treated per centrehave impact on the cost. Charges between $200 and$1250 per treatment session have been reported from re-imbursed health-care units [4,63,65].

Conclusion

The use of HBO as treatment of diabetic foot ulcers hasbeen founded on frail evidence, although consistency inprevious study outcome supports the theoretical frame-work of HBO reversing hypoxia-induced pathology. In re-cent years, two well-designed, randomized, double-blind,placebo-controlled studies have put HBO on firmerground as treatment of diabetic patients with chronic footulcers [4,5,63]. However, the inclusion criteria in thesestudies must be recognized (i.e., only patients without aneed for or a possibility of vascular surgical interventionwere included in one of these), and the positive outcomeneeds to be confirmed in at least another large double-blind RCT.

In conclusion, HBO is only indicated as an adjunctivetherapy in a selected group of patients with chronic dia-betic foot ulcers not responding to optimal treatmentwithin a multidisciplinary approach. Several issues re-main to be addressed, such as cost effectiveness, develop-ing robust criteria to improve treatment protocols,determining which patients are likely to benefit, andwhen to start and stop treatment.

Conflict of interest

None declared.Table

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