Historically, hyperbaric oxygen therapy has been used for treatment of decompression sickness in deep-sea divers. Today, hyperbaric oxygen is commonly used for the treatment of wide variety of surgical and non-surgical conditions, and has persuasively proved its high clinical efficiency in many areas. Currently, established indications include different bacterial (mostly anaerobic) and fungal infections, arterial gas embolism, poorly healing diabetic wounds, osteomyelitis, radiation tissue injury, carbon monoxide poisoning, crush injuries, gangrene, brain abscesses, burns, skin grafts or skin flaps at risk of compromised tissue perfusion, severe anemia, and also conditions like long-standing neurologic deficit, cerebral palsy or autism, and many more. The existing trend of ever-expansion indications to previously untouched areas holds for decades.
The purpose of this review is to examine advantages and disadvantages of the hyperbaric oxygen therapy, and also to explore the underlying physiological mechanisms of the hyperbaric oxygen actions in the ischemic, necrotic and otherwise compromised tissues.
This review will mostly be focused on the discussion of clinical efficacy and practical approach to HBOT use in the treatment of different types of gangrene and necrotizing fasciitis. Role and place of hyperbaric oxygen therapy in the treatment of ischemic and diabetic chronic wounds and ulcers will also be explored.
With currently recommended clinically tested protocols and using contemporary equipment, administration of hyperbaric oxygen therapy is generally considered very safe. However, it is not absolutely innocuous, and certain contraindications, ranged from medical problems to physical abnormalities, while mostly relative, should be carefully considered in every case.
The only absolute contraindication for hyperbaric oxygen therapy is untreated tension pneumothorax. Other contraindications include:
Severe chronic obstructive pulmonary disease with carbon dioxide
retention, pulmonary blebs, and/or dyspnea with slight exertion; restrictive airway disease (possibility of air trapping with barotraumas ensued)
Acute viral infection
Uncontrolled, acute seizures disorders
Upper respiratory tract infection
Uncontrolled high fever
History of prior thoracic or ear surgery, which would make it impossible to equalize middle ear pressure or pulmonary pressure (Foster,1992)
Adverse effects of HBO treatment include reversible myopia (Leach et al, 1998), barotrauma of the ear, claustrophobia (only in small treatment chambers), seizures (1.3 per 10 000 patient treatments), and, very rare, pulmonary oxygen toxicity (Bakker, 1984).Vasoconstiction, that could be expected due to the increased oxygen levels, was not observed in ischaemic or hypoxic tissues (Sheffield, 1988). Worsening of diabetic retinopathy could theoretically occur during hyperbaric oxygen therapy, but up until now this complication has not been reported.
2. Hyperbaric oxygen: mechanisms of action
The principle effect of hyperbaric oxygen treatment is creating hyperoxia in blood and tissues. Hyperbaric oxygen therapy implies administration of 100% under pressure greater than atmospheric. By raising the ambient pressure of oxygen either in the chamber or by breathing 100% oxygen through tight fitting mask, it is possible to increase the inspired PO2 up to 3.0 bar. The most commonly used levels of inspired oxygen range from 2.4 to 2.8 bar. At these levels, amount of dissolved oxygen in plasma could potentially meet oxygen consumption requirements of the whole body. Hemoglobin remains saturated even in the venous capillary blood (Ramaswami &Lo, 2000). At 3 atmospheres of pressure, which is commonly used in the modern hyperbaric oxygen treatment, the alveolar oxygen pressure is about 2,180 mm Hg, the arterial oxygen tension is at least 1,800 mmHg, and tissue oxygen concentration is approximately 500 mmHg. High tissue oxygen concentration remains elevated for variable period of time (likely up to a few hours) after removal from hyperbaric chamber, which depends on tissue density and perfusion. (Sheridan & Shank,1999).
It has been demonstrated, that inhalation of O2 at pressures greater than 1 ATA will increase production of reactive oxygen species, which is fundamental for physiological mechanisms of numerous effects and also therapeutic mechanisms. (Thom,2009). Reactive oxygen species, as well as reactive nitrogen species, play important roles as signaling molecules in transduction cascades, or pathways for a variety of growth factors, cytokines, and hormonal substances.
3. Hyperbaric oxygen for chronic diabetic wound and ulcer healing
Diabetes mellitus is increasing in incidence and currently presents one of the major health problems worldwide. The total number of diabetic patients has been projected to increase from 171 million in 2000 to 366 million in 2030 (Wild et al, 2004), with concomitant rise of the major complications rate, among which chronic non-healing leg diabetic wounds, associated with vascular insufficiency due to accelerated atherosclerotic process, is within area of this review focus. With this trend, the requirements for efficient treatment are obviously expected to increase exponentially.
The most prevalent forms of chronic wounds in diabetic patients are leg and foot ulcerations.(Leung, 2007; Tam & Moschella,1991). Typical chronic, non-healing ischemic and diabetic wounds require prolonged time (more than 8 weeks) to heal, and sometimes do not heal or recur.
The pathophysiology of diabetic foot ulcer and its prolonged healing, however complex, has been extensively studied and is well described. Early development and accelerated progression of the lower extremity peripheral arterial atherosclerotic occlusive disease, with predilection to complete vascular blockade on the level distal to the knee, is a major causing factor. Other contributing factors include progressive development of sensory, vasomotor and autonomic neuropathy, alterations in autoregulation of dermal blood flow (Liu & Velazquez, 2008).It has been shown, that peripheral vascular disease (macroangiopathy), along with diabetic polyneuropathy, constitute the most important factors in the diabetic wound and ulcer development. About 20% of diabetic lower extremity ulcers have impaired arterial flow as primary ethiological factor, approximately 50 % associated with primary diabetic neuropathy, and up to 30% have both conditions (Reiber et al.,1999). Recently, microangiopathy has also been implicated in the pathogenesis of diabetic foot ulcers (La Fontaine et al.,2006; Ngo et al., 2005). Along with rapidly progressing atherosclerotic obstructive vascular disease, diabetic patients commonly exhibit an enhanced vascular responsiveness to vasoconstrictors, attenuated response to vasodilators and impaired regulation of blood flow in many different regions, from cerebral blood flow to local, dermal perfusion. Altered endothelial function of resistance vessels could contribute to altered regulation of regional blood flow and insufficient tissue perfusion in diabetes mellitus (Unfirer et al., 2008).
The fundamental role of oxygen in the physiology of wound healing is well documented (Brakora & Sheffield,1995; Hunt,1988). Measurement of the transcutaneous pressure of oxygen (TcpO2) has been shown to be a valuable tool in predicting healing or non-healing in diabetic foot ulcers (Mathieu et al.,1990). It has been demonstrated, that patients with TcpO2 values <20 mmHg, in comparison to patients with values >40 mmHg, have a 39-fold increase in failure of wound healing (Pecoraro, 1991, Bakker, 2000; Rollins et al., 2006). Hypoxia in the wound tissues promote the ulceration process, whereas a plentiful supply of oxygen is critically important for a variety of healing processes (Liu &Velazquez, 2008). Oxygen tension is positively correlated with key components of the healing process, such as angiogenesis (Knighton et al., 1983), collagen production (Hunt &Pai,1972; Jonsson et al., 1991; Gurdol et al.,2010), bacterial elimination (Knighton et al., 1984;Cimsit et al.,2009) and epithelization (Uhl et al., 1994). In well-oxygenated wounds, all these components are greatly enhanced.
Of all other available oxygen delivery methods, hyperbaric oxygen therapy appears to be the most efficient option (Liu & Velazquez, 2008). Hyperbaric oxygen therapy has proved its efficiency in healing acceleration of ischemic and refractory diabetic wounds (Zamboni et al.,1997;Abidia et al., 2003; Hopf et al., 2005).
Despite the well-known beneficial effects of hyperbaric oxygen therapy on healing process of chronic ischemic and diabetic wounds and ulcers, its mechanisms of action are not completely understood. Restoring an adequate blood flow to the site of chronic wound is an essential prerequisite of successful healing response, which include modifying the altered vascular responsiveness to vasoactive substances and new vessel growth stimulation. It has been suggested, that hyperbaric oxygen is capable of induction of complex changes in the conducted vasomotor responses, thus modifying vascular sensitivity and reactivity to vasoactive substances (Drenjancević-Perić et al.,2009).It has also been hypothesized, that hyperbaric oxygen exerts beneficial effects on vascular function by affecting production or vessel sensitivity to vasoconstrictor and vasodilator metabolites of arachidonic acid and nitric oxide in response to physiological stimuli, namely acetylcholine, hypoxia and flow-mediated dilation, thus effectively restoring vascular reactivity (Unfirer et al., 2008). Available data is quite scarce and almost exclusively experimental. To date, no published results of large-scale, controlled prospective studies could be found.
Angiogenesis, in form of neovascularisation, is one of the essential processes that occur in the course of chronic diabetic wound healing. In conditions of hyperoxia, created by applying the hyperbaric oxygen therapy either locally (isolated extremity treatment) or generally in hyperbaric chamber, neovascularisation in hypoxic tissues occurs by two processes. Regional angiogenic stimuli increase the efficiency of new blood vessel growth by proliferation of microvascular endothelial cells, and also the recruitment and differentiation of circulation stem/progenitor cells (SPCs) to form vessels de novo. In clinically relevant concentrations, hyperbaric oxygen has been shown to influence both these processes (Thom, 2009). It has been demonstrated, that hyperbaric oxygen induces a cytoprotective and angiogenic response in human microvascular endothelial cells by increasing expression of immediate early and cytoprotective genes, which corresponded with increase in cell proliferation and oxidative stress resistance (Godman et al.,2010a,2010b).
Hyperbaric oxygen reduces circulating levels of proinflammatory cytokines, and also increases synthesis of many growth factors. Oxidative stress at the sites of neovascularization stimulates growth factors synthesis by augmenting synthesis and stabilizing hypoxia-inducible factor (HIF)-1. (Hunt et al.,2004, 2007) Vascular endothelial growth factor (VEGF), angiopoetin and also stromal-derived factor-1 influence stromal cells differentiation to endothelial cells. VEGF, the most specific growth factor for neovascularization, has been shown to be increased by hyperbaric oxygen(Sheikh et all.,2000;Thom,2011).
Diabetic foot ulceration is a major predisposing factor for local infections, whereas various immunological disturbances and peripheral polyneuropathy play secondary roles. Diabetic foot ulcers are frequently polymicrobial with a high incidence of anaerobic organisms. Anaerobic infections are especially frequently seen in tissues with low oxygen tensions. Anaerobes are found in about 33% of cases of diabetic foot infections (Calhoun et al.,1992; Calhoun et al.,2002). Among the frequently isolated anaerobic organisms are species of
One of the suggested criteria for hyperbaric oxygen therapy use is transcutaneous oxygen measurement of less than 40 mm Hg at the tissues surrounding the wound, most precisely, at the wound edges. This baseline measurement should be followed by testing the patient’s tissue response to administration of 100% via tight face mask. The trascutaneous oxygen level should increase by at least 10 mm Hg to justify starting of hyperbaric oxygen therapy. After an hyperbaric oxygen trial, the transcutaneaous measurement should be greater than 200 mm Hg (Attinger, 2006; Hunter et al, 2010). It has been also demonstrated, that a transcutaneous oxygen tension (TcPO2) of 200 mmHg, measured in the peri-wound tissues while in-chamber, was the most effective determinant of success or failure of the therapy. It has been found, that TcPO2 in peri-wound tissues at sea level air of less than 15 mm Hg, together with a TcPO2 less than 400 mm Hg, measured in the same tissues in-chamber, proved to be most accurate predictor of hyperbaric oxygen therapy failure (reliability 75.8%, positive predictive value 73.3%)(Fife et all, 2002, 2007).
The commonly used protocols for hyperbaric oxygen therapy administration vary among institutions. No consensus has been reached so far in respect to single session and whole treatment duration. Most commonly, hyperbaric oxygen for diabetic wounds is administered at pressure range of 2 to 2.8 ATA, 5 days a week, with typical session duration of 45 to 90 minutes.(Wang, 2003). Other authors have been using daily treatments of 1.5 to 2 hours duration, for 20 to 40 days (Thom,2010).
The effectiveness of hyperbaric oxygen for diabetic and ischemic wounds treatment may be evaluated from prospective of two most important clinical outcomes: expediting the wound healing and reduction the amputation rate. Clinical efficacy of hyperbaric oxygen therapy in healing of chronic diabetic and ischemic wounds has been demonstrated by many researchers (Hinchliffe et al., 2008). Another group reported 90% healing in the intervention group
It has been well demonstrated, that use of hyperbaric oxygen therapy was associated with decrease in amputation rate in diabetic patients. A decrease by 30% of major amputations rate in Wagner grade 4 patients has been reported in large prospective study (Faglia et al., 1996). Another study demonstrated even more significant (almost in 71%, 2 amputations in the study group versus 7 in control, a total of 30 patients) decrease of amputation rate (Doctor et al., 1992).
4. Hyperbaric oxygen in the treatment of necrotizing fasciitis and Fournier’s gangrene
Necrotizing fasciitis has been defined as rapidly progressing life-threatening bacterial infection, that primarily involves skin and secondary subcutaneous tissues (Jallali et al., 2005). Incidence of necrotizing fasciitis has increased over two decades (1980-2000), yet the disease still remains quite rare. The possible explanation may include increased microbial virulence and resistance because of excessive use of powerful antibiotics, and also possibly disease reporting and statistical work improvement (Sarani et al., 2009).
There are three basic subtypes of necrotizing fasciitis described. Approximately 55 to 75 % of type I caused by combination of gram-positive cocci, gram-negative rods, and anaerobes; less commonly, by species of bacteroides or Clostridium (Childers et al.,2002; Wong et al., 2003;Anaya &Dellinger, 2007). This type of infection tend to occur in the trunk and perineal areas and include Fournier’s gangrene. Type II of necrotizing fasciitis mostly caused by monomicrobial flora, that include group A Streptococcus (S. pyogenes) alone or in association with Staphylococcus aureus. This type may be associated with toxic shock syndrome. During last 5 years, an increasing incidence of methicillin-resistant S. aureus (MRSA) is being reported, especially in IV drug users. Today, MRSA is cultured in approximately 40% of necrotic wounds (Miller et al., 2005; Maltezou & Giamarellou,2006;Thulin et al.,2006). Some sources classified necrotizing infection caused by Vibrio vulnificus as type III, although consensus regarding such classification remains yet to be reached. The biggest risk factors for this, the rarest, type of necrotizing fasciitis include exposure to warm sea water and also moderate to severe liver disease, particularly chronic hepatitis B (Howard et al., 1985).
Bacterial agents, that invade subcutaneous tissues through disrupted viscus of colorectal or urogenital area or perforated skin, rapidly spread over the adjacent tissues, producing endo-and exotoxins, that cause deep tissue ischemia and liquefactive necrosis that eventually lead to systemic disease (Salcido, 2007). Some of the exotoxins, namely M-1 and M-3 surface proteins, produced by S.aureus and Staphyloocci, increase microbial virulence by enhancing their ability to adhere to tissues and resistance to phagocytosis. Other exotoxins, namely A and B exert a variety of ill effects, that include endothelium damage, loss of microvascular integrity, increase of capillary permeability, causing plasma capillary leak, which results in tissue edema and impairment of capillary blood flow. These toxins, along with streptolysin O, stimulate CD4 cells and macrophages to produce large amounts of tumor necrosis factor-a,interleukin1 and 6 (Hackett & Stevens, 1992). Release of these cytokines into the circulation causes systemic inflammatory response and may lead to septic shock, multiorgan failure and eventual death. Superantigenes directly stimulate T-cells, causing activation of complement, bardykinin-kallikrein system and coagulation cascade, with small vessel thrombosis and tissue ischemia ensued (Salcido,2007 ).
Early radical surgical debridement along with aggressive, wide-spectrum antibiotic therapy remains a mainstay of the necrotizing fasciitis treatment. Despite the certain progress, achieved in this field, unfavorable outcome remains quite common.
High mortality rate of 20 to 40% (McHenry et al.,1995) have prompted a search for effective ancillary methods of treatment to improve patients outcome. Hyperbaric oxygen therapy has shown some promising results, which promoted its use as an adjuvant therapeutic modality in this category of patients. Although variety of protocols have been employed, the most common method includes administration of oxygen at 2 to 3 ATA with average duration of 60 to 120 minutes. However, no consensus has been reached so far regarding either duration, timing or number of sessions, and established protocols for HBO therapy in necrotizing fasciitis or Fournier’s gangrene are absent.
Most of clinical evidences, supporting the use of hyperbaric oxygen therapy, are of only anecdotal value at best. Most authors have chosen a decrease of the overall mortality rate as an universal index of HBO therapy efficacy, reporting improved patients survival rates in majority of studies. The reported mortality rates varied significantly, from 0 to 33% (Jallali et al., 2005).
The lowest mortality rate ever reported, essentially zero deaths after combined early surgical debridement and HBO therapy in small group of only 9 patients with Fournier’s gangrene, was shown in the early clinical study of (Eltorai et al.,1986). In this study, however, no data was provided either in respect to details of the treatment protocol details (duration of the study, number of sessions, time intervals between hyperbaric oxygen therapy sessions and surgical debridments). Another study included two series of 32 patients with clostridial gas gangrene and 11 patients wit perineal necrotizing fasciitis, who underwent hyperbaric oxygen therapy at 2.5 ATA for 120 minutes of session duration, and 3 first treatments were administered during first 24 hours after admission, and then repeated twice daily. The overall mortality rate was reported as 28% in gas gangrene group. In the group of patients treated with hyperbaric oxygen, 94% of the survivors healed completely and were able to walk normally (Him, 1993).
In yet another study, 33 patients were treated for perineal necrotizing fasciitis. Their management included wide early surgical debridment and drainage, massive antibiotic therapy and hyperbaric oxygen therapy at 2.5 ATA, 2 to12 times. The reported mortality rate was quite low (9.1%, 3 patients died out of 33) (Korhonen, 2000). Same group of researchers had also managed a group of 53 patients with Clostridial gas gangrene, and protocol here was pretty much identical to that used in patients with Fournier’s gangrene. The reported mortality rate was 22.6%. In this study, substantially higher levels of subcutaneous PO2 at the same O2 pressures of 2.5 ATA during hyperbaric oxygen therapy were found in the vicinity of infected areas than in healthy tissues. Authors concluded, that hyperbaric oxygen therapy appears to be life-, limb, and tissue saving, and that the hyperoxygenation of tissue zone surrounding the infected area may be of significance in preventing the expansion of microorganisms. (Korhonen at al., 1999, 2000). Authors of another study administered hyperbaric oxygen shortly (about 7 hours) after surgical debridement, which resulted in achievement of only 12.5% mortality rate. However, no control group was mentioned in this study, which makes it difficult to draw a definite conclusion regarding the net effect of the hyperbaric oxygen therapy (Gozal et al., 1986) In the controlled study, included group of 17 patients that received hyperbaric oxygen along with surgical debridement and antibiotics versus that of 12 patients, whose treatment did not include hyperbaric oxygen therapy, use of this modality has allowed to decrease overall mortality from 66% to 23%. This result has been achieved despite the fact, that patients received hyperbaric oxygen, were more seriously ill (some of them were in septic shock), which makes the beneficial effect of the therapy in this study particularly noteworthy (Riseman et al., 1990). In larger, albeit without control group study, efficacy of including HBOT in the treatment protocol in 42 consecutive patients has been proved by decreasing of overall mortality from 34%(national reported rate) to 11.9%, with 0% amputations (vs.50% of national average) in hyperbaric oxygen-treated patients (Escobar et all, 2005)
A growing number of studies, in contrast with those reported positive results of hyperbaric oxygen therapy, have demonstrated lack of any advantages of the hyperbaric oxygen therapy. In the large controlled multicenter study, (Brown et al.,1994), hyperbaric oxygen therapy was not associated with statistically significant decrease in mortality (30% in HBO group vs. 42% in control), number of debridements (2.4 in hyperbaric oxygen group vs 1.3 in control) was actually higher, and length of hospital stay was not different between groups(31.6 days in hyperbaric oxygen vs. 31.3 days in control). In this study, however, majority of the patients (66%) received less than 4 sessions, which potentially makes the impact of hyperbaric oxygen therapy substantially weaker. Also, patients who were selected for hyperbaric oxygen therapy, had more advanced stages of sepsis, which potentially may have introduce a bias factor in the results interpretation. Authors of another study found no differences in length of hospital stay, complications rate and mortality between groups of patients with necrotizing fasciitis, where one was treated with hyperbaric oxygen therapy, and another wasn’t; however, 25% of non- hyperbaric oxygen therapy group required amputations, whereas patients from hyperbaric oxygen therapy group needed no such intervention (Hassan et al.,2010 ). Authors of the retrospective study, reviewing 10-year - long experience of using HBOT as an adjuvant treatment for necrotizing fasciitis, found no improvements from hyperbaric oxygen use, but rather worsening of results in respect to mortality rate (36% in hyperbaric oxygen therapy group vs. 25% in control), number of debridements (2.5 with hyperbaric oxygen therapy vs 1.5 in controls). Difference in length of hospital stay, which was, however, shorter in hyperbaric oxygen therapy group (15.9 vs 20 days in controls), was not statistically significant.
Another retrospective study revealed considerably higher mortality among the patients with Fournier’s gangrene, treated with hyperbaric oxygen therapy, in comparison with those received no such treatment (26.9 vs 12.5%). The potential reason for this finding, again, may be attributed to the selection of the much sicker patients for hyperbaric oxygen therapy (Mindrup et al., 2005).
Absolute majority, if not all, of studies investigating the effects of hyperbaric oxygen therapy, are retrospective ones. Even the largest series include several dozen patients at best, with most common sample size around 20 patients, either in study or control groups. Such small numbers of subjects preclude the use of vigorous statistical methods in comparison studies, investigating mortality and morbidity rates, tissue- and limb- salvage efficacy of the hyperbaric oxygen therapy. These limitations substantially diminish the predictive value of quite scarce published studies.
To date, even after thorough literature research, we could not find any prospective, randomized comparison study investigating different effects of hyperbaric oxygen therapy. Regretfully, it appears that truly robust proof of either positive or negative effect of hyperbaric oxygen therapy, at least as an adjuvant therapy for necrotizing fasciitis and gangrene, is currently absent.
There are numerous reasons to this situation. Scarcity of the resources (many hospitals do not possess the hyperbaric oxygenation chambers), lack of established guidelines, differences on clinical protocols (outlining timing, number of sessions, time correlation with debridements, and more), clinicians’ opinions and experience, and also tendency to reserve the hyperbaric oxygen therapy, a quite expensive method, for the sickest, critically ill, oftentimes frankly moribund patients, are among the important limiting factors, making it truly difficult to elucidate the genuine impact of hyperbaric oxygen therapy in practically every area of its use (Jallali et al., 2005). In its current status, based on existent level of pro—and contra- evidences, HBOT efficacy remains controversial at best, and may not be unanimously recommended as therapeutic modality in every case of necrotizing fasciitis or gangrene.
Diabetic foot chronic wounds and ulcerations adjuvant treatment with hyperbaric oxygen appears to be efficient with respect to promoted healing and also in decrease of major amputations rate.
Hyperbaric oxygen therapy may not replace the combination of early aggressive debridements and wide-spectrum antibiotic therapy, but rather remains an adjuvant, however sometimes efficient, method in the management of necrotizing fasciitis and gangrene.
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