Presence of a wound (an injury where skin or another external surface is torn, pierced, cut, or otherwise broken) initiates the wound healing process that progresses through specific phases. In external (skin) wounds, the goal is to restore continuity of the skin surface. Wound healing phases that have been described are: hemostasis, inflammation, proliferation and remodeling. Various factors can affect the normal healing process and these can be local (edema, ischemia, necrosis, hypoxia, infection etc) or systematic (decreased blood flow, diabetes mellitus, inflammatory disease, connective tissue disorders, smoking, drugs etc)
Impairment of wound healing at any stage or significant delay of the process, leads to chronic wound – ulcer. This is more frequent in lower extremities wounds, for various reasons. Chronic wound exposes the patient to complications (infection, gangrene, amputation) and has substantial economic burden. Moreover, healing impairment of the chronic ulcer has social and psychological impact bearing multiplying effect to quality of life of patients and families.
Common denominator of chronic trauma – ulcer is hypoxia, regardless its etiology. Chronic trauma is most often hypoxic (Oxygen tension < 20 mmHg). Background pathology is responsible for that, eg vascular disease (peripheral arterial disease, collagen disease [scleroderma etc]), microvascular disease (diabetes) or chronic ischemia. Repeated injury (such as that occurring in diabetes neuropathy) leads to increased cellular activity and white blood cell infiltration, which decreases further oxygen availability. Low oxygen levels lead to deficient host immunity and impaired wound healing mechanisms, influencing phagocyttosis and bacteria-killing, as well as collagen deposition. The resulting bacterial colonization predisposes to infections, compromises wound healing and may lead to major complications.
Research has shown that main factors leading to chronic wound – ulcer are ischemia/hypoxia, reperfusion injury and bacterial colonization. Hypoxia stimulates angiogenesis, but adequate oxygen is necessary in the proliferation phase for extra-cellular matrix formation that supports the newly form blood vessels. Collagen synthesis and fibroblast proliferation need tissue Oxygen tension > 30-40 mmHg, which is not achieved at the hypoxic chronic wound environment!! Furthermore, maturation of collagen requires oxygen, as polymerization and cross-linking of collagen involves proline hydroxylation that is oxygen-dependant. Also important, oxygen tension > 40 mmHg is required for effective phagocyttosis and bacteria-killing by neutrophils.
During Hyperbaric Oxygen Therapy (HBOT), oxygen carrying capacity of the blood raises > 10fold, compared to breathing air at sea level. In that setting, oxygen is available to previously hypoxic tissues, where circulation is compromised.
Oxygen increase causes vasoconstriction that leads to blood redistribution – increased perfusion to the hypoxic tissues. Hyperbaric Oxygen stimulates angiogenesis (neovascularization) and promotes collagen formation and fibroblast proliferation. It also enhances host immunity against bacteria, reduces edema and breaks the vicious circle of ischemia/hypoxia – inflammation – edema. Moreover, HBO inhibits white blood cells adhesion to the vascular walls and so, attenuates ischemia/reperfusion injury!
As a summary, HBOT: repairs wound healing capacity in chronic hypoxic wounds. Same mechanisms apply for HBOT healing capacity to post-radiation injured tissues where additively, HBOT increases viability of flaps when placed at irradiated tissues.
In addition to some other, more complicated, gene-based mechanisms that explain the beneficial effects of HBOT (eg apoptosis, HIF-1α), studies have shown that HBOT increases the number and differentiation of circulating stem cells – stem cells play key role to the definite cover of the wounded area by newly formed skin.
Relevant to wound healing in chronic wounds, HBOT is approved by UHMS (Undersea & Hyperbaric Medical Society) (hyperlink to UHMS indications) for use in cases of: Selected Problem Wounds (Enhancement of Healing), Delayed Radiation Injury (Soft Tissue and Bony Necrosis), Skin Grafts & Flaps (Compromised) and Osteomyelitis (Refractory)
Conclusively, Hyperbaric Oxygen Therapy is strongly recommended in cases of:
- Diabetic Foot Ulcer, especially when such a chronic ulcer is complicated by an infection
- Radiation Injury leading to chronic ulcers – especially when underlying soft tissues and bones are involved. In case of surgery, even a minor one, involving the irradiated tissues, HBOT is recommended previously and post surgical intervention.
- Selected Problem Wounds. When Peripheral Arterial Disease coexists leading to ischemic trauma, HBOT is used in order to secure wound healing. Rheumatic disease – disease of the connective tissue can also lead to chronic trauma. Venous insufficiency ulcers when becoming chronic benefit from HBOT – the same with chronic trauma following surgical interventions. Coexistence of the above conditions (Diabetes, Venous Insufficiency, Arterial Disease, Rheumatic Disease, Thrombangiitis Obliterans [Buerger’s disease] etc) should lead to early initiation of HBOT, to prevent major complications.
- When chronic trauma is probably or definitely involving an underlying bone, HBOT is strongly recommended to manage the infection (normal bone has Oxygen tension of 40 mmHg, while in the osteomyelitis bone Oxygen tension drops to approximately 23 mmHg).
- Marx R. Radiation injury to tissue. In Kindwall EP, Whelan HT, editors. Hyperbaric Medicine Practice. 2nd ed revised. Flagstaff: Best Publishing Company;2004. p.665-723
- Zamboni WA, Roth AC, Russell RC, Graham B, Suchy H, Kucan JO. Morphologic analysis of the microcirculation during reperfusion of ischemic skeletal muscle and the effect of hyperbaric oxygen. Plast Reconstr Surg. 1993 May;91(6):1110-23.
- Thom SR. Functional inhibition of leukocyte B2 integrins by hyperbaric oxygen in carbon monoxide-mediated brain injury in rats. Toxicol Appl Pharmacol. 1993 Dec;123(2):248-56.
- Buras JA, Stahl GL, Svoboda KK, Reenstra WR. Hyperbaric oxygen downregulates ICAM-1 expression induced by hypoxia and hypoglycemia: the role of NOS. Am J Physiol Cell Physiol. 2000 Feb;278(2):C292-302.
- Yogaratnam JZ, Laden G, Guvendik L, Cowen M, Cale A, Griffin S. Hyperbaric oxygen preconditioning improves myocardial function, reduces length of intensive care stay, and limits complications post coronary artery bypass graft surgery. Cardiovasc Revasc Med. 2010 Jan-Mar;11(1):8-19.