Hyperbaric Oxygen In Diabetic Limb Salvage-Part I: Mechanisms of Action
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This is Doctor Robert Warriner and this is the first of a two part presentation on the role and value of hyperbaric oxygen treatment in diabetic and ischemic wound healing in limb salvage.
Production of this present lecture was made possible by a generous grant from Sechrist, leading the way in hyperbaric medicine.
I am the chief medical officer of Diversified Clinical Services of Jacksonville, Florida and the founding Ameridus Medical Director of the Southeast Texas Center for wound care and hyperbaric medicine located in Conrow Regional Medical Center in suburban north Houston. I have no disclosures that affect the objectivity of this program.
During this presentation, we will understand how oxygen is transported under normobaric and hyperbaric conditions. We will know the definition of hyperbaric oxygen treatment and understand the physiologic and pharmacologic benefits of hyperbaric oxygenation of tissues.
The mechanism by which oxygen is delivered determines its physiologic and potential pharmacological effects. Oxygen can be applied topically, over the skin or over an open wound. Oxygen can be breathed at sea level and oxygen can be breathed in hyperbaric chambers. The effects of oxygen are dramatically different based upon the mode of oxygen delivery, which ultimately determines the maximum achievable pO2 of oxygen in the desired target tissue.
Some oxygen delivery to deeper tissues via the skin can occur; although, in humans severely limited. Newts and salamanders who lack lungs for gas transport absorb all of their oxygen cutaneously.
The concept that some oxygen might be absorbed through the skin led to the development of devices for the topical administration of oxygen to wounds in the early 1980s. To date there is little evidence that suggests a clinical value of these devices in accelerating or supporting ischemic wound healing.
Therefore, while some animals can sort of oxygen cutaneously there is almost no clinical effective cutaneous absorption of oxygen at normal atmospheric pressure across human skin or cross the surface of human wounds.
The second mechanism of oxygen delivery is by breathing an increased fractional inspired oxygen concentration at sea level.
Breathing in an increased concentration of oxygen takes advantage of two transport mechanisms. The first and primary mechanism for oxygen transport to tissues is chemical binding of oxygen to hemoglobin.
Each hemoglobin molecule is capable of binding four molecules of oxygen for each gram of hemoglobin, 1.36 mL of oxygen can be carried affected only by the inspired oxygen concentration, which would determine the degree of saturation of each hemoglobin molecule with available oxygen. This is the primary mechanism of oxygen transport to tissues under normal physiologic conditions.
This is a representation of the oxygen hemoglobin disassociation or association curve. Notice that one hemoglobin is fully saturated, which typically it occurs at an arterial pO2 of around 100 mm of mercury. No further oxygen binding to hemoglobin is possible. In fact, as arterial pO2 increases to significant degrees the amount of oxygen transported back to hemoglobin remains constant.
If we take time to do the math, this is an average representation of oxygen transport by hemoglobin. Assume a hemoglobin concentration of 15g/dL of blood with a maximum carrying capacity of 1.36 mL of oxygen per gram of hemoglobin. If hemoglobin is saturated, that leads us to a maximum oxygen carrying capacity bound to hemoglobin of 20.4 mL of oxygen per deciliter of blood. Breathing air at sea level assuming a slightly lower degree of hemoglobin saturation, say 97% for instance that would leave us with 19.8 mL of oxygen per deciliter of blood oxygen carried down to hemoglobin. Supplemental oxygen breathing cannot increase oxygen carried by hemoglobin above what can be done at 100% saturation.
The second mechanism of oxygen transport to tissues is that physically dissolved and plasma and it is this mechanism of oxygen transport that comes into play during adjunctive hyperbaric oxygen treatment.
As the arterial pO2 increases the amount of oxygen physically dissolved and plasma increases in a linear fashion while oxygen bound to hemoglobin remains constant.
For each millimeter of mercury partial pressure of oxygen 0.0031mL/dL of plasma of dissolved oxygen is carried.
Returning to the view of oxygen hemoglobin association or disassociation curve we can see that even breathing 100% oxygen at sea level or one atmosphere of pressure contributes relatively little oxygen to the overall volume of oxygen transported.
Now, let's turn our attention to hyperbaric oxygen treatment and look at the potential of hyperbaric oxygen treatment to significantly increase oxygen transported dissolved and plasma. Hyperbaric oxygen treatment is the use of 100% oxygen breathed at an increased atmospheric pressure. It requires that the patient being closed in a pressure vessel, that the patient be subjected to an atmospheric pressure of at least 1.5 times sealable or ambient pressure, and that the patient be breathing 100% oxygen.
Now when we look at the oxygen hemoglobin association or disassociation curve, we see a very different relationship with respect to the amount of oxygen dissolved in plasma. For each atmospheric pressure increase while breathing 100% oxygen, approximately 2 volumes percent oxygen is transported dissolved in plasma. In pressure in excess of 2 atmospheres absolute or twice the level pressure clinically significant amounts of oxygen can now be carried to tissues.
If we do the math in a manner similar to our calculations for oxygen transport bound to hemoglobin assuming 0.0031 mL of oxygen per deciliter of blood per millimeter of mercury of arterial pO2 and assuming that 2.2 mL of oxygen per deciliter of blood is carried for each atmosphere of 100% oxygen breathing. At two atmospheres absolute, which is a typical treatment pressure provided in Mono place hyperbaric chamber, 4.4 mL of oxygen per deciliter of blood can be carried at 2.4 ATA; 5.28 mL of oxygen per deciliter of blood or plasma at 3 ATA; 6.6 mL of oxygen per deciliter of blood. We can see then that hyperbaric oxygen treatment can significantly increase the amount of oxygen transported dissolved in plasma in direct relation to the increase in arterial pO2. Remember from basic physiology that normal arterial venous oxygen content difference or normal oxygen in extraction is around five volumes percent at rest enabling us to meet the body's basal metabolic requirements for oxygen under hyperbaric conditions even in the absence of any hemoglobin for oxygen transport.
While the first effective hyperbaric oxygen treatment is to increase the arterial pO2 above normal physiologic range and thereby increase the amount of oxygen transported dissolved in plasma, a second important mechanism involves increasing oxygen diffusion distance from available capillaries. This classic figure represents on the left and arterial venous capillary end in a patient breathing air at one atmosphere and on the right a venous and arterial capillary end in a patient breathing 100% oxygen at 3 atmospheres absolute. What can be seen is that even at the venous end a significant increase and araveos of diffusion has occurred under hyperbaric conditions. This enables improved oxygen delivery in states of decreased vascular density, particularly at the capillary level.
This becomes the primary mechanism for hyperbaric oxygen treatments application and the salvage of ischemic flaps and in limb or tissue reimplementation. The figure on the left is an ischemic flap model in pigs; the design of the flat is such that one would expect complete flap failure as seen in the pig at the bottom of the photograph. Those pigs exposed to hyperbaric oxygen treatment immediately after reattachment of the flap show 75% overall flap salvage based upon taking advantage of the increased diffusion distance for oxygen by the mechanism just described and on the right to reattachment of an ear supported by adjunctive hyperbaric oxygen treatment producing significant tissue preservation until such time is second angiogeneous can occur.
Now, let's turn our attention to a cartoon model for a wound. Note that this wound has a hypoxic center. It is surrounded by a zone of tissue injury and is the case of wounds typically treated with hyperbaric oxygen treatment will be surrounded by a zone of malprofusion. I'll develop this model a little more fully in part two. But for now, this illustration represents what happens during hyperbaric oxygen. Both the zone of malprofusion and the zone of tissue injury are not only restored to normal oxygen delivery but in fact, the come hyper oxygenated. This hyper oxygenation produces a number of unique effects, which will be the focus of the remaining discussion.
Hyperbaric oxygen treatment has been demonstrated in both laboratory and various animal models in tissue culture models and in the clinical setting to induce a number of unique effects. These effects are frequently referred to as the pharmacologic effects of oxygen, rather than simply the expected physiologic effects of transiently reversing local tissue hypoxia. The cellular and energy metabolism affects of hyperbaric oxygen treatment include not only improved local tissue oxygenation including increased diffusion distance for oxygen and increased oxygen availability, but also improved cellular energy metabolism; both of which support salvage of ischemic hypoxic tissue. Decreased local tissue edema also occurs as a result of local regulation of blood flow and vessel diameter on the basis of correction of local tissue hypoxia. An increase in Nitric oxide production through an increase or induction of nitric oxide synthetase is an important mechanism action of hyperbaric oxygen treatment, which is one of the major drivers for the regenerating wound tissue effects, which are listed in the lower right hand corner of this slide. Those regenerating wound tissue effects include enhanced production of growth factors and growth receptors most specifically they include: platelet derived growth factor, transforming growth factor Beta and vascular endofiela growth factor, promotion of collagen deposition, promotion of other deposition extracellular matrix proteins and components, and the direct promotion of angiogenesis.
This slide demonstrates the findings of an animal model study looking at the induction and increase in nitric oxide in mouse bone marrow. The figure on the left shows the response of nitric oxide production increase during 100% oxygen breathing at 2.8 atmospheres absolute with samples taken from the distal femur marrow space of anesthetized mice, on the right shows a similar experiment this time with a nitric oxide synthetase inhibitor being applied showing a prevention of the induction of the nitric oxide.
The Nomo et al in 1998, published an elegance study identify the role of hyperbaric oxygenation of tissue serving as a single transducer leading to the up regulation of platelet derived growth factor beta receptors. The objective of this study was to look at the role of hyperbaric oxygen treatment on growth factor signal transduction pathway and receptors. Animals were exposed to platelet derived factor and to saline in an ear wound model and then exposed to three different breathing gas configurations; ambient air, hyperbaric oxygen at 1.0 atmosphere, and hyperbaric oxygen at 2.0 atmospheres.
A variety of parameters were measured and the particularly interesting finding of this study was that hyperbaric oxygen and not hyperbaric air induced the appearance of PDGF beta beta receptors on wound cell surfaces. This up regulation of the receptor mRNA for PDGF beta receptor has potential significant clinical implications in explaining one of the mechanisms of oxygen of hyperbaric oxygen treatment in stimulating tissue growth. Remember also, that PDGF is an important cofactor in angiogenesis.
A similar finding has been demonstrated in patients with diabetic foot ulcers by aminofluorescent techniques. This is the work of John and Wendy Buras, which represents two diabetic foot ulcer biopsies in the same patient. On the left is the biopsy taken prior to hyperbaric oxygen treatment with aminofluorescent staining for PDGF receptor. On the right is the second biopsy taken 24 hours after hyperbaric oxygen treatment showing a significant increase in the amount of PDGF receptor induced in this diabetic ulcer.
Sheikh and Hunt in 2000 have identified that hyperbaric oxygen treatment also directly stimulates the release of vascular endothelial growth factor by about five days after wounding and once daily hyperbaric oxygen treatment there is a 40% increase in endothelial growth factor present in treated wounds. This decreases to control levels so within about 72 hours after hyperbaric oxygen treatment is discontinued.
Hyperbaric oxygen treatment has specific effects on fibroblasts leading to collagen formation. While collagen mRNA is induced by hypoxia and lactate and increase in pO2 to levels greater than 40 mm of mercury increases collagen mRNA induction by sevenfold significantly greater than the degree of the mRNA induction produced by hypoxia an increase in local lactate levels. Fibroblasts secrete only hydroxylated collagen, which requires a number of cofactors including vitamins C, B6, and so on the critical substrate for a hydroxylated collagen is the presence of oxygen as available oxygen is increased with hyperbaric oxygen exposure; fibroblasts are able to secrete larger amounts of hydroxylated collagen all other factors being equal. Hyperbaric oxygen treatment also inverses the hypoxic induced impairment in fibroblast migration and also the hypoxic induced impairment in fibroblast replication leading to not only increase collagen density but increased fibroblast density in developing granulation tissue.
Recent work by Steve Thom has demonstrated a unique and previously unrecognized response to hyperbaric oxygen treatment, which may play a significant role in when healing. Hyperbaric oxygen treatment has been shown to mobilize stem or progenitor cells from bone marrow through a nitric oxide dependent mechanism. The population of stem or progenitor cells defined as CD34. Cells in the peripheral circulation doubles in response to a single hyperbaric oxygen treatment and over the course of 20 treatments the number of circulating CD34 cells increases eightfold, while total cell count remains unchanged.
This figure from Steve Thomâs work shows the steady and progressive increase in peripheral blood stem cells with successive hyperbaric oxygen treatments reaching a peak at about 20 treatments.
Not only were the number of stem cells increased but those stem cells were activated incapable of forming colonies. While although the activation affect appeared to be present only in samples that were plated immediately after hyperbaric oxygen treatment.
A second observation and Dr. Thomâs work is that the stem cells mobilized by hyperbaric oxygen treatment are capable of forming colonies of new cell growth and this is true at each point in the collection and measurement of peripheral blood stem cells derived from bone marrow in this study.
Hyperbaric oxygen treatment has also been shown to minimize the white blood cell activation response seen in ischemia reperfusion injury while a full discussion of this concept is beyond the scope of this presentation. When reflow is established following periods of significant ischemia receptors on leukocytes are activated causing adherence to the vascular endothelian leading to a local inflammatory response neutrophil plugging vasoconstruction and a subsequent recurrence of a no reflow phenomenon. A single hyperbaric oxygen exposure either prior to the initial ischemic event or immediately following the correction of ischemia appears to significantly blunt this white blood cell mediated ischemia reperfusion injury response.
Finally, hyperbaric oxygen treatment has a number of beneficial effects with respect to host response to local infection. Specifically, hyperbaric oxygen treatment improves leukocyte bacterial killing as well as improved mobility and also increases the effectiveness of certain antibiotics.
The local effectiveness of those antibiotics, which require oxygen for active transport across bacterial sub membranes including the aminoglycosides, clindamycin, penicillins, sulfonamindes, and rifampicin can significantly improve the local effectiveness of these antibiotics in the setting of tissue ischemia and significant local tissue edema.
Hyperbaric oxygen treatment has a number of other antimicrobial effects; specifically, hyperbaric oxygen treatment in bacterialacidal for anaerobic organisms. This is on the basis of a significant increase in superoxide radical production in the setting in which anaerobic organisms, which lacks antioxidant enzymes now are subject to the bactericidal effects of the superoxide radicals. Perhaps, clinically more relevant is the ability of hyperbaric oxygen treatment when tissue pO2âs can exceed approximately 400 mm of mercury to block the production of exotoxins. The most important of these being the Clostridium perfringents alpha toxin but other exotoxin production is blocked as well. In addition, there is an increase in the rate of duration of secreted exotoxins.
On the basis of the mechanisms for the effectiveness of hyperbaric oxygen treatment, which we have just reviewed on the wound side hyperbaric oxygen treatment has demonstrated effectiveness in decreasing tissue injury and the setting of acute thermal burns improving both limb salvage and in increasing morbidity and mortality clostridial myonecrosis and other necrotizing soft tissue infections and support for and in preservation of compromised skin grafts and flaps. In reducing secondary ischemic tissue loss and setting of crush injury compartment syndrome and other acute traumatic ischemiaâs in the reversal of the hypovascularity induced with therapeutic radiation exposure; therefore, in support for the resolution of osteoradionecrosis and soft tissue radionecrosis; particularly involving chest wall and other soft tissue, the bladder and rectum refractory, osteomyelitis, and other wounds with demonstrated persistent periwound hypoxia; particularly diabetic ulcers and some ischemic arterial insufficiency ulcers as well.
Production of this present lecture was made possible by a generous grant from Sechrist, leading the way in hyperbaric medicine.
Thank you for your attention to part one on the role and value of hyperbaric oxygen treatment in diabetic and ischemic wound healing in limb salvage
|Goals and Objectives|
After participating in this activity, the viewer should be better able to:
1. Understand how oxygen is transported under normobaric and hyperbaric conditions.
2. Know the definition of hyperbaric oxygen treatment.
3. Know the physiologic and pharmacologic benefits of hyperbaric oxygenation.
4. Know the rationale for the use of HBO in hypoxic wounds.
Estimated time to complete this activity is 36 minutes.
Physicians, diabetes educators, and other health care professionals who treat patients with diabetes.
Complete the 4 steps to earn CE/CME credit:
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