Rescue for Blunt Trauma, Crush & Acute Traumatic Brain Injury

Oxygen delivered under pressure, Hyperbaric Oxygen Therapy (mHBOT) is one of the most powerful drugs known to man. Simultaneously, mHBOT delivers the substrate of life, oxygen, for which there is no substitute. mHBOT has profound beneficial effects on injury pathophysiologic processes that are common in military casualties. Moreover, it has been shown to positively impact traumatic brain injury, compartment syndrome, burns, hemorrhage, and reperfusion injury. These injuries and injury processes comprise the bulk of battlefield casualties. With timely intervention of mHBOT the morbidity and mortality of injured soldiers should substantially improve as they have in their civilian counterparts. Past foreign military experience strongly suggests this benefit in extremity wounds and it is our conviction that United States soldiers deserve nothing less. This is the goal of the Brain Injury Rescue & Rehabilitation Project (DoDBIRR). mHBOT has both acute and chronic drug effects. mHBOT exerts these effects by obeying the Universal Gas Laws, the most important of which is Henry’s Law (2). Henry’s Law states that the concentration of a gas in solution is proportional to the pressure of that gas interfacing with the solution. At the point of three atmospheres absolute of pure oxygen (3 ATA), just slightly more than the amount the U.S. Navy has used for 50 years in the treatment of divers with decompression sickness, we can dissolve enough oxygen in the plasma to render red blood cells useless. Under these conditions as blood passes through the tiniest blood vessels tissue cells will extract all of the dissolved oxygen in the blood without touching the oxygen bound to hemoblogin. This amount of dissolved oxygen alone can exceed the amount necessary for the tissue to sustain life. In other words, you don’t need red blood cells for life at 3 ATA of 100% oxygen. This ability to maintain life without blood has obvious potential to battlefield casualties awaiting transfusion. As a result of Henry’s Law mHBOT is able to exert a variety of drug effects on acute pathophysiologic processes. These have been well documented over the past 50 years and include reduction of hypoxia (lack of oxygen), inhibition of reperfusion injury (immune response to injury), reduction of edema (swelling), blunting of systemic inflammatory responses, and a multitude of others. In addition, repetitive mHBOT in wound models acts as a DNA stimulating drug to effect tissue growth. mHBOT has been shown to interact with the DNA of cells in damaged areas to begin the production of repair hormones, proteins, and cell surface receptors that are stimulated by the repair hormones. The resultant repair processes include replication of the cells responsible for tissue strength (fibroblasts), new blood vessel growth, bone healing and strengthening, and new skin growth. In the past 12 years scientific research has unequivocally shown that the only drug to completely or nearly completely reverse the reperfusion injury process is hyperbaric oxygen. This is a physiological reaction of the body to trauma is a major source of injury that battlefield casualties experience. In multiple experiments with different animal models, different organ systems, different types of blood flow reduction or absence (e.g., heart attack, stroke, cardiac arrest, 1. carbon monoxide, tourniqueting of an extremity, etc.) timely mHBOT within hours of reperfusion injury has been shown to completely or nearly completely reverse reperfusion injury. Simultaneously, due to mHBOT’s ability to dissolve large amounts of oxygen in the liquid portion of the blood, oxygen-enriched plasma is able to reach damaged areas of tissue not accessible by normal blood flow and restore oxidative function to these areas. The net result is a dramatic reduction in the secondary injury process, improved viability of tissue that would otherwise die, and salvage of the tissue and patient. In addition, twenty percent of the wounded in Iraqi experience traumatic brain injury (TBI) a diffuse cerebral insult characterized by primary mechanical disruption of tissue and secondary injury from ischemia, hypoxia, edema, vasospasm, neurochemicals, and reperfusion injury. A review of the medical literature shows that there is substantial data proving a beneficial effect of mHBOT on the secondary injury processes of acute TBI. mHBOT has been shown indirectly to improve ischemia and hypoxia in acute TBI by its effect on aerobic metabolism and EEG. The neurosurgeon authors of the Rockswold study conclude that \"mHBOT should be initiated as soon as possible after acute severe traumatic brain injury.\" mHBOT also has beneficial effects on vasospasm and cellular reperfusion injury. Multiple studies have shown that mHBOT reduces cerebral edema and decreases intracranial pressure (ICP). A summary of the mHBOT/cerebral edema studies in animals is that mHBOT has two different effects: one reducing brain edema (injured brain), and another producing brain edema (normal brain). This toxic effect on normal brain causes a breakdown in the protective vasoconstriction of arterioles, resulting in a rapid rise in brain blood flow and deterioration in EEG. Rockswold in 1992 reported the most exhaustive, rigorous, and important study to date in acute TBI in an attempt to refute or affirm all of the above animal and human data. Conducted from 1983 to 1989 the study enrolled 168 patients with GCS of 9 or less in a RPCT design and stratified the patients by age and GCS. Patients were treated at 1.5 ATA/60 every 8 hours for a maximum of two weeks immediately post TBI or until awake or deceased during these two weeks. The average patient entered treatment 26 hours post TBI and received 21 treatments. Overall mortality was significantly reduced 50% in the mHBOT group and as high as 56% and 60% in the elevated ICP and GCS 4-6 subgroups. This reduction in mortality has never been equaled by any therapy in the medical armamentarium except possibly the ambulance, or in the case of the military, the helicopter. Adding mHBOT to helicopter evacuation of casualties should further decrease morbidity and mortality of injured soldiers. This is the foundation of the DoD-BIRR Project. References: Harch, Paul, M.D., “FEB Scientific Background & Overview,” 2005 (81 scientific references) Harch, Paul, M.D., “Evidence for Use of Hyperbaric Oxygen Therapy for Acute Traumatic Brain Injury,” 2001 2. Department of Defense Brain Injury Rescue & Rehabilitation Project (DoD-BIRR) SCIENTIFIC BACKGROUND AND OVERVIEW The Use of Hyperbaric Medicine in Acute Trauma By Paul G. Harch, M.D. Clinical Assistant Professor and Director, Hyperbaric Medicine Fellowship, Louisiana State University School of Medicine New Orleans, Louisiana Hyperbaric oxygen therapy (mHBOT) is the use of greater than atmospheric pressure oxygen as a drug to treat basic disease processes and their diseases (1). In the simplest terms mHBOT is a pharmaceutical or prescription medication similar to the thousands of medications routinely prescribed by physicians everyday throughout the world. The key differences with mHBOT, however, are that it is a drug that treats basic disease processes that are common to every disease, that it acts as a repair drug in these processes, and that it replaces an essential element of life for which there is no substitute, oxygen. This effectiveness in treating basic common disease processes explains the ability of mHBOT to act in a generic beneficial fashion to a multitude of diseases, including and especially traumatic injuries to all areas of the body. mHBOT has both acute and chronic drug effects. mHBOT exerts these effects by obeying the Universal Gas Laws, the most important of which is Henry’s Law (2). Henry’s Law states that the concentration of a gas in solution is proportional to the pressure of that gas interfacing with the solution. For example, the amount of oxygen dissolved in a glass of water is directly proportional to the amount of oxygen in the air. Similarly, the amount of oxygen dissolved in our blood is directly proportional to the amount of oxygen we are breathing. According to Henry’s Law, there is a very small amount of oxygen dissolved in the liquid portion of the blood when breathing air (21% oxygen) at sealevel. The remainder and majority of oxygen is bound to hemoglobin in the red blood cells giving a 98% saturation of hemoglobin. As we increase the amount of oxygen in inspired air by applying a nasal cannula or facemask of pure oxygen the final 2% of hemoglobin is quickly bound by oxygen. All of the remaining available oxygen interfaces with and is dissolved in the liquid portion of the blood. Once we reach 15 liters/minute of supplemental oxygen by a tight fitting aviator’s mask or non-rebreather mask we have reached the maximum amount of oxygen that can be dissolved in blood by natural means. However, this is not the absolute limit. By placing a patient in an enclosed chamber, increasing the pressure above ambient pressure, and giving the patient pure oxygen we can cause an increase in dissolved oxygen in blood in direct proportion to the pressure increase. At the point of three atmospheres absolute of pure oxygen (3 ATA), just slightly more than the amount the U.S. Navy has used for 50 years in the treatment of divers with decompression sickness, we can dissolve enough oxygen in the plasma to render red blood cells useless. Under these conditions as blood passes through the tiniest blood vessels tissue cells will extract all of the dissolved oxygen in the blood without touching the oxygen bound to hemoblogin. This amount of dissolved oxygen alone can exceed the amount necessary for the tissue to sustain life. In other words, you don’t need red blood cells for life at 3 ATA of 100% oxygen. This physical phenomenon was proven in a famous experiment in 1960 and published in the first edition of the Journal of Cardiovascular Surgery by Dr. Boerema of the Netherlands (3). Dr. Boerema DOD-BIRR mHBOT Acute Trauma PG Harch 2004 anesthetized pigs, removed nearly all of their blood, and replaced it with salt water while he compressed them to 3 ATA. At 3 ATA in a hyperbaric chamber pigs with essentially no blood were completely alive and well. Dr. Boerema then removed the saline, replaced the blood, and brought the pigs to surface where they remained alive and well. This phenomenon has been proven effective in other experiments and is the basis for clinical use in extreme blood loss anemia (4). The best examples are Jehovah’s Witness patients who have lost massive amounts of blood and because of religious proscription are unable to receive blood transfusions. These patients are kept alive over weeks with repetitive mHBOT until their blood system is able to naturally produce enough blood to sustain life. This ability to maintain life without blood has obvious potential to battlefield casualties awaiting transfusion. As a result of Henry’s Law mHBOT is able to exert a variety of drug effects on acute pathophysiologic processes. These have been well documented over the past 50 years and include reduction of hypoxia (5, 6), inhibition of reperfusion injury (7), reduction of edema (8), blunting of systemic inflammatory responses (9), and a multitude of others (10). In addition, repetitive mHBOT in wound models acts as a DNA stimulating drug to effect tissue growth (11, 12). mHBOT has been shown to interact with the DNA of cells in damaged areas to begin the production of repair hormones, proteins, and cell surface receptors that are stimulated by the repair hormones (13, 14). The resultant repair processes include replication of the cells responsible for tissue strength (fibroblasts) (15), new blood vessel growth (16, 17), bone healing and strengthening (18), and new skin growth (19). To best understand the effectiveness and potential of mHBOT one must understand basic disease processes, commonly referred to as pathophysiologic processes. Every insult or injury to living organisms, particularly human beings, is distinct and different, and can be characterized by the type of force, energy, or peculiar nature of that insult. For example, a blast force is different from a blunt force, an electrical injury, a toxic injury, a biological injury, infectious injury, thermal injury, nuclear injury, gunshot wound, stab wound, burn, or even a surgical wound. Regardless of the exact nature and idiosyncratic character of the injury, however, every acute injury has a common secondary injury called the inflammatory process (20). This secondary injury in fact causes more damage than the primary injury. Moreover, it is a universal process common to every human being regardless of race, color, creed, size, gender, or genetics. The beauty of hyperbaric oxygen therapy is its ability to powerfully impact the inflammatory reaction and its component processes like no other drug in the history of medicine. The inflammatory process begins with tissue injury. The injury can be as innocuous as apposition of tissues that normally do not interface against one another, such as spinal bony compression of a nerve root due to a degenerative disk. Most often, however, tissue injury results from much larger forces such as the type seen in military conflict. Once tissue is disrupted proteins, fat, other molecules, and disrupted tissue is exposed to the circulation. In addition, blood vessels are damaged both directly by mechanical forces and indirectly by tissue fragments that interact with the vessel walls. The net effect is bleeding from broken blood vessels and dilation of the unbroken blood vessels. As the vessels dilate, blood pressure forces the liquid portion of the blood out of the vessels. The extravasated fluid, now referred to as edema, exerts its own pressure that collapses blood vessels, leading to a reduction of blood flow. This compounds the reduction in blood flow already caused by disrupted blood vessels and bleeding. In addition, white blood cells in the circulation are attracted to the damaged tissue by molecules DOD-BIRR mHBOT Acute Trauma PG Harch 2004 2 released from the damaged tissue. The white blood cells traverse the blood vessel walls in a process called emigration (21) and disgorge themselves of their digestive enzymes. These enzymes cause further tissue damage in an attempt to clean up the primary damage, but also cause constriction of blood vessels to limit further bleeding and leakage of fluid. The cumulative effect of all of these processes, including tissue injury, fluid leakage, blood vessel disruption, bleeding, white blood cell accumulation, indiscriminate release of digestive enzymes, and blood vessel constriction is a reduction in blood flow and most importantly, reduction in the crucial element for sustenance of life, oxygen. With the reduction of oxygen, blood vessel walls become activated as do the white blood cell surface proteins. Activation of the white blood cell surface proteins results in their prominence from the cell surface in a manner similar to a sail rising on a sailboat. This drag slows down the white blood cells, resulting in their margination (22) to the walls of blood vessels in an area of injury. The white blood cells then stick to the walls of the blood vessels and generate tiny blood clots. This cascade of events is known as reperfusion injury (23). The white blood cells now emigrate and compound the process described above, resulting in greater reduction in blood flow and hypoxia. Thus, low oxygen leads to further tissue damage, leakage of blood vessels, clotting of blood vessels, and more hypoxia, in essence, the “vicious cycle” described by Holbach (24). This is the sequence of events at the site of every bullet, shrapnel, blast, blunt, electrical, etc. impact in every soldier injured in battle. Finally, if there is enough bleeding, clotting of blood vessels, and blood vessel leakage of fluid in the body to drop blood pressure the entire body becomes activated by hypoxia, undergoes reperfusion injury, and the soldier experiences shock, a critical point of no return for most human beings. In the past 12 years scientific research has unequivocally shown that the only drug to completely or nearly completely reverse the reperfusion injury process is hyperbaric oxygen. In multiple experiments with different animal models, different organ systems, different types of blood flow reduction or absence (e.g., heart attack, stroke, cardiac arrest, carbon monoxide, tourniqueting of an extremity, etc.) timely mHBOT within hours of reperfusion injury has been shown to completely or nearly completely reverse reperfusion injury (25). The mechanism of action has been partly elucidated and shown to be an effect on the white blood cell surface proteins and the inside lining of the blood vessels to which the white blood cells stick (26, 27). The net result is a reduction in clotting, blood vessel leakage, and an increase in oxygenation. In addition, mHBOT has been shown to constrict blood vessels (28), thus reducing bleeding and leakage of fluid that causes swelling and further compression of blood vessels. This breaks the vicious cycle described above. Simultaneously, due to its ability to dissolve large amounts of oxygen in the liquid portion of the blood, oxygen enriched plasma is able to reach damaged areas of tissue not accessible by normal blood flow and restore oxidative function to these areas. The net result is a dramatic reduction in the secondary injury process, improved viability of tissue that would otherwise die, and salvage of the tissue and patient. The goal of the DoD-BIRR Battle Project is to use timely hyperbaric oxygen therapy to hyperacutely interrupt the inflammatory reaction and its injurious cascade, reverse hypoxia that results from disruption of blood vessels and bleeding, restore and prolong tissue viability, and prevent the secondary injury processes that are so devastating. mHBOT is uniquely suited to battlefield casualties for its beneficial effects on five processes or conditions: acute severe traumatic brain injury (TBI), extremity wounds with crush injury and compartment syndrome, burns, acute hemorrhage, and reperfusion injury. DOD-BIRR mHBOT Acute Trauma PG Harch 2004 3 The literature for mHBOT in acute severe TBI is amongst the strongest in hyperbaric medicine. mHBOT effects on brain injury pathophysiology have been well-documented (29-37). In humans Holbach (38) demonstrated improved glucose metabolism in acute severe TBI patients with one mHBOT. He followed this study with a controlled trial of mHBOT in TBI patients with the acute mid-brain syndrome (24). Using 1-7 mHBOT’s, he demonstrated an overall 55% reduction in mortality and 81% improvement in short-term outcome (10d post TBI). These dramatic findings were duplicated in the largest study performed to date, the Rockswold study in 1992 (39). Rockswold showed that mHBOT induced a 47% reduction in mortality overall and a 59% reduction for the most severely injured, nearly identical to Holbach. Rockswold followed his study with two additional studies that reinforced their and Holbach’s findings. The first one in 2001 (40), showed that a single mHBOT improved brain metabolism (similar to Holbach-38) and re-coupled brain blood flow and metabolism in severely injured human brain FOR THE FIRST TIME IN THE HISTORY OF SCIENCE AND MEDICINE. This was a profound discovery and was consistent with all of the previous animal and human experimentation performed with mHBOT in acute TBI. The second study, an animal study (41), proved that mHBOT could increase oxygen consumption, brain tissue oxygen levels, and mitochondrial function (the organelle that is the energy center for every cell in the body). Additional randomized controlled studies by Artru (80) and Ren (81) at somewhat higher pressures have shown the same result as Rockswold and Holbach. Taken collectively the multitude of animal and human studies strongly argue that mHBOT delivered within hours to days of acute severe TBI unequivocally reduces mortality and improves outcome. The reduction in mortality has never been equaled by any therapy in the medical armamentarium except possibly the ambulance, or in the case of the military, the helicopter. Adding mHBOT to helicopter evacuation of casualties should further decrease morbidity and mortality of injured soldiers. This is the foundation of the DOD-BIRR Project. The second important impact of mHBOT in acute battlefield trauma is the effect on extremity injuries which include crush injury, major blood vessel disruption, and compartment syndrome. Extremity gunshot, blast, and other high force military injuries cause massive tissue destruction, hypoxia, and swelling. This swelling leads to what is called compartment syndrome where the various muscle compartments that are bound by their dividing tissues (fascia and bone) increase in pressure and occlude blood vessels. The subsequent lack of blood flow causes more hypoxia leading to the “vicious cycle” described above in traumatic brain injury. A vicious cycle in the extremities results in death of the tissue, loss of function, and often loss of limb. This sequence of events is often complicated and worsened by disruption of major blood vessels that further lowers oxygen levels. Multiple animal studies have demonstrated a benefit of mHBOT in crush injury, lack of blood flow, and compartment syndrome (42-47). A human study in 1987 (48) reinforced these results by showing limb salvage in traumatized extremities with low blood flow who were at risk for amputation after failed surgical therapy. Stronger studies in 1989 (49) and 1996 (50) duplicated the previous animal and human data. In particular the study by Bouachour (50) in open fractures and crush injuries demonstrated significantly improved complete healing and bone healing with a reduction in additional surgical procedures. Actual application to extremity war injuries has been reported by three separate DOD-BIRR mHBOT Acute Trauma PG Harch 2004 4 authors with good results (51, 52, 53). Most of these studies, especially the war studies, involved damage to major blood vessels with its accompanying loss of blood flow and oxygen until surgical repair was complete. Despite this arterial damage, the net result in most of the studies is a reduction in major amputations. Very likely mHBOT ameliorates compartment syndrome by reducing edema and reversing hypoxia. Its most profound effect, however, maybe on prevention of compartment syndrome by impacting reperfusion injury. Reperfusion injury is a normal feature of direct tissue injury, but it can be compounded by the secondary reperfusion injury from tourniqueting a massively bleeding extremity. mHBOT delivered within the first few hours of injury could significantly inhibit reperfusion injury (7, 25, 26) and prevent the major delayed complications of R.I.: infection, compartment syndrome, and amputation. In addition, mHBOT could prevent the reperfusion injury that occurs during surgical repair of the injured extremity as the extremity is tourniqueted during surgery to allow blood vessel reconstruction and bone repair. mHBOT has shown benefit in acute thermal burns since 1965 when Wada discovered that burned patients treated for carbon monoxide poisoning from a coal mine fire experienced accelerated healing of their burns (54). Since that time a plethora of studies in animals has shown improved healing (55), reversal of hypoxia (56), reduction of inflammation/reperfusion injury (57, 58), burn edema (59, 60, 61, 62), increased rate of skin growth (63), improvement in the blood vessels (63, 64, 65), prevention of progression of deep second degree burns to third degree burns (62, 65, 66, 67), reduction in burn shock (68)and a decrease in infections (55). Studies in humans have mirrored the animal literature with clear or likely benefit in 19 of 21 studies (69), demonstrating a drastic reduction in healing time for deep second degree burns (70-73). The effect on third degree burns (all layers of the skin) is less apparent since modern burn care has evolved to early surgical removal of burned tissue. Immediate mHBOT in these cases, however, could likely minimize the amount of questionable second degree burned tissue that would be inadvertently excised with the third degree burn. This could be important in burns of the face, ears, hands and feet where tissue preservation is critical. Lastly, early intervention with mHBOT has reduced the cost of burn treatment (73). Hyperacute mHBOT at a battlefield MASH station should duplicate the civilian experience and have a dramatic impact on the treatment of burned soldiers. The fourth significant impact of mHBOT on military casualties would be in the treatment of massive hemorrhage. As mentioned above in the example of Jehovah’s Witness patients mHBOT can be used as a blood substitute until definitive treatment is available (74). A large volume of animal and human studies consistently show better survival with mHBOT (75) in profound hemorrhage. Relying on Henry’s Law and Boerema’s experiment, massive amounts of oxygen would be delivered to exsanguinating soldiers by its dissolution in the soldier’s plasma. In the 1960’s major hospitals in the United States and Europe utilized Henry’s law to hyperoxygenate babies with congenital heart disease undergoing cardiac surgery. In the absence of the soon to be invented heart-lung bypass machine the dissolved oxygen provided surgeons longer operating times during cardiac standstill. In a MASH unit soldiers could be rapidly compressed to 3 ATA on 100% oxygen in hyperbaric chambers while awaiting or in the process of receiving blood transfusions. Using air breaks between oxygen administration periods they can remain at this pressure for 3-4 hours, 3-4 times per day (75). The reduction of time in the shock state would pay dividends in decreased morbidity and mortality. In addition, in times of mass casualties that overwhelm the blood supply and surgical capabilities, mHBOT could be delivered until blood is available or while the soldier is in flight to another MASH. Alternatively, critical soldiers with massive ongoing bleeding could be DOD-BIRR mHBOT Acute Trauma PG Harch 2004 5 placed in a hyperbaric operating room and receive the benefits of life without blood while time is bought for surgical control of bleeding and blood transfusions. The natural extension of this application is to those soldiers who have cardiac arrest from massive hemorrhage. Should this event occur even minutes before or after arrival at the MASH unit soldiers could be compressed on oxygen while IV’s are placed, volume and blood are infused, and bleeding is controlled. The precedent has been set for this in resuscitation from cardiac arrest in a drowned diver with decompression sickness 22 minutes after loss of consciousness (76) and guinea pigs 15 minutes (77) and swine 25 minutes post induced cardiac arrest (78). While the human case was a partial exsangination and the animals had normal blood volume they suggest an untapped potential for application to soldiers. The time has come to introduce to the military medical therapeutics arsenal both this potential and the more certain application to near-exsanguinated soldiers or soldiers in shock. The fifth area of impact for mHBOT in acute military casualty treatment is reperfusion injury. As mentioned above, reperfusion injury is a ubiquitous process post injury. Specifically, it is a secondary injury that occurs upon restoration of blood flow (23). In the case of battlefield injuries it occurs with any blunt, blast, bullet, shrapnel, stab, electrical, burn, or other wound. In addition, it causes tissue destruction post resuscitation from shock, upon release of any tourniquet placed to control bleeding in the field or in the operating room, and upon restoration of blood flow to re-attached limbs. mHBOT’s effect on reperfusion injury has been argued to be a generic drug that applies regardless of the affected organ system or species (25). It appears to also be a dominant mechanism in the prevention of brain lipid peroxidation in the swine resuscitation experiments above (79). When delivered in timely fashion after injury it protects the body from further reperfusion injury should the soldier have to undergo surgery or have other complications. Coupled with the known effects on bone healing and the ability to salvage marginally viable tissue mHBOT has the potential to significantly reduce major amputations. Overall, mHBOT’s effect on reperfusion injury could be huge in military casualty management. In conclusion, mHBOT is one of the most powerful drugs known to man. Simultaneously, mHBOT delivers the substrate of life, oxygen, for which there is no substitute. mHBOT has profound beneficial effects on injury pathophysiologic processes that are common in military casualties. Moreover, it has been shown to positively impact traumatic brain injury, compartment syndrome, burns, hemorrhage, and reperfusion injury. These injuries and injury processes comprise the bulk of battlefield casualties. With timely intervention of mHBOT the morbidity and mortality of injured soldiers should substantially improve as they have in their civilian counterparts. Past foreign military experience strongly suggests this benefit in extremity wounds and its our conviction that United States soldiers deserve nothing less. This is the goal of the DoD-BIRR Project. REFERENCES: 1 Harch PG, Neubauer RA. Hyperbaric oxygen therapy in global cerebral ischemia/ anoxia and coma. In Jain KK (ed) Textbook of Hyperbaric Medicine, 4th Revised Edition, Chapter Hogrefe & Huber Publishers, Seattle WA 2004: 223-261. 2 NOAA Diving Manual, Diving for Science and Technology, U.S. Dept. of Commerce, National Oceanic and Atmospheric Administration, 1991. DOD-BIRR mHBOT Acute Trauma PG Harch 2004 6 3 Boerema I, Meyne NG, Brummelkamp WK, et al. Life without blood: a study of the influence of high atmospheric pressure and hypothermia on dilution of blood. J Cardiovasc Surg, 1960;1:133-146. 4 Van Meter K. Exceptional Anemia. In: Hyperbaric Oxygen 2003, Indications and Results The Hyperbaric Oxygen Therapy Committee Report, ed. John J. Feldmeier. 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Arch Neurol, 1971;24:210-16. 34 Kanshepolsky J. Early and Delayed Hyperbaric Oxygenation in Experimental Brain Edema. Bull Los Angeles Neurol Soc, 1972;37(2):84-9. 35 Miller J.D. The Effects of Hyperbaric Oxygen at 2 and 3 Atmospheres Absolute and Intravenous Mannitol on Experimentally Increased Intracranial Pressure. Europ Neurol, 1973;10:1-11. 36 Contreras F.L., Kadekaro M, Eisenberg H.M. The effect of hyperbaric oxygen on glucose utilization in a freeze-traumatized rat brain. J Neurosurg, 1988;68:137-141. 37 Nida T.Y., Biros M.H., Pheley A.M., Bergman T.A., Rockswold G.L. Effect of Hypoxia or Hyperbaric Oxygen on Cerebral Edema following Moderate Fluid Percussion or Cortical Impact Injury in Rats. J of Neurotrauma, 1995;12(1):7785. 38 Holbach KH, Caroli A, Wassmann H. Cerebral Energy Metabolism in Patients with Brain Lesions at Normo- and Hyperbaric Oxygen Pressures. J Neurol, 1977;217:17-30. 39 Rockswold GL, Ford SE, Anderson DC, Bergman TA, Sherman RE. Results of a prospective randomized trial for treatment of severely brain-injured patients with hyperbaric oxygen. J Neurosurg, 1992;76:929-34. 40 Rockswold SB, Rockswold GL, Vargo JM, Erickson CA, Sutton RL, Bergman TA, et al. Effects of hyperbaric oxygenation therapy on cerebral metabolism and intracranial pressure DOD-BIRR mHBOT Acute Trauma PG Harch 2004 8 in severely brain injured patients. J Neurosurg, 2001:94:403-411. 41 Daugherty WP, Levasseur JE, Sun E, Rockswold GL, Bullock MR. Effects of hyperbaric oxygen therapy on cerebral oxygenation and mitochondrial function following moderate lateral fluid-percussion injury in rats. J Neurosurg, 2004;101(3):499-504. 42 Bartlett RL, Stroman RT, Nickels M, et al. Rabbit model of the use of fasciotomy and hyperbvaric oxygen in the treatment of compartment syndrome. Undersea and Hyper Med, 1998;25(Suppl):29(#77). 43 Nylander G, Nordstr H, Franz L, et al. Effects of hyperbaric oxygen in postischemic muscle. Scand J Plast Reconst Surg, 1988;22:31-39. 44 Nylander G, Otamiri DH, Larsson J, et al. Lipid products in post-ischemic skeletal muscle and after treatment with hyperbaric oxygen. Scand J Plast Reconst Surg, 1989;23:97-103. 45 Skylar MJ, Hargens AR, Strauss MB, et al. Hyperbaric oxygen reduces edema and necrosis of skeletal muscle in compartment syndromes associated with hemorrhagic hypotension. J Bone Joint Surg, 1986;68A:1218-1224. 46 Strauss MB, Hargens AR, Gershuni DH, et al. Reduction of skeletal muscle necrosis using intermittent hyperbaric oxygen for treatment of a model compartment syndrome. J Bone Joint Surg, 1983;60A:656-662. 47 Strauss MB, Hargens AR, Gershuni DH, et al. Delayed use of hyperbaric oxygen for treatment of a model compartment syndrome. J Orthop Res, 1986;4:108-111. 48 Shupak A. Gozal D, Ariel A, et al. Hyperbaric oxygenation in acute peripheral posttraumatic ischemia. J Hyperbaric Med, 1987;2:7-14. 49 Strauss MB, Hart GB. Hyperbaric oxygen and the skeletal muscle compartment syndrome. Contemporary Orthopedics, 1989;18:167-174. 50 Bouachour G, Cronier P, Gouello JP, et al. Hyperbaric oxygen therapy in the management of crush injuries: A randomized double-blind placebo-controlled clinical trial. J Trauma, 1996;41:333-339. 51 Radonic V, Baric D, Petricevic A, et al. Military injuries to the popliteal vessels in Croatia. J Cardiovasc Surg, 1994;35:27-32. 52 Schramek A, Hashmonai M. Vascular injuries in the extremities in battle casualties. Brit J Surg, 1977;64:644-648. 53 Slack WD, Thomas DA, DeJode LRJ. Hyperbaric oxygen in the treatment of trauma, ischemic disease of limbs, and varicose ulceration. Proceedings of the Third International Conference on Hyperbaric Medicine 1966, IW Brown, BG Cox, Eds. National Academy of Science, National Research Council, Publ 1404, Washington DC, 621-624. 54 Wada J, Ikeda T, Kamata K, Ebuoka M. Oxygen hyperbaric treatment for carbon monoxide poisoning and severe burn in coal mine (hokutanyubari) gas explosion. Igakunoaymi (Japan), 1965;5:53. 55 Ketchum SA, Zubrin JR, Thomas AN, Hall AD. Effect of hyperbaric oxygen on small first, second, and third degree burns. Surg Forum, 1967;18:65-67. 56 Gruber RP, Brinkley B, Amato JJ, Mendelson JA. Hyperbaric oxygen and pedicle flaps, skin grafts, and burns. Plast and Recon Surg, 1970;45:24-30. 57 Hartwig J, Kirste G. Experimentele untersuchungen uber die revaskularisierung von verbrennungswunden unter hyperbarer sauerstofftherapie. Zbl Chir, 1974;99:1112-1117. 58 Germonpre P, Reper P, Vanderkelen A. Hyperbaric oxygen therapy and piracetam decrease the early extension of deep partial thickness burns. Burns, 1996;22(6):468-473. 59 Ikeda K, Ajiki H, Nagao H, et al. Experimental and clinical use of hyperbaric oxygen in DOD-BIRR mHBOT Acute Trauma PG Harch 2004 9 burns. In: Wada J and Iwa T (eds.), Proceedings of the Fourth International Congress on Hyperbaric Medicine. Tokyo: Igaku Shoin Ltd., 1970 p. 370. 60 Wells CH, Hilton JG. Effects of hyperbaric oxygen on post-burn plasma extravasation. In: Davis JC and Hunt TK, eds. Hyperbaric Oxygen Therapy. Bethesda: Undersea Medical Society, Inc., 1977, 259-265. 61 Nylander G, Nordstrom H, Eriksson E. Effects of hyperbaric oxygen on oedema formation after a scald burn. Burns, 1984;10:193-196. 62 Kaiser W, Voss K. Influence of hyperbaric oxygen on the edema formation in experimental burn injuries. Iugoslaw Physiol Pharmacol Acta, 1992;28(9):87-98. 63 Korn HN, Wheeler ES, Miller TA. Effect of hyperbaric oxygen on second-degree burn wound healing. Arch Surg, 1977;112:732-737. 63 Ketchum SA, Thomas AN, Hall AD. Angiographic studies of the effect of hyperbaric oxygen on burn wound revascularization. In: Wada J and Iwa T (eds), Proceedings of the Fourth International Congress on Hyperbaric Medicine. Tokyo: Igaku Shoin Ltd., 1970, p.388. 64 Saunders J, Fritz E, Ko F, et al. The effects of hyperbaric oxygen on dermal ischemia following thermal injury. Proceedings of the American Burn Association, New Orleans, 1989, p. 58. 65 Kaiser W, Schnaidt U, von der Leith H. Auswirkungen hyperbaren sauerstoffes auf die fresche brandwunde. Handchir Mikrochir Plast Chir, 1989;21:158-163. 66 Stewart RJ, Yamaguchi KT, Cianci PE, et al. Effects of hyperbaric oxygen on adenosine triphosphate in thermally injured skin. Surg Forum, 1988;39:87. 67 Bleser F, Benichoux R. Experimental surgery: The treatment of severe burns with hyperbaric oxygen. J Chir (Paris), 1973;106:281-290. 68 Cianci P, Slade JB. Thermal Burns. In: Hyperbaric Oxygen 2003, Indications and Results. The Hyperbaric Oxygen Therapy Committee Report. John J. Feldmeier, ed. Undersea and Hyperbaric Medical Society, 2003. Kensington Maryland, p. 113. 69 Niu AKC, Yang C, Lee HC, et al. Burns treated with adjunctive hyperbaric oxygen therapy: A comparative study in humans. J Hyperbar Med, 1987;2:75. 70 Cianci P, Lueders HW, Lee H, et al. Adjunctive hyperbaric oxygen therapy reduces length of hospitalization in thermal burns. J Burn Care Rehabil, 1989;10:432-435. 71 Cianci P, Lueders H, Lee H, et al. Adjunctive hyperbaric oxygen reduces the need for surgery in 40-80% burns. J Hyperbar Med, 1988;3:97. 72 Cianci P, Williams C, Lueders H, et al. Adjunctive hyperbaric oxygen in the treatment of thermal burns-an economic analysis. J Burn Care Rehabil, 1990;11:140-143. 73 McLoughlin PL, Cope TM, Harrison JC. Hyperbaric oxygen therapy in management of severe acute anemia in a Jehovah’s Witness Anesthes, 1999;54:879-898. 74 Van Meter K. Exceptional Anemia. In: Hyperbaric Oxygen 2003, Indications and Results. The Hyperbaric Oxygen Therapy Committee Report. Undersea and Hyperbaric Medical Society, Kensington, MD. p. 57-62. 75 Van Meter K, Weiss L, Harch PG. HBO in Emergency Medicine. In Jain KK (ed) Textbook of Hyperbaric Medicine, 4th Revised Edition, Chapter 37. Hogrefe & Huber Publishers, Seattle WA 2004: 421-449. 76 Van Meter K, Gottlieb SF, Whidden SJ. Hyperbaric oxygen as an adjunct in ACLS in guinea pigs after 15 minutes of cardiopulmonary arrest. Undersea Biomed Res, 1988;15(Suppl):55. DOD-BIRR mHBOT Acute Trauma PG Harch 2004 10 77 Van Meter KW, Swanson HT, Sheps SS, Barratt DM, Roycraft EL, Moises J, Killeen J, Harch PG. Oxygen dose response in open-chest ACLS in swine after a 25-minute cardiopulmonary arrest. Annals of Emergency Medicine, 1999, 34(4):S11. 78 Van Meter K, Moises J, Marcheselli V, Murphy-Lavoie H, Barton, C, Harch P, Bazan N. Attenuation of Lipid Peroxidation in Porcine Cerebral Cortex After A Prolonged 25- Minute Cardiopulmonary Arrest by High-Dose Hyperbaric Oxygen (HBO). Undersea Hyper Med, 2001;28 Suppl: 79 Artru F, Chacornac R, Deleuze R. Hyperbaric Oxygenation for Severe Head Injuries. Eur Neurol, 1976;14:310-318. 80 Ren H, Wang W, Zhaoming GE. Glasgow Coma Scale, brain electric activity mapping and Glasgow Outcome Scale after hyperbaric oxygen treatment of severe brain injury. Chinese Journal of Traumatology (English Edition), 2001;4(4):239-241. DOD-BIRR mHBOT Acute Trauma PG Harch 2004 11 EVIDENCE FOR USE OF HYPERBARIC OXYGEN THERAPY FOR ACUTE TRAUMATIC BRAIN INJURY Traumatic brain injury (TBI) affects over 1.6 million United States residents annually and a far greater number internationally (Ghajar). Over 50,000 of these individuals will die from their brain injury and greater than 80,000 will have permanent severe neurological disability (Ghajar). Since the development of modern emergency medical system (EMS) management of acute trauma no therapeutic modality has further reduced the mortality of traumatic brain injury. The data below will show that the only modality in the history of science and medicine with a scientifically proven reduction in mortality in acute severe traumatic brain injury is timely low-pressure hyperbaric oxygen therapy (mHBOT). Some of this data also suggests a benefit for functional improvement. Any discussion of the effect of mHBOT on a medical condition should be based on the concept of drug dosage. A comprehensive definition of mHBOT as a drug is necessary: mHBOT is the use of greater than ambient atmospheric pressure oxygen as a drug to treat basic pathophysiologic processes/states and their diseases (Harch, Jain). The dose of mHBOT is a function of the fractional percentage of oxygen, rapidity of pressurization and depressurization, depth of pressurization, length of time at depth, frequency of treatments, presence or absence and duration of air breaks and surface intervals, number of treatments, and time of intervention in the natural history of the disease, which identifies the pathological targets. The data in this paper will be discussed and evaluated in terms of dosing and will emphasize the absolute pressure, time at depth, frequency and number of treatments, and time of intervention. The medical literature will be reviewed to first answer the question of efficacy of mHBOT on the underlying pathology, pathophysiology, and outcomes of acute TBI in animals and second to see if this efficacy is duplicated and reinforced by the human clinical literature. TBI is a diffuse cerebral insult characterized by primary mechanical disruption of tissue (Peerless), (Strich), (Adams) and secondary injury from ischemia (Bouma), hypoxia(Adams), (van den Brink), (Zhi), edema (Adams), (Schoettle), (Bullock), vasospasm (Martin), (Zurynski), neurochemicals (McIntosh), (Hovda),and reperfusion injury (Zhuang), (Schoettle). A review of the medical literature shows that there is substantial data proving a beneficial effect of mHBOT on the secondary injury processes of acute TBI. mHBOT has been shown indirectly to improve ischemia and hypoxia in acute TBI by its effect on aerobic metabolism and EEG. Contreras (ref) recorded a persistent increased cerebral glucose utilization in 5 of 21 areas of brain remote from a cryogenic injury 24 hours after the fourth mHBOT. Treatments began 30 minutes after the injury and continued daily at 2 ATA/90 minutes. Holbach (J. Neurol) obtained a similar result in humans with acute severe TBI (23 patients), and stroke (7 patients) a few days post injury/ictus. Measuring the glucose oxidation quotient, he found aerobic metabolism to be maximal in injured brain at 1.5 ATA. A single 10-15 minute excursion to 2.0 ATA had a toxic effect on glucose uptake and metabolism that persisted after return to room air. Holbach (6th Int. Congress) reinforced this finding by demonstrating simultaneously improved EEG and decreased regional cortical blood flow (rCBF) in a similar or the same group of acute severe TBI patients at 1.5 ATA. Upon presure increase to 2.0 or 2.5 ATA for 30 minutes EEG markedly deteriorated and rCBF increased significantly. Some patients experienced persistence of these toxic effects upon return to room air. mHBOT also has beneficial effects on vasospasm. Yufu showed that 30 minutes after subarachnoid hemorrhage a single mHBOT at 2.0 ATA/60 minutes reversed reductions in Na+, K+- ATPase activity and cell membrane alterations. Similarly, Kohshi documented a clinical benefit of Evidence for use of Hyperbaric Oxygen Therapy for Acute Traumatic Brain injury - Harch mHBOT on vasospasm in a controlled human study. He found that mHBOT at 2.5 ATA/60 once or twice/day (average 10 treatments) soon after symptomatic vasospasm in post-op SAH/aneurysm patients decreased strokes and improved neurological outcome and EEG over controls. Multiple studies have shown that mHBOT reduces cerebral edema and decreases ICP. Coe used a single 3.0 ATA/120 mHBOT immediately after cryogenic brain injury in rats to improve neuronal destruction, cerebral edema, and length of survival from 2 hours to 12.5 hours. Coe reinforced these results with a follow-up percussion brain injury experiment. He showed that a single 3.0 ATA/60 mHBOT with 2% carbogen immediately after injury resulted in a significant improvement in maze running ability over controls at seven days that was nearly equal to non-injured animals. Sukoff (1968), using cerebral implantation of psyllium seeds in dogs, delivered mHBOT beginning 24 hours after surgery at 3.0 ATA/ 45 (total dive time?) three times/day tapering to once or twice/day, and found a reduction in cerebral edema and cisternal fluid pressures and an increase in survival. In another model of cryogenic injury Miller, Ledingham, and Jennett showed that a single mHBOT at 2.0 ATA/15-30, beginning minutes after injury, reduced ICP, but at 40-60 minutes the reduction in ICP began to reverse and rebounded (in some dogs) above baseline on return to air breathing. With the same model Miller and Ledingham later showed that mHBOT at 2.0 ATA/4 hours, beginning one hour after injury, caused an initial reduction in ICP that progressively reversed and then significantly rebounded post mHBOT. Simultaneously, CSF lactate increased to the levels of controls, contrary to Holbach’s experiment above. A third experiment by this group in the same model confirmed the benefit of short exposures of mHBOT at 2.0 ATA. Dogs subjected to 2.0 ATA/15 had a 33% reduction in ICP and an improvement in perfusion pressure while dogs at 3.0 ATA/15 had a reversal of ICP reduction and rebound after return to surface, indicating a toxic effect of this pressure. Kanshepolsky subjected cats to cryogenic brain injury and treated with mHBOT at 2.5 ATA/90 three times/day for upto three days, beginning either two or 6 hours after injury. mHBOT increased survival and decreased brain edema if begun two hours after injury, but had no significant effect if treatment was delayed to six hours. A summary of the mHBOT/cerebral edema studies in animals is that mHBOT has two different effects (Hayakawa): one reducing brain edema (injured brain), and another producing brain edema (normal brain). This toxic effect on normal brain causes a breakdown in the protective vasoconstriction of arterioles, resulting in a rapid rise in brain blood flow and deterioration in EEG (Holbach). If not reversed seizures follow (Bean), (Chavko). It appears that high pressures (greater than or equal to 2.0 ATA) maybe beneficial for very short periods of time (15- 30 minutes) if delivered within a few hours after acute brain trauma. A similar conclusion has been reached in global ischemia/anoxia/coma (Harch, Jain). These pressures, however, have a toxic effect if used for greater duration and beyond the 2-3 hour post injury period. During this later period 1.5 ATA/30 minutes appears to be the optimal pressure/duration (human data). mHBOT also has beneficial effects on cellular reperfusion injury. Both Zamboni and Thom have reported inhibition of white blood cell mediated reperfusion injury at 2.0 and from 2.0 to 2.8 ATA, respectively, when mHBOT is initiated within approximately one hour after brain insult. This is consistent with the data above on high pressure mHBOT in cerebral edema immediately after brain injury. Unfortunately, this may not be applicable to human TBI and its associated reperfusion injury since time to initiation of mHBOT is often many hours after injury. The non-controlled human data is equally positive and consistent with the animal data. Mogami, in 66 acute coma cases, 50 of which were severe TBI, reported neurological improvement in 50% and EEG improvement in 33% of cases with a decrease in CSF pressure, occurring mostly at depth, that regressed or rebounded post treatment. The patients also exhibited a slight improvement 2 Copyright Paul G. Harch, M.D., June, 2001 Evidence for use of Hyperbaric Oxygen Therapy for Acute Traumatic Brain injury - Harch in cerebral aerobic metabolism with a slight decrease in the lactate/pyruvate ratio. The best responses were in the least injured patients. Treatment pressures were 2 ATA/60 minutes, once or twice/day with an average of two treatments. The preponderance of benefit at depth with regression/rebound post treatment suggests an excessive pressure of oxygen as reviewed above in the cerebral edema animal studies. Hayakawa achieved similar results in 9 acute TBI and 4 post-op brain tumor patients at 2ATA/60 minutes, measuring CSFP. He found three patterns of response, the most common of which was a reduction of CSFP at the beginning and a rise at the end of mHBOT. He proposed the edema reducing effect of mHBOT on injured brain and edema producing effect on normal brain mentioned above. Both of these studies are reinforced by the two companion studies of Holbach on EEG and rCBF above in 14 acute severe TBI patients exposed to different pressure profiles.. This data is strongly supported by Holbach’s additional report in 1977 on metabolic data in the same or a similar group of severe acute TBI (n=23) and CVA (n=7) patients, also noted above. This metabolic data is further supported by Holbach’s 1974 report on crude outcomes of 102 patients, 43 with “lifethreatening” acute TBI, who were treated with an average 2.6 mHBOT’s within a few days of injury: 52 at 2-3 ATA and 50 at 1.5 ATA. The TBI subset treated at 1.5 ATA demonstrated a 33% increase in the number of markedly improved patients. Additionally, Lareng published two cases of deepening coma secondary to TBI who were treated 4 and 10 days post TBI at 2.0 ATA/45 bid for 42 treatments. One patient was completely well with a normal EEG and the other had complete neurological recovery. Belokurov treated 23 acute pediatric coma cases, 13 of which were traumatic, at 1.7-2.0 ATA/60, once/day for four days. He found: a 50% reduction in time of coma if mHBOT was initiated within the first 24 hours after injury (indicating mHBOT responsive pathology in this period of time), a statistically significant improvement in coma score after the first mHBOT, especially in the TBI patients, and further improvement in eight of ten patients who were retreated with mHBOT after relapse into vegetative coma. In contrast, Artru measured CBF and metabolism in 6 severe acute TBI patients 5-47 days post injury with 2.2 or 2.5 ATA/90 minute mHBOT exposures and found variable responses due to differential effects of mHBOT on injured and normal brain. Curiously, systemic arterial PO2 declined in 8 of 9 measurement trials, indicating a pulmonary or severe brainstem toxicity/complication with this profile. All of the above human studies were performed on severe acute TBI patients a few days post injury. The data is remarkably consistently positive, but the exact dose of oxygen is less clear. In general, the data suggests that approximately 48 hours or more after injury pressures from 1.5 to 2.0 ATA and treatment times less than or equal to one hour have reproducible beneficial effects and that pressures above 2.0 ATA have negative effects on CBF, EEG, CSFP, and aerobic metabolism. Specifically, higher pressures seem to reverse the brain’s protective vasoconstrictive capacity leading to a marked increase in CBF/CSFP and simultaneous deterioration in EEG/aerobic metabolism. Moreover, there may be competing effects in injured and normal brain that determine whether the final result is positive or negative based on the relative proportions and possibly locations of the two types of tissue. Unfortunately, due to small numbers of patients and inadequate data this complex relationship cannot be adequately defined for all of the different levels of injury at different times of intervention. The more rigorously controlled human clinical studies recapitulate all of the above data/conclusions and lead to more powerful conclusions. Holbach followed his 1971 study with a randomized prospective controlled study of mHBOT vs. standard intensive care in 99 acute TBI coma (mid-brain syndrome) patients, 2-10 days post injury. The mHBOT patients received 1-7 treatments at 1.5 ATA/45 minutes. The mHBOT group achieved a 21% decrease in mortality and the apallic state (vegetative coma) and a 450% increase in complete recovery. Artru published a similar RPCT on 60 3 Copyright Paul G. Harch, M.D., June, 2001 Evidence for use of Hyperbaric Oxygen Therapy for Acute Traumatic Brain injury - Harch acute coma TBI patients 4.5 days post injury. mHBOT patients were delivered 2.5 ATA/90 minute treatments once/day on a 10 day schedule with a four day break and then repeat of the cycle until consciousness or death. Despite multiple breaks in protocol, delays to treatment, and use of the a high pressure, one of 9 subgroups, the brainstem contusion group, experienced a significantly higher rate of recovery of consciousness at one month. Lastly, and most importantly, Rockswold in 1992 reported the most exhaustive, rigorous, and important study to date in acute TBI in an attempt to refute or affirm all of the above animal and human data. Conducted from 1983 to 1989 the study enrolled 168 patients with GCS of 9 or less in a RPCT design and stratified the patients by age and GCS. Patients were treated at 1.5 ATA/60 every 8 hours for a maximum of two weeks immediately post TBI or until awake or deceased during these two weeks. The average patient entered treatment 26 hours post TBI and received 21 treatments. Overall mortality was significantly reduced 50% in the mHBOT group and as high as 56% and 60% in the elevated ICP and GCS 4-6 subgroups, respectively, however there was no difference in the good outcome categories between the groups at 12 months. A summarization of the above data demonstrates an undeniable beneficial effect of mHBOT on mortality and recovery of consciousness and a suggestion of improved neurological outcome. The best results were achieved at pressures less than 2.0 ATA, specifically 1.5 ATA. Unfortunately, there is not a large amount of data generated from finely adjusted dose escalations of mHBOT, but rather a preponderance of studies performed at 1.5 ATA based on early dose escalation studies, with some comparison data at 2.0 ATA and higher. These conclusions are derived from a number of RPCT’s that en block constitutes one of the most powerful and consistent bodies of scientific evidence for any accepted indication for mHBOT. The TBI controlled trials alone already exceed the data for at least six of the thirteen indications, including the last addition, cerebral abscess. While internally consistent and stand alone sufficient this body of data was recently strengthened by the addition of the follow up article of the Rockswold group in March, 2001. On a group of severe TBI patients similar to those in the 1992 study the authors methodically and meticulously studied brain metabolism at 1.5 ATA, once/day for 5-7 days post injury. They found that mHBOT improved the cerebral metabolic rate for oxygen and decreased CSF lactate , especially in those with reduced CBF or with ischemia, normalized the coupling of CBF and cerebral metabolism, exerted a persistent effect on CBF and metabolism, and reduced elevated levels of ICP and CBF. Notably, mHBOT’s recoupling of flow and metabolism is the only demonstration of such in the history of science. They recommended that shorter (30 minutes) more frequent (every 8 hours— identical to their first study) treatments would optimize treatment. This final study reaffirms the multiple studies above at both lower and higher pressures that show reversal or deterioration of a beneficial mHBOT effect after 30+ minutes in the chamber. The data and scientific argument is strong and supports/demands low pressure mHBOT in acute severe traumatic brain injury. Some of the studies suggest that even a few treatments can have a profound effect. The protocol is uncertain beyond the first two weeks, but should probably be delivered according to the principle employed in medicine for any therapeutic modality: treat until clinical plateau. While the data is not so consistent on long-term neurological outcome, this goal should be left to further research and multi-modality therapy. After all, the first priority in life-threatening illness is to save the patient. As a matter of perspective, the American Heart Association has spent hundreds of millions if not billions of dollars on CPR education, training, and research, yet has still have made very little 4 Copyright Paul G. Harch, M.D., June, 2001 Evidence for use of Hyperbaric Oxygen Therapy for Acute Traumatic Brain injury - Harch progress in successful resuscitation of cardiac arrest. Very few survive and almost all who survive are severely neurologically impaired. Despite these dismal results the research largesse continues in an effort to find even the smallest improvement in mortality. At our fingertips is possibly the therapeutic modality with the greatest and most dramatic effect on reduction of acute TBI mortality in the history of medicine. The neurosurgeon authors of the Rockswold study conclude that “mHBOT should be initiated as soon as possible after acute severe traumatic brain injury.” I believe the UHMS and medical profession should follow their lead and the UHMS list acute TBI as an accepted indication for mHBOT. I am ready, willing, and eager to defend this position. Thank you for the opportunity. Sincerely, Paul G. Harch, M.D. Clinical Assistant Professor Department of Medicine LSU School of Medicine New Orleans, Louisiana ADDENDUM TO: EVIDENCE FOR USE OF HYPERBARIC OXYGEN THERAPY FOR ACUTE TRAUMATIC BRAIN INJURY Paul G. Harch, M.D. June 13, 2001 The evidence for use of hyperbaric oxygen therapy for acute traumatic brain injury is based on a general review of the scientific animal and human data. While this body of consistent studies constitutes stand alone proof of the efficacy of mHBOT in acute TBI, scoring of efficacy using the Gottlieb and American Heart Association schemes strengthens the argument. The scoring results are tabulated below, acknowledging that some of the studies are difficult to classify by the Gottlieb system: A. Gottlieb system: Assigned Points Known etiology (known to be or logically can be expected to be positively 4 out of 4 (4/4) Affected by HBO). (Bouma, Adams, van den Brink, Zhi, Adams, Schoettle, Bullock, Martin, Zurynski, Zhuang studies). Pathophysiology (irrespective of whether specific etiology is known) 5/5 demonstrated to be amenable to mHBOT. [Contreras, Holbach (J. of Neurol, 6th Int Congress—two studies), Yufu, Kohshi, Coe, Sukoff, Miller (three studies), Kanshepolsky, Hayakawa, Zamboni, Thom]. Natural History of disease known to be “downhill.” (Ghajar). 7/7 In vitro data. (None). 0/6 Animal experimentation (one or more species). (Contreras, Yufu, Coe, Sukoff, 8/8 Miller, Kanshepolsky, Zamboni, Thom). Human data: anecdotal (Lareng paper). 1/5 5 Copyright Paul G. Harch, M.D., June, 2001 Evidence for use of Hyperbaric Oxygen Therapy for Acute Traumatic Brain injury - Harch Human data: patient controlled study(ies). Hayakawa, Mogami, and Sukoff studies). 7/7 Human data: longitudinal study(ies). (Belokurov, Holbach-5th and 6th Int. 7/8 Congresses). Human data: double blind (with or without crossover) study(ies). (Holbach, 10/10 S. Rockswold). Human data: double blind [comparative therapeutic study(ies), “head-to-head” 10/10 comparison with currently accepted therapeutic agents]. (Artru, Holbach, G. Rockswold). _ TOTAL: 59/70 Minimum of 35 points is necessary for inclusion. The total of 59 easily surpasses this requirement. B. American Heart Association Class I: Definitely recommended. One or more Level 1 studies are present, study results are consistently positive and compelling. Artru, Holbach, and Rockswold studies. Supported by additional Rockswold and Holbach metabolic studies. The lowest level of grading would be a Class IIa if one questions effectiveness, however Class IIa studies have Level 1 studies that are absent, inconsistent, or lack power. This is not the case for mHBOT/acute TBI: there are a minimum of three Level 1 studies, all positive with two of the three statistically significant. The third was not subjected to statistical analysis. Adams JH, Graham DI, et al: Brain damage in fatal non-missile head injury. J Clin Pathol 1980; 33:1132-1145. Artru F, Chacornac R, Deleuze R (1976): Hyperbaric oxygenation for severe head injuries: Preliminary results of a controlled study. Euro Neurol 14; 310-318. Bean JW et al (1972): Cerebral O2, CO2, regional cerebral vascular control, and hyperbaric oxygenation. J Applied Physiology May 1972; 32(5):650-657. Belokurov MIu, Stepankov AA, Kirsanov BI (1988): Hyperbaric oxygenation in the combined therapy of comatose states in children. Pediatriia (2): 84-87. Bouma GJ, et al: Cerebral circulation and metabolism after severe traumatic brain injury: The elusive role of ischemia. J Neurosurg 1991; 75: 685-693. Bullock R, Smith R, et al: Brain specific gravity and CT scan density measurements after human head injury. J Neurosurg 1985; 63: 64-68. Chavko M et al : Role of cerebral blood flow in seizures from hyperbaric oxygen exposure. Brain Research 791, 1998:75-82. Coe JE, Angyan AJ: The effect of hyperbaric oxygenation upon recovery of maze performance after experimental concussion. The Journal of Trauma 1971; 11(5):436-439 Coe JE, Hayes TM: Treatment of experimental brain injury by hyperbaric oxygenation: preliminary report. The American Surgeon July 1966; 32(7):493-495. Contreras FL, Kadekaro M, Eisenberg HM: The effect of hyperbaric oxygen on glucose utilization in a freezetraumatized rat brain. J Neurosurg 1988; 68: 137-141. 6 Copyright Paul G. 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