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               Research Program Summary

David N. Herndon, MD
Chief of Staff and Director of Research
Shriners Burns Hospital - Galveston, Texas

Director, Combined Burn Service
University of Texas Medical Branch at Galveston

   Research efforts at the Shriners Hospital for Children in Galveston, Texas continue to be directed at understanding one of the most severe and complex injuries a child can sustain.  Burn investigators, both clinical and basic science, are focusing their efforts on clinical problems pertinent to improving survival and the quality of life for all burned children.  We continue to direct our interest in the areas of cardiopulmonary pathophysiology, metabolism, responses to thermal injury at the molecular level, infection, wound healing, and integrated long term outcomes of burned children.



Cardiopulmonary Pathophysiology

   Traumatized acute lung injury is responsible for a great deal of the mortality which we see in thermally injured patients, in fact, few of our children die from their burn wounds who do not have a concomitant inhalation injury.  Investigators at the Shriners Burns Hospital-Galveston have demonstrated that there is a marked increase in systemic blood flow to the airways following inhalation injury.  Most recently we have accumulated evidence that hyperemia is mediated by a neural inflammatory response.  In addition to these studies, we have demonstrated that if the airway and one lung are subjected to inhalation injury, the opposite lung, although not exposed to smoke, develops edema and evidence of tissue damage.  These studies confirm the neural influence in the response.  These studies demonstrate that the treatment of the airway may prevent life-threatening changes that occur in the gas exchange areas of the lung.


Acute Lung Injury

   Recently, smoke inhalation studies have focused on airway damage as the major cause of lung injury.  Investigators have determined that blood from injured airway flows through the gas exchange area.  This broncho-pulmonary shunt transports toxic mediators from the injured airway to the areas where gas exchange takes place.  It is now possible to determine if the reduction of blood flow through the shunt minimizes injury to the gas exchange areas.  This discovery is important since drugs applied to the airway by nebulization would be absorbed into the brochial circulation and carried to the parenchyma to prevent or minimize damage.  Thus far, two compounds appear successful in treating the inhalation injury by nebulization into the airway.

   Mediators released from the bronchial circulation cause white blood cells called neutrophils to stick in the pulmonary microvasculature and to release cytotoxins, such as free oxygen radicals and proteases, which in turn damage the air exchange areas of the lung.  We have been studying this phenomenon and now show that a different mechanism is involved for the adherence and movement of neutrophils into the air exchange areas of the lung that is seen in systemic tissues.

   Burned patients frequently must be placed on a ventilator since their lungs may be damaged to the extent that they cannot support life.  This support ventilation itself can cause damage to the lung.  We have continued to work in the development of a catheter, which can be placed in the circulation and act as a gas exchanger.

   We are further investigating the morphological and physiological alternations in alveolar macrophage function after smoke inhalation.  These abnormalities may contribute to diminished pulmonary host defense during smoke inhalation injury.  In order for survival to take place following inhalation injury the cellular damage to the airway must heal.  We are now studying techniques that accelerate the healing process.  Investigations have demonstrated that the healing can be accelerated by 30% with the combination of epidermal and platelet derived growth factors and a 40% increase if the growth factor was combined with Vitamin A.  This study is important since acceleration of the healing process may minimize scarring processes, which may cause chronic lung disease.

   The healing process can also be delayed by infection.  Our research team has studied the effects of Pseudomonas aeruginosa; bacteria commonly associated with airway infections and have determined that these organisms adhere to airway epithelial cells.  The understanding of this adherence has led to investigating compounds that can block or reverse infections caused by these bacteria.

 

Thermal Injury and Resuscitation

   The Thermal Injury and Resuscitation Group has an active program that includes close collaborations among Shriners burn doctors, nurses, and researchers. The overall goal of our resuscitation research is to develop regimens for optimal cardiovascular function with minimal volume loading. Over resuscitation is a problem at all burn centers and demands a “solution.”

New paradigms in resuscitation of burn injury are being developed to include:

   Burn Decision Support System (DSS): A PC-based Burn DSS of our design is now used as standard of care at the UTMB Blocker Burn Unit. Co-developed with the US Army Burn Center, the Burn DSS uses an algorithm based on adult patient data collected at UTMB and the US Army Burn Center. We are working on a variety of approaches for a pediatric database to develop a pediatric DSS.

   Autonomous Fluid Resuscitation Systems (AFRS): We have demonstrated the feasibility of performing closed loop resuscitation in animals. We are now developing algorithms, software, and hardware on a system for clinical testing. Such smart resuscitation systems (DSS and AFRS) will define how burn units of the future administer care. Smart systems allow Shriners expertise to be exported to other pediatric burn centers.

   Multi-Center Data Collection: UTMB and Shriners, Galveston are founding members of Resuscitation-Nurses.org. Along with the Shriners Hospital in California, we are organizing nurses to collect detailed hourly records of fluid balance during burn resuscitation. This is to be a living database that will define our standard of care, be a tool for quality improvement, and provide data to model the development of better Burn DSS.

   Enteral Resuscitation: We define enteral resuscitation as drinking in conscious patients and rectal infusion or colonic delivery in unconscious patients. Enteral Resuscitation could provide a life-saving treatment for burn patients from mass casualty events, under-developed countries, combat casualty care, expeditionary space flight, and any scenario where there are limitations on the personnel or supplies available to start and deliver IV fluids. Shriners’ grants have supported the testing of gastric delivery of electrolyte-glucose-fatty acid formulations in pigs and rats. Data show volume expansion and cardiac output restoration with enteral resuscitation being comparable to IV resuscitation, albeit with a 1-hour delay in effect.

   Cardiac Dysfunction: Both animal work and our recent clinical studies have demonstrated that diastolic and systolic cardiac function are reduced after burn injury. The cardiac dysfunction associated with burn injury negatively impacts outcome (increases length of ICU stay). Strategies are being developed and implemented to better risk-stratify sicker patients by using advanced hemodynamic monitors and optimizing earlier use of inotropic and pressors support. Our work suggests these agents should be used during the initial burn resuscitation.

   Hyperpermeability of Burn Injury: We have better defined mechanisms underlying increases in microvascular hyperpermeability after burn and smoke inhalation injury leading to massive tissue edema and compartment syndrome. Compartment syndrome significantly complicates the management of burn patients and increases morbidity and mortality. Based on our translational studies, we have proposed effective treatment options to prevent or reduce the massive vascular leakage.

 

Metabolism

   Severely injured patients are tremendously hypermetabolic.  In the past, investigators at the Shriners Burns Institute-Galveston Unit have established that an increase occurs in two of the major glucose regulatory hormones, glucagon and insulin.  We have also discovered that elevation of these two hormones contributes to an increase in blood glucose and the transport of the sugar into cells of various body organs.  The elevation in intracellular glucose then drives the metabolism of this sugar in a more rapid fashion to pyruvate, the end product of the major glucose metabolic pathway.  This latter compound can be metabolized in three different ways.  It can be converted into lactate and be released into the blood where it circulates to the liver to be resynthesized into glucose.  This occurs in burn patients, but this cycle will not account for all of the elevated pyruvate formed.  It can go into a cycle called the Krebs cycle that breaks it down into water and carbon dioxide.  The rate at which this cycle operates is determined by the body’s energy expenditure.  In burn patients, energy utilization is minimally increased compared to the elevation in total pyruvate load.  Consequently, this overabundant material must be shuttled into the other two pathways.  The amino acid glutamine can donate an amine group to the pyruvate to convert it into the amino acid alanine.  It has been determined this occurs in thermally injured patients. It is unfortunate for this depletes the body of its glutamine stores.  Many cells (e.g., epithelial cells of the gastrointestinal tract) are dependent upon this particular amino acid for their viability and may atrophy as a result of glutamine depletion.  Glutamine is also an important substrate for metabolism in white blood cells. Thus, a deficiency of this amino acid may compromise immune function.  These discoveries are a major accomplishment by our metabolism group.  Importantly, preliminary data suggest that this phenomenon is reduced by the administration of propranolol. We have also shown that high glucose levels are detrimental in terms of morbidity and mortality.  We found that patients with higher glucose levels have greater loss of lean body mass, more infections, more sepsis, and die more often.  Normal subjects on typical diets are able to break down 20 to 50% of the urea that would otherwise be excreted in urine and can re-use the nitrogen contained in the urea for synthesis of the amino acids, which are the building blocks of proteins.  We have shown that this metabolic process is absent in burned children maintained on clinical diets.  A failure to recycle this nitrogen may thus contribute to the muscle wasting that accompanies burn injury.

   It has previously been reported that thermally injured patients undergo bone demineralization.  This causes their bones to easily fracture, a problem that can greatly prolong their hospitalization.  Burned patients are likewise immobile.  This can result in demineralization.  Sheep have proven to be an excellent experimental model for the study of burn-induced bone demineralization because, unlike burned patients, they are mobile.  Using this model, Investigators at the Burns institute in Galveston have obtained evidence that the bone demineralization can occur from thermal injury alone.

   Finally, we have tested different therapeutic interventions to alter the aforementioned adverse responses. Our group has found that oxandrolone improves lean body mass, bone mineral density, and strength after burn injury.  We have also discovered that incorporating a resistance and aerobic exercise program into the standard hospital rehabilitation plan improves total lean body mass, strength, and overall cardiopulmonary capacity . Importantly, synergistic increases in weight and lean body mass were found to occur when oxandrolone is combined with exercise therapy. Like oxandrolone and exercise, growth hormone has shown promise in aiding recovery of burn patients.  Our group has shown that long-term treatment with recombinant growth hormone improves growth and lean body mass, reduces hypermetabolism, increases IGF-1/IGFBP-3 serum levels, diminishes cardiac stress, and attenuates scarring.  More recently, we have shown that long-term treatment with the beta blocker, propranolol, decreases hypermetabolism, improves lean body mass, and helps prevent bone loss.  We are currently conducting clinical trials to validate the importance of these approaches.  If our results hold true in a larger setting we introduced new standards of care for patients with severe burn injuries world-wide.

 

Molecular Responses to Injury

   Shriners Burns Institute in Galveston, Texas has developed a strong focus on the molecular mechanism underlying cellular responses to injury.  Investigators are examining the molecular mechanisms that regulate changes in gut and hepatic gene expression following injury and burn stress.  The hepatic acute phase response is an alteration in liver function that occurs during the systemic inflammatory response.  Gut mucosal injury is also a prominent feature of a large burn injury, and it is important to determine the molecular mechanisms underlying burn-induced gut injury and the repair sequence.  A better understanding of these mechanisms may provide novel targets for pharmacologic therapy aimed at preventing complications such as overwhelming sepsis and multiple organ failure, which are determinants of mortality in burn patients.

   Burn leads to marked alterations in liver integrity and function.  To date, no study has shown whether the liver governs morbidity and mortality.  Our studies have revealed that liver integrity and function is causally linked to post-burn morbidity and mortality.  We have recently shown that burn causes vast cellular and molecular responses (e.g., signal transduction activation, inflammatory responses, and cell organelle stress).  We have further shown that burn injury leads to gross alterations in ER calcium and increased cytosolic calcium concentrations.  Increased cytosolic calcium induces mitochondrial damage, which releases cytochrome c. Cytochrome c binds to the IP3R, augmenting the depletion of ER calcium stores.  ER stress/UPR due to calcium store depletion leads to apoptosis (cell death) and activation of JNK, which phosphorylates IRS-1 at Ser612 to block its Tyr phosphorylation.  ER stress/UPR also impairs the pro-survival PI3K/Akt signaling pathway, resulting in an increased activation of IP3R and further increasing ER stress/UPR.

   We have not only shed light on basic cellular and molecular mechanisms underlying responses to burn injury, but also investigated possible treatment options to improve these responses.  Insulin decreases hepatocyte apoptosis after a burn injury, which is associated with activation of Akt, decreased ER stress/UPR, and improved hepatic mitochondrial respiration.  We hypothesize that insulin activates PI3K/Akt to decrease IP3R activation, an outcome that will improve calcium abnormalities and insulin resistance.  We further found that decreased IP3R activation reverses hepatic calcium abnormalities and attenuates ER stress/UPR.  We are now investigating whether these observed beneficial effects are due to activation of insulin-specific signaling pathways or glucose modulation.  We will compare the effects of insulin to those of metformin.  In summary, we have gained tremendous knowledge about cellular and molecular responses after burn injury, and we plan on altering these responses to improve patient outcome.

 

Sepsis

   Ultimately, the major cause of death in thermally injured trauma patients is gramnegative sepsis.  With this syndrome, several of the organs fail to function.  Researchers at this institute have determined, in a model of sepsis, that the kidneys, heart, and lung fail.  For several years, they have conducted studies to identify mediators of this response.  Most recently, they have discovered that a thromboxane synthetase inhibitor (an aspirin-like compound) can prevent this multiorgan failure due to endotoxin.

   Many thermally injured patients develop blood-borne infections or sepsis, yet the source of the organisms cannot be determined.  Some investigators have speculated that the gastrointestinal tract is the source of these organisms.  Recently, a group of investigators at the Galveston Unit have demonstrated that, following thermal injury, smoke inhalation or the administration of bacterial toxins causes a constriction of the blood vessels that go to the intestine.  The lack of blood flow, or ischemia, that results is associated with the appearance of bacteria from the gastrointestinal tract and several other systemic areas of the body, suggesting that the hypoxia compromises the barrier that prevents bacteria from entering the body.  They have demonstrated that vasodilator agents will reverse this phenomenon and more recently, that the same agent studied by the endotoxin group (the thromboxane synthetase inhibitor) also reverses the vascular constriction after thermal injury and prevents bacterial translocation.  This is a most important finding that may yield life-saving results in the future.

   Researchers at the Shriners Burn Institute in Galveston have developed an animal preparation that mimics the phenomena of sepsis (blood-borne infection or blood poisoning) observed in our patients.  This syndrome is responsible for severe complications in the majority of burn patients and is the case of death in the majority of burned children.  In this syndrome, dilators released cause vasodilatation, diverting lifegiving blood from vital tissues to those that are not metabolically active.  This shunt leads to the failure of many organs and death of the patient.  Investigators at Shriners Burns Institute have determined that a drug capable of blocking a natural dilator released during sepsis can reverse this process.  The results of these investigations have led to multiple clinical trials of this agent in Europe and soon in the U.S.  Preliminary results indicate that the compound will prevent morbidity and mortality in septic humans in the same manner that it worked in sheep.

 

Blood Borne Infections (Sepsis)

   The mechanism by which bacteria enter the body in burned patients has been a mystery in many situations.  Dr. David Herndon and his research team have determined that bacteria enter the circulation from the gastrointestinal tract following thermal injury.  Dr. Herndon’s group also has recently reported that sepsis is the number one cause of burn patient death.  In addition to infected burn wound and gastrointestinal bacterial translocation to blood stream, pneumonia frequently leads to development of sepsis.  Our group is focused on the pathophysiology of cardiopulmonary responses to pneumonia/sepsis due to various bacteriological agents such as Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus, E. coli, and Methicillinsensitive S. aureus (MRSA).  We have demonstrated that acute lung injury is more severely pronounced in Pseudomonas sepsis, while vascular leakage and organ edema is more severe in MRSA sepsis.  We have also described mechanistic aspects of those pathological responses and have offered many effective, novel, and safe treatment options to prevent/reduce the mortality and morbidity of septic burn patients.  For instance, our recent research on the use of mesenchymal stem cells and arginine vasopressin V1a receptor agonist as a novel treatment for sepsis led us to undertake two clinical trials, which are ongoing (phase one and phase 2, respectively).

 

Wound Healing

   Growth factors released by traumatized cells promote cell migration into the wound, epithelial cell growth, growth of blood vessels, matrix formation, and remodeling.  Wound healing has also been studied by our research team.  Our research team has developed techniques for evaluating the tensile and breaking strength of wounds.  They have also shown that growth hormone stimulates wound healing in burned children.  We continue to investigate growth hormone-stimulated wound healing with the addition of studies examining the growth-promoting factor, insulin-like growth factor-one.

  

Improving Psychological Adaptation to Trauma from Burn Injury

   Trauma significantly impacts not only children with burns, but also the child’s family and community.  Focusing on the burned child/family as a model, a team of investigators at Shriners Hospitals for Children—Galveston has continued to conduct a series of studies to identify psychosocial outcomes and factors that enhance positive long-term adaptation.  The data indicate that, although most pediatric burn survivors do not develop serious behavioral pathology as children, many may fail to develop positive adaptive behaviors that would enhance their psychosocial adjustment.  To understand these phenomena better, the Galveston group has focused on three major areas of research: pain and anxiety management, Posttraumatic Stress Disorder (PTSD), and long-term psychosocial outcomes.

   The Galveston group has been a major leader in the area of pain, anxiety, and itch management.  They have developed and instituted an aggressive protocol to ensure that every child is monitored closely for pain, anxiety, and itch.  The concept of a pain management protocol, which was developed at Shriners in Galveston, has been used in many burn centers around the world.  The overall medication management at our hospital has been assessed regularly, and the protocol has been updated twice.  This process results in excellent pain, anxiety, and itch management.  To improve our monitoring of itch problems, we have standardized the itch scale developed by Blakeney and Marvin in Galveston.  We have also been funded for 5 years to implement virtual reality as an adjunctive therapy for the pain and anxiety associated with wound cleaning, physical therapy, and exercise.  We think the improved management of pain, anxiety, and itch in the acutely burned patient influences long-term psychosocial outcomes.

   PTSD has been a major target for research and intervention.  We assessed PTSD in a group of young adults who sustained burns as children and who were treated in the late 1980’s and early 1990.  We found that the lifetime prevalence of PTSD was 21%.  In children and adolescents treated in the late 1990’s and early 2000’s, PTSD prevalence was reduced to 6 to 7%.  Our recently completed Shrine-funded study of over 170 children treated at the Galveston hospital revealed that Acute Stress Disorder (ASD) does not predispose someone to PTSD if the ASD is aggressively treated with pharmacotherapy and psychotherapy.  In another study, we demonstrated that ASD symptoms could be well controlled using either imipramine or fluoxetine in over 80% of the children who developed ASD.  We have been funded to investigate the influence of propranolol on ASD and PTSD.  We have shown that it does not influence ASD.  The PTSD study is currently being conducted.

   One issue of importance to Shriners is the long-term psychosocial outcomes of the children who had major burns.  We have analyzed data from 101 young adults who were treated as children for a greater than 30% burn.  The average age of burn was 7 years, and the time of follow-up was 14 years later.  Our data revealed that these individuals completed school, obtained employment, and married at a rate similar to the general population of their age.  What is of concern is that approximately 50% had a detectable major mental illness (usually an anxiety disorder or mood disorder).  This is considerably higher than that seen in the general population.  In addition, the quality of life of the entire group was diminished.  These individuals were all treated acutely prior to 1993.  It is extremely important to repeat this study now that our surgical and medical (pain and anxiety) management has improved so much.  We also have instituted techniques of teaching them social skills, so that their coping and integration into society is more complete.  We are also measuring the impact of exercise therapy on the recovery and quality of life of the children.

 

Exercise Rehabilitation

   Severe burns result in persistent and extensive skeletal muscle catabolism and weakness that leads to low functional capacity and reduced muscle strength.  This catabolism poses a major obstacle to burn victims, hindering their ability to perform daily living activities and their return to school and work.  The Children’s Wellness and Exercise Center applies exercise as a strategy for reducing catabolism and/or increasing anabolism.  We use exercise modalities, alone or in conjunction with other anabolic therapies such as nutrition or steroids, to study ways to synergistically improve physical function, body composition, and whole-body and muscle protein metabolism in children with severe burns.  Our center also studies thermoregulation as well as cardiopulmonary responses during exercise.  Our broad, long-term goal is to determine the optimal strategy for the rehabilitation of children that have suffered severe burns.

 

Mechanisms of Brain Injury by Acute Smoke Inhalation

   Acute inhalation of combustion smoke causes mortality and morbidity with immediate and delayed neurological deficits in survivors.  Pathophysiological mechanisms responsible for neurological sequelae of smoke inhalation, however, are not clear, hampering the development of effective intervention strategies.  To address this need, we have developed an awake-rodent model designed to mimic the real life scenario of acute exposure to combustion smoke and described the early and delayed molecular manifestations of smoke inhalation in the brain.  Genome-wide analyses of gene expression profiles have revealed significant changes in expression patterns of genes associated with energy metabolism and the nitric oxide system.  In addition, changes in levels of many common biomarkers of oxidative stress, including lipid peroxidation, protein nitration, and oxidative DNA damage have also been detected.  In combination, the analyses have revealed smoke-induced molecular patterns consistent of excessive oxidative stress in the brain.  In a search for potential intervention strategies, we have focused on the novel neuron specific oxygen-binding heme protein, neuroglobin, which affords neuroprotection in many paradigms of hypoxic-ischemicnoxious injuries via improved oxygen delivery and neutralization of free radicals.  We hypothesize that neuroglobin might also protect targets in the brain that are adversely affected by acute exposure to combustion smoke.  Specifically, neuroglobin binds oxygen with increasing affinity with declining pH, a phenomenon that might have biological significance in the context of hypoxic insults such as smoke inhalation that are typically accompanied by acidosis.  Similar to other globins, neuroglobin has been implicated in detoxification of reactive oxygen and nitrogen species.  In addition, involvement of neuroglobin in G-protein signaling, shifting threshold of apoptosis in favor of cellular survival via reduction of ferric cytochrome c, and preventing apoptosis via a pathway independent of cytochrome c reduction have also been proposed.  To explore the possibility of neuroprotection by neuroglobin in the setting of combustion smoke, we have engineered a transgenic mouse where neuroglobin overexpression is targeted and limited to the physiologically relevant neuronal cells.  We have been investigating the benefits of neuroglobin in our smoke inhalation model in the awake mouse.  Our studies have revealed that overexpressed neuroglobin attenuates the formation of oxidative DNA damage in the brain in the setting of smoke inhalation.  Because damaged or ill-repaired DNA generates faulty transcripts, in the long term it is likely to disrupt neuronal function.  Hence, reduced formation of DNA damage in the neuroglobin-overexpressing brain might effectively reduce secondary accumulation of damaged DNA and thereby, the risk of neuronal dysfunction and the development of secondary brain pathology.  We predict that overexpression of neuroglobin selectively modulates events associated with oxygen and nitrogen homeostasis and oxidative stress.  The physiologically relevant neuronal overexpression of Ngb is expected to help sustain brain homeostasis under conditions of acute exposure to combustion smoke and in the long term, help pioneer approaches to reduce smoke-induced neurotoxicity.

 

Immune Function

   Thermal injury-induced alterations to the immune system leave patients susceptible to infections, sepsis, and uncontrolled inflammation that can lead to organ dysfunction and mortality.  The immune response to infection is dynamic and orchestrated by many different types of immune cells.  Dendritic cells are immune cells that are central in the activation and regulation of these dynamic responses, through surveillance of tissues for invading microorganisms and activation of other immune cells to eliminate infection.  Investigators at the Galveston Unit have determined that dendritic cells can be manipulated by treatment with a specific growth factor (Flt3L) to enhance their ability to recognize infection and activate appropriate immune responses.  Using an animal model of burn wound-associated sepsis, we have shown that treatment with Flt3L prevents spread of infection and increases survival after thermal injury and that this protection is dependent upon the ability of dendritic cells to activate other immune cells.  This drug has significant potential as a prophylactic treatment to prevent infections in patients after burn injury, and studies are now underway to determine the mechanisms of protection so that this or similar drugs can be used to treat burn patients.

 

 

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