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NIDRR Burn Model Systems Priorities and Galveston Studies

Importance of the Problem

This proposal presents a model system of rehabilitation for burned children that will conduct studies on behalf of those children who have large and severe burn injuries.

Many burn survivors are children with severe burn injuries. The National Burn Repository 2006 Report1 registered 142,318 burn center admissions from 1996-2005 and the first 6 months of 2006. Of these, 95% or 134,754 persons survived. Almost one-third of the survivors (32.3%) were under age 20 years; 15% were under 5 years old and 17.3% were 5-19.9 years. It is clear that a large number of children suffer burn injuries and survive to return to their home communities. Many of these will be recovering from large severe burns. At Shriners Hospital for Children in Galveston (SHC-G), approximately 17% of our admissions (60 children) per year can be expected to have burns > 40% Total Body Surface Area (TBSA); 8.5 % of our admissions (30 per year) will have suffered burns of over 60% TBSA and almost half of these will have burns over 80% TBSA. Mortality of children with large burns has diminished dramatically. Half the children under age 14 who are admitted to us with burns of TBSA=99% can be expected to survive; half the children over 14 who are admitted to us with burns of TBSA=88% can be expected to survive.2

Pediatric injuries present unique challenges at the time of acute treatment and throughout rehabilitation. Although there are similarities in treatment of adults with burns, children have special needs requiring treatment protocols designed for them. Whereas the adult body and brain are mature and relatively static, the body and brain of a child are constantly evolving. Skin grafts in children must be placed with a consideration for the changes that occur during growth and development, and scar contractures limiting movement are more common. The child's self-concept and cognitive schema of the world are rudimentary. There is little known of how a severe burn and intrusive treatments may impact children cognitively and emotionally; even less is understood about the varying impact at different developmental stages.

Our research emphasis is on children with large and severe burns because they present the greatest challenges to the burn care team, acutely and throughout the years of very expensive recovery, extensive rehabilitation, and reconstructive procedures. The problems addressed by research in this proposal threaten the survival of persons with large and severe burn injuries; for those who do survive, these problems impede their rehabilitation and badly interfere with their successful resumption of participatory life in their homes and communities.

A hypermetabolic/catabolic stress response occurs with severe burn injury and lasts for about 1 year post-burn.3,4 This stress response is characterized by a number of events that are life-threatening,5 to the patient, e.g. tachycardia and cardiac dysfunction, increased cardiac output, increased resting energy expenditure, increased protein catabolism and peripheral protein wasting, hyperpyrexia, and increased lipolysis. The erosion of body mass that occurs with catabolism can lead to impaired immune function, decreased wound healing, pneumonia, pressure sores, and eventually death. Children with large burns suffer arrested vertical growth6. Bone formation is slowed, and bones are weakened7. In no other disease or trauma is the hypermetabolic response as severe as it is following a thermal injury5. Even when the patient survives, the debilitating effects of hypermetabolism delay and limit restoration of function for the patient. Without intervention directed toward mitigating the effects of this stress response, such debilitated survivors are destined to return to their communities still struggling with the fatigue and frailty secondary to this stress response. Survivors of large burns, during the critical first year post-burn, are reestablishing body competence with daily painful physical therapy exercises and application of appliances to assist in their rehabilitation. They must reintegrate into society and interpersonal relationships with attendant insecurities about their changed appearances; they are returning to work and/or school; they are grieving their losses. At a time when they most need strength, their bodies are in a catabolic state resulting in muscle wasting, bone weakness, and extreme fatigue.

They must endure their physical rehabilitation and return to activities such as school or work in spite of their physical exhaustion, for delaying these activities would further debilitate them physically, psychologically, and socially. Often, they are experiencing psychological symptoms of the response to trauma, Post-traumatic Stress Disorder, concomitantly with the hypermetabolic stress response, and are additionally plagued by such symptoms as sleep disturbance, irrational fear, and flashbacks8. Their performance in daily activities is impaired by stress and fatigue, so, in addition to their other difficulties, they may now fail to achieve success in school or at work. During that first year post-burn, survivors of large severe burns suffer stigmatization, not only because their appearance is different from non-burned peers, but also because they cannot keep pace with those peers. Burn survivors must develop new self-concepts to allow for the changes in their bodies; for survivors of severe burns, the rudimentary changes to self-image are established during these months when it is probable that they begin to define their “new selves” as less competent than others.

Because SHC-G receives so many children and adolescents with massive burn injuries that survive and because we follow these patients into early adulthood, we have both a need and an opportunity to explore venues that have the possibility of diminishing their difficulties and assisting them in recovery and long-term gains to achieve maximal success.

The vision that has guided our research for 25 years is to diminish mortality from burn injuries and to improve the quality of life for survivors of burn injuries; for the last 10 years, our research has emphasized the importance of finding means to mitigate the effects of the hypermetabolic/catabolic response to large severe burn injury. We envision patients with life-threatening severe burns who survive with shorter hospital stays and less overall debilitation. The survivors in our vision will be stronger, have greater endurance, and will return to active, participatory lives suffering less from physical fatigue, constricted movement, and psychological terror. They will begin the tasks of relating to the non-burned world and building a new self-concept with more energy and a more positive attitude. We predict they will have even better outcomes and at an earlier time post-injury than expected with current usual care.

The studies we propose directly address this vision:

  1. We propose a collaborative study of the efficacy of propranolol administered for 1 year post-burn to moderate the effects of the hypermetabolic response for patients of all ages; because propranolol has been suggested as a means of secondary prevention of post-traumatic stress disorder (PTSD), we include in the collaborative study a method for studying this effect of propranolol as well. The target population for this study is survivors of large burns, Total Body Surface Area burns (TBSA) ≥ 30%, ages 0-90 years. Although we include adults in this target group, our center will contribute a large number of pediatric patients as subjects with a lesser number of adults who can be recruited from the Blocker Burn Unit at the University of Texas Medical Branch. Our collaborators would also contribute subjects, thus increasing the number of adults sufficiently to conduct the study.
  2. For children ages 7-19 with large burns, TBSA ≥ 30%, we propose (2) a study of the efficacy of long-term propranolol in addition to a 3 month in-house resistance training and aerobic exercise program previously shown to ameliorate many effects of the hypermetabolic/catabolic response9,10. As part of the exercise study, we propose continuing to study the efficacy of a similar program that was begun during the previous funding cycle for children under the age of 7 with TBSA ≥ 30%; we also will examine these data for benefits of adding propranolol to the exercise regime.
  3. Finally we propose a study of the natural history, treatment efficacy, and predictors of acute stress disorder (ASD) and post-traumatic disorder (PTSD) in children (ages 3-18) who have survived burn injury and who are treated at SHC-G with the expectation that this study will facilitate early diagnosis and improved treatment of those conditions that plague a sizeable group of burn survivors.

The first 2 studies are extensions of work initiated in Galveston in 1997 with the inception of the Burn Model System at SHC-G and continued through the 2002-2007 funding cycle. As detailed in Section C, those studies have demonstrated that the anabolic agents growth hormone and oxandrolone and a resistance and aerobic exercise program, separately and together, significantly diminished the negative impact of the early and enduring hypermetabolic state. However, growth hormone must be given by daily injection and can be dangerous for older patients. Cost of oxandrolone is prohibitive for most situations. Propranolol can be administered orally, is much less expensive, and is safer for patients of elder ages. Pilot studies with propranolol indicate it to be very promising in mitigating effects of the hypermetabolic/catabolic response, and some evidence suggests it to be effective in preventing the development of PTSD. Thus, it seems a logical choice for study.

The 3 month in-house exercise program for children 7 years and older, with or without addition of anabolic agents, presented such clear evidence of efficacy that, by 2004, it was accepted as state of the art “usual” care for large burns at SHC-G. Unfortunately, such a program has not been integrated into care in most other burn centers. There are reasons to believe that the beneficial effects of this exercise program may be enhanced by the long-term administration of propranolol, and that is the purpose of proposing it as a site specific study here. Additionally, we have begun to develop a comparable “play” program accompanied by music for the children under age 7 that should be studied in the same way as that for the older children.

The ASD-PTSD study is also an extension of a project begun during the last funding cycle, and as reported in Section C it is producing interesting results. Thus, we include it here in the belief that the findings will facilitate efforts to assist children suffering the debilitating effects of these disorders.

References

  1. American Burn Association Advisory Committee. National Burn Repository 2006 Report,, 2007.
  2. Pereira CT et al. Age-dependent differences in survival after severe burns. J Am Coll Surg 202(3):536-48, 2006.
  3. Hart DW, SE Wolf, R Mlcak, DL Chinkes, PI Ramzy, MK Obeng, RR Wolfe, Herndon DN. Persistence of muscle catabolism after severe burn. Surgery 128 (2):312-319, 2000.
  4. Hart DW, Wolf SE, Chinkes DL, Gore DC, Mlcak RP, Beauford, RB, Obeng MK, Lal S, Gold WF, Wolfe RR, Herndon DN. Determinants of skeletal muscle catabolism after severe burn. Annals of Surgery 232(4):455-465; 2000.
  5. Spies M, Muller MJ, Herndon DN. Modulation of the hypermetabolic response after burn. In Total Burn Care(2nd Edition), DN Herndon (Ed.):363-381. WB Saunders, London, 2002.
  6. Low JFA, Herndon DN, Barrow RE. Growth hormone ameliorates growth delay in burned children: a 3-year follow up study. The Lancet, 354:1789, 1999.
  7. Klein GL, Herndon DN, Goodman WG, et al. Histomorphometric and biochemical characterization of bone following acute severe burns in children. Bone, 17(5):455-60, 1995.
  8. Saxe G, Stoddard F, Sheridan R. PTSD in children with burns: a longitudinal study. J Burn Care Rehabil 1998; 19(1, part 2): S206.
  9. Pitman RK, Sanders KM, Zusman RM, Healy AR, Cheema F, Lasko NB, Cahill L, Orr SP. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol. Psychiatry 51:189-142, 2002.
  10. Zatzick D & Roy-Byrne PP. From bedside to bench: How the epidemiology of clinical practice can inform the secondary prevention of PTSD. Psychiatric Services 57(12):1726-1730, 2006.