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            Advances in Burn Care


David. N. Herndon, M.D., Chief of Staff and Director of Research
Shriners Hospitals for Children-Galveston



Recent discoveries and new therapies resulting from clinical and basic research are continually being incorporated into burn care worldwide.  As a result, the mortality of burned children and length of the hospital stay have been greatly reduced over the last 25 years. In the 1960’s, the likelihood of survival was only 50% in children with burns covering 35 – 44% of the total body surface area (TBSA), and few patients with burn sizes exceeding 45% TBSA survived.  The average length of stay for the acutely burned child was 103 days.  Today, the lethal burn size for 50% of children exceeds 95% TBSA, and the average length of hospital stay for most serious burn injuries can be expected to be only 0.5 days per percent of burned TBSA.  Advances in the last 25 years have not only improved the length of hospital stays and survival rates, but also tremendously improved the long-term outcomes of severely burned patients.  The last decade has seen major advances that have allowed burn patients to be effectively rehabilitated and reintegrated into society.  These patients have skills and developmental improvements that are truly outstanding, making them effective, productive, and thoughtful members of society.

   These remarkable achievements have been made possible through discoveries in a myriad of areas.  This article will summarize some of the most important advances that have been made in these areas through the support of the Shriners Hospitals for Children.  Particular emphasis will be placed on achievements in early excision and wound treatment, fluid resuscitation, infection control, metabolism and nutrition, inhalation injury, and scar development and rehabilitation.

Early Excision and Wound Treatment

   As early as 1947 researchers (1) recognized that prompt eschar removal and immediate wound closure improved outcomes in burn injuries.  Nevertheless, application of this approach to large burns was not practical before the 1970s due to the fact that it was associated with high rates of infection, bleeding complications, and wound failure.  Instead, many burn units adopted the excision technique (2), which involved introduction of a single tangential slice to remove the superficial layer of second-degree injuries.  The application of this tangential excision method to superficial injuries often resulted in excessive blood loss in the case of large burns and burns with full-thickness depths.  However, the development of effective topical antimicrobials and systemic antibiotics in the 1960s, combined with hypotensive anesthetic techniques and other blood-conservation measures, allowed prospective, but non-randomized, clinical trials to be conducted.  These trials (3) revealed that tangential excision improved survival and length of hospital stay, increasing the popularity of this surgical approach.

   The exact contribution of prompt eschar excision and immediate wound closure to the outcome of patients with large burns has remained largely unknown because prospective randomized clinical trials have not been conducted.  However, a few prospective studies have been performed by Shriners Hospitals for Children (4,5). These studies have shown that prompt excision shortens hospital stay (6) and improves survival (7).  Survival and hospital stay are not the only outcomes that have been found to improve.  Several centers have reported improvements in long-term function and the cosmetic appearance of burns, leading to a decreased need for reconstructive procedures.  Further developments have allowed for safer operations and minimized blood loss (8).  Together, these advances have allowed this approach to be effectively used in burns of all sizes and have made it the standard method for treating burn injuries (9,10).

   A clear clinical need for a skin replacement material was evident by 1981.  This need prompted the development of a bilayer artificial skin for permanent wound closure, and preliminary clinical results of its use were reported (11,12).  An 11-center clinical trial was conducted to compare this artificial dermis to conventional grafting techniques after the early excision of the burns in patients with major thermal injuries (13).  This trial showed that artificial skin provided a permanent wound cover that was at least as satisfactory as currently available skin-grafting techniques.  The take of the “thin” epidermal grafts on the artificial skin was 80% successful, and at the completion of the study, less hypertrophic scarring was seen with artificial dermis.  In addition, patients preferred the artificial skin to conventional grafting methods.  Continued experience with this artificial skin has been extremely favorable, and a potential survival benefit has been associated with its use in massive burns (14).

   Findings from research conducted over the last 10 to 15 years provide the underpinnings for current standards of care and have opened new directions for wound coverage during early excision and grafting.  New approaches that will potentially be new standards of care in the near future include the use of liposomal gene transfer (15), artificial skin substrates such as dermal matrices with epidermal components (16), amniotic wound coverage devices (17), dermal component matrices (18), and stem cells (19).  Several new studies have been conducted by the four Shriners Burn Hospitals to determine the efficacy and role of stem cells in severely burned patients.  These studies suggest that stem cells have tremendous potential for the treatment of severely burned children.  Despite this potential, the use of stem cells is limited due to ethical concerns.  However, these concerns can be circumvented by using adult stem cells.  Currently, many studies funded by the Shriners are being conducted on adult stem cells.  Several groups at the Shriners Hospitals for Children are studying the efficacy and potency of adult stem cells in enhancing regeneration of the skin, liver, kidney, heart, pancreas, or gut.  The importance of these cells is clearly shown in recent publications.

   Gene therapy is another emerging technique that can be used to alter dermal and epidermal regeneration and to improve wound healing.  Shriners Hospitals for Children is currently studying this cutting-edge technique, which may become a standard therapeutic approach in 10 to 20 years.  Liposomal (non viral) transfection of certain gene constructs has been shown to induce cells to produce and release growth factors and other signaling factors that improve dermal and epidermal regeneration (20).  This approach appears to have therapeutic potential and relevance, as liposomes can be effectively used to deliver gene constructs into dermal stem cells (21).  Gene therapy also has applications beyond enhancing wound healing.  For example, it could also be used to promote the survival of other organs affected by burn injury.  This futuristic technology has evolved from cell cultures and small animal models to large animal models.  New data have demonstrated that this technique is possible in large animal models.  This is the final step before possible clinical trials.

   The aforementioned approaches (i.e., stem cells and gene therapy) have bright futures in the treatment of burn wounds.  However, in terms of artificial skin, the future has already arrived, as seen by a skin substitute developed by the Shriners Hospitals in Cincinnati and Boston.  Shriners in Boston first developed a dermal substitute known as Integra.  This material was then used by the Cincinnati group to construct an artificial skin called Cultured Skin Substitute (CSS).  CSS is a full-skin substitute consisting of the patient’s skin (epithelium) and Integra (dermal substitute).  Prior to the development of CSS, an urgent need existed for such a skin substitute, making this newly developed functional skin a major advance for the coverage of large burns (22).  This advance will open doors for new developments and approaches that will reduce the amount of donor sites taken from the patient and improve cosmesis, which is closely linked to quality of life in severely burned patients.


Fluid Resuscitation

   Research supported by Shriners Hospital has also yielded major improvements in resuscitation therapy.  In the early 1960s, formulas for fluid resuscitation in adults had already been established.  However, a major controversy existed concerning the use of colloids as a part of the fluid resuscitation regimen (23).  A resuscitation formula was then developed that was based upon body surface area and body weight (24).  This formula proved to be more appropriate for pediatric patients (25,26) and is now used worldwide.  It has remarkably increased the survival of thermally injured pediatric patients, decreasing mortality from renal failure from 100% before 1984 to 56% after 1984 (27).  Studies have further shown that patients with smoke inhalation injury require 2 cc per kg per percent burned TBSA more fluid than patients with equivalent size burns without smoke inhalation injury.

   Investigations have revealed that thermal injury induces massive systemic vasoconstriction that is independent of sympathetic nervous system activity (28).  Studies have implicated antidiuretic hormones and the renin angiotensin systems in this response (29).  This response bears an important relationship to bacterial translocation after thermal injury (i.e., the passage of bacteria from the intestine into the circulation), which may contribute to the development of multiorgan failure (30).

   Recent studies from all four centers indicate that early initiation of resuscitation within 2 to 4 hours improves survival, organ function, morbidity, and long-term outcomes in severely burned patients (31).  Aside from the timing of resuscitation, individual differences in resuscitation needs are also becoming evident.  That is, the formulas do not really reflect the need of the patient.  New formulas developed from several laboratories as well as the four Shrine centers show that patients’ cardiovascular, urinary, and pulmonary system should be intensively monitored.  Studies originating from the Shriners Hospitals have investigated new catheter devices and have demonstrated that online, non-invasive monitoring of cardiopulmonary functions has tremendous potential to individually direct fluid resuscitation (32).  Other groups have gone one step further (33).  They have used a closed-loop system to adjust resuscitation rates in conjunction with the non-invasive cardiovascular and pulmonary systems.  This has improved the initial resuscitation and treatment of severely burned children (33).  This research, which is supported by the Shriners Burns Hospitals for Children centers, will become a major milestone in future patient care and will improve the acute outcome in severely burned children.


Infection Control

   Infections in severely burned children are one of the main causes of mortality.  Indeed, a recent study originating from one of the Shriners centers found that 30 to 50% of burned children die due to infections or sepsis (34).  Studies conducted at Shriners Hospitals for Children have shown that early excision and grafting not only improves scarring and cosmesis, but also decreases the incidence of infections and sepsis (35).  Removal of the burn scar dramatically decreases colonization of bacteria and fungi that can lead to systemic infection or sepsis.  Bacterial and fungal colonization of the burns can also be decreased by soaks developed at Shriners Hospitals.  Shrine studies have demonstrated that these antimicrobial anti-fungal soaks are of great benefit in preventing tissue infection, systemic infection, or sepsis.  Mafenide acetate, silver sulfadiazine, and 0.5% Dakins solution are current topical treatments and have shown to greatly improve graft take and prevent infections (36).

   A high incidence of gram-negative sepsis exists in thermally injured patients without an obvious source of bacteria.  This led to the hypothesis that the gram-negative bacteria were derived from the gastrointestinal tract.  The concept that the burn wound became infected as a result of microorganisms from the gut entering the circulation was proposed.  This idea has been tested in dogs by infecting the gastrointestinal tract with Pseudomonas labeled with a fluorescein tag.  Bacteria crossing the mucosal barrier in burned animals were identified from fluorescence tags in the plasma.  Later, this tagged material was found in the burn wound itself (37).

   Recently, the importance of bacterial translocation after cutaneous thermal injury, endotoxin administration, or inhalation injury has been recognized (30,38).  Bacterial translocation associated with reduced blood flow can be prevented with vasodilators (39).  These events may be clinically important since a reduction in blood flow to abdominal organs is associated with the release of myocardial depressants (40-42).  This could explain the increase in mortality seen in patients with combined thermal and inhalation injury, since the combination of these two insults produces a greater increase in abdominal vascular resistance than either insult alone.  The need to prevent “under resuscitation” of burned patients is well recognized (43-45).  Most recently, a drug (a thromboxane synthetase inhibitor) that inhibits the formation of a vasoconstrictive mediator that is released after burn injury (thromboxane) (46) has been shown to reverse bacterial translocation following thermal injury (47) and myocardial depression following administration of endotoxin (48).  Preliminary data indicate that compounds with anti-thromboxane activities may also be effective in preventing the mesenteric vasoconstriction and myocardial depression that occurs following inhalation injury (48,49).

   Burn patients are severely immunocompromised and unable to fight off infections and bacteria.  Research from the Shrine centers is focused not only on the treatment of infections, but also the improvement of patient defenses against infections.  At all four centers, several grant applications propose new ways to improve the immune system.  New pathways, receptors, cell populations, drugs, and interventions are currently being investigated to change the immune compromised patient into an immune competent patient to improve survival.  Examples of ongoing research include studies determining the effects of propranolol (a non-selective β1/β2 receptor antagonist) on the immune system.  Preliminary data show that propranolol is able to change immune incompetent macrophages and monocytes to functional cells that increase bacterial clearance.  This exciting finding suggests that we may have a new treatment to reverse the devastating immune compromised state of severely burned children.

   Another discovery that originated from research performed at Shriners Hospitals is the finding that severe burn injury triggers a remarkable upregulation of the inflammatory response in the immune system.  Recent studies (49-50) have shown that a dramatic upregulation of many cytokines, inflammatory markers, hormones, stress hormones, and stress markers persists for a prolonged time, leading to alterations in the immune system and the body’s metabolic response.  Therefore, the immune system and the inflammatory response play a major role as mediators of the post-burn response. Interventions to alter these “mediators” would be expected to improve outcomes in severely burned children.


Metabolism and Nutrition

   Fundamental questions regarding the metabolic demands of the thermally injured patient have been investigated.  These questions include the following.  1) How many calories do thermally injured patients require?  2) How many carbohydrate (glucose) calories should these injured patients be given to avoid starvation and to promote protein synthesis?  3) How many protein calories should these patients be given to achieve net protein synthesis?  4) What treatments should be given to reduce diabeticlike symptoms such as insulin resistance?  As discussed below, studies conducted at Shriners Hospitals for Children have yielded several practical answers.

   While the body of a burn victim undergoes many changes, the rampant acceleration of metabolism places an increased load on the heart, liver, kidneys, and lungs as well as other vital organs that provide normal body stability.  Massively burned children exhibit a two- to three-fold elevation in both heart rate and catecholamine levels, leading to the digestion of peripheral muscles to support the voracious need for building materials necessary to heal wounds (51).  Part of this high metabolic rate is useful, as it helps provide building materials for the wound-healing process.  However, it is also problematic, as the elevated metabolic rate may complicate respiratory problems.  In addition, not all of the increased energy mobilized peripherally goes to wound healing.  Burn patients undergo muscle wasting and become centrally fat because the liver is apparently unable to process the large amount of peripheral fuel presented to it.  In many cases, the metabolism in non-injured areas is so high that wound healing becomes retarded.

   In light of the above events, choosing the proper level and source of energy is one of the most critical aspects of helping patients recover from a severe burn.  Large amounts of carbohydrates and fat must be converted to energy to satisfy the requirements needed to nourish the traumatized body and fuel the rapid growth of new cells.  An insufficient diet can be extremely detrimental to the burn patient.  On the other hand, excess calories can also be harmful.  One major cause of mortality in burn patients is respiratory failure.  Decreased respiratory and peripheral muscle mass reduces the ability to breathe and exercise.  Excessive carbohydrate administration may increase carbon dioxide production and further complicate the respiratory status.  Therefore, determining the optimal caloric intake requires giving sufficient, but not excess, calories.  This has been an intense area of research funded by Shriners.


   Carbohydrate metabolism is greatly altered in burn patients, and burn centers have investigated how to best compensate for these changes (52,53).  One of the more dramatic burn-induced alterations is the increase in glucose uptake rates and gluconeogenesis.  Despite these increased rates, researchers have identified a practical limit in the glucose infusion rate (5 mg/kg/min), beyond which the excess glucose is not oxidized for energy but simply becomes stored as fat (53).  Excess fat is stored in the liver.  The resulting fatty liver elevates the diaphragm and compromises breathing.  At glucose infusion rates above 5 mg/kg/min, the respiratory quotient exceeds unity, causing excess carbon dioxide production and increasing minute alveolar ventilation requirements.  The combination of diaphragmatic elevation and increases in carbon dioxide exacerbates respiratory difficulties in burn patients.

   Malnutrition and burn injuries have been associated with infection and death.  Burn physicians in various cities began continuously feeding patients milk to reduce the incidence of gastric and duodenal ulcers (54,55).  As a result, stress ulcers rarely occurred in milk-fed patients.  Milk was also shown to prevent weight loss in children who were recovering from severe burns.  This led to the practice of milk feeding up to one hour before any surgical procedure.  Accurate formulas for the precise amount of calories required to maintain weight in burned children of different ages have continued to develop (56-59).  However, the use of supplemental parenteral hyperalimentation has been shown to be not only unnecessary, but also detrimental (60, 61).  Early enteral and continuous feeding has now decreased mortality in burned children and is an accepted practice in burn units around the world.  Because giving fat rather than carbohydrate can exacerbate fatty liver, there has been a recent shift away from providing high-fat formulations such as milk toward high-carbohydrate formulations.

   Marked changes in organ and whole-body protein metabolism often accompany a severe thermal injury.  Much of our knowledge about the nature of whole-body protein metabolism after trauma has been obtained from nitrogen-balance studies.  These studies uncover changes in total body nitrogen content, though they do not reveal the pathways through which these changes occur.  Many studies using stable isotopes and steady-state kinetic models have greatly contributed to our understanding of changes in whole-body protein metabolism after burn injury, and they have helped us to understand how to best compensate for burn-induced changes in whole-body nitrogen content (62).  Unlike most studies, these studies do not involve laboratory animals or in vitro environments.  Instead, they are performed on patients using nonradioactive isotopic tracers (stable isotopes).  Stable isotopes are naturally occurring atoms that possess an extra neutron, allowing them to be easily distinguished from their more abundant natural form.  By collecting expired air, blood, or tissue samples containing these stable isotopes, research scientists can track the transformation of amino acids into protein used to build muscle tissue.

   Protein metabolism is the process by which tissues (such as muscle) are constantly being built up and broken down.  After thermal injury, protein breakdown exceeds synthesis, causing a net release of amino acids (the basic building blocks of protein) (63).  When elevated in the serum, these amino acids are converted to glucose in the liver, a process known as gluconeogenesis.  Glucose is then broken down to smaller compounds in peripheral tissues through anaerobic or aerobic metabolism to generate energy.  During anaerobic metabolism, the smaller sugars are converted into lactate and pyruvate. This appears to be the primary energy-producing process in thermally injured patients (64,65).  The elevation of lactate and pyruvate can be detrimental to the patient.  The resulting acidosis (generated by lactate build-up) is accompanied by compensatory changes in the utilization of glutamine, an essential fuel for cells lining the gastrointestinal tract and of the immune system.  Depletion of this amino acid causes the starvation of these cells, allowing toxic materials and bacteria from the gut to enter the systemic circulation.  A potential therapy to combat this is being tested and involves the administration of compounds that stimulate the incorporation of amino acids into protein.  Administration of treatments such as oxandrolone and human recombinant growth hormone reverse the net protein breakdown produced by thermal injury and stimulate the use of amino acids for muscle synthesis (66,67).  This not only redirects metabolism away from gluconeogenesis, but also increases incorporation of amino acids into healing wounds.  An increase in the rate of donor site healing and a decrease in the length of the hospital stay have been shown to occur when burned children are treated with growth hormone and other anabolic agents.  Patients with 60% burn wounds experience a decrease in the length of the hospital stay from 46 to 32 days (68).

   After thermal injury, a reorganization of protein synthesis occurs.  Several enzymes and proteins involved in the body’s defense system are increased.  These factors include blood coagulation factors, proteolytic enzyme inhibitors, and enzymes involved in the destruction of bacteria.  At the same time, other proteins such as albumin are reduced.  A reduction in albumin can be detrimental since this plasma protein plays an important role in preventing edema.  Investigators are now beginning to identify the genetic and proteomic mechanisms responsible for these changes and have identified several factors that participate in regulating these genes and proteins.

   Optimizing the hormonal milieu is also a critical area of burn care that is undergoing important advances.  Researchers have demonstrated that very high levels of the hormone epinephrine (adrenaline) are present in thermally injured patients (69,70).  This hormone can increase metabolism by stimulating -adrenergic receptors.  Propranolol, a competitive antagonist of -adrenergic receptors, has been shown to lower heart rates in burned children, decrease the amount of oxygen needed to keep the heart pumping, and reduce anxiety caused by burn-induced epinephrine release, without impairing the ability of the patient to respond to stress (71,72).  In thermally injured patients, the rate of fat metabolism is 2.5 times higher than that in normal individuals.  This appears to be due to elevated catecholamines and -adrenergic stimulation, since this increase can be blocked by propranolol (73,74).  The deposition of excess fat in the liver causes fatty liver, which is thought to induce insulin resistance in burned children.  Accordingly, burned children display many symptoms similar to those seen in diabetic patients.  Importantly, Shriners researchers have shown that reducing fatty liver in burned children with treatments such as propranolol and fenofibrate improves insulin sensitivity.

   Finally, one of the recent contributions of Shriners Hospitals to burn care is the discovery that the hypermetabolic response produces effects at the cellular level.  Hypermetabolism is associated with cell death (apoptosis) in skeletal muscle, fat, liver, kidney, lung, heart, and gut.  These detrimental cellular events are associated with dysfunction of cellular organelles such as the mitochondria and endoplasmic reticulum.  New studies clearly show that a burn injury is not limited to the skin.  Rather, it causes dysfunction of almost every cell in the body, leading to alterations in cellular functions and cellular signaling pathways.  New strategies to alter these pathways may restore cellular function and productivity.  This, in turn, may lead to improved energy metabolism, cell survival, morbidity, and mortality not only during acute hospitalization, but also long term.  In the past, burn patients typically lost 40 – 50% of lean body mass, an occurrence that almost always resulted in death.  Several new approaches have been successfully used to alter hypermetabolic responses, including use of adequate nutrition, ventilation, and fluid resuscitation; early excision and grafting; growth factors; air beds; and a warm environment.  These approaches have decreased the loss of lean body mass, muscle, fat, and bone to 5 – 8%.  This is a dramatic improvement given that loss of 5 – 8% lean body mass is associated with a dramatic increase in survival.  Decreasing loss of lean body mass also improves strength, endurance, rehabilitation, and reintegration into society.  These findings as well as others from Shriners Hospitals for Children clearly show that the hypermetabolic response to burns plays a key role in burn injury and is a major determinant of survival.  Research originating from all four centers at Shriners Hospitals for Children has advanced knowledge of how to attenuate and reverse the hypermetabolic response as well as of how to improve patient outcomes, including quality of life.


Inhalation Injury

   Inhalation injuries presently account for the majority of the deaths in thermally injured patients (93,94).  For this reason, research and clinical advances in these areas have become the new horizons for improved patient outcomes.  Inhalation injury studies often focus on two main pathways, one relating to parenchymal injury and the other to damage of the airway of the tracheobronchial tree (75-77).  Inhalation injury has been found to be associated with a marked increase in the transvascular fluid flux across the lungs (78).  This fluid flux occurs as the result of changes in both microvascular pressure and permeability to protein (78, 79).  Later studies revealed that the formation of lung edema is associated with polymorphonuclear cells (80).  These cells injure the lungs by releasing proteolytic enzymes (81) and free oxygen radicals (80).  Other studies have shown that the amount of fluid resuscitation required after smoke inhalation is greater than that required for a burn alone and that appropriate fluid resuscitation reduces, rather than enhances, transvascular fluid flux (82, 83).  These findings have led to greater fluid resuscitation in patients with concomitant thermal and inhalation injury.  Other findings have also been applied to patient care.  For example, techniques for measuring extravascular lung water by the thermal dilution technique have been applied to patients to evaluate the extent of pulmonary edema (84).

   Hyperemia (excessive amounts of blood) of the tracheobronchial tree occurs after inhalation injury and is used for diagnosis of inhalation injury (85).  Investigators have shown that hyperemia is associated with a ten-fold increase in bronchial blood flow (86-90) and an increase in the permeability of the affected tracheobronchial areas.  Reducing hyperemia has been shown to reduce pulmonary edema seen after smoke inhalation (88,91).  In addition, treating animals with capsaicin, a compound that depletes sensory nerves of neuropeptides, markedly reduces elevations in bronchial blood flow and transvascular fluid flux commonly occurring after inhalation injury.

   Several concomitant changes occur in the systemic circulation following inhalation injury.  The heart muscle is depressed, the vasomotor tone of the gut is increased, and systemic microvascular permeability is elevated.  Initial investigations have shown that blockade of a potent arachidonic acid derivative, thromboxane A2, markedly reduces these changes (92).

   The finding that airway damage is associated with pulmonary changes following inhalation injury has changed how patients with inhalation injury are treated.  Initially, placement of endotracheal tubes in patients with existing damage to the airway was expected to only aggravate the injury.  For this reason, endotracheal tubes were not used in patients with bronchoscopic evidence of inhalation injury, and the placement of tubes was avoided, even for anesthetic procedures.  Endotracheal tubes are now used only if arterial oxygen is markedly reduced, carbon dioxide is increased, or evidence of severe respiratory distress exists.  The practice of avoiding endotracheal intubation has reduced the number of ventilator days and morbidity (unpublished data).


Scar Development, Rehabilitation, and Psychological Adjustment

   One of the major issues that burn victims face once they survive the acute phase is the formation of hypertrophic scars.  Current research performed at several centers is focused on how the development of the hypertrophic scar can be attenuated and altered.  One of the goals of this research is to determine whether hypertrophic scars result from a genetic predisposition, a proteomic predisposition, or a surgical technique.  These answers are extremely relevant because hypertrophic scarring requires repeated operations for burn patients.  The debilitating appearance of hypertrophic scars limits the reintegration and rehabilitation of burn patients.  It also diminishes the patient’s self perception.  These research endeavors funded by Shriners Hospitals for Children are relevant not only for burn patients, but also for other surgical patients who develop hypertrophic scars or keloids.  Major advances are expected over the next decade.  One of the main achievements that has already taken place is the use of pressure garments to attenuate hypertrophic scar development.

   Pressure garments, which are used to reduce scarring, were developed 20 years ago.  Traditionally, elastic bandages were placed on the legs of burn patients to improve venous return and decrease bruising or blood blister formation.  These bandages were also applied to splints to reduce and prevent contractures.  Therapists observed that burn patients rarely developed hypertrophic scars when these pressure garments were applied (95,96).  Unsightly scars could be prevented if the pressure garments were continuously worn, and they could be reversed if the pressure garments were applied.  Investigators studying scar formation have found that collagen fiber deposition in nonhypertrophic scars is parallel, whereas fibers in hypertrophic scars predominantly form nodular or whorl-like patterns (96-99).  With the application of pressure, these diffuse, disorganized fibers become parallel.  The relationship of the whorl-like fibers depends on the quantity of proteoglycan that makes up the scar tissue.  In hypertrophic scars, this material is more abundant.  Several researchers have concluded that pressure application reduces the scar by limiting blood supply to the wound.  Other studies have shown that the macrophages of patients with keloids and hypertrophic scars produce elevated levels of interleukin 6,  interferon, and tumor necrosis factor, suggesting that these inflammatory cytokines participate in scar formation (100,101).

   Although compression has beneficial effects on scar formation, pressures may increase over time and decompression of burn wounds is often necessary.  Failure to decompress extremities with elevated pressures may lead to significant, but preventable, complications (102).  These complications can be avoided by monitoring compartment pressures in burn patients.  Interestingly, monitoring pulse is not an acceptable substitute, as it is not predictive of ischemia (102).  Models of burn treatment strongly rely on the integration of basic science, clinical research, and clinical treatment that share information in a continuous feedback loop.  Clinical innovations are usually based on empirical data and then evaluated for effectiveness through scientific study.

   In the last 5 – 7 years, advances in multiple aspects of burn care have improved the quality of life of burned victims.  Quality of life has been improved by attenuating the hypermetabolic response as well as by increasing the patient’s physical function, performance, and well-being.  A 12-week exercise training regimen developed by Shriners Hospitals for Children has been shown to improve body composition (lean mass and muscle content), strength, rehabilitation, reintegration, and life quality of the burned patient (103-106).  It has also decreased the need for reconstructive surgery by lessening scarring.  This is a significant achievement since we have not only decreased mortality and hypermetabolism in burned patients acutely, but also improved the rehabilitation and reintegration of patients.

   Other findings are also expected to lead to improvements in the quality of life of burn patients.  Research support through Shriners Hospitals for Children has enabled development of a database to follow patients longitudinally on specific measures of physical and psychosocial recovery.  Four hundred patients have been entered into this database, which includes longitudinal assessments of cardiopulmonary functions, physical growth, maturation, and bone density; measures of functional capability, including range of motion and daily living activities, scar formation, and reconstructive needs; and several measures of the psychosocial adjustment of the child/patient and parent(s).

   One important finding from the collected data is that the long-term successful psychosocial adjustment of burned children largely depends on the enduring qualities of the families with which they live (107-109).  Based on these data, a treatment program has been developed that centers on strengthening the welfare of the family/patient unit.  We emphasize the importance of having at least one parent/guardian available.  Studies consistently indicate that, regardless of burn size, the majority of the children eventually function satisfactorily as socially integrated, behaviorally well-adjusted individuals with positive self-regard.  Only about 20 – 30% of each sample has moderate behavior problems.  These outcomes have been consistent.  This is true even for survivors of the most massive injuries, many of whom have now grown into young adults with careers and families of their own.  In terms of physical impairment, children are remarkably independent in their capabilities, even those with the most severe injuries (110,111).



   As can be seen from the preceding discussions, research conducted over the last couple of decades has dramatically improved multiple aspects of pediatric burn care, including early excision and grafting, resuscitation, infection control, nutrition, scar management, and rehabilitation.  The Shriners Hospitals for Children have contributed in a major way to these remarkable improvements through their very sound and sustained investment of substantial resources towards pediatric burn research at all four centers.  These advances have not only markedly decreased morbidity and mortality, but also improved reintegration into society and quality of life.  These achievements have truly expanded horizons for the treatment of severely burned children and opened new avenues for future discoveries to come.


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References Cited


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16. Boyce ST, Kagan RJ, Yakuboff KP, Meyer NA, Rieman MT, Greenhalgh DG, Warden GD. Cultured skin substitutes reduce donor skin harvesting for closure of excised, full-thickness burns. Ann surg, 2002 Feb; 235(2):269-279.

17. Branski LK, Herndon DN, Masters OE, Celis M, Norbury WB, Jeschke MG. Amnion in the treatment of pediatric partial-thickness facial burns. Burns, 2007 Oct 4.

18. Schulz JT 3rd, Tompkins RG, Burke JF. Artificial skin. Ann Rev Med, 2000; 51:231-244.

19. Branski LK, Gauglitz GG, Herndon DN, Jeschke MG. Novel strategies in wound healing: Gene therapy an dstem cells. Burns 2008, Jul 4.

20. Jeschke MG, Herndon DN. The combination of IGF-I and KGF cDNA improves dermal and epidermal regeneration by increased VEGF expression and neovascularization. Gene Ther 2007 Aug; 14(16):1235-1242.

21. Pereira CT, Herndon DN, Perez-Polo JR, Burke A, Jeschke MG. Scar Tech: Follicular Frontiers I nSkin Replacement Therapy. Genetic Mol Res 2007, 6(1):243-249.

22. Boyce ST, Kagan RJ, Yakuboff KP, Meyer NA, Rieman MT, Greenhalgh DF, Warden GD. Cultured skin substitutes reduce donor skin harvesting for closure of excised, full-thickness burns. Ann Surg, 2002 Feb; 235(2):269-279.

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25. Carvajal, H.F. Fluid therapy for the acutely burned child. Comprehensive Therapy 3:17-24, 1977.

26. Carvajal, H.F. A physiologic approach to fluid therapy in severely burned children. Surgical Journal of Gynecology and Obstetrics 150:379-384, 1980.

27. Jeschke M.G., Barrow R.E., Wolf S.E., Herndon D.N. Mortality in burned children with acute renal failure. Archives of Surgery 134: 752-756, 1998.

28. Turner, R., Carvajal, H.F., Traber, D.L. Effects of ganglionic blockade upon the renal and cardiovascular dysfunction induced by thermal injury. Circulatory Shock 4:103-113, 1977.

29. Traber, D.L., Bohs, C.T., Carvajal, H.F., Linares, H.A., Miller, T.H., Larson, D.L. Early cardiopulmonary and renal function in thermally injured sheep. Surgical Journal of Gynecology and Obstetrics 148:753-758, 1979.

30. Morris, S.E., Navaratnam, N., Herndon, D.N. A comparison of effects of thermal injury and smoke inhalation on bacterial translocation. Journal of Trauma 30:639-643, 1990.

31. Wolf SE, Rose JK, Desai MH, Mileski JP, Barrow RE, Herndon DN. Mortality determinants in massive pediatric burns. Ann Surg, 1997 May; 225(5):554-565.

32. Branski LK, Herndon DN, Jeschke MG. PICCO a new monitoring device to improve patient outcomes. Abstract ABA 2007.

33. Salinas J, Drew G, Gallagher J, Cancio LC, Wolf SE, Wade CE, Holcomb JB, Herndon DN, Kramer GC. Closed-loop and decision-assist resuscitation of burn patients. J Trauma, 2008 Apr; 64(4 Suppl):S321-32.

34. Pereira CT, Barrow RE, Sterns AM, Hawkins HK, Kimbrough CW, Jeschke MG, Lee JO, Sanford AR, Herndon DN. Age-dependent differences in survival after severe burns: a unicentric review of 1,674 patients and 179 autopsies over 15 years. J Am Coll Surg, 2006 Mar; 202(3):536-48.

35. Ong YS, Samuel M, Song C. Meta-analysis of early excision of burns. Burns, 2006 Mar;32(2):145-50.

36. Bessey PQ.. Wound Care Herndon DN, Total Burn Care, Saunders 127-135, 2007.

37. Howerton, E.E., Kolmen, S.N. The intestinal tract as a portal of entry of Pseudomonas in burned rats. Journal of Trauma 12:335-340, 1972.

38. Herndon, D.N., Morris, S.E., Coffey, J.A.J., Milhoan, R.A., Barrow, R.E., Traber, D.L., Townsend, C.M.. The effect of mucosal integrity and mesenteric blood flow on enteric translocation of microorganisms in cutaneous thermal injury. Progress in Clinical Biology Research 308:377-382, 1989.

39. Morris, S.E., Navaratnam, N., Herndon, D.N. Changes in mesenteric blood flow affect translocation in sheep. In: Shock, sepsis, and organ failure: First Wiggers Bernard conference. Schlag, G., Redl, H., Siegel, J.H., Eds., Springer-Verlag, New York, NY., pp. 548-557, 1990.

40. Redl, G., Abdi, S., Nichols, R.J., Traber L.D., Flynn J.T., Herndon D.N., Traber D.L. The effects of a selective thromboxane synthetase inhibitor on the response of the right heart to endotoxin in sheep. Critical Care Medicine 19:1294-1302, 1991.

41. Fujioka, K., Sugi, K., Isago, T., Flynn, J.T., Traber, L.D., Herndon, D.N., Traber, D.L. Thromboxane synthetase inhibition and cardiopulmonary function during endotoxemia in sheep. Journal of Applied Physiology 71:1376-1381, 1991.

42. Sugi, K., Theissen, J.L., Traber, L.D., Herndon, D.N., Traber, D.L. Impact of carbon monoxide on cardiopulmonary dysfunction after smoke inhalation injury. Circulatory Research 66:69-75, 1990.

43. Herndon, D.N., Thompson, P.B., Traber, D.L. Pulmonary injury in burned patients. Critical Care Clinicals 1:79-96, 1985.

44. Prien, T., Traber, D.L. Toxic smoke compounds and inhalation injury--a review. Burns Including Thermal Injuries 14:451-460, 1988.

45. Traber, D.L., Linares, H.A., Herndon, D.N., Prien, T. The pathophysiology of inhalation injury--a review. Burns Including Thermal Injuries 14:357-364, 1988.

46. Herndon, D.N., Abston, S., Stein, M.D. Increased thromboxane B2 levels in the plasma of burned and septic burned patients. Surgical Gynecology and Obstetrics 159:210-213, 1984.

47. Tokyay, R., Loick, H.M., Traber, D.L., Heggers, J.P., Herndon, D.N. Effects of thromboxane synthetase inhibition on postburn mesenteric vascular resistance and the rate of bacterial translocation in a chronic porcine model. Surgical Gynecology and Obstetrics 174:125-132, 1992.

48. Fujioka, K., Sugi, K., Traber, L.D., Herndon, D.N., Traber, D.L. The effect of thromboxane synthetase inhibition on cardiopulmonary function during endotoxemia in sheep. Journal of Burn Care and Rehabilitation 11:531-537, 1990.

49. Snapper, J.R., Hutchison, A.A., Ogletree, M.L., Brigham, K.L. Effects of cyclooxygenase inhibitors on the alterations in lung mechanics caused by endotoxemia in the unanesthetized sheep. Journal of Clinical Investigation 72:63-76, 1983.

50. Finnerty CC, Herndon DN, Przkora R, Pereira CT, Oliveira HM, Queiroz D, Rocha A, Jeschke MG. Cytokine expression profile over time in severely burned pediatric patients. Shock 2006 Jul; 26(1):13-19.

51. Jeschke MG, Finnerty CC, Norbury W, Branski LK, Kulp G, Mlcak RP, Herndon DN. The pathophysiologic response to severe burn injury. Ann Surg 2008 (in press)

52. Wolfe, R.R., Burke, J.F. Effect of burn trauma on glucose turnover, oxidation, and recycling in guinea pigs. American Journal of Physiology 233: E80-E85, 1977.

53. Burke, J.F., Wolfe, R.R., Mullany, C.J., Mathews, D.E., Bier, D.M. Glucose requirements following burn injury: Parameters of optimal glucose infusion and possible hepatic and respiratory abnormalities following excessive glucose intake. Annals of Surgery 190: 274-285, 1979.

54. Watson L.C., Abston S. Prevention of upper gastrointestinal hemorrhage in 582 burned children. American Journal of Surgery 132: 790-793, 1976.

55. Abston, S. Burns in children. Clinical Symposium 28: 1-36, 1976.

56. Hildreth, M.A., Herndon, D.N., Parks, D.H., Desai, M.H., Rutan, T. Evaluation of a caloric requirement formula in burned children treated with early excision. Journal of Trauma 27: 188-189, 1987.

57. Hildreth, M.A., Herndon, D.N., Desai, M.H., Duke, M.A. Reassessing caloric requirements in pediatric burn patients. Journal of Burn Care and Rehabilitation 9: 616-618, 1988.

58. Hildreth, M.A., Herndon, D.N., Desai, M.H., Duke, M.A. Caloric needs of adolescent patients with burns. Journal of Burn Care and Rehabilitation 10: 523-526, 1989.

59. Hildreth, M.A., Herndon, D.N., Desai, M.H., Broemeling, L.D. Current treatment reduces calories required to maintain weight in pediatric patients with burns. Journal of Burn Care and Rehabilitation 11: 405-409, 1990.

60. Herndon, D.N., Barrow, R.E., Stein, M., Linares, H., Rutan, T.C., Rutan, R., Abston, S. Increased mortality with intravenous supplemental feeding in severely burned patients. Journal of Burn Care and Rehabilitation 10:309-313, 1989.

61. Herndon, D.N., Stein, M.D., Rutan, T.C., Abston, S., Linares, H. Failure of TPN supplementation to improve liver function, immunity, and mortality in thermally injured patients. Journal of Trauma 27: 195-204, 1987.

62. Kien, C.L., Young, V.R., Rohrbaugh, A.M., Burke, J.F. Increased rates of whole body protein synthesis and breakdown in children recovering from burns. Annals of Surgery 187: 383-391, 1987.

63. Jahoor, F., Desai, M., Herndon, D.N., Wolfe, R.R. Dynamics of the protein metabolic response to burn injury. Metabolism 37:330-337, 1988.

64. Wolfe, R.R., Jahoor, F., Herndon, D.N., Miyoshi, H. Isotopic evaluation of the metabolism of pyruvate and related substrates in normal adult volunteers and severely burned children: Effect of dichloroacetate and glucose infusion. Surgery 110:54-67, 1991.

65. Gore, D.C., Honeycutt, D., Jahoor, F., Rutan, T., Wolfe, R.R., Herndon, D.N. Effect of exogenous growth hormone on glucose utilization in burn patients. Journal of Surgical Research 51:518-523, 1991.

66. Gore, D.C., Honeycutt, D., Jahoor, F., Wolfe, R.R., Herndon, D.N. Effect of exogenous growth hormone on whole-body and isolated-limb protein kinetics in burned patients. Archives of Surgery 126: 38-43, 1991.

67. Cioffi, W.G., Gore, D.C., Rue, L.W., Carrougher, G., Guler, H-P., McManus, W.F., Pruitt, B.A. Insulin-like growth factor-1 lowers protein oxidation in patients with thermal injury. Annals of Surgery 220(3): 310-319, 1994.

68. Herndon, D.N., Barrow, R.E., Kunkel, K.R., Broemeling, L., Rutan, R.L. Effects of recombinant human growth hormone on donor-site healing in severely burned children. Annals of Surgery 212:424-429, 1990.

69. Goodall, M.G. Sympathetic nerve and adrenal medullary response to thermal burn. Clinical analysis of adrenaline and noradrenaline depletion. American Surgeon;32:448-452, 1966.

70. Goodall, M. Sympatho-adrenal medullary response to thermal burn. Annals of the New York Academy of Science 150:685-689, 1968.

71. Minifee, P.K., Barrow, R.E., Abston, S., Desai, M., Herndon, D.N. Improved myocardial oxygen utilization following propranolol infusion in adolescents with postburn hypermetabolism. Journal of Pediatric Surgery 24:806-810, 1989.

72. Herndon, D.N., Barrow, R.E., Rutan, T.C., Minifee, P., Jahoor, F., Wolfe, R.R. Effect of propranolol administration on hemodynamic and metabolic responses of burned pediatric patients. Annals of Surgery 208:484-492, 1988.

73. Wolfe, R.R., Herndon, D.N., Peters, E.J., Jahoor, F., Desai, M.H., Holland, O.B. Regulation of lipolysis in severely burned children. Annals of Surgery 206:214-221, 1987.

74. Aarsland, A., Chinkes, D., Wolfe, R.R., Barrow, R.E., Nelson, S.O., Pierre, E.J., Herndon, D.N. Beta-blockade lowers peripheral lipolysis in burned patients receiving growth hormone: Rate of hepatic VLDL triglyceride secretion remains unchanged. Annals of Surgery 223(6): 777-789, 1996.

75. Herndon, D.N., Traber, D.L., Niehaus, G.D., Linares, H.A., Traber, L.D. The pathophysiology of smoke inhalation injury in a sheep model. Journal of Trauma 24:1044-1051, 1984.

76. Traber, D.L., Herndon, D.N., Stein, M.D., Traber, L.D., Flynn, J.T., Niehaus, G.D. The pulmonary lesion of smoke inhalation in an ovine model. Circulatory Shock 18:311-323, 1986.

77. Barrow, R.E., Wang, C.Z., Cox, R.A., Evans, M.J. Cellular sequence of tracheal repair in sheep after toxic smoke inhalation. Lung 170: 331-338, 1992.

78. Isago, T., Fujioka, K., Traber, L.D., Herndon, D.N., Traber, D.L. Derived pulmonary capillary pressure changes after smoke inhalation in sheep. Critical Care Medicine 19:1407-1413, 1991.

79. Isago, T., Noshima, S., Traber, L.D., Herndon, D.N., Traber, D.L. Analysis of pulmonary microvascular permeability after smoke inhalation. Journal of Applied Physiology 71:1403-1408, 1991.

80. Basadre, J.O., Sugi, K., Traber, D.L., Traber, L.D., Niehaus, G.D., Herndon, D.N. The effect of leukocyte depletion on smoke inhalation injury in sheep. Surgery 104:208-215, 1988.

81. Niehaus, G.D., Kimura, R., Traber, L.D., Herndon, D.N., Flynn, J.T., Traber, D.L. Administration of a synthetic antiprotease reduces smoke-induced lung injury. Journal of Applied Physiology 69:694-699, 1990.

82. Herndon, D.N., Traber, D.L., Traber, L.D. The effect of resuscitation on inhalation injury. Surgery 100:248-251, 1986.

83. Hilton, J.G. Effects of H-R upon post-burn plasma volume loss in the nonresuscitated dog. Burns Including Thermal Injuries 7:211-214, 1980.

84. Herndon, D.N., Barrow, R.E., Traber, D.L., Rutan, T.C., Rutan, R.L., Abston, S. Extravascular lung water changes following smoke inhalation and massive burn injury. Surgery 102:341-349, 1987.

85. Moylan, J.A., Alexander, L.G.J. Diagnosis and treatment of inhalation injury. World Journal of Surgery 2:185-191, 1978.

86. Abdi, S., Herndon, D., Mcguire, J., Traber, L., Traber, D.L. Time course of alterations in lung lymph and bronchial blood flows after inhalation injury. Journal of Burn Care and Rehabilitation 11:510-515, 1990.

87. Barrow, R.E., Morris, S.E., Herndon, D.N. Selective permeability changes in the airways of sheep. Respiratory Physiology 79:1-8, 1990.

88. Kramer, G.C., Herndon, D.N., Linares, H.A., Traber, D.L. Effects of inhalation injury on airway blood flow and edema formation. Journal of Burn Care and Rehabilitation 10:45-51, 1989.

89. Stothert, J.C.,Jr., Ashley, K.D., Kramer, G.C., Herndon, D.N., Traber, L.D., Ashley, K.D., Traber, D.L. Intrapulmonary distribution of bronchial blood flow after moderate smoke inhalation. Journal of Applied Physiology 69:1734-1739, 1990.

90. Abdi, S., Herndon, D.N., Traber, L.D., Ashley, K.D., Stothert, J.C., Jr., Maguire, J., Butler, R., Traber, D.L. Lung edema formation following inhalation injury: Role of the bronchial blood flow. Journal of Applied Physiology 71:727-734, 1991.

91. Montero, K., Lübbesmeyer, H.J., Traber, D.L., Kimura, R., Traber, L.D., Herndon, D.N. Inhalation injury increases systemic microvascular permeability. Surgical Forum 38:303-305, 1987.

92. Noshima, S., Fujioka, K., Isago, T., Traber, L.D., Herndon, D.N., Traber, D.L. The effect of a thromboxane synthetase inhibitor, OKY-046, on cardiopulmonary function after smoke inhalation injury. Journal of the Federation of American Societies for Experimental Biology 5:A371, 1991.

93. Thompson, P.B., Herndon, D.N., Traber, D.L., Abston, S. Effect on mortality of inhalation injury. Journal of Trauma 26:163-165, 1986.

94. Traber, D.L., Herndon, D.N. Pathophysiology of smoke inhalation. In: Respiratory Sequelae of Burns. Haponik, E.F., Munster, A.M., Eds., McGraw Hill, Inc., New York, NY., pp. 62-71, 1989.

95. Linares, H.A., Kischer, C.W., Dobrkovsky, M., Larson, D.L. On the origin of the hypertrophic scar. Journal of Trauma 13:70-75, 1973.

96. Linares, H.A., Kischer, C.W., Dobrkovsky, M., Larson, D.L. The histiotypic organization of the hypertrophic scar in humans. Journal of Investigative Dermatology 59:323-331, 1972.

97. Linares, H.A., Larson, D.L. Early differential diagnosis between hypertrophic and nonhypertrophic healing. Journal of Investigative Dermatology 62:514-516, 1974.

98. Baur, P.S., Larson, D.L., Stacey, T.R., Barratt, G.F., Dobrkovsky, M. Ultrastructural analysis of pressure-treated human hypertrophic scars. Journal of Trauma 16:958-967, 1976.

99. Linares, H.A., Larson, D.L. Proteoglycans and collagenase in hypertrophic scar formation. Journal of Plastic and Reconstructive Surgery 62:589-593, 1978.

100. Xue, H., McCauley, R.L., Zhang, W., Martini, D. Altered interleukin-6 expression in fibroblasts from burn hypertrophic scars. Journal of Burn Care & Rehabilitation 19 (1): S189, 1998.

101. McCauley, R.L., Chopra, V., Li, Y.Y., Herndon, D.N., Robson, M.C. Altered cytokine production in black patients with keloids. Journal of Clinical Immunology 12:300-308, 1992.

102. Brown, R.L., Greenhalgh, D.G., Kagan, R.J., Warden, G.D. The adequacy of limb escharotomies-fasciotomies after referral to a major burn center. Journal of Trauma 37(6): 916-920, 1994.

103. Suman OE, Spies RJ, Celis MM, Mlcak RP, Herndon DN. Effects of a 12-wk resistance exercise program on skeletal muscle strength in children with burn injuries. J Appl Physiol 91:1168-1175, 2001.

104. Suman OE, Mlcak RP and Herndon DN. Effects of exercise training on pulmonary function in children with thermal injury. J Burn Care Rehab. 23:288-293, 2002.

105. Celis MM, Suman OE, Huang TT, Yen P and Herndon DN. Effect of a supervised exercise and physiotherapy program on surgical interventions in children with thermal injury. J. Burn Care Rehab. 24(1): 57-61, 2003.

106. Suman OE, Thomas SJ, Wilkins JP, Mlcak RP, Herndon DN. Effect of exogenous growth hormone and exercise on lean mass and muscle function in children with burns. J Appl Physiol. 94: 2273-2281, 2003.

107. Blakeney, P., Herndon, D.N., Desai, M., Beard, S., Wales-Seale, P. Long-term psychosocial adjustment following burn injury. Journal of Burn Care & Rehabilitation 19(6): 661-665, 1998.

108. Blakeney, P., Portman, S., Rutan, R. Familial values as factors influencing long-term psychological adjustment of children after severe burn injury. Journal of Burn Care & Rehabilitation 11(5): 472-475, 1990.

109. Meyer, W., III, Blakeney, P., Moore, P., Murphy, L., Robson, M. and Herndon, D.N. Parental well being and behavioral adjustment of pediatric burn survivors. Journal of Burn Care & Rehabilitation 15: 62-68, 1994.

110. LeDoux, J., Meyer, W., III, Blakeney, P., Herndon, D. Relationships between parental emotional states, family environment and the behavioral adjustment of pediatric burn survivors. Burns 24: 425-432, 1998.

111. LeDoux, J., Meyer, W., III, Blakeney, P., Herndon, D. Positive self-regard as a coping mechanism for pediatric burn survivors. Journal of Burn Care & Rehabilitation 17: 472-476, 1996.




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