|Year : 2016 | Volume
| Issue : 1 | Page : 1-5
Use of growth hormone in the treatment of pediatric burns
Yasser A Salem
Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||30-Nov-2015|
|Date of Acceptance||09-Dec-2015|
|Date of Web Publication||17-Mar-2016|
Yasser A Salem
Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo - 11371
Source of Support: None, Conflict of Interest: None
Hypermetabolic response is characterized by a hyperdynamic circulatory response, with increased body temperature; increased oxygen and glucose consumption; increased carbon dioxide production; hyperglycemia (raised blood sugar levels); peripheral insulin resistance; glycogenolysis, proteolysis, and lipolysis (i.e. the breakdown of glycogen, protein, and lipids, respectively); the loss of lean body mass; and muscle and bone wasting. These symptoms can last for 1-2 years after the burn injury. Failure to satisfy overwhelming energy and protein requirements results in multiorgan dysfunction and an increased susceptibility for infection and death. Immunocompromization and delayed wound healing usually result in severe sepsis, which is the most common direct cause of death in these patients. Nevertheless, providing adequate caloric and protein requirements alone was found to be insufficient to attenuate the hypermetabolic response efficiently. Thereby, various pharmacologic modalities to modulate metabolic response have become a corner stone in the management of severely burned patients. Recombinant growth hormone is the most frequently prescribed agent in pediatrics. This review will focus on the metabolic and immune responses to the use of recombinant growth hormone in pediatric burn patients. It will explore what is beyond growth hormone and the role of insulin-like growth factor-1 in modulation of immunity and apoptosis.
Keywords: apoptosis, burn, growth hormone, pediatrics
|How to cite this article:|
Salem YA. Use of growth hormone in the treatment of pediatric burns. Ain-Shams J Anaesthesiol 2016;9:1-5
| Introduction|| |
Over 95% of the fatal fire-related burns occur in low-income and middle-income countries. Risk for burn accidents in females is twice that of males. This is often attributed to accidents in the kitchen or to domestic violence. Fire-related mortality rates are especially high in South-East Asia (11.6 deaths per 100 000 population per year), the Eastern Mediterranean (6.4 deaths per 100 000 population per year), and Africa (6.1 deaths per 100 000 population per year)  .
Unfortunately, there is no official data about Egyptian burn accidents. From our practice in Aldemerdash Hospital Burn Unit, which serves not less than one-third of all burn cases in Cairo and the delta area, 50% of the patients that are admitted are below 8 years of age. This coincides with the report by WHO, which states that fire-related death ranks among the 15 leading causes of death among children and young adults between the ages of 5 and 29 (http://www.who. int).
History and cumulative experience
Growth hormone is produced by the anterior lobe of pituitary gland. For decades, it could only be obtained by extracting it from pituitary glands of animals and cadavers, but later on it has been produced through genetic engineering and made available for therapy as a recombinant human growth hormone (rGH)  . The modulation of hormonal imbalances after burn injuries was introduced in the 1990s in animal studies, and investigated along the last 20 years in multiple clinical trials ,, . One of the earliest review articles about the use of rGH in the management of burned patients was that introduced in a study by Rose and Herndon in 1997  , in which they stated that hyperaminoacidemia alone is not sufficient enough to prevent protein catabolism from proceeding at a higher rate than does protein anabolism. This conclusion points to the concept of using drug combination to manipulate metabolic rate together with adequate caloric and protein supply. The most commonly used medications are rGH and oxandrolone to accelerate anabolism. On the other hand, propranolol was used to decelerate metabolic rate in hyperdynamic patients. Hence, oxandrolone, a nonaromatizable androgen, previously had limited use in pediatrics  ; recombinant human growth hormone was the only safe anabolic agent that could be used for pediatric population.
A study by Herndon and colleagues (1990) showed reduced donor site healing times and a reduced length of hospital stay in children with burns, who were treated with rGH. Its administration was associated with side effects, including hyperglycemia and reactions at the injection site (e.g. nodules, erythema, pain and swelling)  . Recently, Breederveld and Tuinebreijer in their study stated that there is some evidence suggesting that using rGH in people with large burns (more than 40% of the total body surface area) could result in more rapid healing of the burn wound and donor sites in adults and children, and in reduced length of hospital stay, without increased mortality or scarring, but with an increased risk for hyperglycemia. This evidence is based on studies with small sample sizes and risk for bias, and thus requires confirmation in higher quality and adequately powered trials  . This conclusion was drawn from a meta-analysis of 13 randomized controlled clinical trials that included 701 participants. These results indicate some preliminary evidence that burn wounds and donor sites in children and adults heal more rapidly when rGH is administered and that the duration of hospital stay in adults is also shorter with rGH compared with placebo. The statistically significant differences between rGH and placebo administration are clinically meaningful and include a 9-day reduction in the wound healing time in adults, a 3-day reduction in the donor site healing time in adults, and a nearly 2-day reduction in the donor site healing time in children. No evidence of a shorter hospital stay was reported when rGH was administered to children  .
Effect of rGH in adults is somehow mysterious. In a study, 54 adult burn patients, who had survived the first 7 postburn days and showed difficulty with wound healing, were treated with rGH and then compared with those being treated with the standard therapy. Mortality of rGH-treated patients was 11% compared with 37% of those not receiving rGH (P = 0.027)  . On the other hand, two phase III double-blind randomized controlled trials of rGH treatment in adults following cardiac or abdominal surgery, multiple trauma, or acute respiratory failure found increased hospital mortality rates in patients receiving rGH  . This controversy prompted additional studies on critically burned pediatric patients. Ramirez et al.  retrospectively studied 263 pediatric burn patients; those treated with rGH had no increase in mortality compared with matched patients who did not receive rGH.
Severe burn injury is followed by a profound hypermetabolic response that persists up to 24 months after injury. It is mediated by up to 50-fold elevations in plasma catecholamines, cortisol, and inflammatory cells that lead to whole body catabolism, elevated resting energy expenditures, and multiorgan dysfunction  . Blunted growth, insulin resistance, and increased risk for infection are constant clinical situations encountered during the management of severely burned patients ,, .
Eventually, postburn pediatrics usually possess growth retardation and stunted growth up to 3 years. This effect was an inspiration for the long-term use of rGH. A total of 72 severely burned children were treated with rGH for 1 year after discharge from intensive care resulted in significantly increased height in a placebo-controlled, randomized, double-blinded trial  . Long-term therapy at doses of 0.1 mg/kg/day has been considered safe and well tolerated  .
Growth hormone/insulin-like growth factor-1 axis
rGH induces the generation of insulin-like growth factor-1 (IGF-1, also called somatomedin 1) in the liver and regulates the paracrine production of IGF-1 in many other tissues  .
Recently it was discovered that insulin-like growth factor binding proteins (IGFBP-1), which bind IGF-1, are excreted in response to an inflammatory reaction. Elevated levels of IGFBP-1 after burn injury have been proven. Moreover, this elevation has been correlated with severity of burn injury and sepsis coupled with poor outcome  . Serine phosphorylation of IGFBP-1 was proved to increase the affinity of IGFBP-1 to bind IGF-1 and eventually decrease the bioavailability of IGF-1  .
Hormonal metabolic response to burn injury
Cytokine levels peak immediately after burn, approaching normal levels only at 3-6 months after the burn injury. Serum hormones, constitutive and acute phase proteins, are abnormal throughout the acute hospital stay. Serum IGF-1, IGFBP-3, parathyroid hormone, and osteocalcin drop immediately after the injury and remain decreased until 2 months postburn compared with normal levels. Sex hormones and endogenous growth hormone levels decrease around 3 weeks postburn and remain low  .
Of interest is that children were shown to have transient growth hormone deficiency following severe burns, the explanation for which was not readily apparent. This transient deficiency was associated with low circulating concentrations of IGF-1. Treatment with recombinant human growth hormone at a dose of 0.05-0.1 mg/kg/day subcutaneously quickly raised IGF-1 concentrations in the blood to normal levels. However, while serum concentrations of osteocalcin were also initially low, raising circulating IGF-1 concentrations in the blood failed to raise osteocalcin concentration in the blood to normal levels  .
Because of its potent anabolic properties, rGH can be used to limit the catabolism in burn victims , . Its anabolic effects increase the cellular uptake of amino acids, nitrogen retention and protein synthesis and the release of IGF. It can have a direct effect on the skin because of the presence of growth hormone receptors on epidermal cells. The hypermetabolic response after burn injuries persists, despite improvements in surgical and nursing care  .
Immunomodulatory effect of recombinant growth hormone
Burn is associated with apoptosis of lymphocytes in the thymus and in the peripheral lymphoid organs , . The consequence of these events is the suppression of the inflammatory immune response in burn patients, thereby leading to an increased susceptibility to infection. IGF-1 has been shown to be immunomodulatory, primarily through its ability to act as a potent stimulator of T-cell survival and function.
IGFs are known to have diverse effects including metabolic insulin-like effects and effects on cell growth, differentiation, and survival by acting in an endocrine, autocrine, and paracrine manner. Specifically, in the case of T cells, IGF-1 has been shown to protect activated T cells from apoptosis , .
IGFBP-1 is the major modulator of the bioactivity of free IGF-1. The majority of IGF-1 in circulation is bound to IGFBP-3  . Serine phosphorylation of IGFBP-1 increases its affinity for IGF-1  , thereby sequestering IGF-1 away from its receptor and reducing its bioactivity  . It has been suggested that a sustained high serum concentration of IGFBP-1 can predict poor outcome from sepsis and critical illness  . It has been shown in critically ill patients, as it was shown in mouse models previously, that there is an increase in the amount of phosphorylated IGFBP-1 in circulation  . Burn injury has been associated with a similar decrease in IGF-1 levels and an increase in IGFBP-1 levels in burn patients  . These changes in the IGF-1 axis were found to persist for 40 days postburn, but the phosphorylation status has not been reported  .
Keeping in mind the potential role of IGF-1 as a T-cell survival factor, decrease in IGF-1 may contribute to the loss of T-cell function. Clinical studies in which IGF-1 (associated with its principal binding protein IGFBP-3, which prolongs its half-life and reduces associated side effects, notably hypoglycemia) was administered to burn patients showed improvement in outcome  . An alteration in the cytokine profile of patients following IGF-1/IGFBP-3 administration was observed, suggesting that the positive effects of IGF-1 were mediated at least partially through its ability to modify the immune response  . It was hypothesized that the decrease in IGF and increase in IGFBP-1 levels after burn are associated with IGFBP-1 phosphorylation. This hypothesis was tested and confirmed in a study by April and his colleagues in 2013,  as they measured serum insulin and IGF-1 in addition to serum IGFBP-1. Serine phosphorylation of IGFBP-1 was measured by using the Western blot method with and without the incubation of calf intestinal phosphatase. There was a significant positive correlation of increasing percentage of total burn surface area and increasing levels of serum IGFBP-1. Levels of IGF-1 also decreased with increasing percentage of total burn surface area. Moreover, IGFBP-1 is serine phosphorylated in burn patients  .
The IGF-1 axis has critical roles in cell survival, particularly in the immune system. Modulating the IGF-1 axis appears to offer many potential benefits to burn patients ,,,,,,, . Ironically, it appears that treatment with IGF-1 alone is not therapeutically sufficient  . There is a complex interaction between IGF-1 and its binding proteins  . Administration of IGF-1 with IGFBP-3 has been shown to restore proinflammatory and anti-inflammatory homeostasis, improve organ function and restore anabolic status ,, . IGFBP-3 is the principal binding protein of IGF-1, and is essential in enhancing the half-life of IGF-1  .
Another pathway for the actions of IGF-1 is mediated through a tyrosine kinase receptor that leads to the activation of phosphoinositide 3-kinase (PI3-kinase) and the mitogen-activated protein kinase  . Several studies have demonstrated that IGF-1 induces cell survival through activation of the PI3-kinase pathway , . In addition, the PI3-kinase/Akt pathway also increases the levels of antiapoptotic proteins including Bcl-2 and Bcl-xL (stand for B-cell lymphoma proteins, which are apoptotic regulators)  . The mechanism by which PI3-kinase/Akt offers cytoprotection remains unclear. Several factors involved in apoptosis and cellular survival have been shown to be regulated by Akt. The effects of IGF-1 on cell survival were mediated by this complex pathway. Experimental results indicate that IGF-1 induces a rapid and sustained stimulation of the Akt phosphorylation, suggesting that Akt may play a critical role in promoting IGF-1-dependent survival in primary pituitary cells  .
Studies on cord blood mononuclear cells concluded that IGF-1 has an important role in the maturation of T lymphocytes. This maturation process is mediated by interleukin-6 and other agents, some of them still not well known  . Nonetheless, effect of IGF-1 on T-cell maturation is undeniable.
To summarize, elevated levels of IGF-1 provide a survival benefit in critically ill patients, and improve survival in sepsis ,,,,,,,,,,,,, . IGF-1 is also significantly decreased in nonsurvivors of multiorgan failure , . The mechanism for this is thought to be that IGF-1 improves survival of immune effector cells such as T cells , and other multiple immune cell types. IGF-1 activates specific signaling pathways including Akt and Jun N-terminal kinases, which in turn promote T-cell survival from Fas (first apoptosis signal)-induced cell death , .
Finally, rGH is an established therapy in the management of severe burn injury in pediatrics. Its therapeutic effect penetrates far beyond the traditional anabolic effect. Immunomodulatory effect, which is exerted through the elevation of IGF-1 serum level, is much more important and simultaneously is not well studied. Survival of burn patients needs both the anabolic and immunomodulatory effects.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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