HORMONAL PROFILE IN SEVERE BURNS

Abstract

Acute or chronic burn injuries require hormonal responses that significantly influence patient prognosis. Elevated cortisol, catecholamines, and glucagon levels, lead to important metabolic changes, such as hyperglycaemia, insulin resistance, protein catabolism, free fatty acids oxidation, and secondary metabolic acidosis. These alterations impair immune function and wound healing and trigger a systemic inflammatory response.

A multidisciplinary approach is needed in order to correctly manage the aforementioned endocrine and metabolic changes. During the acute phase, glucose monitoring, corticosteroid administration for transient or iatrogenic adrenal insufficiency and electrolyte balance maintenance are critical. Chronic phase requires hormonal replacement, nutritional optimization, and anabolic agents administration to counteract catabolic states.

Despite continuous advances in burn care, understanding the complex interplay between hormonal changes and immune dysfunction remains challenging. Managing burn-associated endocrine responses could lead to the development of new therapeutic strategies, including personalised and stage- adapted treatment.

INTRODUCTION

Burn injury is a group of physio-pathological changes, associated with peripheral tissue damage and internal organ dysfunction. Stress hormones, mainly catecholamines and cortisol, but also glucagon, are released immediately after acute injury onset.

Systemic response leads to rapid liver damage, soon followed by changes in the metabolic environment, followed by the release of pro-inflammatory cytokines. Liver injury and stress hormones secretion contribute to an insulin resistance status, followed by hyperglycaemia, proteolysis and lipolysis (1). Burns constitute serious and debilitating injuries forcing the organism to trigger hypermetabolic and catabolic responses. Advances in acute burn care, such as early fluid resuscitation, early wound excision and closure, antibiotic therapy, and appropriate nutrition, have significantly decreased mortality after severe injuries, thus increasing the number of patients entering rehabilitation.

Catecholamines have important metabolic effects, in both lipid and glucose metabolism, by activating bothalpha- and beta-adrenergic receptors. They stimulate lipolysis, produce free fatty acids and glycerol, and enhance glycemia levels by enhancing both glycogenolysis and gluconeo-genesis. This hypermetabolic response is associated with cytokine release. Gluconeo-genesis is the process through which amino acids are used to synthesize glucose, thus being responsible for triggering muscle catabolism. Catecholamine excess in acute stress response is held responsible for muscle loss, secondary diabetes and may be reversed through beta-blockers administration. Propranolol decreases catecholamine- induced effects and improves insulin action.

The stress hormone cortisol, has a synergic effect on glucose metabolism with catecholamines, also promoting hyperglycaemia. Cortisol response is prolonged and is directly proportional with the surface area of the injury (2).

Burn injury is also associated with an immuno-suppressive state triggered partially by cortisol increase, along with the release of various cytokines. Catecholamine release is the primary triggered mechanism, while cortisol secretion is slightly delayed to sustain and prolong their effect. Intense lipolysis is associated with insulin resistance, a factor that favours switching to a chronic stress environment, especially in patients with long- term evolution. Adipose tissue represents an important participant in severe burn response (3).

Our mini review aims to explain the potential future use of hormonal therapy as an adjuvant in the management of severe burns. Research and understanding of the endocrine system involvement in burn- associated systemic response, might be helpful in developing new therapeutic strategies and a more positive long-term outcome of this complex pathology.

Acute response in severe burns

Acute stress response in burn patients is characterized by a complex hormonal reaction that significantly impacts metabolic and physiological pathways. A marked increase in the secretion of stress hormones such as catecholamines, cortisol and glucagon is noted to immediately follow a severe burn injury, contributing to hyperglycaemia and a systemic catabolic state (4).

Neuroendocrine dysregulation in burn injuries is a complex and multifaceted response involving several hormonal axes and systems. Severe burns trigger a multisystem neuroendocrine response characterized by increased secretion of stress hormones, as well as cytokines, which contribute to hyperglycaemia, systemic catabolic states, and multiple organ dysfunctions. The neuroendocrine response in acute stress starts with hypothalamus pituitary axis (HPA axis) activation (CRH, ACTH, cortisol), and catecholamines within minutes. These levels are closely correlated with the extent of the burn, as measured by the total body surface area affected (5). Hormonal responses to severe burns, while initially adaptive, often disrupt the delicate balance required for effective tissue repair. Sustained hypercortisolism inhibits key reparative processes by suppressing fibroblast proliferation, collagen synthesis, and angiogenesis. These disruptions lead to delayed wound closure, reduced tensile strength of the healed tissue and increased susceptibility to wound breakdown.

Other hormones involved in burn injuries are those that belong to the somatotroph axis (growth hormone- GH and insulin- like growth factor 1- IGF1) with a tendency to hyperglycaemia and protein anabolism. The release of both cortisol and GH involves sustained hormonal activity but lacks a corresponding increase in muscle work, (due to the massive tissue injury and the body's need to manage the extensive metabolic and immune challenges induced by the burn) (6).

Prolactin (PRL) and growth hormone (GH) are intricately involved in the body's stress response and metabolic regulation, sharing common regulatory pathways, which can be disrupted in pathological conditions such as burns (7). During stress, including burn- related, there is often a hypersecretion of these hormones. For instance, GH plays a crucial role in growth, glucose homeostasis, muscle and bone metabolism, while PRL significantly influences energy metabolism. Related to somatotropic axis changes, total ghrelin concentrations well as the responsiveness of GH, IGF-1, and IGF binding globulin 3 (IGFBP-3) in burn injuries also modifying severe burn subjects. IGF-1/IGFBP-3 variation in burn patients exhibit a typical pattern: reduced in the first day of thermal injury, become more severe during the following 2 weeks, and then improve progressively until day 28, when they finally normalize (8).

In contrast, in the chronic intensive care-dependent phase of severe illness, pulsatile GH secretion substantially decreases, while the nonpulsatile fraction remains relatively elevated, resulting in an abnormally flat GH secretory pattern and low-normal mean nocturnal GH serum concentrations. Acute critical illness leads to activated GH release whereas circulating levels of IGF-I and IGFBP-3 decrease.GH levels are elevated but total ghrelin levels are decreased. Total ghrelin levels were lower in the subjects with inhalation burn compared with the subjects without respiratory injury (9).

Severely burned patients exhibit an increase in ghrelin levels during recovery, suggesting a potential link between ghrelin and tissue repair processes. Ghrelin's protective effects on the endothelium include enhancing nitric oxide activity, reducing apoptosis, and inhibiting inflammation. Ghrelin attenuates thrombin-induced changes in the permeability of human umbilical vein endothelial cells barrier.

In a double-blind, placebo-controlled, randomized case–control study with 33 patients with severe burn injuries who were randomly assigned to receive placebo (control group; n=15) or slow release- hGH treatment (SR-hGH group; n=18), during the rehabilitation phase, hGH administration showed a beneficial= effect. The lean body mass at 3 months was higher in the SR-hGH group compared to the control group; the exercise capacity, IGF-1 and adiponectin levels were significantly higher in the SR-hGH group than in the control group (10). SR-hGH treatment during the rehabilitation of adult burn survivors has a positive effect on physical fitness levels, muscle contraction force, and metabolic processes, with no specific effects on burn scar evolution.

Growth hormone (GH) therapy with recombinant human growth hormone (rhGH) has shown promising in counteracting the catabolic effects of burns. GH stimulates protein synthesis, enhances nitrogen retention, and promotes the regeneration of muscle mass, making it particularly beneficial for patients experiencing severe muscle wasting. It also supports wound healing by improving collagen deposition and granulation tissue formation, while mitigating the hypermetabolic state by reducing energy expenditure. However, its use is associated with risks such as hyperglycaemia, insulin resistance and an increased susceptibility to infections, requiring careful dose management and glucose monitoring.

Chronic response and long term adaptation - adipose tissue

Long-term endocrine system dysregulation following major burns involves complex and multifaceted changes across various hormonal axes. The hypothalamic-pituitary axis is notably affected, with fluctuations in the pituitary hormones levels persisting for months post-injury. Bone health is also compromised, with significant reduction in bone mineral density. Sex hormone levels, particularly in males, observed up to a year after the burn are also decreased. Hypermetabolism is universal in the severely burned and is characterized by lean mass and body fat catabolism with associated insulin resistance. Adipokines are likely to play a role in these changes. Adipose tissue and related hormones play a key role in the systemic response to severe trauma, sepsis, and critical illness. In severe burns adiponectin, leptin, and resistin significantly influence the hypermetabolic state, systemic inflammation, immune function but also the healing process (11,12).

Plasma levels of leptin, adiponectin, and the gut hormone, ghrelin are all lower in burn subjects when compared to controls. Associations between leptin and adiponectin plasma concentrations and inflammatory markers, indicators of metabolism, and insulin resistance were not found. Leptin concentration showed a moderate correlation with body mass index (BMI). There was also a moderate correlation of ghrelin levels with the metabolic needs and daily insulin administration in the injured patient (13). While fat mobilization provides an important energy source during acute stress, sustained lipolysis contributes to overproduction of lactic acid and metabolic acidosis, also increasing the risk of complications such as fatty liver. Nutritional support, especially high-protein diets, is critical in mitigating the effects of protein catabolism and promoting recovery in burn patients.

Adiponectin and ghrelin have been observed to exert anti-inflammatory and antifibrotic effects on the skin. Leptin has been shown to enhance human epidermal keratinocyte and epithelial cell proliferation, differentiation and migration, as well as to promote angiogenesis within dermal connective tissues. In the absence of differences in plasma glucose concentrations, plasma insulin levels in the burn subjects were 217% higher than controls. Thus, based on the HOMA-IR, burned subjects were more insulin resistant than controls (14).

Hormonal treatment in severe burns

Effective management of endocrine changes in burn patients is critical to prevent complications, promote recovery and improve long-term outcomes. Management strategies differ between the acute and chronic phases of care and require a multidisciplinary approach tailored to the patient's individual needs.

During the acute phase, managing the hypercortisolism and glucose metabolic imbalance induced by the burn stress response is essential. Corticosteroids may be carefully administered in cases of therapy-induced adrenal insufficiency, though their use requires close monitoring due to the risk of exacerbating immuno-suppression. Simultaneously, glucose monitoring and control are compulsory to address hyperglycaemia and prevent complications such as wound infections and delayed healing. Corticosteroid use in critically ill patients is supported by the guidelines to address treatment-refractory shock. Corticosteroids ameliorate vasoplegia and shock duration, restoring hemodynamic stability. Similar positive findings were reported in burn patients.

Burn patients frequently experience electrolyte imbalances due to fluid shifts, resuscitation, and adrenal dysfunction. Close monitoring and correction of serum sodium, potassium, calcium and magnesium levels are crucial to prevent complications such as cardiac arrhythmias, muscle weakness and impaired cellular function. Tailored fluid replacement therapy and electrolyte supplementation should be guided by regular laboratory assessments.

Oxandrolone is a synthetic oral non-aromatizable testosterone derivative that modulates the systemic inflammatory response and promotes wound healing during burn injury. Oxandrolone is used to attenuate post-burn hypermetabolic responses, improve lean body mass, and aid in weight restoration following injury (15).

Oxandrolone use was independently associated with reduced risk of 28-day mortality, in-hospital mortality and sepsis. However, oxandrolone use was independently associated with increased risk of multi-organ failure. Death within 28 days following thermal injury and during hospital admission occurred in 12% and 29% oxandrolone-treated patients compared to 33% and 44% in the non- treated group, respectively. In-hospital mortality and sepsis rates were significantly higher among corticosteroid-treated burns patients, with these individuals also exhibiting a significantly reduced number of days alive and free of sepsis. In contrast, oxandrolone was associated with improved survival and sepsis rates following burn injury, with patients exhibiting increased number of days alive (16).

For treatment options, emerging therapies aim to target specific pathways involved in burn-induced endocrine changes. For example, agents that modulate insulin sensitivity, such as GLP-1 receptor agonists, show promise in addressing hyperglycaemia and metabolic dysfunction. Anti-inflammatory drugs targeting cytokine-mediated pathways could mitigate the systemic effects of the inflammatory response, while personalized hormonal therapies tailored to the patient’s unique profile may optimize outcomes. Advances in biomarker-driven care and the integration of artificial intelligence to predict hormonal responses and guide therapy are also likely to transform the management of burn patients in the future.

In conclusion, burn injuries elicit profound endocrine changes that significantly impact patient outcomes, encompassing acute stress responses, hypermetabolic states and long-term hormonal dysregulation. The interplay between elevated cortisol levels, insulin resistance and disrupted thyroid and gonadal function underscores the complexity of these physiological alterations. These disturbances contribute to delayed wound healing, increased susceptibility to infections and long-term metabolic complications, highlighting the critical role of endocrine management in burn care.

Effective management strategies must address both the acute and chronic phases of endocrine dysfunction. Acute phase interventions, such as glucose monitoring, insulin therapy, corticosteroid therapy for iatrogenic adrenal insufficiency, fluid replacement and electrolyte management are essential for stabilizing patients. In the chronic phase, hormone replacement therapies, comprehensive nutritional management and psychological and social support are pivotal in mitigating catabolic states and promoting long-term recovery. Advances in precision medicine, including the use of biomarkers and targeted therapies hold promise for improving the diagnosis and treatment of hormonal imbalances in burn patients.

Conflict of interest

The authors declare that they have no conflict of interest.