Chapter 49 Mitigation of burn-induced hypermetabolic and catabolic response during convalescence

Oscar E. Suman, David N. Herndon, Celeste C. Finnerty, Elisabet Borsheim

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Background

Advances in burn management and critical-care have greatly improved acute outcomes following severe burn injuries in recent decades. This has led to an increased focus on measures to improve long-term outcomes by enhancing rehabilitation and reintegration of burn survivors back into fulfilling and productive roles in society. Long-term debilitation following severe burns results from a combination of physical and psychological factors, including persistent hypermetabolism and physiological derangements, severe skeletal muscle wasting, deformity, scar contracture, pain and itch, limb amputation, multiple operative interventions over the course of years, and psychological and social factors related to loss, disfigurement, identity, and bereavement. Burn team scientists and clinicians have barely begun to gain knowledge into what the long-term quality of life for these survivors can be.^1,² Rehabilitative challenges for such children are numerous, and the best methods of achieving good outcomes in children with severe burns are still being developed.³

Despite the similarities in treatment of pediatric and adult burns, pediatric injuries present unique challenges, both at the time of acute treatment and throughout rehabilitation. Increased experience and new data, gathered in large part from courageous young survivors, have allowed burn team clinicians and scientists to identify many long-term problems associated with large burns. A major problem during convalescence of the pediatric burn patient is the prolonged hypermetabolic state associated with catabolism and growth delay. Recent gene expression studies have demonstrated that, of the thousands of genes which are altered by a severe burn injury in peripheral blood leukocytes, the expression of 21% of the genes are age-specific.⁴ Many of these genes play important roles in mitochondrial and immune function. These studies demonstrated that there is a temporal component of the response to burn injury as well, with complete resolution of the genomic response to injury taking up to (and in some cases beyond) 1 year. Although the direct role that these genes play in mediating age-specific manifestations of burn-induced sequelae, on-going studies will improve our ability to personalize treatment in pediatric and adult burn patients.

In response to a severe burn, afferent stimuli are activated causing a hypothalamic thermoregulatory re-set to occur. This results in increased heat production, a faster heart rate and a greater cardiac output, in addition to an exaggerated increase in resting energy expenditure.⁵ The control and treatment of prolonged postburn hypermetabolism remain an unsolved problem.⁶ Whereas the cause is still not well understood, catecholamines are the major mediators.⁷ Catecholamine and cortisol levels can be elevated for up to 1 year post-burn.⁸ With this elevation in stress hormones, there is a long-lasting increase in resting energy expenditure, glucose production and catabolism. The effect of this hypermetabolic, hypercatabolic state is rapid muscle breakdown.⁹

The self-catabolism, which is manifested as an increase in protein degradation with a lesser increase in synthesis, persists, despite state-of-the-art nutritional care.¹⁰ As a result, the rate of protein degradation continues to exceed that of synthesis. The protein catabolic response to injury leaves patients debilitated for months and severely delays the rehabilitation process. Protein is degraded to provide amino acids for energy as well as building blocks for host defense protein synthesis. Most of the required amino acids are taken from active muscle which serves as a pool for amino acids. The increase in amino acid loss from muscle causes muscle wasting and loss of strength. Severe muscle wasting is closely related to overall morbidity and mortality in the burned patients.

Finally, associated with the prolonged hypermetabolic, hypercatabolic state, there is also reduced bone formation, resulting in severe osteopenia or osteoporosis ¹¹ as well as linear growth retardation.¹²^–¹⁴ This may partly be caused by the continuous elevation in endogenous glucocorticoids that decrease osteoblasts on the mineralization surface of bone, blocking of osteoclastogenesis leading to low bone turnover and bone loss, and a reduced synthesis of vitamin D from skin from burned patients.¹⁵

Mitigation of hypermetabolism

Propranolol

Herndon et al. proposed that beta-blockade would mitigate the catecholamine driven hypermetabolic response.¹⁶ Their initial study demonstrated that propranolol, given to decrease severe burn-induced tachycardia, attenuates catabolism of skeletal muscle, reduces resting energy expenditure, and decreases hypermetabolism during the acute hospitalization period in severely burned children.¹⁶ This mitigation of the catabolic response is associated with alterations in genes for key proteins, including dynein, heat shock protein 70, and myosin.¹⁷ Decreases in free fatty acid availability by inhibition of peripheral lipolysis and reduction of hepatic blood flow through the use of propranolol lead to the reduction of fatty infiltration of the liver.^18,¹⁹ These studies of short treatment regimens of beta-blockade (2–4 weeks) have been extended up to 2 years. Preliminary analysis demonstrates that reduction in cardiac work is the major benefit noted 6 months following the injury. Long-term improvements in lean body mass, increased bone mineral content, and decreased formation of hypertrophic scar persist as well, indicating that extended treatment of severely burned children with propranolol continues to improve patient recovery. Studies to determine the impact of beta-blockade on muscle strength, cardiopulmonary function, and growth will elucidate whether propranolol in combination with exercise can cause even greater improvements in post-burn recovery.