Significance of the Hormonal, Adrenal, and Sympathetic Responses to Burn Injury

Cardiovascular Response

The chapters on multisystem organ failure and shock describe the physiology of the “ebb” phase from distributive shock and myocardial depression in which cardiac function is depressed. By 48 h post-burn the myocardium becomes hyperdynamic in a β-adrenergic–mediated manner transitioning to the “flow phase.” Even small burns are associated with significant changes in cardiac function and long-term pathologic changes. One sympathetic reflex arc begins when hypotension stimulates baroreceptor (carotid sinus and aortic arch) afferent nerve activity, with resultant increases in efferent sympathetic outflow. This sympathetic signal for peripheral vasoconstriction and consequent increase in peripheral vascular resistance is mediated in part by the nerve-stimulated release of norepinephrine. Angiotensin II (AII) and arginine vasopressin (AVP) also act to increase vascular tone. Additionally a complex interplay of AII and catecholamines further modulates vascular tone. Concurrently AVP has been shown to reversibly depress myocardial function in the isolated heart. AVP and catecholamine overstimulation may thus contribute to myocardial depression following burn injury early in the compensation of the “ebb phase.”

As the heart transitions to the “flow phase” within 48 h after insult, sympathetic outflow is likely an important driver in maintaining supranormal cardiac function during recovery from thermal injury. In a group of burned patients undergoing visceral blood flow and metabolic measurements, the average cardiac index was 8.2 +/−0.5 L/m ² min. In the same study, liver and kidney metabolic and blood flow measurements were also conducted, and all were found to be elevated. These data allude to a supraphysiologic circulatory need requisite for recovery from severe burn injury. Guillory and Finnerty reviewed the menagerie of animal studies demonstrating the centrality of β-receptor dysfunction in mediating this cardiac pathophysiology and have given mechanistic insight into the efficacy of modern burn therapy with β-blockade.

The sympathetic surge continues long after volume status is restored and baroreceptor signaling ends. Despite elevated levels of circulating norepinephrine and epinephrine, there is a paradoxical decreased peripheral vascular resistance during the hyperdynamic “flow” phase. Accompanying reduced cardiac afterload is increased cardiac preload and thus increased cardiac output. There is abundant evidence that mediators of neural, humoral, and metabolic origins are involved in driving the decrease in vascular resistance following thermal injury. The significance of β ₂ -adrenergic receptors in vasodilation has been demonstrated using knockout mice, thus pointing to the significance of epinephrine. The situation is complicated in the burn patient by the increase in nerve-stimulated release of norepinephrine, which can potentially mediate vasoconstriction. However evidence exists that the local distribution of adrenergic receptors mediating either vasodilation or vasoconstriction will determine the effect of circulating epinephrine and nerve-stimulated norepinephrine release on peripheral vascular resistance. Blood flow regulation to the burned extremity remains intact: even in legs with 85% surface burned, increasing the surface temperature causes increases in blood flow comparable to unburned legs. In addition, increased tissue metabolism has been recognized to produce metabolites that mediate increased blood flow by reducing vascular resistance. With markedly increased metabolism in major burns, these metabolites, along with catecholamines, nitric oxide (NO), and atrial natriuretic peptide, may contribute to decreased vascular resistance.

When decreases in peripheral vascular resistance compromise tissue perfusion and lead to end-organ damage (e.g., the urinary granular casts of tubular necrosis), pressor agents may be required to maintain adequate tissue perfusion in the setting of adequate volume status. Epinephrine is the drug of choice, providing optimal vasoconstrictor and inotropic effects. In cases of resuscitated burn shock, the additional inotropic support of epinephrine is essential to maintain tissue perfusion without overly constricting the cutaneous vasculature needed to heal burn injuries. For example dobutamine, a β-adrenergic inodilator, is an important inotrope in select burn patients, and the novel non-adrenergic inodilator, levosimendan, may find utility in treating cardiac failure in burn patients.

Catecholamine Resistance

Acidosis is the most common cause of catecholamine resistance. Macarthur et al. described inactivation of catecholamines by superoxide anions contributing to the observed hypotension of septic shock in rat models. They found treatment with superoxide dismutase not only abrogated endotoxin-induced hypotension in anesthetized rats, but also elevated circulating levels of catecholamines. These findings suggest that compensatory sympathetic activation, which counteracts hypotension during conditions of sepsis, may be blunted by inactivation of catecholamines by superoxides in the extracellular milieu. In a conscious rat model of sepsis, superoxide inhibition enhanced plasma levels of catecholamines, increased blood pressure, and improved survival. They also found that NO reduces the biologic activity of norepinephrine without altering nerve-stimulated release. Case et al. showed increased superoxide release for T cells in a norepinephrine-stimulated manner. These findings may provide insight into the clinical observations involving critically ill patients in which pharmacologic norepinephrine administration is ineffective in correcting hypotension.

Catecholamines and Hypermetabolism

Despite myriad factors reported to promote or inhibit the development of the post-burn hypermetabolic state, many investigators have demonstrated sympathetic catecholamines (norepinephrine more so than epinephrine) to be the effector limb of the transition to and maintenance of this hypermetabolic state. Herndon et al. clearly showed this using a 50% full-thickness scald burn rodent model, with groups pretreated with thyroidectomy, adrenalectomy (+/− dexamethasone replacement), and reserpine depletion of catecholamines. Adrenalectomy or reserpine blunted more than half of the hypermetabolic response. Wilmore et al. demonstrated catecholamines to be the mediator of the human hypermetabolic response to thermal injury. Several key findings were generated by that study: the β-adrenergic (but not α-adrenergic) blockade reduced metabolic rate, pulse, blood pressure, and free fatty acids. Additionally the investigators documented the “nonliving” response to thermal injury: poikilothermia. They noted that when burned patients were placed in cooler environments (21°C), their metabolic rates generally increased, with urinary catecholamine excretions increasing in parallel, excepting four nonsurvivors who showed less catecholamine elaboration, became hypothermic, and did not elevate their metabolic rates. The reason these patients failed to develop sufficient hypermetabolic responses to permit survival remains only partially understood. Burned patients consistently selected a higher room temperature (~30°C) and also had skin and core temperature increases of 1.7°C –2°C above controls. Elevations in energy requirements could be partially modulated through adjustments in environmental temperature. Burn patients treated in warm environments of 32°C exhibited reduced metabolic rates compared to those treated at 25°C, although both groups remained hypermetabolic. After injury, and concurrent with an elevated hypothalamic temperature set-point and cardiac index, qualitative and quantitative changes occur in the flow of biological energy and mass (substrate) through the patient.

Experimental studies of Wolfe and Durkot suggest that the adrenergic drive following burn facilitates lipolysis, influencing fatty acid oxidation. The importance of adrenergic drive on lipid metabolism in burn was shown in human patients through the use of stable isotopic studies as well as adrenergic antagonists. The profile of the plasma lipids is dramatically changed as well. These results indicate that not only is lipolysis following thermal injury mediated by β ₂ -adrenergic receptors, but also suggest increased intracellular and extracellular triglyceride–fatty acid cycling, with resultant heat production. Elijah et al. further elucidated the effects of peroxisome proliferator activated receptor (PPAR) on lipolysis and hyperglycemia in the severely burned.

Wilmore developed experimental paradigms suggesting the role of catecholamines in mediating the hypermetabolic response to thermal injury. Findings included a positive correlation of increased plasma catecholamines and whole-body oxygen consumption following thermal injury, as well as demonstrating that adrenergic blockade lowers the burn-induced increase in metabolic rate and cardiac output to control levels in animal models.

Experimental findings in rats suggested that the adrenal medulla, while essential for high rates of heat production following thermal injury, is not the primary driver of the hypermetabolic response. Animals with hypothalamic lesions did not increase metabolism following thermal injury and were chronically hypothermic, not unlike experiments in which the adrenal medulla was removed prior to thermal injury. These results are consistent with clinical observations of burn patients in whom reductions in heat loss were achieved with occlusive dressings and for whom elevated environmental temperatures demonstrate partial reductions in metabolic rate and catecholamine secretion.

β-Blockade

Building on findings that catecholamines drive post-burn hypermetabolism, Herndon et al. demonstrated that pediatric patients could be treated with the β-adrenergic blocker propranolol to successfully reduce metabolic rate without compromising cardiovascular function. In a more recent study by this group, β-adrenergic blockade in pediatric patients for 4 weeks during recovery from severe burns reduced the elevation in resting energy expenditure and reversed the reduction in net muscle–protein balance by 82%. Such treatment also prevented fatty liver and loss in fat-free whole-body mass and provided for a more efficacious recovery in these children. Subsequent studies built on these findings demonstrated improvements when dosing was continued for 1 year post-burn. Recent animal studies have further established a cyclooxygenase-2 role in inflammatory proliferation in the liver. Downregulation of fructose-1,6-bisphosphatase-2 mRNA has been observed in muscle tissue following treatment with propranolol; this enzyme may play a role in gluconeogenesis, although the metabolic significance of this tissue-specific transcriptional alteration remains to be determined. Propranolol leaves α-adrenergic receptors unopposed, resulting in peripheral vasoconstriction and increasing vascular resistance. Reduced blood loss has been observed, with postoperative hematocrit 5–7% higher with propranolol. The exercise-induced enhancements in muscle mass, strength, and VO ₂ peak were not impaired by propranolol; instead, aerobic response to exercise was improved in massively burned children. β-Blockade in nonburned septic patients has become an area of active research and, based on these findings in burned patients, demonstrates value for some patients, although the overall indications and patient selection have yet to be fully elucidated.

Sympathetic Influences on Immune Function

New data have clarified the interconnections between the immune and sympathetic nervous systems and are well reviewed by Pedro et al. Understanding these interactions may be important to comprehending the implications of our pharmacologic treatments with β-adrenergic antagonists and agonists on immune function.

Immunohistochemical staining demonstrates substantial sympathetic innervation of all primary (thymus and bone marrow) and secondary (spleen and lymph nodes) lymphoid organs. Innervation has been shown to reach immune cell compartments of the spleen (the white pulp), periarterial lymphoid sheath, marginal zone, and marginal sinus areas, as well as the splenic capsule and trabeculae. Sympathetic nerve terminals have been described in direct apposition to T cells, interdigitating dendritic cells, and B cells.

Immune modulation by adrenergic signaling was recently reviewed by Sanders. Lymphocytes (including activated and resting B cells, naïve CD4 ⁺ T cells, T-helper [T _h 1] cell clones, and newly generated T _H 1 cells) express β-adrenergic receptors, but they are not expressed in newly generated T _H 2 cells. Furthermore there is significant evidence that norepinephrine can modulate the function of CD4 ⁺ T cells, which in turn can modulate antibody production of B cells. Sympathetic neurons suppress CD8 ⁺ T-cell receptor response and cytotoxic activity. In addition, norepinephrine can directly influence B-cell antibody production depending on the time of exposure following activation. The physiologic importance of these in vitro findings is supported by a series of in vivo experiments involving severe combined immunodeficient ( scid ) mice depleted of norepinephrine prior to reconstitution with antigen-specific T _H 2 and B cells. These experiments demonstrate that norepinephrine is necessary to maintain a normal level of antibody production in vivo. Furthermore other whole-animal experiments also involving scid mice provide evidence that the immune response itself stimulates the release of norepinephrine from adrenergic nerve terminals in bone marrow and the spleen, which in turn can influence antibody production by B cells. β-Blockade in 20 pediatric burn patients significantly reduced serum tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). The parasympathetic system further conditions the immunomodulatory role of the SNS. Recently it was shown that the vagal synapses trigger acetylcholine release from memory T cells, in turn reducing TNF-α through α-7-nicotinic acetylcholine receptor. These findings suggest the potential of sympathetic/parasympathetic activation in mediating immune responses.

In animal models, blocking β-adrenergic receptors soon after injury partially restored the lipopolysaccharide (LPS)-stimulated TNF-α secretory potential of circulating monocytes lost during the course of burn injury and sepsis. Apart from adrenergic inhibition of LPS-stimulated TNF-α release in isolated macrophages, similar inhibition of LPS-stimulated TNF-α production has also been demonstrated in human mast cells, microglial cells, astrocytes, and cytotoxic T lymphocytes. In contrast to adrenergic stimulation of TNF-α release, experiments with isolated atria, myenteric plexus, and brain tissue have proved that TNF-α can negatively affect the release of norepinephrine.

Although the precise mechanisms of the negative modulation of proinflammatory cytokines by catecholamines are poorly understood, it may be achieved through the ability of catecholamines to induce the antiinflammatory cytokine IL-10. Whole-animal studies involving assessment of circulating levels of IL-10 as well as studies of human whole blood and mononuclear cells stimulated with LPS in the presence of adrenergic agonists support this premise. Immunomodulatory effects were further elucidated by Takenaka et al. demonstrating the effects on T-cell differentiation to CD4+ via a dendritic cell-mediated pathway. Additionally experimental neurotrauma resulted in increased IL-10 consequent to endogenous adrenergic stimulation in the absence of LPS or other evidence of infectious challenge.