The chapters on multisystem organ failure and shock describe the physiology of the “ebb” phase from distributive shock and myocardial changes by which cardiac function is depressed. By 48 hours postburn, 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 possibly long-term pathologic changes.

With the onset of burn shock/postburn physiology, a 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 stimulated release of adrenomedullary norepinephrine. Angiotensin II (AII) and arginine vasopressin (AVP) also act to increase vascular tone. ^, Additionally a complex interplay of AII and the autonomic nervous system further modulates vascular tone. Concurrently, AVP has been shown to reversibly depress myocardial function in the isolated heart. AVP, wound-derived factors including thromboxanes, and the initial catecholamine storm triggered by burn injury thus conspire with the profound and progressive fluid shifts (losses) of burn injury. This shock state is characterized by a “triple jeopardy” of increased peripheral vascular resistance, depressed cardiac contractility, and intravascular volume depletion. This combination attempts to sustain a deleterious feed-forward event and permit a potentially fatal state of burn shock during the “ebb” phase. ^, Painful experience has taught that survivors successfully transition to a hypermetabolic, hyperthermic, hyperdynamic, high-cardiac output flow state, whereas in the first 96 hours nonsurvivors become progressively poikilothermic and fail to exhibit the necessary increase in biochemical energetic and substrate fluxes necessary to preserve life and support tissue recovery. The progressive cooling-off of potential nonsurvivors reflects an organism-wide, cellular metabolic failure, primarily of oxidative phosphorylation and its attendant heat generation, which gives the striking appearance of the fire of a patient’s life diminishing and, if not rapidly supported, extinguishing. It is no coincidence that the subjects of this chapter are the primary systems that internally regulate metabolism and determine heat flux. Intervening to rebalance these equations preserves life through the initial phase of burn injury; is one of the great success stories of medicine in the latter half of the 20th century; is not always easy; but is possible in nearly every case. It is achieved by supporting internal temperature and permitting reasonably supranormal temperature and always preventing/treating decreases in body temperature. Heat is generated from within the organism metabolically and absorbed or lost environmentally. While insulating the patient from excessive heat loss, heat generation is supported by ensuring adequate substrate availability, which is especially important in malnourished and undernourished individuals. Flow of substrates must be maintained, which is indicated on an organism level by adequate (supranormal) cardiac index, accounting for the triple jeopardy referenced above. This may require complex inotropic and vasodilator support, in addition to exacting hourly resuscitation to maintain intravascular volume without triggering immediate or future volume overload. Bedside echocardiography can rapidly discriminate between a volume problem or a pump problem, but the latter may be due to varying combinations of inappropriate vasoconstriction (excess afterload) and myocardial depression. Other devices (PiCCO and similar), which permit monitoring of real-time parameters such as lung water, systemic vascular resistance, and contractility, can be of assistance in these situations. A useful maxim is that a normal (healthy) cardiovascular system will typically respond to correct fluid resuscitation alone, whereas cardiovascular impairment usually requires advanced, individualized intensive care unit (ICU) hemodynamic support informed by requisite monitoring.

On a tissue level, adequate end-organ perfusion is indicated by improving mental status, adequate urine output, clearance of lactate, stabilization of pH, and the absence of compartment syndromes or mesenteric ischemia. Identification of these tissue- and organ-failure syndromes is not always easy or straightforward, but like burn survival itself, perception of these critical findings is almost always possible. Finally, factors that impair cellular energy flux (usually metabolic poisons) must be identified and addressed; in the burn patient these include carbon monoxide and cyanide exposures, among others. If present, these are often the dominant cause of myocardial dysfunction, which typically will not improve until the intoxication is addressed. Viewed through the above lens, the theory and management of the early phase of burn shock is not dissimilar from the understanding and care required for bushcraft fire-making under adverse conditions; and done in a requisite manner it is similarly rewarding.

As the organism transitions to the “flow phase” around 48 hours after insult, sympathetic outflow is 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 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 the supraphysiologic circulatory need requisite for sustained recovery from severe burn injury. Guillory and Finnerty reviewed the menagerie of animal studies demonstrating the centrality of β-adrenergic (dys)function 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, and in stark contrast with the earlier “ebb” phase, 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 after thermal injury. The significance of β ₂ -adrenergic receptors in vasodilation has been demonstrated using knockout mice, thus pointing to the importance 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 abnormally catecholamine signaling, nitric oxide, and atrial natriuretic peptide (ANP), may contribute to decreased vascular resistance.

When decreases in peripheral vascular resistance (especially with superimposed sepsis) compromise tissue perfusion via maldistribution, end-organ damage can result (e.g., the urinary granular casts of tubular necrosis). In this circumstance, pressor agents may be required to maintain adequate tissue perfusion despite 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 nonadrenergic inodilator levosimendan may find utility in treating cardiac failure in burn patients.

Conversely, supplemental norepinephrine is essentially never helpful, although it may improve hemodynamics especially in sepsis, during which burned patients live or die by the success or failure of their integumentary recovery. For burn patients, norepinephrine and stronger vasoconstrictors reliably lead to conversion of partial-thickness burns to full thickness, conversion of donor sites to new full-thickness wounds, and ischemic gangrene of at-risk/healing tissue. A vicious cycle of superinfection of these areas and progressive sepsis usually heralds a fatal outcome. We do not use norepinephrine drips in burned patients; they already have an endogenous excess.

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 sympathetic signaling, 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 nitric oxide 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 why critically ill patients lose responsiveness to pharmacologic norepinephrine administration and suffer refractory hypotension.

Despite myriad factors reported to promote or inhibit the development of the postburn hypermetabolic state, investigators, led by Basil A. Pruitt, 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, discussed earlier. Their translational research found that when burned patients were placed in cooler environments (21°C), 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 early hypermetabolic responses to permit survival remains only partially understood, but these data suggest an inability to mount a sufficiently powerful sympathetic response.

Burned patients consistently selected a higher room temperature (~30°C) and also had skin and core temperature increases of 1.7°C to 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 with 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 biologic energy and mass (substrate) through the patient.

Experimental studies of Wolfe and Durkot suggest that the adrenergic drive after burn facilitates lipolysis, influencing fatty acid oxidation. The importance of adrenergic drive on lipid metabolism in burns 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 after thermal injury mediated by β ₂ -adrenergic receptors, but they 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 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 after 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 suggest that the adrenal medulla, although essential for high rates of heat production after thermal injury, is not the upstream driver of the hypermetabolic response. ^, Animals with hypothalamic lesions did not increase metabolism after thermal injury and were chronically hypothermic, not unlike experiments in which the adrenal medulla was removed before 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.

Building on findings that catecholamines drive postburn 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 over 80%. Such treatment also prevented fatty liver and loss in fat-free whole-body mass (measured by dual-energy x-ray absorptiometry) and provided for a more efficacious recovery in these children. ^, Subsequent studies extended these findings to show prolonged improvement when dosing was continued for 1 year postburn. Recent animal studies have further established a cyclooxygenase-2 role in postburn hepatocellular proliferation and histologic remodeling in the liver. Downregulation of fructose-1,6-bisphosphatase-2 mRNA has been observed in muscle tissue after 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 somewhat increasing vascular resistance. Reduced blood loss has been observed, with postoperative hematocrit 5% to 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.

New data have clarified the interconnections between the immune and sympathetic nervous systems and are well reviewed by Padro 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 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 after 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 before 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 may influence antibody production by B cells in a more local manner. 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 the 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 with 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.

In a series of fascinating studies, Ma et al. recently demonstrated that a murine depression-like phenotype, induced by LPS injection, could be abrogated by splenic denervation before LPS administration. They showed splenic denervation prevented changes in hippocampal synapse protein expression and strikingly decreased the levels of proinflammatory cytokine IL-6. Splenic denervation did not affect levels of TNF-α. Also recently, a murine model of posttraumatic stress disorder (PTSD) termed “repeated social defeat stress” (RSDS) was shown to recapitulate the behavioral, autonomic, and inflammatory aspects of PTSD. Targeted splenic denervation did not alter antisocial or anxiety-like behaviors induced by RSDS; however, IL-2, IL-17a, and IL-22, T-lymphocyte specific cytokines, were significantly reduced. T lymphocyte T _{HHh H} 17 polarization was also ameliorated. These and similar studies by Elkhatib et al. suggest important metabolically and immunologically important neurotransmission, likely both afferent and efferent, via splenic innervation. They allude to the tantalizing possibility of temporary interruption to aid burn/critical illness recovery and providing a deepening understanding of these intricate and interconnected regulatory mechanisms.

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.

Burn injury is commonly complicated by transient bacteremia, infection, and sepsis (see chapters on Infection [ Chapter 10 ] and Multisystem Organ Failure [ Chapter 24 ]). Infection causes a marked sympathetic response proportional to the degree of insult in which there are simultaneous and opposing forces of hyperinflammation versus immunosuppression. Sepsis is accompanied by an enormous catecholamine surge leading to changes in cardiovascular output, immunomodulatory effects, and catabolism. Propranolol has been shown to attenuate those changes. The use of an adrenergic blockade as an immunomodulator has found further utility in other traumatic injuries. Furthermore, animal models of septic peritonitis suggest that initial sympathetic activation, as measured by elevated levels of plasma norepinephrine and greater norepinephrine turnover, persists for many hours. ^,

Collectively, these data clearly support a complex trophic interconnection between the SNS and immune system. Burn- and sepsis-induced sympathetic responses exert significant influence on bone marrow cellular events. Evidence for norepinephrine regulation of myelopoiesis in experimental thermal injury with sepsis is detailed in Chapter 18 on hematology.

Adrenocortical response is critical to coordinating the systemic response to thermal injury. The glucocorticoid surge after burn injury has long been measured by both serum and urinary excretion markers. Regulation of glucocorticoid secretion is complex, with multiple determinants of the adrenal cortex secretion of cortisol, including pituitary ACTH, but also afferent neural control and hyperthermia, which blunts the adrenal response to ACTH. Furthermore, the usual circadian rhythm of cortisol secretion is dampened after burn injury. In 1982, Vaughan et al. showed elevated circulating and urinary cortisol, with a weak correlation to the level of ACTH. Stronger correlations were noted between cortisol and total body surface area (TBSA) burned, metabolic rate, and average body temperature. These observations in burned patients indicate that adrenal hypersecretion of cortisol is in response to temperature, circulating mediators of hypermetabolism, direct adrenal innervation, and a decrease in adrenal cortex responsiveness to ACTH. As a result, the authors concluded that cortisol may play a secondary role in permitting and promoting the changes seen in postinjury hypermetabolism. On this basis, they attributed postinjury metabolic and thermal changes primarily to sympathetic tone and circulating catecholamines (norepinephrine and epinephrine).

Danner and colleagues carefully mapped the HPA axis response to a massive septic insult in their lethal canine pneumonia model as they attempted to define the “critical illness-related corticosteroid insufficiency.” They found a massive surge in total, bound, and free serum cortisol and in ACTH. Additionally, they determined that ACTH failed to promote a further increase in cortisol and that dexamethasone did not suppress cortisol, possibly because the adrenals were already maximally stimulated. Significantly in sepsis-surviving animals, the HPA axis recovered to normal levels, whereas ACTH and dexamethasone responsiveness recovered by 10 hours compared with nonsurvivors. In contrast, the mineralocorticoid response with hyperaldosteronism remained past 72 hours and did not regain dexamethasone suppression. Thus mineralocorticoids are ACTH independent in the setting of sepsis. These data support the adrenal exhaustion hypothesis.

In a postmortem study of adrenal glands of ICU patients, it was found that the adrenocortical structure was disrupted after critical illness. These patients tended to have adrenal glands that weighed less than controls, with significantly less protein content and greater fluid content. There was also considerable downregulation of ACTH-regulated genes.

Elevated plasma-cortisol levels have been shown during critical illness, especially during an episode of systemic inflammatory response syndrome (SIRS). However, cortisol production during the day in patients with SIRS, although elevated, is less than doubled. ACTH is suppressed in these patients, implying a non–ACTH-driven response. It has been demonstrated that during critical illness clearance of plasma cortisol is significantly reduced, playing a significant role in the hypercortisolism of the critically ill stress response. Other investigators determined in the setting of septic shock that only serial hormonal measurements and provocative testing were useful for HPA axis function assessment. They further identified high aldosterone levels in a population with poor outcomes from sepsis.

Norbury et al. followed urinary cortisol levels in 212 severely burned children, finding three- to fivefold increases in cortisol excretion up to 100 days postburn. Urinary norepinephrine levels were significantly increased up to 20 days, as shown in Fig. 19.1 . Hypercortisolemia has been suggested as a driver of whole-body catabolism after severe burn. To test this hypothesis, Jeschke et al. blocked cortisol production with ketoconazole in 55 severely burned children. They found normalization of the eightfold elevation in urine cortisol in the treatment group. Counterintuitively, no change was seen in inflammatory response, acute-phase proteins, body composition, muscle protein breakdown or synthesis, or organ function. Their data suggest that postburn hypercortisolemia does not play a central role in the catabolic response.

Urinary cortisol and catecholamine excretion after burn injury in children.

(From Norbury WB, Herndon DN, Branski LK, Chinkes DL, Jeschke MG. Urinary cortisol and catecholamine excretion after burn injury in children. J Clin Endocrinol Metab . 2008;93(4):1270-1275.)

Jeschke and Herndon characterized the long-term inflammatory and acute-phase responses in 977 pediatric burn patients with greater than 30% TBSA with 24-hour urinary excretion. They found significant elevations of cortisol, catecholamines, cytokines, and acute-phase proteins for up to 3 years, as seen in Fig. 19.2 . They also observed insulin resistance, increased fracture risk, hepatomegaly, increased cardiac output and cardiac dysfunction, and impaired strength over the same period. ^,

Long-term persistence of the pathophysiologic response to severe burn injury.

(From Jeschke MG, Gauglitz GG, Kulp GA, et al. Long-term persistence of the pathophysiologic response to severe burn injury. PLoS One. 2011;6(7):e21245.)

In burn patients likely to recover, plasma glucocorticoid levels are moderately elevated or in the upper-normal range, can persist beyond a month, ^, and return to normal as healing progresses. In contrast, patients with severe thermal injury (90% TBSA) have markedly lower levels of glucocorticoids.