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How does critical illness alter metabolism?
63 How Does Critical Illness Alter Metabolism? Mark E. Nunnally and Greta Piper
Critical illness increases metabolism globally. The body provides and consumes basic substrates taken from its own structures to run at an accelerated metabolic rate, a rate that cannot be sustained indefinitely. Clinicians in the critical care setting are familiar with the long-term consequences of catabolic processes; in patients whose illness is not alleviated, outcomes are poor and mortality is high. These patients contrast with those undergoing an acute stress response that transitions to a later period of recovery and anabolism. Patterns vary, but all critically ill patients experience increased metabolism in a neurologic, hormonal, and immunologic milieu that reprioritizes many physiologic functions to healing. This process is both adaptive and, in prolonged and uncontrolled situations, pathogenic. In the latter state, globally increased metabolism fuels critical illness. The stress response is a pattern of metabolic changes in injured patients.1 In this framework the physiology of critical illness is adaptive. Metabolic changes from “normal” are necessary to heal serious injury, and patients may become so ill as to require aggressive therapies. Supporting organ system function continues to be a core element of critical care practice: another is the search for ways to attenuate the process leading to illness, which extends to nutrition, care of endocrine systems, and intervention in immunologic signaling. Many metabolic changes in this syndrome have been described, but the meaning of these changes remains subject to a dearth of clear evidence, a glut of theory, and an absence of consensus. This chapter considers the predictable pattern in response to injury, the interventions that alter this pattern, pathologic deviations from that pattern, and the diagnostic utility of comparing a patient’s clinical data with the stress response pattern.
PATHOPHYSIOLOGY AND MECHANISM OF ACTION Cells metabolize glucose, lactate, amino acids, fatty acids, ketones, and their derivatives. They assemble these components into larger carbohydrates (glycogen), proteins, and triglycerides for energy storage and cellular function. Catabolic processes deconstruct larger molecules and generate energy. Anabolic processes assemble them and store energy. Catabolism is the trademark of critical illness, the hypermetabolic 444
recovery period of “flow” that follows the “ebb” of shock.2 These two phases are followed by an anabolic recovery phase after the stress response resolves. This recovery phase may persist for weeks to months (Fig. 63.1). Changes affect each organ system and the connections between them. Examples include immune, endocrine, and neurologic changes, such as alterations in circadian rhythms. Available evidence supports the theory that this adaptive response enables tissue healing. Resting energy expenditure increases in critical illness. Glucose and fatty acids are consumed at accelerated rates. Serum levels of both exceed the normal range. Proteins are catabolized to amino acids, which in turn are converted by the liver to glucose. Patients develop hyperglycemia. Levels of lactate increase because of a metabolic shift and do not necessarily reflect tissue hypoperfusion, as is the case in acute shock. The catabolism of critical illness is not the same as that of starvation. In catabolism, tissue protein is consumed preferentially rather than spared. The liver produces more acute phase reactants, such as C-reactive protein, immunoglobulins, fibrinogen, and haptoglobin, and less of other proteins such as prealbumin, albumin, and transferrin. Muscle tissue provides most of the amino acids for fuel and protein synthesis. Ketosis is rare, because insulin levels still suppress ketogenesis. Additional nutrition cannot stop the loss of body proteins. The intestines maintain glutamine absorption, but conversion to citrulline drops, suggesting nutritional reprioritization.3 Serum amino acid profiles change in septic patients in concert with their illness trajectory.4 These findings underscore that nutrients have different effects during critical illness and metabolic priorities are changed. Critically ill patients will not respond to endocrine, nutritional, or metabolic therapies the same way that unstressed patients do. End-organ cells lose part of their ability to oxidize fuels in the mitochondria.5 For these cells, metabolism and oxygen utilization decrease, leading to a metabolic “shunt” and organ dysfunction. This bioenergetic failure correlates with illness severity. Recovery is sometimes possible, but resulting organ dysfunctions frequently require additional medical support. Thiamine deficiency, exacerbated by heightened pyruvate dehydrogenase activity and carbohydrate oxidation, may also cause a form of bioenergetic failure. Endocrine and neurologic axes promote and reflect the change in metabolism. The anterior pituitary releases large
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“Flow”: hypermetabolism Cardiac output Oxygen delivery Substrate delivery Stress hormones
Peak amplitude influenced by type of stressor
Time Time course varies by stress: classically 6–7 days
Anabolic recovery “Ebb”: shock and hypoperfusion Fig. 63.1 Stress Response Curve, as Described by Cuthbertson. A period of shock may or may not precede the hyperdynamic phase during which nutrient and oxygen delivery are increased to peripheral tissues. For details on organ-specific alterations, see chapter text.
amounts of growth hormone, thyroid-stimulating hormone, luteinizing hormone, and prolactin, but there is peripheral resistance to normal metabolic effects.6–10 Metabolism and cardiovascular function change as a consequence of elevated levels of catecholamines and vasopressin. Although insulin levels are increased, the anabolic effects of the hormone are attenuated. Changes in organ systems function characterize the acute phase of critical illness. These findings can sometimes herald a new diagnosis, such as sepsis, and clinicians should recognize the pattern to increase monitoring, consider empiric therapy, and search for illness sources. Only source control can definitively resolve an acute phase response. Failure to do so can lead to chronic dysfunction.
Neurologic Brain tissue uses a wide variety of metabolic fuel. During acute illnesses, glucose, amino acid, and lactate metabolism increases. Encephalopathy frequently develops, possibly related to the presence of elevated levels of aromatic amino acids and their metabolites.11–13 Global cerebral function declines, manifested as alterations ranging from delirium to overt coma. Survivors of critical illness may have ongoing cognitive deficits that may be severe in chronic critical illness.14
Cardiovascular Acute illness accelerates oxygen consumption in the periphery. To compensate, cardiac output increases and peripheral vascular tone decreases, augmenting blood flow to peripheral tissues, possibly at the expense of flow to other vascular beds. Oxygen consumption is highest in leukocyte-dense tissues, suggesting oxygen delivery is destined for cells that repair tissue and control infection.15,16 Capillary beds leak because of alterations in glycocalyx function.17 The balance between fluid extravasation and reabsorption
consequently favors the formation of edema, as plasma proteins accumulate outside vessel walls, pulling fluid and electrolytes with them. The result of these changes is a hyperdynamic circulation and edema. In some patients, there may be myocardial injury. Damage may lead to a failure to supplement oxygen delivery, which is associated with a high mortality in critical illness lung injury.18 A hyperdynamic circulation is adaptive, but there is generally no benefit from attempts to enhance normal oxygen delivery with inotropes or blood products.19,20 Right ventricle-limited circulation may be an exception.21
Fluids, Electrolytes, and Nutrition Tissue edema and intravascular resuscitation increase body water, and patients characteristically gain kilograms in weight. Extracellular and vascular compartments expand,22–25 but intracellular water is lost. This finding suggests that water shifts from the intracellular space to the extracellular space and back again as edema resolves, which has implications for electrolyte balance. Insensible water loss and diuretic use produce hypernatremia. At times, renal water retention causes hyponatremia. As the acute response abates, water shifts dilute potassium, magnesium, phosphate, and proteins; as a result, hypokalemia, hypomagnesemia, and hypophosphatemia are common. Hypermetabolism or the refeeding syndrome exacerbates hypophosphatemia.26,27 Whole-body glucose delivery increases as a consequence of decreased peripheral uptake28,29 and increased production. Hepatic gluconeogenesis converts amino acids and glycerol to glucose, even during hyperglycemia.30,31 Amino acids, freed from peripheral protein stores, are the substrate. Glucose uptake is reduced in many tissues, but hyperglycemia fuels leukocyte demand in injured areas. Hyperglycemia and edema formation deliver glucose to avascular injured areas.
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Lipid metabolism increases in the stress response, more so triglyceride hydrolysis and re-esterification, resulting in elevated serum triglycerides.32,33 Patients with chronic critical illness generally retain most of their fat stores but are severely depleted of protein,34 which manifest as susceptibility to injuries and inability to heal wounds.
Pulmonary Pulmonary insufficiency accompanies the acute critical illness. Enhanced oxygen consumption and carbon dioxide production tax the pulmonary system. Tachypnea and type I (oxygenation) and II (ventilation) failure occur. Perivascular fluid flux forces fluids and proteins into alveoli. Inflammatory cell infiltration exacerbates extravasation. Altered immune function and risk for aspiration foment pulmonary infection. Such changes culminate in pulmonary failure, including the acute respiratory distress syndrome (ARDS). Respiratory muscles lose strength and coordination, worsening ventilatory function and secretion clearance. Chronic illness is frequently accompanied by a need for ongoing respiratory support.
Gastrointestinal Intestinal villi atrophy and the gut swells.35 Ileus heralds worsening stress. These changes confound attempts to provide enteric nutrition and raise the risk of bowel obstruction. Hepatic metabolic changes include impaired excretion of bilirubin and other metabolites. Chronic illness is marked by problems in nutrient absorption and gastrointestinal motility.36
Renal Peripheral vasodilatation steals blood flow from the kidneys. Reduced perfusion and circulating mediators produce a syndrome of oliguria. Metabolically active tubular cells suspend function and become quiescent until the acute phase initiator has long resolved. The extreme example of this condition is acute kidney injury. With recovery, renal function often returns.37 Chronic states may impede effective renal recovery, with subsequent changes in distribution and metabolism of drugs, including antibiotics.
Immunologic Cell-mediated immunity is suppressed during inflammation.38 Susceptibility to infection increases as systemic inflammatory signals are elevated. Chronic illness is marked by susceptibility to a variety of bacterial, viral, and fungal pathogens,39–41 many of which are rarely pathologic in healthy patients. Myeloid-derived suppressor cells (MDSCs) play a key role in the pathophysiology of persistent inflammatory, immunosuppressed, catabolic syndrome (PICS). MDSCs suppress T-lymphocyte proliferation as well as Th1 and Th2 cytokine release. Early expansion of MDSCs in sepsis portends early mortality, and persistent MDSC expansion correlates with longer intensive care unit (ICU) stays and increased nosocomial infections.42
Endocrine Cortisol, catecholamines, and glucagon accelerate metabolism and hyperglycemia.29 Relative cortisol deficiency worsens vasodilatory shock and stalls recovery.43 Muscle and fat anabolic responses to insulin diminish.44–47 Changes in endocrine signaling include the euthyroid sick syndrome, disorders of sleep cycles, and altered immunologic function. Eventually, pituitary hypersecretion and altered peripheral sensitivity may give way to endocrine exhaustion. If critical illness continues unabated, metabolic signaling changes. Adiponectin levels decrease with acute critical illness but then normalize as illness continues,48 part of changing immune and metabolic signaling. Catabolism continues. Anterior pituitary hormone levels, including thyroid stimulating hormone, growth hormone, and prolactin, decline in a functional state of neuroendocrine exhaustion. In chronic critical illness, neuroendocrine exhaustion is compounded by widespread bioenergetic mitochondrial failure, organ failure, kwashiorkor-like protein malnutrition, and a stymied immune response. Regular biologic oscillators fail to fluctuate,49 suggesting that a loss of organ systems interconnectivity is part of the disorder. PICS has been described in trauma patients, pancreatitis, enterocutaneous fistulae, burns, and sepsis.50–53 Following the initial insult, patients manifest proinflammatory and antiinflammatory processes. Patients surviving critical illness for 14 or more days with persistent organ dysfunction express classic chronic illness changes. Despite often optimized traditional nutritional support, a smoldering inflammatory state persists, characterized by chronic illness, high levels of inflammatory markers, low albumin and prealbumin, and low lymphocyte count. Patients with PICS have sarcopenia, are prone to recurrent infections, and have poor wound healing. Recovery from any of these phases entails source control followed by prolonged anabolism. In PICS and chronic states, full recovery may not be possible. Tissue protein stores recover slowly. It takes time to replete proteins, endocrine axes, and immune responses to normal function. Myopathies, neuropathies, and poor wound healing are the most visible manifestations of the slow recovery. While traditional nutritional therapies have focused on the acute phase of illness, future nutritional optimization will probably need to better address the recovery phase.
AVAILABLE DATA Multiple clinical trials suggest ways in which metabolism in critical illness is mediated and how attempts to interfere with it might help or harm. Beta blockade can attenuate the loss of muscle mass, as demonstrated in severely burned children.54 This finding supports the idea that neuroendocrine signaling is related to acute phase metabolism. Endocrine studies support the role of this system in metabolism. Steroids are supported as adjunctive therapy for refractory septic shock.55 Reversal of shock is a reproducible outcome in
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trials of steroid administration,43,56–59 as is hyperglycemia, but mortality has been unchanged in several key studies.57,58 This leaves open the question of utility. Unresolved issues include the role of continuous vs. bolus infusion, mineralocorticoid co-administration, and the appropriate selection of patients likely to be relatively steroid deficient or, more importantly, likely to benefit. Other adverse effects of steroids include hypernatremia and neuromuscular weakness. Circadian rhythms are frequently disrupted in critically ill patients due to artificial lighting, auditory stimulation, and pharmacologic agents, including analgesics and sedatives, vasopressors, inotropes, and beta agonists. These changes also likely reflect abnormalities of normal patterns of physiologic oscillation and organ coordination.60 Mechanical ventilation and continuous enteral nutrition disrupt normal rhythms of metabolism, including cortisol levels. Melatonin administration to regulate day/night cycles may decrease the need for sedatives, and delirium.61 Vitamin C may play a role in circulatory and metabolic abnormalities in sepsis. Because septic patients consume their stores of vitamin C and are unable to generate more, supplementation may be beneficial. Recent data suggest vitamin C administration with hydrocortisone and thiamine may improve recovery from sepsis,62 although thiamine alone also demonstrates benefit.63 These dramatic results await replication. Vitamin D receptors are expressed in immune cells, including T cells, activated B cells, and dendritic cells, and regulate antimicrobial peptides. Vitamin D deficiency is common in critically ill patients and is associated with increased infection severity, organ failure, and mortality.64,65 Supplementation, while relatively safe and inexpensive, requires high doses of vitamin D to normalize levels. Although a randomized trial demonstrated no improvement in overall mortality or length of stay, there was improvement in mortality in severely deficient patients.66 Vitamin D deficiency is probably a problem in some critically ill patients, but the role of supplementation is unresolved. The adequate amount of nutrition needed during critical illness is an ongoing conundrum. Nutritional support modestly prevents excessive protein loss, hyperglycemia, or hyperlipidemia, and may improve organ and immune function. The available literature is highly prone to bias. A few findings are consistent. Very high levels of nutrients are associated with worse outcomes, “underfeeding” may be beneficial, and parenteral nutrients do not have the same effects as enteric nutrition.67 Obese critically ill patients warrant additional consideration.68 Nutritional topics are treated elsewhere in this text. Controlling the drivers of catabolism (i.e., source control) is likely to have more impact than the provision of nutrition. Attempts to alter stress metabolism can have adverse consequences. Although administration of anabolic hormones might attenuate loss of lean muscle mass and improve outcomes in critical illness, studies of androgen supplementation show mixed results.69 In one study, growth hormone supplementation increased mortality.70 In a surgical population, aggressive insulin therapy improved survival and reduced
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organ dysfunction when serum glucose was driven to nonstress levels.71 Subsequent studies failed to replicate these results.72–75 The original study was criticized for its large proportion of cardiac surgery patients, the restriction of benefit to patients who stayed in the ICU longer, and the aggressive nutrition given to the patients.76 Given the changes and variability in stress metabolism during critical illness, it is quite conceivable that the goals of insulin therapy should vary with a patient’s position on the stress curve such that catabolism is not overly suppressed early and anabolism is supported late.
INTERPRETATION OF DATA Acute phase metabolism is incompletely characterized, variable, and multifaceted. Attempts to regulate specific elements on the arc of inflammation have been mostly unsuccessful, but available data do provide useful tools for the care of critically ill patients. It is likely that inflammation is mostly adaptive and necessary for survival. The stress response model is a template on which a patient’s progress can be mapped. Signs of increased metabolism and neurohormonal stress should prompt a search for a cause, and aggressive, sometimes empiric, therapy. As an example, the triad of encephalopathy, hyperglycemia, and impaired intestinal motility may herald the onset of sepsis. Conversely, signs that stress is abating, such as negative spontaneous fluid balance and hypokalemia, can inform decisions to de-escalate monitoring and therapy, reducing iatrogenic risk. In the future, aminograms, lipograms, and even biograms of endogenous flora may help inform clinicians about these transitions.77 Given that bacteria outnumber somatic cells and mostly fulfill commensal roles, cultivating and monitoring a healthy resident flora should be the subject of ongoing investigation. Nutrition goals are incompletely characterized and should be tailored to patient response. Clinicians should decrease the provision of dextrose if it worsens hyperglycemia in a patient. Protein and fat goals, and the best way to provide them, beg further study. Using lactate as a marker for adequate resuscitation may be helpful in early shock, but lactate has a limited effect once the stress response commences. Therapies must be tested in patients with acute, prolonged, and chronic critical illness.78–80 As a whole, the evidence suggests that preventing the transition to chronic critical illness with aggressive source control is the best available strategy.
SUMMARY Metabolism increases with critical illness. The pattern of increase and decline is predictable, affects every organ system, and is known as the stress response. Increased oxygen and nutrient delivery underlies the observed physiologic changes. The stress response pattern is a useful tool to guide clinical therapy. The most reliable method of controlling the response is to reverse the conditions that drive it, i.e., source control. Repeated or ongoing sources can lead to chronic pathologic dysfunction.
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AUTHORS’ RECOMMENDATIONS • Critical illness increases global metabolism. • The process of elevated global metabolism can be thought of as an adaptive response to facilitate tissue healing. • Critically ill patients undergo a predictable pattern of metabolic and physiologic changes in the stress response. After injury (with or without initial shock), metabolism accelerates with gradual (days to week) recovery followed by a longer (weeks to months) period of anabolic recovery of proteins. The response is manifested in every organ system in the body. • Astute clinicians can exploit their knowledge of the stress response by predicting the pattern, mapping patient physiology to the expected changes, and making diagnostic and therapeutic decisions based on expected trajectory or unexpected variation from the common stress response pattern. • Prolonged or ongoing injuries lead to chronic dysfunctions that include catabolic depletion of protein and nutrient stores, organ dysfunction, and an inhibited immune response.
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72. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354: 449-461. 73. Arabi YM, Dabbagh OC, Tamim HM, et al. Intensive versus conventional insulin therapy: a randomized control trial in medical and surgical critically ill patients. Crit Care Med. 2008;36:3190-3197. 74. Gandhi GY, Nuttall GA, Abel MD, et al. Intensive intrao perative insulin therapy versus conventional glucose management during cardiac surgery. Ann Intern Med. 2007; 146:233-243. 75. NICE-SUGAR Investigators, Finfer S, Chitlock DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360:1283-1297.
76. Nunnally ME. Con: tight perioperative glycemic control: poorly supported and risky. J Cardiothorac Vasc Anesth. 2005;19:689-690. 77. Langley RJ, Tsalik EL, van Velkinburgh JC, et al. An integrated clinic-metabolomic model improves prediction of death in sepsis. Sci Transl Med. 2013;5:195ra95. 78. Nunnally ME, Neligan P, Deutschman CS. Metabolism in acute and chronic illness. In: Rolandelli RH, Bankhead R, Boullata JI, Compher CW, eds. Clinical Nutrition: Enteral and Tube Feeding. 4th ed. Philadelphia, PA: Elsevier; 2008:80-94. 79. Vanhorebeek I, Langouche L, Van den Berghe G. Endocrine aspects of acute and prolonged critical illness. Nat Clin Pract Endocrinol Metab. 2006;2:20-31. 80. Van den Berghe G. Neuroendocrine pathobiology of chronic critical illness. Crit Care Clin. 2002;18:509-528.
e1 Abstract: Metabolism increases with critical illness. The pattern of increase and decline is predictable, affects every organ system, and is known as the stress response. Increased oxygen and nutrient delivery underlies the observed physiologic changes. The stress response pattern is a useful tool to guide clinical therapy.
The most reliable method of controlling the response is to reverse the conditions that drive it, i.e., source control. Repeated or ongoing sources can lead to chronic pathologic dysfunction. Keywords: metabolism, critical illness, stress response, chronic critical illness, catabolism
Critical illness increases metabolism globally. The body provides and consumes basic substrates taken from its own structures to run at an accelerated metabolic rate, a rate that cannot be sustained indefinitely. Clinicians in the critical care setting are familiar with the long-term consequences of catabolic processes; in patients whose illness is not alleviated, outcomes are poor and mortality is high. These patients contrast with those undergoing an acute stress response that transitions to a later period of recovery and anabolism. Patterns vary, but all critically ill patients experience increased metabolism in a neurologic, hormonal, and immunologic milieu that reprioritizes many physiologic functions to healing. This process is both adaptive and, in prolonged and uncontrolled situations, pathogenic. In the latter state, globally increased metabolism fuels critical illness. The stress response is a pattern of metabolic changes in injured patients.1 In this framework the physiology of critical illness is adaptive. Metabolic changes from “normal” are necessary to heal serious injury, and patients may become so ill as to require aggressive therapies. Supporting organ system function continues to be a core element of critical care practice: another is the search for ways to attenuate the process leading to illness, which extends to nutrition, care of endocrine systems, and intervention in immunologic signaling. Many metabolic changes in this syndrome have been described, but the meaning of these changes remains subject to a dearth of clear evidence, a glut of theory, and an absence of consensus. This chapter considers the predictable pattern in response to injury, the interventions that alter this pattern, pathologic deviations from that pattern, and the diagnostic utility of comparing a patient’s clinical data with the stress response pattern.
PATHOPHYSIOLOGY AND MECHANISM OF ACTION Cells metabolize glucose, lactate, amino acids, fatty acids, ketones, and their derivatives. They assemble these components into larger carbohydrates (glycogen), proteins, and triglycerides for energy storage and cellular function. Catabolic processes deconstruct larger molecules and generate energy. Anabolic processes assemble them and store energy. Catabolism is the trademark of critical illness, the hypermetabolic 444
recovery period of “flow” that follows the “ebb” of shock.2 These two phases are followed by an anabolic recovery phase after the stress response resolves. This recovery phase may persist for weeks to months (Fig. 63.1). Changes affect each organ system and the connections between them. Examples include immune, endocrine, and neurologic changes, such as alterations in circadian rhythms. Available evidence supports the theory that this adaptive response enables tissue healing. Resting energy expenditure increases in critical illness. Glucose and fatty acids are consumed at accelerated rates. Serum levels of both exceed the normal range. Proteins are catabolized to amino acids, which in turn are converted by the liver to glucose. Patients develop hyperglycemia. Levels of lactate increase because of a metabolic shift and do not necessarily reflect tissue hypoperfusion, as is the case in acute shock. The catabolism of critical illness is not the same as that of starvation. In catabolism, tissue protein is consumed preferentially rather than spared. The liver produces more acute phase reactants, such as C-reactive protein, immunoglobulins, fibrinogen, and haptoglobin, and less of other proteins such as prealbumin, albumin, and transferrin. Muscle tissue provides most of the amino acids for fuel and protein synthesis. Ketosis is rare, because insulin levels still suppress ketogenesis. Additional nutrition cannot stop the loss of body proteins. The intestines maintain glutamine absorption, but conversion to citrulline drops, suggesting nutritional reprioritization.3 Serum amino acid profiles change in septic patients in concert with their illness trajectory.4 These findings underscore that nutrients have different effects during critical illness and metabolic priorities are changed. Critically ill patients will not respond to endocrine, nutritional, or metabolic therapies the same way that unstressed patients do. End-organ cells lose part of their ability to oxidize fuels in the mitochondria.5 For these cells, metabolism and oxygen utilization decrease, leading to a metabolic “shunt” and organ dysfunction. This bioenergetic failure correlates with illness severity. Recovery is sometimes possible, but resulting organ dysfunctions frequently require additional medical support. Thiamine deficiency, exacerbated by heightened pyruvate dehydrogenase activity and carbohydrate oxidation, may also cause a form of bioenergetic failure. Endocrine and neurologic axes promote and reflect the change in metabolism. The anterior pituitary releases large
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“Flow”: hypermetabolism Cardiac output Oxygen delivery Substrate delivery Stress hormones
Peak amplitude influenced by type of stressor
Time Time course varies by stress: classically 6–7 days
Anabolic recovery “Ebb”: shock and hypoperfusion Fig. 63.1 Stress Response Curve, as Described by Cuthbertson. A period of shock may or may not precede the hyperdynamic phase during which nutrient and oxygen delivery are increased to peripheral tissues. For details on organ-specific alterations, see chapter text.
amounts of growth hormone, thyroid-stimulating hormone, luteinizing hormone, and prolactin, but there is peripheral resistance to normal metabolic effects.6–10 Metabolism and cardiovascular function change as a consequence of elevated levels of catecholamines and vasopressin. Although insulin levels are increased, the anabolic effects of the hormone are attenuated. Changes in organ systems function characterize the acute phase of critical illness. These findings can sometimes herald a new diagnosis, such as sepsis, and clinicians should recognize the pattern to increase monitoring, consider empiric therapy, and search for illness sources. Only source control can definitively resolve an acute phase response. Failure to do so can lead to chronic dysfunction.
Neurologic Brain tissue uses a wide variety of metabolic fuel. During acute illnesses, glucose, amino acid, and lactate metabolism increases. Encephalopathy frequently develops, possibly related to the presence of elevated levels of aromatic amino acids and their metabolites.11–13 Global cerebral function declines, manifested as alterations ranging from delirium to overt coma. Survivors of critical illness may have ongoing cognitive deficits that may be severe in chronic critical illness.14
Cardiovascular Acute illness accelerates oxygen consumption in the periphery. To compensate, cardiac output increases and peripheral vascular tone decreases, augmenting blood flow to peripheral tissues, possibly at the expense of flow to other vascular beds. Oxygen consumption is highest in leukocyte-dense tissues, suggesting oxygen delivery is destined for cells that repair tissue and control infection.15,16 Capillary beds leak because of alterations in glycocalyx function.17 The balance between fluid extravasation and reabsorption
consequently favors the formation of edema, as plasma proteins accumulate outside vessel walls, pulling fluid and electrolytes with them. The result of these changes is a hyperdynamic circulation and edema. In some patients, there may be myocardial injury. Damage may lead to a failure to supplement oxygen delivery, which is associated with a high mortality in critical illness lung injury.18 A hyperdynamic circulation is adaptive, but there is generally no benefit from attempts to enhance normal oxygen delivery with inotropes or blood products.19,20 Right ventricle-limited circulation may be an exception.21
Fluids, Electrolytes, and Nutrition Tissue edema and intravascular resuscitation increase body water, and patients characteristically gain kilograms in weight. Extracellular and vascular compartments expand,22–25 but intracellular water is lost. This finding suggests that water shifts from the intracellular space to the extracellular space and back again as edema resolves, which has implications for electrolyte balance. Insensible water loss and diuretic use produce hypernatremia. At times, renal water retention causes hyponatremia. As the acute response abates, water shifts dilute potassium, magnesium, phosphate, and proteins; as a result, hypokalemia, hypomagnesemia, and hypophosphatemia are common. Hypermetabolism or the refeeding syndrome exacerbates hypophosphatemia.26,27 Whole-body glucose delivery increases as a consequence of decreased peripheral uptake28,29 and increased production. Hepatic gluconeogenesis converts amino acids and glycerol to glucose, even during hyperglycemia.30,31 Amino acids, freed from peripheral protein stores, are the substrate. Glucose uptake is reduced in many tissues, but hyperglycemia fuels leukocyte demand in injured areas. Hyperglycemia and edema formation deliver glucose to avascular injured areas.
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Lipid metabolism increases in the stress response, more so triglyceride hydrolysis and re-esterification, resulting in elevated serum triglycerides.32,33 Patients with chronic critical illness generally retain most of their fat stores but are severely depleted of protein,34 which manifest as susceptibility to injuries and inability to heal wounds.
Pulmonary Pulmonary insufficiency accompanies the acute critical illness. Enhanced oxygen consumption and carbon dioxide production tax the pulmonary system. Tachypnea and type I (oxygenation) and II (ventilation) failure occur. Perivascular fluid flux forces fluids and proteins into alveoli. Inflammatory cell infiltration exacerbates extravasation. Altered immune function and risk for aspiration foment pulmonary infection. Such changes culminate in pulmonary failure, including the acute respiratory distress syndrome (ARDS). Respiratory muscles lose strength and coordination, worsening ventilatory function and secretion clearance. Chronic illness is frequently accompanied by a need for ongoing respiratory support.
Gastrointestinal Intestinal villi atrophy and the gut swells.35 Ileus heralds worsening stress. These changes confound attempts to provide enteric nutrition and raise the risk of bowel obstruction. Hepatic metabolic changes include impaired excretion of bilirubin and other metabolites. Chronic illness is marked by problems in nutrient absorption and gastrointestinal motility.36
Renal Peripheral vasodilatation steals blood flow from the kidneys. Reduced perfusion and circulating mediators produce a syndrome of oliguria. Metabolically active tubular cells suspend function and become quiescent until the acute phase initiator has long resolved. The extreme example of this condition is acute kidney injury. With recovery, renal function often returns.37 Chronic states may impede effective renal recovery, with subsequent changes in distribution and metabolism of drugs, including antibiotics.
Immunologic Cell-mediated immunity is suppressed during inflammation.38 Susceptibility to infection increases as systemic inflammatory signals are elevated. Chronic illness is marked by susceptibility to a variety of bacterial, viral, and fungal pathogens,39–41 many of which are rarely pathologic in healthy patients. Myeloid-derived suppressor cells (MDSCs) play a key role in the pathophysiology of persistent inflammatory, immunosuppressed, catabolic syndrome (PICS). MDSCs suppress T-lymphocyte proliferation as well as Th1 and Th2 cytokine release. Early expansion of MDSCs in sepsis portends early mortality, and persistent MDSC expansion correlates with longer intensive care unit (ICU) stays and increased nosocomial infections.42
Endocrine Cortisol, catecholamines, and glucagon accelerate metabolism and hyperglycemia.29 Relative cortisol deficiency worsens vasodilatory shock and stalls recovery.43 Muscle and fat anabolic responses to insulin diminish.44–47 Changes in endocrine signaling include the euthyroid sick syndrome, disorders of sleep cycles, and altered immunologic function. Eventually, pituitary hypersecretion and altered peripheral sensitivity may give way to endocrine exhaustion. If critical illness continues unabated, metabolic signaling changes. Adiponectin levels decrease with acute critical illness but then normalize as illness continues,48 part of changing immune and metabolic signaling. Catabolism continues. Anterior pituitary hormone levels, including thyroid stimulating hormone, growth hormone, and prolactin, decline in a functional state of neuroendocrine exhaustion. In chronic critical illness, neuroendocrine exhaustion is compounded by widespread bioenergetic mitochondrial failure, organ failure, kwashiorkor-like protein malnutrition, and a stymied immune response. Regular biologic oscillators fail to fluctuate,49 suggesting that a loss of organ systems interconnectivity is part of the disorder. PICS has been described in trauma patients, pancreatitis, enterocutaneous fistulae, burns, and sepsis.50–53 Following the initial insult, patients manifest proinflammatory and antiinflammatory processes. Patients surviving critical illness for 14 or more days with persistent organ dysfunction express classic chronic illness changes. Despite often optimized traditional nutritional support, a smoldering inflammatory state persists, characterized by chronic illness, high levels of inflammatory markers, low albumin and prealbumin, and low lymphocyte count. Patients with PICS have sarcopenia, are prone to recurrent infections, and have poor wound healing. Recovery from any of these phases entails source control followed by prolonged anabolism. In PICS and chronic states, full recovery may not be possible. Tissue protein stores recover slowly. It takes time to replete proteins, endocrine axes, and immune responses to normal function. Myopathies, neuropathies, and poor wound healing are the most visible manifestations of the slow recovery. While traditional nutritional therapies have focused on the acute phase of illness, future nutritional optimization will probably need to better address the recovery phase.
AVAILABLE DATA Multiple clinical trials suggest ways in which metabolism in critical illness is mediated and how attempts to interfere with it might help or harm. Beta blockade can attenuate the loss of muscle mass, as demonstrated in severely burned children.54 This finding supports the idea that neuroendocrine signaling is related to acute phase metabolism. Endocrine studies support the role of this system in metabolism. Steroids are supported as adjunctive therapy for refractory septic shock.55 Reversal of shock is a reproducible outcome in
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trials of steroid administration,43,56–59 as is hyperglycemia, but mortality has been unchanged in several key studies.57,58 This leaves open the question of utility. Unresolved issues include the role of continuous vs. bolus infusion, mineralocorticoid co-administration, and the appropriate selection of patients likely to be relatively steroid deficient or, more importantly, likely to benefit. Other adverse effects of steroids include hypernatremia and neuromuscular weakness. Circadian rhythms are frequently disrupted in critically ill patients due to artificial lighting, auditory stimulation, and pharmacologic agents, including analgesics and sedatives, vasopressors, inotropes, and beta agonists. These changes also likely reflect abnormalities of normal patterns of physiologic oscillation and organ coordination.60 Mechanical ventilation and continuous enteral nutrition disrupt normal rhythms of metabolism, including cortisol levels. Melatonin administration to regulate day/night cycles may decrease the need for sedatives, and delirium.61 Vitamin C may play a role in circulatory and metabolic abnormalities in sepsis. Because septic patients consume their stores of vitamin C and are unable to generate more, supplementation may be beneficial. Recent data suggest vitamin C administration with hydrocortisone and thiamine may improve recovery from sepsis,62 although thiamine alone also demonstrates benefit.63 These dramatic results await replication. Vitamin D receptors are expressed in immune cells, including T cells, activated B cells, and dendritic cells, and regulate antimicrobial peptides. Vitamin D deficiency is common in critically ill patients and is associated with increased infection severity, organ failure, and mortality.64,65 Supplementation, while relatively safe and inexpensive, requires high doses of vitamin D to normalize levels. Although a randomized trial demonstrated no improvement in overall mortality or length of stay, there was improvement in mortality in severely deficient patients.66 Vitamin D deficiency is probably a problem in some critically ill patients, but the role of supplementation is unresolved. The adequate amount of nutrition needed during critical illness is an ongoing conundrum. Nutritional support modestly prevents excessive protein loss, hyperglycemia, or hyperlipidemia, and may improve organ and immune function. The available literature is highly prone to bias. A few findings are consistent. Very high levels of nutrients are associated with worse outcomes, “underfeeding” may be beneficial, and parenteral nutrients do not have the same effects as enteric nutrition.67 Obese critically ill patients warrant additional consideration.68 Nutritional topics are treated elsewhere in this text. Controlling the drivers of catabolism (i.e., source control) is likely to have more impact than the provision of nutrition. Attempts to alter stress metabolism can have adverse consequences. Although administration of anabolic hormones might attenuate loss of lean muscle mass and improve outcomes in critical illness, studies of androgen supplementation show mixed results.69 In one study, growth hormone supplementation increased mortality.70 In a surgical population, aggressive insulin therapy improved survival and reduced
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organ dysfunction when serum glucose was driven to nonstress levels.71 Subsequent studies failed to replicate these results.72–75 The original study was criticized for its large proportion of cardiac surgery patients, the restriction of benefit to patients who stayed in the ICU longer, and the aggressive nutrition given to the patients.76 Given the changes and variability in stress metabolism during critical illness, it is quite conceivable that the goals of insulin therapy should vary with a patient’s position on the stress curve such that catabolism is not overly suppressed early and anabolism is supported late.
INTERPRETATION OF DATA Acute phase metabolism is incompletely characterized, variable, and multifaceted. Attempts to regulate specific elements on the arc of inflammation have been mostly unsuccessful, but available data do provide useful tools for the care of critically ill patients. It is likely that inflammation is mostly adaptive and necessary for survival. The stress response model is a template on which a patient’s progress can be mapped. Signs of increased metabolism and neurohormonal stress should prompt a search for a cause, and aggressive, sometimes empiric, therapy. As an example, the triad of encephalopathy, hyperglycemia, and impaired intestinal motility may herald the onset of sepsis. Conversely, signs that stress is abating, such as negative spontaneous fluid balance and hypokalemia, can inform decisions to de-escalate monitoring and therapy, reducing iatrogenic risk. In the future, aminograms, lipograms, and even biograms of endogenous flora may help inform clinicians about these transitions.77 Given that bacteria outnumber somatic cells and mostly fulfill commensal roles, cultivating and monitoring a healthy resident flora should be the subject of ongoing investigation. Nutrition goals are incompletely characterized and should be tailored to patient response. Clinicians should decrease the provision of dextrose if it worsens hyperglycemia in a patient. Protein and fat goals, and the best way to provide them, beg further study. Using lactate as a marker for adequate resuscitation may be helpful in early shock, but lactate has a limited effect once the stress response commences. Therapies must be tested in patients with acute, prolonged, and chronic critical illness.78–80 As a whole, the evidence suggests that preventing the transition to chronic critical illness with aggressive source control is the best available strategy.
SUMMARY Metabolism increases with critical illness. The pattern of increase and decline is predictable, affects every organ system, and is known as the stress response. Increased oxygen and nutrient delivery underlies the observed physiologic changes. The stress response pattern is a useful tool to guide clinical therapy. The most reliable method of controlling the response is to reverse the conditions that drive it, i.e., source control. Repeated or ongoing sources can lead to chronic pathologic dysfunction.
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AUTHORS’ RECOMMENDATIONS • Critical illness increases global metabolism. • The process of elevated global metabolism can be thought of as an adaptive response to facilitate tissue healing. • Critically ill patients undergo a predictable pattern of metabolic and physiologic changes in the stress response. After injury (with or without initial shock), metabolism accelerates with gradual (days to week) recovery followed by a longer (weeks to months) period of anabolic recovery of proteins. The response is manifested in every organ system in the body. • Astute clinicians can exploit their knowledge of the stress response by predicting the pattern, mapping patient physiology to the expected changes, and making diagnostic and therapeutic decisions based on expected trajectory or unexpected variation from the common stress response pattern. • Prolonged or ongoing injuries lead to chronic dysfunctions that include catabolic depletion of protein and nutrient stores, organ dysfunction, and an inhibited immune response.
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SECTION 12
Metabolic Abnormalities in Critical Illness
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e1 Abstract: Metabolism increases with critical illness. The pattern of increase and decline is predictable, affects every organ system, and is known as the stress response. Increased oxygen and nutrient delivery underlies the observed physiologic changes. The stress response pattern is a useful tool to guide clinical therapy.
The most reliable method of controlling the response is to reverse the conditions that drive it, i.e., source control. Repeated or ongoing sources can lead to chronic pathologic dysfunction. Keywords: metabolism, critical illness, stress response, chronic critical illness, catabolism