e3 93 Malik AN, Czajka A Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? Mitochondrion 2013;13 481 492 94 Simmons JD, Lee YL, Mulekar S, et al Elevated levels of plasm[.]
e3 93 Malik AN, Czajka A Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? Mitochondrion 2013;13: 481-492 94 Simmons JD, Lee YL, Mulekar S, et al Elevated levels of plasma mitochondrial DNA DAMPs are linked to clinical outcome in severely injured human subjects Ann Surg 2013;258:591-596, discussion 596-598 95 Kilbaugh TJ, Lvova M, Karlsson M, et al Peripheral Blood Mitochondrial DNA as a Biomarker of Cerebral Mitochondrial Dysfunction following Traumatic Brain Injury in a Porcine Model PLoS One 2015;10(6):e0130927 96 Viscomi C, Bottani E, Zeviani M Emerging concepts in the therapy of mitochondrial disease Biochim Biophys Acta 2015;1847:544-557 97 Berger MM, Chiolero RL Antioxidant supplementation in sepsis and systemic inflammatory response syndrome Crit Care Med 2007;35(suppl 9):S584-S590 98 Galley HF Bench-to-bedside review: targeting antioxidants to mitochondria in sepsis Crit Care 2010;14:230 99 von Dessauer B, Bongain J, Molina V, Quilodrán J, Castillo R, Rodrigo R Oxidative stress as a novel target in pediatric sepsis management J Crit Care 2011;26(1):103.e1-e7 100 Szeto HH Mitochondria-targeted cytoprotective peptides for ischemia-reperfusion injury Antioxid Redox Signal 2008;10:601-619 101 van den Berghe G, Wouters P, Weekers F, et al Intensive insulin therapy in critically ill patients N Engl J Med 2001;345:1359-1367 102 Macrae D, Tasker RC, Elbourne D A trial of hyperglycemic control in pediatric intensive care N Engl J Med 2014;370:1355-1356 103 Agus MS, Steil GM, Wypij D, et al Tight glycemic control versus standard care after pediatric cardiac surgery N Engl J Med 2012; 367:1208-1219 104 Stump CS, Short KR, Bigelow ML, Schimke JM, Nair KS Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts Proc Natl Acad Sci USA 2003;100:7996-8001 105 Vanhorebeek I, De Vos R, Mesotten D, Wouters PJ, De WolfPeeters C, Van den Berghe G Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients Lancet 2005;365:53-59 106 Ferreira FL, Ladriere L, Vincent JL, Malaisse WJ Prolongation of survival time by infusion of succinic acid dimethyl ester in a caecal ligation and perforation model of sepsis Horm Metab Res 2000;32: 335-336 107 Kilbaugh TJ, Bhandare S, Lorom DH, Saraswati M, Robertson CL, Margulies SS Cyclosporin A preserves mitochondrial function after traumatic brain injury in the immature rat and piglet J Neurotrauma 2011;28:763-774 108 Wainwright MS, Mannix MK, Brown J, Stumpf DA L-carnitine reduces brain injury after hypoxia-ischemia in newborn rats Pediatr Res 2003;54:688-695 109 Dare AJ, Phillips AR, Hickey AJ, et al A systematic review of experimental treatments for mitochondrial dysfunction in sepsis and multiple organ dysfunction syndrome Free Radic Biol Med 2009; 47:1517-1525 110 Piel DA, Gruber PJ, Weinheimer CJ, et al Mitochondrial resuscitation with exogenous cytochrome c in the septic heart Crit Care Med 2007;35:2120-2127 111 Donnino MW, Andersen LW, Chase M, et al Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study Crit Care Med 2016;44(2): 360-367 112 Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J Hydrocortisone, Vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study Chest 2017;151(6):1229-1238 113 Haden DW, Suliman HB, Carraway MS, et al Mitochondrial biogenesis restores oxidative metabolism during Staphylococcus aureus sepsis Am J Respir Crit Care Med 2007;176:768-777 114 MacGarvey NC, Suliman HB, Bartz RR, et al Activation of mitochondrial biogenesis by heme oxygenase-1-mediated NF-E2-related factor-2 induction rescues mice from lethal Staphylococcus aureus sepsis Am J Respir Crit Care Med 2012;185:851-861 115 Fredenburgh LE, Perrella MA, Hess DR, et al A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS JCI Insight 2018;3(23) 116 Gunst J, Derese I, Aertgeerts A, et al Insufficient autophagy contributes to mitochondrial dysfunction, organ failure, and adverse outcome in an animal model of critical illness Crit Care Med 2013;41:182-194 117 Bogacka I, Xie H, Bray GA, Smith SR Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo Diabetes 2005;54:1392-1399 118 Baur JA, Pearson KJ, Price NL, et al Resveratrol improves health and survival of mice on a high-calorie diet Nature 2006;444: 337-342 119 Thomas RR, Khan SM, Portell FR, Smigrodzki RM, Bennett Jr, JP Recombinant human mitochondrial transcription factor A stimulates mitochondrial biogenesis and ATP synthesis, improves motor function after MPTP, reduces oxidative stress and increases survival after endotoxin Mitochondrion 2011;11:108-118 120 Hittel DS, Storey KB Differential expression of mitochondriaencoded genes in a hibernating mammal J Exp Biol 2002;205 (Pt 11):1625-1631 121 Hampton M, Melvin RG, Andrews MT Transcriptomic analysis of brown adipose tissue across the physiological extremes of natural hibernation PLoS One 2013;8:e85157 122 Kaza AK, Wamala I, Friehs I, et al Myocardial rescue with autologous mitochondrial transplantation in a porcine model of ischemia/ reperfusion J Thorac Cardiovasc Surg 2017;153:934-943 123 Emani SM, McCully JD Mitochondrial transplantation: applications for pediatric patients with congenital heart disease Transl Pediatr 2018:7:169-175 e4 Abstract: Cellular respiration is a highly regulated network of enzymatic reactions that align energy demand with energy production In critical illness, this delicate homeostatic balance may be disrupted and has been identified as a possible final common pathway for organ dysfunction and death This chapter reviews (1) major pathways of cellular respiration with a focus on the mitochondria; (2) the role of impaired cellular respiration in critical illness, particularly in shock and multiple-organ dysfunction syndrome; (3) clinical assessment of oxygen utilization and mitochondrial function; and (4) potential therapeutic strategies to improve mitochondrial respiration and restore bioenergetic homeostasis Key words: Respiration, mitochondria, oxidative phosphorylation, energy, homeostasis 80 Biology of the Stress Response STEPHEN WADE STANDAGE PEARLS • • • The stress response is a universal, stereotypical, and integrated neurogenic, endocrine, inflammatory, and metabolic systems response with multiple feed-forward and feed-backward modulation signaling designed to maximize host survival The brain is the paramount organ of the stress response, as it determines what constitutes stress as well as the appropriate type and extent of reaction Multiple afferent stress signals are integrated at the level of the hypothalamus, which coordinates the subsequent response Excessive or prolonged stress stimuli can precipitate a dysregulated stress response Humans demonstrate tremendous adaptability that has allowed them to inhabit and flourish in widely variable climates and environments The resilience of human physiology has permitted the achievement of tremendous feats of endurance and survival under the most inhospitable circumstances The biological systems that facilitate detection and response to stresses in the internal and external environments have been crucial to human success as a species These same systems are at play in the intensive care unit (ICU) when children confront life-threatening conditions and affect how they respond to both injury and treatment This chapter addresses the nature and function of the various physiologic systems that comprise the stress response as it applies to critical illness Definitions and Background For the purpose of this discussion, stress is defined as any force or influence on an organism that perturbs its usual state of equilibrium Strain is the magnitude of deviation from baseline norms that the organism experiences in response to the inciting stressor Resilience is the organism’s ability to adapt to or cope with the stresses and strains imposed on it The process of host adaptation to an environmental, biological, or psychosocial insult is referred to as the stress response Living organisms require a relatively high degree of stability to maintain vital functions Enzymes perform optimally at specific temperatures and hydrogen ion concentrations Action potentials are promulgated along cell membranes based on a narrow range of ionic concentrations Two competing principles relate to stability: homeostasis and allostasis Homeostasis is the process of achieving • • A complicated critical illness course may reflect elements of an ongoing stress response manifested as protein catabolism with poor wound healing and diffuse weakness and immunosuppression associated with hospital-acquired infections Therapeutic intervention must respect physiologic alterations necessary to accommodate the stress response Pursuing “normal” values as physiologic target parameters may ultimately be counterproductive stability through maintaining systemic variables within a fairly narrow dynamic range Allostasis is the process of achieving stability through physiologic or behavioral changes.1,2 Whereas normal physiology imposes homeostatic forces on our vital function to maintain constancy within an optimal range, the stress response pursues physiologic change to adapt to otherwise fatal stressors This allostatic response is designed to be temporary so that once the stressor has resolved, the organism can return to baseline physiologic function To illustrate this concept, consider an appropriately engineered skyscraper built in an earthquake-prone area Rising high above the earth and bearing thousands of tons of steel, concrete, and glass, the structure normally moves very little However, in the event of an earthquake, the building is engineered to tolerate a significant amount of sway to avoid structural damage and collapse The physical attributes that allow the building to bend without breaking comprise its resilience This resilience accommodates the strain imposed by the stress of the earthquake Likewise, the stress response in humans provides resilience to adapt to various stressors around and within us without catastrophic physiologic decompensation Strain is evident in the physiologic changes undertaken in response to stress that allow survival.3 Stress System Primary Elements The stress response comprises a universal, stereotypical, and integrated set of biological activities that respond to both internal and external stimuli.3 The stress system has an afferent, sensory 971 972 S E C T I O N V I I I Pediatric Critical Care: Metabolic and Endocrine various organs that it innervates.10 Multiple afferent stress signals are integrated at the level of the hypothalamus, where the stress response is initiated.6,11,12 Stress response Neurogenic (Dop, Norepi, Ach) Peripheral Responses Inflammatory (TNF-α, IL-6) Endocrine (Cortisol, GH) Metabolic (Glc, Protein, Lipid) • Fig 80.1 Major elements of the stress response Ach, Acetylcholine; Dop, dopamine; GH, growth hormone; Glc, glucose; IL-6, interleukin-6; Norepi, norepinephrine; TNF-a, tumor necrosis factor-alpha limb allowing it to detect stress signals as well as an efferent, effector limb, which brings about physiologic responses to address the stressors Fig 80.1 depicts the stress system as an integrated network of neurogenic, endocrine, inflammatory, and metabolic subsystems that interact through multiple feed-forward and feedbackward signaling channels Initiation and regulation of the stress response occurs in the brain In this regard, the brain is the paramount organ of the stress response, as it determines what constitutes stress as well as the appropriate type and extent of reaction.4 Stress Response The effector stress response can be compartmentalized into central, peripheral, and cellular components.5 The interaction of all of these subsystems is coordinated to achieve three primary objectives: (1) maintain perfusion of the heart, brain, and other vital organs; (2) deploy energy resources from body fuel storage depots; and (3) optimize adenosine triphosphate availability to vital cells and tissues at the expense of nonessential tissues Central Activation and Integration A multitude of signals may activate a stress response, including physical, physiologic, biochemical, and sensory stimuli, as well as psychological distress.6,7 Common stressors in critical illness include hypoperfusion, hypoxia, tissue injury, and infection Hypotension is sensed as a decreased stretch of baroreceptors located in the carotid sinus and aortic arch Peripheral chemoreceptors in the carotid and aortic bodies sense oxygen levels Tissue injury and infection are detected by the innate immune system that recognizes both pathogen-associated molecular patterns and host damage-associated molecular patterns that may occur as a result of direct tissue injury.8,9 Innate immune cells elaborate cytokines that signal stress to the rest of the body These cytokines and various other soluble mediators provide afferent signaling to the brain Additionally, the vagus nerve facilitates bidirectional communication between the brain and immune system as well as the Efferent signaling from the brain involves descending neuroendocrine and autonomic pathways that ultimately control hemodynamic, endocrine, immune, and metabolic aspects of the stress response Activation of the stress system triggers release of the corticotropin-releasing hormone from the hypothalamus, which induces release of adrenocorticotropic hormone (ACTH) from the anterior pituitary ACTH, in turn, stimulates the adrenal cortex to produce cortisol, which is essential to the stress response to critical illness and injury.13 Cortisol affects the transcription of approximately 25% of the entire genome,14 mediating a wide range of hemodynamic, immunologic, and metabolic actions Detailed discussion of cortisol metabolism in critical illness is provided in Chapter 84 The parvicellular neurons of the hypothalamus secrete thyrotropin releasing hormone, which acts on the anterior pituitary gland to release thyroid-stimulating hormone (TSH) Early in critical illness, TSH and T4 levels increase transiently, but this is associated peripherally with a rapid decline in T3 levels and an increase in rT3 levels due to alterations in peripheral conversion of T4.15–17 Elevated TSH levels quickly return to normal but T3 levels remain low, resulting in the sick-euthyroid syndrome, which is discussed in more detail in Chapter 84 Activation of the stress response also causes anterior pituitary growth hormone release in response to hypothalamic growth hormone–releasing hormone secretion Prolactin production, which facilitates the immune response by augmenting lymphocyte activation, is under tonic inhibition from dopaminergic neurons in the hypothalamus Its secretion is enhanced by decreased dopaminergic signaling from the hypothalamus under stress Vasopressin is another early response to stress that is crucial to survival in critical illness.18,19 The magnocellular neurons of the hypothalamic supraoptic and paraventricular nuclei project their axons through the pituitary stalk and onto the capillary bed of the posterior pituitary gland where they release vasopressin directly into the circulation Vasopressin induces peripheral vasoconstriction to counteract hypotension and increases renal water reabsorption to maintain or restore circulating blood volume, which is particularly important in shock states Receiving inputs from the hypothalamus and limbic system, the autonomic nervous system, is also activated in the stress response The locus ceruleus, located in the posterior area of the rostral pons, is an important center of sympathetic outflow, which results in increased arousal, concentration, and alertness Additionally, noradrenergic signals originating in the locus ceruleus descend through autonomic efferent pathways to stimulate a peripheral sympathetic response.6 Simultaneously, a parasympathetic response is initiated in order to balance the magnitude of initial proinflammatory aspects of the stress response This balancing of the stress response has been called the inflammatory reflex.20 Increased vagal efferent signaling suppresses peripheral cytokine release through macrophage nicotinic receptors and the cholinergic antiinflammatory pathway.21 The peripheral effects of the stress response are seen most quickly with activation of the sympathetic arm of the autonomic nervous system The heart, blood vessels, bronchioles, and most CHAPTER 80 Biology of the Stress Response endocrine cells are richly innervated with adrenergic nerve fibers Norepinephrine release from sympathetic axon terminals in the adrenal medulla stimulates secretion of epinephrine into the blood The combination of circulating epinephrine and release of norepinephrine from adrenergic neurons increases heart rate and blood pressure, augmenting cardiac output and maintaining perfusion to vital organs An important arm of the peripheral stress response system that works in concert with the adrenergic and vasopressin arms is the renin-angiotensin-aldosterone system The primary purpose of this system is to help regulate sodium and water balance in the body Renin is released from the juxtaglomerular granular cells of the afferent renal arterioles in the setting of (1) decreased afferent renal arteriole blood pressure, (2) sympathetic stimulation from noradrenergic autonomic input, and (3) decreased sodium flow through the nephron Renin release results in the generation of angiotensin II, which is a potent vasoconstrictor that stimulates secretion of aldosterone from the adrenal cortex Aldosterone increases sodium and water reabsorption in the kidneys, augmenting intravascular volume Counterregulatory hormones mediate important aspects of the stress response Adrenergic stimulation triggers the release of glucagon from a-cells in the pancreatic islets while inhibiting the release of insulin from the b-cells This effect of the sympathetic response has important metabolic ramifications Glucagon—in concert with cortisol, growth hormone, and circulating epinephrine—initiates widespread catabolic mechanisms that affect tissues throughout the body The initiation of this catabolic state mobilizes energetic substrate and molecular building blocks for the highly resourceintensive functions of the stress response These counterregulatory hormones stimulate hepatic gluconeogenesis and glycogenolysis, thereby increasing blood glucose levels Peripheral tissues become resistant to the effects of insulin under the influence of glucagon and growth hormone, which leads to critical illness–associated hyperglycemia This phenomenon, associated with a decrease in the thyroid hormone T3, reduces the metabolism and energy consumption of nonessential tissues, allowing circulating glucose to be used primarily by processes directly involved in immune response and tissue repair.16 In adipose tissue, epinephrine and glucagon activate hormonesensitive lipase, which catalyzes the first step in triglyceride hydrolysis and liberates free fatty acids and glycerol into the circulation Glycerol is used as a gluconeogenic substrate in the liver, and the fatty acids are taken up by metabolically active cells to provide energy for essential functions or to provide structural components necessary for cellular growth and division Leukocytes, for example, undergo rapid clonal expansion in inflammatory states and require abundant lipid substrate for both activation and production of cell membranes.22,23 Skeletal muscle is also significantly affected by the stressimposed catabolic state Epinephrine, cortisol, and glucagon initiate glycogenolysis in the muscle However, because myocytes lack the glucose-6-phosphatase enzyme expressed by the liver, they cannot release glucose into the bloodstream Any glucose liberated from glycogen that is not used for the energy demands of the myocyte is converted to lactate and released into the bloodstream Indeed, significant b-adrenergic stimulation (e.g., exogenous epinephrine) can induce the production of lactate even in the presence of adequate oxygen by inhibiting pyruvate decarboxylase, the final step of glycolysis that converts pyruvate 973 into acetyl-CoA for incorporation in the mitochondrial citric acid cycle.24 Some tissues, such as the myocardium, can use lactate as a primary energy source, but most of the lactate is taken up by the liver and used as gluconeogenic substrate Protein catabolism in the muscle releases amino acids into the circulation, which are also used by the liver for gluconeogenesis and for the elaboration of acute-phase proteins necessary for the stress response The protein catabolism in muscle tissues is significantly enhanced by cytokine stimulation from the inflammatory response.25 Cellular Responses The stress response extends down through organismal and tissue hierarchies to individual cells, which also employ conserved, stereotypical allostatic mechanisms to promote survival in the face of maladaptive environmental changes These include the cellular integrated stress response, which deactivates protein translation for the majority of cellular messenger ribonucleic acids (mRNAs) but allows translation of transcripts involved with cell survival.26 The deoxyribonucleic acid (DNA) damage response activates systems to stop cell growth and division and to repair altered or disrupted nucleotide sequences The unfolded protein response seeks to resolve the accumulation of unfolded or misfolded polypeptides at the endoplasmic reticulum.27 Cells can also enter a catabolic state by activating autophagy, a process that breaks down damaged or dysfunctional organelles for recycling or to provide energy for other essential survival mechanisms.28 Mitochondria are central to cellular stress responses because they generate the energy necessary to fuel survival mechanisms and because they form a central node within the intracellular danger signaling system.29,30 Beyond maintaining cellular respiration, mitochondrial function determines cell fate in the face of significant stressors If strain on the cell exceeds its capacity of resilience, the mitochondria direct the cell toward senescence (a state of functional arrest and metabolic hibernation) or programmed cell death (apoptosis).27 These end points may contribute to mechanisms of the multiple-organ dysfunction syndrome (see Chapter 111) Stress Response in Critical Illness Critical illness reflects the ultimate manifestation of severe stress Three phases of the stress response may be observed in the ICU: Acute phase: During this early time period after exposure to the critical stressor, analogous to the “golden hour” of resuscitation, the stress response comprises primarily those rapidly acting mechanisms designed to preserve tissue perfusion and oxygenation Blood pressure, cardiac output, and intravascular volume are all maintained through adrenergic signaling, vasopressin secretion, and activation of the renin-angiotensin-aldosterone system The response time in these systems is rapid because they rely on preformed mediators to bring about their physiologic effects Established phase: As time passes, the full breadth of the stress response is brought to bear as endocrine and metabolic mechanisms come into play These are slower to activate because they rely predominantly on neuroendocrine regulation of gene transcription and protein translation The focus of this phase of the response is to adapt host ... production In critical illness, this delicate homeostatic balance may be disrupted and has been identified as a possible final common pathway for organ dysfunction and death This chapter reviews (1)... our vital function to maintain constancy within an optimal range, the stress response pursues physiologic change to adapt to otherwise fatal stressors This allostatic response is designed to be... resilience This resilience accommodates the strain imposed by the stress of the earthquake Likewise, the stress response in humans provides resilience to adapt to various stressors around and within