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J Mol Cell Cardiol 2009;46(6):821-831 73 Izzo V, Bravo-San Pedro JM, Sica V, Kroemer G, Galluzzi L Mitochondrial permeability transition: new findings and persisting uncertainties Trends Cell Biol 2016;26(9):655-667 74 Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, et al Regulated necrosis: the expanding network of non-apoptotic cell death pathways Nat Rev Mol Cell Biol 2014;15(2):135-147 75 Larche J, Lancel S, Hassoun SM, et al Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality J Am Coll Cardiol 2006;48(2):377-385 76 Lemasters JJ, Nieminen AL, Qian T, et al The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy Biochim Biophys Acta 1998;1366(1-2): 177-196 77 Bernardi P, Di Lisa F The mitochondrial permeability transition pore: molecular nature and role as a target in cardioprotection J Mol Cell Cardiol 2015;78:100-106 78 Kenny EM, Fidan E, Yang Q, et al Ferroptosis contributes to neuronal death and functional outcome after traumatic brain injury Crit Care Med 2019;47(3):410-418 79 Stockwell BR, Friedmann Angeli JP, Bayir H, et al Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease Cell 2017;171(2):273-285 80 David KK, Andrabi SA, Dawson TM, et al Parthanatos, a messenger of death Front Biosci (Landmark Ed) 2009;14:1116-1128 81 Panzeter PL, Realini CA, Althaus FR Noncovalent interactions of poly(adenosine diphosphate ribose) with histones Biochemistry 1992; 31(5):1379-1385 82 Andrabi SA, Kim NS, Yu SW, et al Poly(ADP-ribose) (PAR) polymer is a death signal Proc Natl Acad Sci U S A 2006;103(48):1830818313 83 Kameshita I, Matsuda Z, Taniguchi T, et al Poly (ADP-Ribose) synthetase Separation and identification of three proteolytic fragments as the substrate-binding domain, the DNA-binding domain, and the automodification domain J Biol Chem 1984;259(8):4770-4776 84 Wang Y, Dawson VL, Dawson TM Poly(ADP-ribose) signals to mitochondrial AIF: a key event in parthanatos Exp Neurol 2009; 218(2):193-202 85 Wang H, Yu SW, Koh DW, et al Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death J Neurosci 2004;24(48):10963-10973 86 Zhao H, Ning J, Lemaire A, et al Necroptosis and parthanatos are involved in remote lung injury after receiving ischemic renal allografts in rats Kidney Int 2015;87(4):738-748 87 Branzk N, Papayannopoulos V Molecular mechanisms regulating NETosis in infection and disease Semin Immunopathol 2013; 35(4):513-530 88 Papayannopoulos V Neutrophil extracellular traps in immunity and disease Nat Rev Immunol 2018;18(2):134-147 e3 89 Papayannopoulos V, Metzler KD, Hakkim A, et al Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps J Cell Biol 2010;191(3):677-691 90 Brinkmann V, Reichard U, Goosmann C, et al Neutrophil extracellular traps kill bacteria Science 2004;303(5663):1532-1535 91 Jorgensen I, Rayamajhi M, Miao EA Programmed cell death as a defence against infection Nat Rev Immunol 2017;17(3):151-164 92 Clark SR, Ma AC, Tavener SA, et al Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood Nat Med 2007;13(4):463-469 93 McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis Cell Host Microbe 2012;12(3):324-333 94 Yipp BG, Petri B, Salina D, et al Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo Nat Med 2012;18(9):1386-1393 95 Vercammen D, Beyaert R, Denecker G, et al Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor J Exp Med 1998;187(9):1477-1485 96 Vercammen D, Brouckaert G, Denecker G, et al Dual signaling of the Fas receptor: initiation of both apoptotic and necrotic cell death pathways J Exp Med 1998;188(5):919-930 97 Cauwels A, Janssen B, Waeytens A, et al Caspase inhibition causes hyperacute tumor necrosis factor-induced shock via oxidative stress and phospholipase A2 Nat Immunol 2003;4(4):387-393 98 Kaiser WJ, Upton JW, Long AB, et al RIP3 mediates the embryonic lethality of caspase-8-deficient mice Nature 2011;471(7338): 368-372 99 Vanden Berghe T, Kaiser WJ, Bertrand MJ, et al Molecular crosstalk between apoptosis, necroptosis, and survival signaling Mol Cell Oncol 2015;2(4):e975093 100 Koshinuma S, Miyamae M, Kaneda K, et al Combination of necroptosis and apoptosis inhibition enhances cardioprotection against myocardial ischemia-reperfusion injury J Anesth 2014; 28(2):235-241 e4 Abstract: Cell death occurs as a part of normal development and is an essential homeostatic mechanism necessary for host survival In order to regulate cell loss, the host has machinery dedicated to controlled elimination of ineffective or dangerous cells Multiple forms of regulated cell death exist, including apoptosis, necroptosis, pyroptosis, mitochondrial permeability transition mediatedregulated necrosis, ferroptosis, and parthanatos Regulated cell death has been implicated in multiple aspects of critical care, including sepsis, trauma, acute respiratory distress syndrome, and multiple-organ dysfunction syndrome Targeting the mechanisms of cell death may play an important role in the future treatment of human critical illness Key words: Cell death, apoptosis, necroptosis, autophagy, pyroptosis, ferroptosis, parthanatos 84 Endocrine Emergencies KATHERINE RATZAN PEELER AND MICHAEL S.D AGUS PEARLS • • • Cortisol is a key mediator of the stress response—influencing immunity, metabolism, and modulating the transcription of perhaps 25% of the entire genome Relative adrenal insufficiency and critical illness–related corticosteroid insufficiency are poorly understood concepts in terms of both pathophysiology and therapeutic intervention Critical illness hyperglycemia is the result of inflammationmediated increased endogenous glucose production and The endocrine system is closely aligned with the neurogenic and inflammatory systems, particularly as an aspect of the stress response Multiple servo feed-forward and feed-back signals normally provide precise control over this integrated system There are several important primary endocrine emergencies that the pediatric intensivist must understand, as their monitoring and treatment require critical care Additionally, critical illness of all types and their treatment frequently generate unique secondary endocrinopathies affecting the multiple endocrine axes While these acute responses of the endocrine axes are considered an evolutionarily driven adaptive response to stress, chronic hormonal changes are likely the result of advances in critical care and are the basis of much intensive care unit (ICU)-related morbidity.1 Hypothalamic-Pituitary-Adrenal Axis A schematic overview of the classic regulation of cortisol synthesis and secretion is provided in Fig 84.1.2 A variety of stimuli converge on the paraventricular nucleus of the hypothalamus, resulting in release of corticotropin-releasing hormone (CRH).3–5 CRH is transported via hypophyseal portal capillaries to the anterior pituitary, facilitating the production of pro-opiomelanocortin, a peptide that includes primary protein sequences for adrenocorticotropic hormone (ACTH), b-lipotropin, b-endorphin, and melanocyte-stimulating hormone ACTH is then transported by the blood to the zona fasciculata of the adrenal gland, where it binds to type melanocortin receptors (MC2R) MC2R is a seven-transmembrane domain protein coupled with G proteins that uses intracellular cyclic adenosine monophosphate signaling to modulate adrenal steroidogenesis.6 Single nucleotide polymorphisms in MC2R may be responsible for some of the variability in cortisol response to pediatric critical illness,7 and familial cortisol • decreased utilization secondary to insulin resistance, the latter of which promotes catabolism and lipolysis, ultimately leading to lipotoxicity, glucotoxicity, and further inflammation Sick euthyroid syndrome, common among critically ill patients, is characterized by a rapid decrease in T3 and variable increase in rT3 that appears to be proportional to the intensity of illness severity and concentration of tumor necrosis factor-a deficiency—a lethal condition associated with hypoplastic adrenal glands—is caused by another mutation in the MC2R gene.8 During critical illness, activation of the hypothalamic-pituitaryadrenal (HPA) axis frequently reflects activation of the systemic inflammatory response syndrome (e.g., by interleukin-6).9,10 Interleukins 1, 2, and are generally thought to stimulate cortisol production, whereas tumor necrosis factor–alpha (TNF-a), macrophage inhibitory protein (MIP), and corticostatin, a protein with anti-ACTH activity, are generally considered to be inhibitory for cortisol production Cortisol Biochemistry and Biology Within the adrenal cortex, several enzymes lead to the conversion of cholesterol to the steroid hormones cortisol, aldosterone, and androstenedione Normal adrenal production of cortisol is equivalent to hydrocortisone administration of approximately to 12 mg/m2 per day Stress production of cortisol may reach 200 to 300 mg/day, resulting in a plasma total cortisol concentration occasionally exceeding 60 µg/dL In addition, reduced cortisol breakdown, related to suppressed expression and activity of cortisol catabolic enzymes, contributes significantly to hypercortisolemia and associated ACTH suppression.11,12 If the latter is maintained during prolonged critical illness, adrenal lipid depletion and reduced ACTH-regulated gene expression may occur in conjunction with adrenal atrophy and insufficiency.13 Hypercortisolemia in critical illness is correlated with severity of illness.14 Mean and range of plasma cortisol concentrations as a function of age have been reported for normal children and may be found in Table 84.1.15 Although the plasma half-life for cortisol ranges from 80 to 115 minutes, biological duration of action of cortisol is approximately hours A diurnal rhythm of cortisol production is noted 1003 ... response Multiple servo feed-forward and feed-back signals normally provide precise control over this integrated system There are several important primary endocrine emergencies that the pediatric... critical illness of all types and their treatment frequently generate unique secondary endocrinopathies affecting the multiple endocrine axes While these acute responses of the endocrine axes are... generally considered to be inhibitory for cortisol production Cortisol Biochemistry and Biology Within the adrenal cortex, several enzymes lead to the conversion of cholesterol to the steroid hormones