974 SECTION VII I Pediatric Critical Care Metabolic and Endocrine physiology to preserve vital functions while directing re sources toward resolving the inciting stressor Nonessential systems are deac[.]
974 S E C T I O N V I I I Pediatric Critical Care: Metabolic and Endocrine physiology to preserve vital functions while directing resources toward resolving the inciting stressor Nonessential systems are deactivated To achieve their desired ends, these allostatic changes may permit, or even seek, physiologic parameters incongruent with baseline homeostasis For example, cytokines stimulate the hypothalamic thermostat to increase body temperature Though abnormal relative to baseline conditions, fever is an important physiologic adaptation that facilitates leukocyte eradication of infectious agents This ability to adapt to the needs of the circumstances is the physiologic resilience referred to at the outset of this chapter Recovery or repair phase: When the inciting stressor is removed, the stress response is attenuated, the strain on host systems is relieved, and the body returns incrementally to normal homeostatic parameters From a teleologic point of view, the acute stress response is intended to be self-terminating within hours to a few days at most rather than a prolonged condition persisting weeks or more Clearly, failure to mount an adequate stress response is associated with worse outcomes However, excessive and/or chronic stress compromises the body’s allostatic responses and may itself promote pathology.1,31 Due to the magnitude and nature of life-threatening conditions, the stress response in critical illness can become dysregulated and prolonged When this occurs, the stress response devolves into a “distress response” as pathologic results emerge from misdirected or excessive allostatic adaptations This is observed very frequently in the ICU Decreased neurologic function secondary to the inciting disease process itself or iatrogenic sedation precludes appropriate threat appraisal and stress system regulation by the central nervous system Excessive adrenergic output can directly impair cardiac function.32,33 The antiinflammatory neurogenic reflex may play a role in the immunoparalysis seen so often after trauma and sepsis.20,34 Both very high and low cortisol levels are observed in critically ill children and are associated with increased mortality.15,16 Elevated levels of cortisol likely contribute to immune dysfunction and metabolic dysregulation whereas insufficient cortisol secretion is associated with cardiovascular collapse The debate over steroid administration in critical illness has raged for decades and will likely continue for several more.35 These topics are reviewed in much greater depth in Chapter 84 The overall tone of the stress system in severe or prolonged critical illness is one of generalized depression As noted earlier, thyroid hormone levels are suppressed, which may be an adaptive response, to a degree, decreasing global cellular metabolism to allow energy resources to be consumed by more vital processes When taken to an extreme, however, very depressed thyroid levels are associated with mortality.36,37 Growth hormone and prolactin release surges early in the stress response but drops to very low levels with persistent critical illness, resulting in dysregulated metabolism and immunity.15,16 Vasopressin is elevated early in the acute phase of shock states, but very rapidly declines and remains quite low through prolonged critical illness.18,38 In septic shock, regulation of vasopressin is characterized by decreased plasma concentrations, unaltered clearance, depleted neurohypophyseal vesicles, and altered osmolar signaling.39 Likewise, the renin-angiotensinaldosterone system can be dysregulated in critical illness Elevated renin and angiotensin are observed in sepsis and correlate with measures of microvascular dysfunction and organ system failure.40 In a subset of critically ill patients, however, aldosterone levels are inappropriately low despite elevated plasma renin activity.41–43 Therefore, mineralocorticoid deficiency may contribute to the hyponatremia sometimes observed in pediatric ICU (PICU) patients Significant metabolic dysregulation can be seen with severe and persistent stress responses The combined effect of increased glucose production and peripheral insulin resistance can result in extremely elevated blood sugar levels, which correlate with organ system dysfunction and survival.44–46 Intense hypercytokinemia and adrenergic stimulation both mobilize lipid and amino acid substrate from adipose tissue and skeletal muscle, which can result in hypertriglyceridemia and severe muscle wasting.25,47,48 The clinical significance of elevated serum triglyceride levels is uncertain, but muscle wasting leads to critical illness–related weakness and prolonged mechanical ventilation, with all of their comorbidities.49 Analogous to inflammation, stress is beneficial acutely but when prolonged may generate collateral damage Complicated or prolonged critical illness may represent a stress-related decompensation syndrome.3 A complicated ICU 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, all of this reflecting a persistent inflammation immunosuppression catabolism syndrome (PICS).50,51 When stress evolves into distress, allostatic overload occurs, resulting in mitochondrial hibernation as an antecedent of metabolic shutdown and widespread energy failure associated with multiple organ dysfunction syndrome.52 Maladaptive response to stress can outlast the actual stress phase by months or even years, and chronic stress can lead to development of the metabolic syndrome long after discharge from the PICU.53 Recommendations and Conclusions An understanding of the stress response should influence the care that children receive in the PICU Because pathophysiology can change rapidly in critical illness and varies along the continuum from injury to resolution, the clinical posture of PICU providers must adapt to fluctuating physiologic parameters in different phases of the stress response Acute phase: In the golden hour, emphasis is directed at avoiding hypoxemia and ischemia Attention must also be paid to removing the inciting stressor that has precipitated the stress response as quickly as possible For example, in infectious causes of critical illness, achieving early source control is paramount The longer the stimulus persists, the more intense and prolonged the stress response it elicits Established phase: During this interval, clinicians should focus on permissive treatment that respects the stress response and avoids iatrogenic injury, recognizing that many ICU interventions can exacerbate stress system dysregulation (vasoactive infusions, systemic steroids, and so on) Healthy physiologic values routinely targeted in the critically ill may not be appropriate considering the adaptations necessary for the stress response The therapeutic implication here is that most of the acute endocrine and metabolic responses are likely to be adaptive and thus should probably not be aggressively treated.15 In CHAPTER 80 Biology of the Stress Response many situations, providing less intervention may yield greater long-term benefit.54 Recovery or repair phase: In this phase, clinicians refocus on targeting normal physiologic values Here, the environment of the ICU plays a key role in terms of avoiding prolongation or reinitiation of an acute stress response In addition to providing critical care interventions targeted at removing the primary pathophysiologic stressors, the multidisciplinary care team can optimize long-term outcomes by implementing interventions to destress their critically ill patients: avoiding supraphysiologic resuscitation, facilitating sleep, reestablishing circadian rhythms, decreasing noise levels, avoiding pain and discomfort, providing anxiolysis, promoting early mobilization, providing natural light, and restoring entitlement 975 Key References Boonen E, Van den Berghe G Endocrine responses to critical illness: novel insights and therapeutic implications J Clin Endocrinol Metab 2014;99(5):1569-1582 Brame AL, Singer M Stressing the obvious? An allostatic look at critical illness Crit Care Med 2010;38(suppl 10):S600-S607 Chrousos GP Stress and disorders of the stress system Nat Rev Endocrinol 2009;5(7):374-381 Galluzzi L, Yamazaki T, Kroemer G Linking cellular stress responses to systemic homeostasis Nat Rev Mol Cell Biol 2018;19(11):731-745 McEwen BS Physiology and neurobiology of stress and adaptation: central role of the brain Physiol Rev 2007;87(3):873-904 The full reference list for this chapter is available at ExpertConsult.com e1 References Brame AL, Singer M Stressing the obvious? An allostatic look at critical illness Crit Care Med 2010;38(suppl 10):S600-S607 McEwen BS, Wingfield JC What is in a name? Integrating homeostasis, allostasis and stress Horm Behav 2010;57(2):105-111 Cuesta JM, Singer M The stress response and critical illness: a review Crit Care Med 2012;40(12):3283-3289 McEwen BS Physiology and neurobiology of stress and adaptation: central role of the brain Physiol Rev 2007;87(3):873-904 Charmandari E, Tsigos C, Chrousos G Endocrinology of the stress response Annu Rev Physiol 2005;67:259-284 Molina PE Neurobiology of the stress response: contribution of the sympathetic nervous system to the neuroimmune axis in traumatic injury Shock 2005;24(1):3-10 Baumann H, Gauldie J The acute phase response Immunol Today 1994;15(2):74-80 Abreu MT, Arditi M Innate immunity and toll-like receptors: clinical implications of basic science research J Pediatr 2004;144(4):421-429 Zhang Q, Raoof M, Chen Y, et al Circulating mitochondrial DAMPs cause inflammatory responses to injury Nature 2010;464(7285):104-107 10 Ulloa L The vagus nerve and the nicotinic anti-inflammatory pathway Nat Rev Drug Discov 2005;4(8):673-684 11 Besedovsky HO, del Rey A Immune-neuro-endocrine interactions: facts and hypotheses Endocr Rev 1996;17(1):64-102 12 Turnbull AV, Rivier CL Regulation of the hypothalamic-pituitaryadrenal axis by cytokines: actions and mechanisms of action Physiol Rev 1999;79(1):1-71 13 Chrousos GP The hypothalamic-pituitary-adrenal axis and immunemediated inflammation N Engl J Med 1995;332(20):1351-1362 14 Galon J, Franchimont D, Hiroi N, et al Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells FASEB J 2002;16(1):61-71 15 Boonen E, Van den Berghe G Endocrine responses to critical illness: novel insights and therapeutic implications J Clin Endocrinol Metab 2014;99(5):1569-1582 16 Vanhorebeek I, Langouche L, Van den Berghe G Endocrine aspects of acute and prolonged critical illness Nat Clin Pract Endocrinol Metab 2006;2(1):20-31 17 Shih JL, Agus MS Thyroid function in the critically ill newborn and child Curr Opin Pediatr 2009;21(4):536-540 18 Choong K, Kissoon N Vasopressin in pediatric shock and cardiac arrest Pediatr Crit Care Med 2008;9(4):372-379 19 Russell JA Bench-to-bedside review: Vasopressin in the management of septic shock Crit Care 2011;15(4):226 20 Tracey KJ Physiology and immunology of the cholinergic antiinflammatory pathway J Clin Invest 2007;117(2):289-296 21 Levy G, Fishman JE, Xu D, et al Parasympathetic stimulation via the vagus nerve prevents systemic organ dysfunction by abrogating gut injury and lymph toxicity in trauma and hemorrhagic shock Shock 2013;39(1):39-44 22 Pearce EJ, Everts B Dendritic cell metabolism Nat Rev Immunol 2014;15(1):18-29 23 Buck MD, O’Sullivan D, Pearce EL T cell metabolism drives immunity J Exp Med 2015;212(9):1345-1360 24 Meert KL, Clark J, Sarnaik AP Metabolic acidosis as an underlying mechanism of respiratory distress in children with severe acute asthma Pediatr Crit Care Med 2007;8(6):519-523 25 Puthucheary ZA, Rawal J, McPhail M, et al Acute skeletal muscle wasting in critical illness JAMA 2013;310(15):1591-1600 26 Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM The integrated stress response EMBO Rep 2016;17(10):1374-1395 27 Galluzzi L, Yamazaki T, Kroemer G Linking cellular stress responses to systemic homeostasis Nat Rev Mol Cell Biol 2018;19(11):731-745 28 Dikic I, Elazar Z Mechanism and medical implications of mammalian autophagy Nat Rev Mol Cell Biol 2018;19(6):349-364 29 Manoli I, Alesci S, Blackman MR, Su YA, Rennert OM, Chrousos GP Mitochondria as key components of the stress response Trends Endocrinol Metab 2007;18(5):190-198 30 Galluzzi L, Kepp O, Kroemer G Mitochondria: master regulators of danger signalling Nat Rev Mol Cell Biol 2012;13(12):780-788 31 Chrousos GP Stress and disorders of the stress system Nat Rev Endocrinol 2009;5(7):374-381 32 Wittekind SG, Yanay O, Johnson EM, Gibbons EF Two pediatric cases of variant neurogenic stress cardiomyopathy after intracranial hemorrhage Pediatrics 2014;134(4):e1211-e1217 33 Boland TA, Lee VH, Bleck TP Stress-induced cardiomyopathy Crit Care Med 2015;43(3):686-693 34 Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA The sepsis seesaw: tilting toward immunosuppression Nat Med 2009; 15(5):496-497 35 Patel GP, Balk RA Systemic steroids in severe sepsis and septic shock Am J Respir Crit Care Med 2012;185(2):133-139 36 Peeters RP, Wouters PJ, van Toor H, Kaptein E, Visser TJ, Van den Berghe G Serum 3,3’,5’-triiodothyronine (rT3) and 3,5,3’-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities J Clin Endocrinol Metab 2005;90(8):4559-4565 37 Wang F, Pan W, Wang H, Wang S, Pan S, Ge J Relationship between thyroid function and ICU mortality: a prospective observation study Crit Care 2012;16(1):R11 38 Landry DW, Levin HR, Gallant EM, et al Vasopressin deficiency contributes to the vasodilation of septic shock Circulation 1997;95(5):1122-1125 39 Siami S, Bailly-Salin J, Polito A, et al Osmoregulation of vasopressin secretion is altered in the postacute phase of septic shock Crit Care Med 2010;38(10):1962-1969 40 Doerschug KC, Delsing AS, Schmidt GA, Ashare A Renin-angiotensin system activation correlates with microvascular dysfunction in a prospective cohort study of clinical sepsis Crit Care 2010;14(1):R24 41 Findling JW, Waters VO, Raff H The dissociation of renin and aldosterone during critical illness J Clin Endocrinol Metab 1987;64(3): 592-595 42 Lichtarowicz-Krynska EJ, Cole TJ, Camacho-Hubner C, et al Circulating aldosterone levels are unexpectedly low in children with acute meningococcal disease J Clin Endocrinol Metab 2004;89(3): 1410-1414 43 Tolstoy NS, Aized M, McMonagle MP, et al Mineralocorticoid deficiency in hemorrhagic shock J Surg Res 2013;180(2):232-237 44 Faustino EV, Apkon M Persistent hyperglycemia in critically ill children J Pediatr 2005;146(1):30-34 45 Yung M, Wilkins B, Norton L, Slater A, Paediatric Study Group, Australian and New Zealand Intensive Care Society Glucose control, organ failure, and mortality in pediatric intensive care Pediatr Crit Care Med 2008;9(2):147-152 46 Weiss SL, Alexander J, Agus MS Extreme stress hyperglycemia during acute illness in a pediatric emergency department Pediatr Emerg Care 2010;26(9):626-632 47 Klein S, Peters EJ, Shangraw RE, Wolfe RR Lipolytic response to metabolic stress in critically ill patients Crit Care Med 1991;19(6):776-779 48 Tappy L, Chioléro R Substrate utilization in sepsis and multiple organ failure Crit Care Med 2007;35(suppl 9):S531-S534 49 Hermans G, Van den Berghe G Clinical review: intensive care unit acquired weakness Crit Care 2015;19:274 50 Vanzant EL, Lopez CM, Ozrazgat-Baslanti T, et al Persistent inflammation, immunosuppression, and catabolism syndrome after severe blunt trauma J Trauma Acute Care Surg 2014;76(1):21-29; discussion 29-30 51 Mira JC, Brakenridge SC, Moldawer LL, Moore FA Persistent inflammation, immunosuppression and catabolism syndrome Crit Care Clin 2017;33(2):245-258 52 Singer M, De Santis V, Vitale D, Jeffcoate W Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation Lancet 2004;364(9433):545-548 53 Schmidt MV, Sterlemann V, Müller MB Chronic stress and individual vulnerability Ann N Y Acad Sci 2008;1148:174-183 54 Singer M The key advance in the treatment of sepsis in the last 10 years doing less Crit Care 2006;10(1):122 e2 Abstract: The stress response is a universal, stereotypical, integrated reaction to internal or external stressors that permits temporary adaptations in physiologic function to promote survival through what might otherwise be fatal challenges to homeostasis The human stress system comprises multiple afferent inputs and efferent effector responses, all coordinated by the brain as its central regulator Appropriate stress responses are necessary for survival in critical illness and are observed frequently in the intensive care unit Excessive or prolonged stress stimuli can precipitate dysregulated stress responses Therapeutic intervention in critical illness must respect physiologic alterations necessary to accommodate the stress response Key words: stress, stress response, stress system, neuroendocrine response, critical illness 81 Inborn Errors of Metabolism CARY O HARDING AND AMY YANG • Metabolism can be defined as the sum of all biochemical processes that convert food to smaller molecules and energy for the purposes of structure and function An inborn error of metabolism (IEM) is an inherited deficiency of any critical step in metabolism Although genetic deficiency of catalytic enzymes in intermediary metabolic pathways is the classic paradigm for IEM, the pathophysiology of metabolic disorders may involve abnormalities of any number of cellular processes, including transmembrane transport, cell signaling, cell differentiation and development, energy production, and others Many IEMs are individually rare, although a few—including phenylketonuria (PKU)1 and mediumchain acyl-coenzyme A (acyl-CoA) dehydrogenase deficiency (MCADD),2 a defect in fatty acid oxidation—exhibit a population incidence approaching 1:10,000 live births Specific IEMs may be more common in certain ethnic groups with a history of relative reproductive isolation Collectively, the population incidence of all IEMs may approach 1:1500 live births, depending on how broadly IEM is defined Many IEMs are associated with catastrophic illness necessitating advanced life support Although IEM may present rarely within the professional lifetime of the average medical practitioner, critically ill children with IEM will not be uncommon visitors to the pediatric intensive care unit, especially in a tertiary care center Other textbooks on the diagnosis and treatment of IEM provide an exhaustive list of known disorders.3,4 Rather than recapitulate an encyclopedia of possible diseases, this chapter presents a diagnostic rationale based on specific clinical symptom complexes that are likely to occur in the critically ill child Algorithms for the differential diagnosis of specific clinical scenarios are provided in support of this rationale Symptoms often begin during early infancy in the biochemically most severe IEM Naturally, 976 • Unexpected and unexplained clinical deterioration in a previously healthy infant or child is an important clue to the presence of an inborn error of metabolism (IEM) Loss of previously attained developmental milestones during childhood is an important clue to the presence of a neurodegenerative disorder, such as lysosomal storage disease Blood glucose less than 40 mg/dL is distinctly unusual after the first 24 hours of life, particularly in infants who have started feeding, and should be thoroughly investigated • • • PEARLS Laboratory evaluation for IEM should be undertaken in any child with a suggestive clinical history regardless of the results of newborn screening A normal newborn screen, although perhaps reassuring, does not rule out the possibility of an IEM With catastrophic illness in a previously well child without signs of any particular IEM, the “shotgun” diagnostic evaluation should minimally include plasma amino acid analysis, plasma acylcarnitine profile, and urine organic acid analysis by gas chromatograph–mass spectrometry these IEMs with neonatal onset are the focus of the discussion in this chapter However, “milder” or late-onset variants of virtually every IEM have been described with onset of symptoms occurring at all ages, even during adulthood Some IEMs uniformly present after the neonatal period; age of symptom onset (late infancy, childhood, or adulthood) often is an important clue to the specific diagnosis The clinical presentation, diagnostic workup, and treatment of neonatal onset disorders provide a paradigm for the evaluation and management of possible IEMs in a child of any age Pathophysiology of Inborn Errors of Metabolism Under the classic paradigm, an IEM is associated with deficiency of a specific protein, often a catalytic enzyme, involved in a critical metabolic pathway (Fig 81.1) This deficiency leads to a block in the pathway and the accumulation of the enzyme substrate In this model, three distinct pathogenic mechanisms represent possible proximate causes of the symptoms associated with an IEM The specific pathogenic mechanism involved in any given IEM dictates the appropriate treatment strategy First, accumulation of the substrate may lead to toxic effects at very high levels; successful therapy requires effective elimination of the substrate or a method to block its toxic effects An example for this mechanism is PKU, in which elevated phenylalanine levels adversely affect neuronal development, and the reduction of tissue phenylalanine content through dietary phenylalanine restriction largely prevents the major clinical features of PKU.5 Second, deficiency of the reaction product, should it be a critically important metabolite, may ... involved in a critical metabolic pathway (Fig 81.1) This deficiency leads to a block in the pathway and the accumulation of the enzyme substrate In this model, three distinct pathogenic mechanisms... adaptation: central role of the brain Physiol Rev 2007;87(3):873-904 The full reference list for this chapter is available at ExpertConsult.com e1 References Brame AL, Singer M Stressing the obvious?... with catastrophic illness necessitating advanced life support Although IEM may present rarely within the professional lifetime of the average medical practitioner, critically ill children with