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230 Mouncey PR, Osborn TM, Power GS, et al Trial of early, goaldirected resuscitation for septic shock N Engl J Med 2015: 372(14):1301-1311 231 de Oliveira CF, Troster EJ, Carcillo JA A beneficial role of central venous oxygen saturation-targeted septic shock management in children: follow the pediatric story, not only the adult story Pediatr Crit Care Med 2014:15(4):380-382 232 Khanna A, English SW, Wang XS, et al Angiotensin II for the treatment of vasodilatory shock N Engl J Med 2017:377(5): 419-430 233 Perez AC, Eulmesekian PG, Minces PG, Schnitzler EJ Adequate agreement between venous oxygen saturation in right atrium and pulmonary artery in critically ill children Pediatr Crit Care Med 2009:10(1):76-79 234 Oliveira CF, Troster EJ, Vaz FA Description of technique for continuous monitoring of central venous oxygen saturation in infants and children with septic shock Revista Brasileria Terapia Intensiva 2005:17:305-308 235 Fernandez EG, Green TP, Sweeney M Low inferior vena caval catheters for hemodynamic and pulmonary function monitoring in pediatric critical care patients Pediatr Crit Care Med 2004:5(1): 14-18 236 Magder S Central venous pressure: A useful but not so simple measurement Crit Care Med 2006:34(8):2224-2227 237 Kumar A, Anel R, Bunnell E, et al Pulmonary artery occlusion pressure and central venous pressure fail to predict ventricular filling volume, cardiac performance, or the response to volume infusion in normal subjects Crit Care Med 2004:32(3):691-699 238 Vincent JL, Weil MH Fluid challenge revisited Crit Care Med 2006:34(5):1333-1337 239 Hadian M, Pinsky MR Functional hemodynamic monitoring Curr Opin Crit Care 2007:13(3):318-323 240 Reinhart K, Kuhn HJ, Hartog C, Bredle DL Continuous central venous and pulmonary artery oxygen saturation monitoring in the critically ill Intensive Care Med 2004:30(8):1572-1578 241 Dueck MH, Klimek M, Appenrodt S, Weigand C, Boerner U Trends but not individual values of central venous oxygen saturation agree with mixed venous oxygen saturation during varying hemodynamic conditions Anesthesiology 2005:103(2):249-257 242 Kim JJ, Dreyer WJ, Chang AC, Breinholt JP 3rd, Grifka RG Arterial pulse wave analysis: An accurate means of determining cardiac output in children Pediatr Crit Care Med 2006:7(6): 532-535 243 Calamandrei M, Mirabile L, Muschetta S, Gensini GF, De Simone L, Romano SM Assessment of cardiac output in children: a comparison between the pressure recording analytical method and Doppler echocardiography Pediatr Crit Care Med 2008:9(3): 310-312 244 Richard C, Warszawski J, Anguel N, et al Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial JAMA 2003:290(20):2713-2720 245 Greenberg SB, Murphy GS, Vender JS Current use of the pulmonary artery catheter Curr Opin Crit Care 2009:15(3):249-253 246 Bochud PY, Bonten M, Marchetti O, Calandra T Antimicrobial therapy for patients with severe sepsis and septic shock: an evidence-based review Crit Care Med 2004:32(11 suppl): S495-S512 247 Kumar A, Roberts D, Wood KE, et al Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock Crit Care Med 2006:34(6):1589-1596 248 Kumar A, Ellis P, Arabi Y, et al Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock Chest 2009:136(5):1237-1248 249 Garnacho-Montero J, Aldabo-Pallas T, Garnacho-Montero C, et al Timing of adequate antibiotic therapy is a greater determinant of outcome than are TNF and IL-10 polymorphisms in patients with sepsis Crit Care 2006:10(4):R111 250 Leligdowicz A, Dodek PM, Norena M, Wong H, Kumar A Association between source of infection and hospital mortality in patients who have septic shock Am J Respir Crit Care Med 2014:189(10):1204-1213 251 Barton P, Garcia J, Kouatli A, et al Hemodynamic effects of i.v milrinone lactate in pediatric patients with septic shock A prospective, double-blinded, randomized, placebo-controlled, interventional study Chest 1996:109(5):1302-1312 252 Lindsay CA, Barton P, Lawless S, et al Pharmacokinetics and pharmacodynamics of milrinone lactate in pediatric patients with septic shock J Pediatr 1998:132(2):329-334 253 Delgado AF, Okay TS, Leone C, Nichols B, Del Negro GM, Vaz FA Hospital malnutrition and inflammatory response in critically ill children and adolescents admitted to a tertiary intensive care unit Clinics (Sao Paulo) 2008:63(3):357-362 e7 254 Marik PE, Zaloga GP Early enteral nutrition in acutely ill patients: a systematic review Crit Care Med 2001:29(12):2264-2270 255 Krejci V, Hiltebrand LB, Sigurdsson GH Effects of epinephrine, norepinephrine, and phenylephrine on microcirculatory blood flow in the gastrointestinal tract in sepsis Crit Care Med 2006:34(5): 1456-1463 256 Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock N Engl J Med 1987;317(11):653-658 257 Sprung CL, Caralis PV, Marcial EH, et al The effects of high-dose corticosteroids in patients with septic shock A prospective, controlled study N Engl J Med 1984:311(18):1137-1143 258 Pizarro CF, Troster EJ, Damiani D, Carcillo JA Absolute and relative adrenal insufficiency in children with septic shock Crit Care Med 2005:33(4):855-859 259 Sarthi M, Lodha R, Vivekanandhan S, Arora NK Adrenal status in children with septic shock using low-dose stimulation test Pediatr Crit Care Med 2007:8(1):23-28 260 Annane D, Sebille V, Charpentier C, et al Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock JAMA 2002:288(7):862-871 261 Annane D, Renault A, Brun-Buisson C, et al Hydrocortisone plus Fludrocortisone for Adults with Septic Shock N Engl J Med 2018:378(9):809-818 262 Venkatesh B, Finfer S, Cohen J, et al Adjunctive glucocorticoid therapy in patients with septic shock N Engl J Med 2018:378(9): 797-808 263 Sprung CL, Annane D, Keh D, et al Hydrocortisone therapy for patients with septic shock N Engl J Med 2008:358(2):111-124 264 Keh D, Trips E, Marx G, et al Effect of hydrocortisone on development of shock among patients with severe sepsis: the HYPRESS randomized clinical trial JAMA 2016:316(17):1775-1785 265 Van den Berghe G, Boonen E, Walker BR Reduced cortisol metabolism during critical illness N Engl J Medicine 2013:369(5):481 266 Valoor HT, Singhi S, Jayashree M Low-dose hydrocortisone in pediatric septic shock: an exploratory study in a third world setting Pediatr Crit Care Med 2009:10(1):121-125 267 Markovitz BP, Goodman DM, Watson RS, Bertoch D, Zimmerman J A retrospective cohort study of prognostic factors associated with outcome in pediatric severe sepsis: what is the role of steroids? Pediatr Crit Care Med 2005:6(3):270-274 268 Menon K, McNally D, Choong K, Sampson M A systematic review and meta-analysis on the effect of steroids in pediatric shock Pediatr Crit Care Med 2013:14(5):474-480 269 Zimmerman JJ, Williams MD Adjunctive corticosteroid therapy in pediatric severe sepsis: observations from the RESOLVE study Pediatr Crit Care Med 2011:12(1):2-8 270 El-Nawawy A, Khater D, Omar H, Wali Y Evaluation of early corticosteroid therapy in management of pediatric septic shock in pediatric intensive care patients: a randomized clinical study Pediatr Infect Dis J 2017:36(2):155-159 271 Funk D, Doucette S, Pisipati A, Dodek P, Marshall JC, Kumar A Low-dose corticosteroid treatment in septic shock: a propensitymatching study Crit Care Med 2014:42(11):2333-2341 272 Atkinson SJ, Cvijanovich NZ, Thomas NJ, et al Corticosteroids and pediatric septic shock outcomes: a risk stratified analysis PloS One 2014:9(11):e112702 273 Zimmerman JJ A history of adjunctive glucocorticoid treatment for pediatric sepsis: moving beyond steroid pulp fiction toward evidence-based medicine Pediatr Crit Care Med 2007:8(6):530-539 274 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 275 Kim WY, Jo EJ, Eom JS, et al Combined vitamin C, hydrocortisone, and thiamine therapy for patients with severe pneumonia who were admitted to the intensive care unit: Propensity scorebased analysis of a before-after cohort study J Crit Care 2018:47:211-218 276 Fowler AA 3rd, Syed AA, Knowlson S, et al Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis J Transl Med 2014:12:32 277 Zabet MH, Mohammadi M, Ramezani M, Khalili H Effect of high-dose ascorbic acid on vasopressor’s requirement in septic shock J Res Pharm Pract 2016:5(2):94-100 278 Wong HR Personalized medicine, endotypes, and intensive care medicine Intensive Care Med 2015;41(6):1138-40 279 Schefold JC, Hasper D, Volk HD, Reinke P Sepsis: time has come to focus on the later stages Med Hypotheses 2008:71(2):203208 280 Pugin J Immunostimulation is a rational therapeutic strategy in sepsis Novartis Found Symp 2007:280:21-27; discussion 27-36, 160-164 281 Turrel F, Guignant C, Venet F, Lepape A, Monneret G Innovative therapeutic strategies for restoring lymphocyte functions in septic patients Inflamm Allergy Drug Targets 2008:7(3):181-186 282 Hotchkiss RS, Monneret G, Payen D Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy Nat Rev Immunol 2013:13(12):862-874 283 Marshall JC Sepsis: rethinking the approach to clinical research J Leukoc Biol 2008:83(3):471-482 283a Knox DB, Lanspa MJ, Kuttler KG, et al Phenotypic clusters within sepsis-associated multiple organ dysfunction syndrome Intensive Care Med 2015;41(5):814–22 284 Nowak JE, Wheeler DS, Harmon KK, Wong HR Admission chemokine (C-C motif ) ligand levels predict survival in pediatric septic shock Pediatr Crit Care Med 2010;11(2):213–6 285 Wong HR, Cvijanovich NZ, Anas N, et al Pediatric sepsis biomarker risk model-II: redefining the pediatric sepsis biomarker risk model with septic shock phenotype Crit Care Med 2016:44(11): 2010-2017 286 Wong HR, Cvijanovich NZ, Anas N, et al Improved risk stratification in pediatric septic shock using both protein and mRNA biomarkers PERSEVERE-XP Am J Respir Crit Care Med 2017: 196(4):494-501 287 Wong HR, Atkinson SJ, Cvijanovich NZ, et al Combining prognostic and predictive enrichment strategies to identify children with septic shock responsive to corticosteroids Crit Care Med 2016:44(10):e1000-e1003 e8 Abstract: The complexity of septic shock warrants a systematic and multifaceted approach on the part of the pediatric intensivist Optimal management requires a strong working knowledge not just of cardiovascular physiology and infectious diseases but also of multiple-organ function and interaction, inflammation-related biology, immunity, coagulation, pharmacology, and molecular biology The pediatric intensivist also needs a working knowledge of genomic medicine for the future management of patients with septic shock This chapter provides a comprehensive description of the many aspects influencing the development and outcome of septic shock, pathophysiology at the physiologic and molecular levels, contemporary management of septic shock, and the next important future directions in the field Ultimately, this information must be integrated with bedside experience and clinical acumen Key words: Epidemiology, inflammation, infection, physiology, mediators, heterogeneity, shock, immunology, cytokines 111 Multiple-Organ Dysfunction Syndrome PIERRE TISSIERES AND MELANIA M BEMBEA 1310 Three overlapping phenotypes of pediatric MODS have been proposed: (1) thrombocytopenia-associated multiple-organ failure (TAMOF); (2) immunoparalysis-associated multiple-organ failure (IPAMOF); and (3) sequential (viral-induced, lymphoproliferative disease–induced) liver failure–associated multiple-organ failure (SMOF) This inflammatory classification of sepsis-induced MODS is associated with a threefold increase in mortality (23.8% vs 6.7%) in patients with one of these phenotypes versus none Timely source control (removal of the inflammation source using appropriate antibiotics for infections and necrotic tissue nidus elimination for trauma-driven injury) and reversal of shock/ ischemia prevent the development of MODS Of all MODS cases, 78% are noted on the first day of PICU admission New and progressive MODS (NPMODS) is defined as dysfunction of two or more organ systems occurring after PICU admission with no or single-organ dysfunction or additional dysfunctional organs following admission with MODS A higher number of dysfunctional organs is associated with increased mortality (ranging from 0.6% of children with one organ dysfunction to 50% of children with six organ dysfunctions) regardless of the patient population under study • • Pediatric multiple-organ dysfunction syndrome (MODS) occurs in more than a quarter of children admitted to the pediatric intensive care unit (PICU).1–3 It represents the leading final pathway to death among children who suffer critical illness triggered by acute insults such as sepsis, trauma, burns, pancreatitis, inborn errors of metabolism, transplantation, and others.4 Children with MODS have mortality rates of 10% to as high as 57% in selected populations.1,3–8 First defined in 1986 as the simultaneous presence of two or more organ dysfunctions,9,10 the definition, criteria, and monitoring of pediatric MODS have undergone several transformations over time.11–14 It has been postulated that MODS may have an underlying unifying pathophysiologic mechanism, which has remained elusive thus far However, basic and translational research studies support the hypothesis that multiple organs are affected by a severe, unregulated systemic inflammatory response with associated immune, mitochondrial, epithelial, and endothelial cell dysfunction.15 • Pathophysiology and Targeted Therapies MODS encompasses the association of diverse states of organ failure, insufficiency, or injury Although the panel of organ insults may be diverse, systemic (indirect), or limited (direct) to an organ or tissue, it eventually triggers a physiologic response on the part of the host Understanding the pathophysiology of MODS is directly linked to the understanding of the physiologic response to insults as well as to the interconnectedness among organs Three concepts need to be considered: Organ functional reserve: Individual organ failure criteria are either related to functional biomarkers depicting the impact of the organ failure to its functionality (e.g., creatinine, international normalized ratio or prothrombin time, partial pressure of arterial oxygen/fraction of inspired oxygen [Pao2/ Fio2 ratio], systemic blood pressure, etc.), or to tissue injury biomarkers (e.g., aspartate transaminase, troponins, cystatin C, • Pediatric multiple-organ dysfunction syndrome (MODS) represents the leading final pathway to death in children who suffer critical illness triggered by acute insults such as sepsis (leading cause of MODS), trauma, burns, pancreatitis, inborn errors of metabolism, transplantation, and others Of children admitted to the pediatric intensive care unit (PICU), 14% to 30% have MODS on PICU day The incidence of new MODS during the PICU stay is estimated to be 22% to 39% MODS encompasses the association of diverse states of organ failure, insufficiency, or injury Three concepts should be considered to understand the pathophysiology of MODS: (1) organ functional reserve; (2) kinetics of organ injury/failure; and (3) decompartmentalization of the organ injury and interactions between organs The pathophysiologic host response to an injury and subsequent organ failure is complex, involving diverse cellular, immune, neurohumoral, and vascular responses: mitochondrial dysfunction, innate and adaptive immune alterations, microcirculatory dysfunction and ischemia-reperfusion injury, epithelial dysfunction, and neurohumoral changes • • • • PEARLS CHAPTER 111 Multiple-Organ Dysfunction Syndrome 1311 Initial injury Organ injury Resolving organ failure Organ functionality Normal function Secondary organ failure Residual functional capacity End-stage organ failure No function Time • Fig 111.1 Organ dysfunction kinetics following injury neuron-specific enolase) Severity of organ failure is directly related to organ functional incapacity, which may range from a limited alteration of the function (or some selected function) to an end-stage dysfunction with no or insufficient functionality to maintain homeostasis Similar to respiratory function, one may consider that each organ has a residual functional capacity that allows it to withstand insults or injury up to a final end-stage failure state requiring specific extracorporeal organ support or transplantation Kinetics of organ injury/failure: Another parameter that needs to be considered is the high variability of organ dysfunction kinetics following an injury (Fig 111.1) The kinetics of organ failure is rarely linear, as such injury can be direct or indirect, recurrent, or aggravated by external cofactors such as comorbidities, therapeutic interventions, or recently recognized autocrine/paracrine danger signals These external factors may have an important impact on the development of MODS and need to be targeted by intensive therapies Usually recognized as factors that will aggravate organ injury, this second-hit concept has been extensively described and is characterized as the potentiation by the host response to the organ injury For example, it is demonstrated that mechanical ventilation potentiates inflammatory response of the host lung exposed to pathogens and that prone positioning may limit this response.16 Decompartmentalization of the organ injury and interactions between organs: The third concept to be considered is the decompartmentalization of the host response outside the injured organ environment This is not only limited to organs but also to the scaffolding tissues, such as musculoskeletal and conjunctive tissues During bacteremia, endothelial cells are directly and indirectly activated by pathogens and circulating cells (see later discussion) and trigger changes in endothelial permeability that result in interstitial exudation of cells, various proteins that will trigger a remote inflammatory response outside the circulating compartment This is a major mechanism related to acute lung injury Organ interactions have been recognized for a long time As stated by Lawrence J Henderson in 1914, “a necessary postulate of biology is that no function of an organ is independent of any other.”17 Organ interactions occur not only under healthy conditions but also in specific pathologic situations Some examples are hepatorenal syndrome, hepatopulmonary syndrome, volume dysregulation, and protein catabolism Ranieri et al., in a landmark study, showed that inappropriate mechanical ventilation was able to generate a systemic inflammatory response and remote organ dysfunction.18 The pathophysiologic host response to an injury and subsequent organ failure is complex, involving diverse cellular, immune, neurohumoral, and vascular responses Mitochondrial Dysfunction Mitochondria are recognized to largely influence host response to injury by modulating cell metabolism and the production of high-energy phosphate (e.g., adenosine triphosphate [ATP]) as well as by regulating cell signaling, gene expression, cellular calcium levels, and activation of cell death pathways through caspase activation.19 Recently recognized mitochondrial DNA (mtDNA) has been shown to be an important activator of innate immunity through (1) Toll-like receptor (TLR) pathway and (2) NLRP3 inflammasome Release of mtDNA into the circulation may trigger local and remote inflammatory responses, referred to as dangerassociated molecular patterns (DAMPs) or danger signals This is one of the mechanisms of sterile inflammation seen after traumatic or burn injury, in which mtDNA released from injured tissues activates innate immunity and generates a secondary inflammatory response DAMPs play a significant role in the development of acute lung injury.20 Among other pathophysiologic mechanisms related to the mitochondria, electron transport chain (ETC) dysfunction may result in increased production of superoxide and superoxide-derived reactive oxygen species (ROS) and promote oxidative damage to the mitochondria themselves and to related organelles mtDNA is specifically sensitive to the effects of ROS owing to a lack of protective histones Calcium transport alterations—such as those following ischemia-reperfusion (I-R) injury, along with increased production of mitochondrial ROS— can produce a synergistic effect on mitochondria permeability with release of cytochrome C and subsequent activation of mitochondrial cell death pathways through the interaction with cytosolic proapoptotic proteins (e.g., BCL-2/BAX protein family) and caspase activation Sepsis provides the best example of mitochondrial dysfunction in modulating organ failure As such, it is now recognized that the sympathetic outflow during the early phase of sepsis that results in massive activation of Kupffer cells and release of cytokines responsible for remote organ failure is related to the mitochondrial generation of free radicals by Kupffer ... 283 Marshall JC Sepsis: rethinking the approach to clinical research J Leukoc Biol 2008:83(3):471-482 283a Knox DB, Lanspa MJ, Kuttler KG, et al Phenotypic clusters within sepsis-associated multiple... pathogens and that prone positioning may limit this response.16 Decompartmentalization of the organ injury and interactions between organs: The third concept to be considered is the decompartmentalization... 2007:8(6):530-539 274 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