1312 SECTION XI Pediatric Critical Care Immunity and Infection cells 21,22 Similarly, caspase mediated cardiac, diaphragm, and peripheral muscle dysfunction—as well as other organ energy failure (comp[.]
1312 S E C T I O N X I Pediatric Critical Care: Immunity and Infection cells.21,22 Similarly, caspase-mediated cardiac, diaphragm, and peripheral muscle dysfunction—as well as other organ energy failure (complex I activity)—are related to mitochondrial dysfunction and shock severity.23 Therapies targeting mitochondria have been tested and mostly focused on antioxidants For example, N-acetylcysteine appears effective in reducing the intensity of liver injury in patients with liver failure, and vitamin C may improve arteriolar hyporeactivity and vasogenic shock in sepsis.24,25 Recently, the combination of hydrocortisone, vitamin C, and thiamine in adult patients with septic shock suggested some potential hemodynamic benefit.26 Innate and Adaptive Immune Response Immunologic effectors play a significant role in the development of organ dysfunction related to recognition of pathogens and response to tissue injury as well as through indirect or remote inflammation mediated via circulating mediators such as cytokines (e.g., interleukin-6 [IL-6], IL-8, IL-10, IL-18, IL-33, interferon-g [IFN-g], tumor necrosis factor-a [TNF-a]), soluble receptors (e.g., sCD95, IFNAR1, sRAGE, sCD25, sCD163), and circulating leukocytes (neutrophils, monocytes, myeloid-derived suppressor cells, T- and B-regulatory cells, natural killer [NK] cells, histiocytes, dendritic cells) Cytokines target most cell functions, from gene expression, receptor regulation and cell signaling, intercellular communications, to bioenergetics They are central regulators of all immunologic mechanisms, including hematopoiesis, cell proliferation, cellular differentiation (e.g., macrophages, lymphoid cell lines, neutrophils), and apoptosis Macrophage activation syndrome (MAS) is a prototypic life-threatening systemic inflammation involving all organs MAS is characterized by prolonged cell-to-cell (innate and adaptive immune cells) interactions and amplification of a proinflammatory cytokine cascade The cytokine storm results in activation of macrophages, causing hemophagocytosis as well as contributing to MODS.27 Activation of macrophages in tissue (primarily liver and bone marrow) is the definitive characteristic of MAS Its diagnosis is based on the HLH-2004 diagnostic criteria and encompasses at least five of the following criteria summarized in Box 111.1 MAS affects all organ functions, but hepatobiliary consequences may be severe, as most children develop liver failure.28,29 Similarly, cytokine release syndrome (CRS; see Chapter 92) can be seen following chimeric antigen receptor T-cell (CART) therapy.30 Prolonged cytokine-induced hyperinflammation, or persistent intractable inflammation syndrome (PICS), can occur and result in MODS and death.31 Conversely, cytokines also trigger transient or prolonged immunodepressive states.31 In most • BOX 111.1 Diagnostic Criteria for Macrophage Activation Syndrome • Fever • Splenomegaly • Cytopenias (affecting 2/3 cell lines: hemoglobin ,9 g/dL, platelets ,100,000 /uL, neutrophils ,1000/uL) • Hypertriglyceridemia (265 mg/dL) • Hypofibrinogenemia (#1.5 g/L) • Hemophagocytosis in bone marrow or spleen or lymph nodes • Low or absent natural killer cell activity • Ferritin 500 mg/L • sCD25 2400 U/mL cases, this transient induced immunodepression is a physiologic mechanism aimed at reprograming the immune response to limit and define organ-specific immune responses in order to reset compartmentalization of the host response.32 Such physiologically transient immunodepression occurs after cardiopulmonary bypass, ventricular-assist device use, and trauma, spontaneously resolving within to7 days.33–35 Nonresolving immunodepression, also called persistent immunodepression is currently recognized as an important complication of acute illness and is associated with occurrence of secondary infection and mortality It is generally identified as persistent TNF-a level of less than 200 pg/mL in response to endotoxin ex vivo stimulation of whole blood or persistent low monocyte human leukocyte antigen–DR (mHLA-DR) cell surface expression of less than 8000/cell (Table 111.1).36,37 Therapies targeting inflammation have been successfully developed for each selected entity MAS and CRS therapy encompass the use of nonselective immunosuppressive drugs (e.g., intravenous immunoglobulin, cyclosporin, methylprednisolone) or blocking antibodies such IL-1 receptor antagonist (anakinra, canakinumab), anti-IL-6 receptor (tocilizumab), and CTLA4-Ig (abatacept).30,38–41 In addition, plasma exchange and high-flow continuous venovenous hemofiltration (see Chapter 75) have been associated with hemodynamic stabilization.28,42,43 Use of extracorporeal cytokine removal therapies (CytoSorb, oXiris) may show some selective efficacy in such patients.44–47 In patients with persistent immunodepression, immunostimulatory therapies (granulocyte-macrophage colony-stimulating factor [GM-CSF], IFN-g) may prove to be of some benefit.36,48,49 Other immuno stimulatory therapies—such as PD-1 and PD-1L antibodies, and IL-7—are currently being investigated Microcirculatory Dysfunction, Ischemia-Reperfusion Injury The vascular endothelium is a highly specialized tissue involved in modulating immune response and physiologic response to injury (see Chapter 25) Among its pivotal functions, the endothelium plays important roles in thrombosis/fibrinolysis, platelet and leukocyte adhesion, and regulation of vascular tone Direct or indirect damage to the endothelium results in an increase in vascular permeability as well as an alteration in vasomotor function that typically resolves within 48 hours after injury.50 Recently, the concept of hemodynamic coherence describing the relationship between changes in microcirculation and macrocirculation has emerged.51 The loss of hemodynamic coherence may result in depressed microcirculation despite an improvement in macrocirculation, a condition associated with the development of MODS and increased mortality risk Vasomotor alterations result from four main mechanisms: (1) alteration of endothelial cell surface receptor expression, (2) modified signal transduction pathways (endothelial constitutive nitric oxide synthase [ecNOS]) coupling, (3) altered function and/or density of ecNOS, and (4) changes in pathways leading to NO release Microcirculation (vessels ,250 mm) may be severely impaired in children with MODS Microcirculatory injury is characterized by a decrease in perfused capillary density and tissue oxygenation It results from various causes, including erythrocyte and leukocyte adhesion/clotting abnormalities, and impaired vasoreactivity For example, accumulation of activated neutrophils (CD18 positive) in pulmonary capillaries is followed by extravasation of sequestered, activated neutrophils within the pulmonary interstitium CHAPTER 111 Multiple-Organ Dysfunction Syndrome 1313 TABLE Multiple-Organ Dysfunction Syndrome (MODS): Phenotypes, Diagnosis, and Therapies 111.1 Phenotype Diagnosis Therapy TAMOF New-onset thrombocytopenia (,100,00/uL) renal failure and OFI 3 Diagnosis biomarkers: ADAMTS-13 ,57% Plasma exchange until resolution of TAMOF Eculizumab for atypical HUS/TTP form IPMOF OFI 2 Secondary or healthcare–associated infection Diagnosis biomarkers: ex vivo whole blood TNF-a response to LPS stimulation ,200 pg/mL or mHLADR expression ,8000/cell on day and/or latera Rapidly taper immunosuppressive drugs if present Consider immunostimulatory therapies (GM-CSF, IFN-g) Give IVIG if low SMOF Respiratory and hepatic failure after day Can be associated with PTLD–EBV Diagnosis biomarkers: soluble Fas ligand 200 pg/mL after day Stop immunosuppressive drugs if present Consider rituximab if EBV-induced PTLD Secondary hemochromatosis- associated cardiac hepatopancreatic MODS History of multiple transfusions Diagnosis biomarkers: ferritin 1000 pg/L, Fe binding 50% Iron chelation Antifungal coverage for aspergillus during chelation Sepsis-induced MODS Septic shock 2020 Pediatric Surviving Sepsis Campaign recommendationsb Screen for TAMOF, IPMOF or SMOF Aggressive extracorporeal lung, kidney, and cardiac support as needed Postoperative MODS OFI 3 Aggressive hemodynamic support Consider CVVH, high-flow CVVH, or cytokines removal if shock refractory to vasopressors or oliguria/anuria Trauma-induced MODS OFI 3 Treat injury Support failing organs Primary organ failure MODS OFI 3 Support failing organs Prevent progressive organ injury Macrophage activation syndrome Hepatobiliary dysfunction disseminated intravascular coagulation and OFI 3 Methylprednisone, IVIG Plasma exchange or high-flow CVVH Anakinra and/or tocilizumabc a Immunodepression phenotypes may be observed: high regulatory T cells, myeloid-derived suppressor cells, immature neutrophils Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children Pediatr Crit Care Med 2020;21(2):e52–e106 c In cases of cytokines release syndrome, use anti-IL-6 tocilizumab OFI definitions: cardiovascular, inotrope or vasopressors infusion requirement; pulmonary, PaO2/FiO2 ,300 mm Hg and mechanical ventilation; hepatic, ALT 100 U/L and either bilirubin 1.0 mg/dL or INR 1.5; renal, creatinine mg/dL with oliguria or renal replacement therapy; hematologic, platelet count ,100,000/uL and INR 1.5; central nervous system, Glasgow Coma Scale score ,12 in absence of sedative ADAMTS-13, A disintegrin and metalloproteinase with a thrombospondin type motif, member 13; ALT, alanine transaminase; ARDS, acute respiratory distress syndrome; CVVH, continuous venovenous hemofiltration; EBV, Epstein-Barr virus; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-g, interferon-g; INR, international normalized ratio; IPMOF, immunoparalysis-associated multiorgan failure; IVIG, intravenous immunoglobulin; HUS, hemolytic uremic syndrome; LDH, lactase dehydrogenase; LPS, lipopolysaccharide; mHLA-DR, monocyte human leukocyte antigen–DR; MOF, multiorgan failure; OFI, organ failure index; Pao2 /Fio2, partial pressure of arterial oxygen/fraction of inspired oxygen; PTLD, posttransplantation lymphoproliferative disease; SMOF, sequential liver failure–associated multiorgan failure; TAMOF, thrombocytopenia-associated multiorgan failure (thrombotic microangiopathy); TNF-a, tumor necrosis factor-a; TTP, thrombotic thrombocytopenic purpura b and alveolus.52 This capacity, called sieving, is also observed in the heart and brain and may participate in some specific pathophysiologic mechanisms, including malignant pertussis.53,54 I-R injury (see Chapter 34) plays a significant role in organ delivery alterations, immune activation, and mitochondrial dysfunction Although function of most organs may be altered by I-R injury, the kidney is a well-recognized target Renal failure remains central in MODS progression and severity Ischemia is recognized as an important mechanism of renal failure through depletion of metabolic substrates and accumulation of products of anaerobic metabolism Depleted cellular ATP results in rapid hypoxanthine accumulation Upon reperfusion, hypoxanthine is converted into xanthine with simultaneous generation of superoxide anion and other ROS that ultimately trigger cell death, inflammation, and necrosis (i.e., acute tubular necrosis) Children with MODS have increased circulating tissue factor and plasminogen activator-1 (PAI-1) activity, an increase in circulating adhesion proteins intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), and an activated prothrombotic/antifibrinolytic endothelium A disintegrin and metalloproteinase with a thrombospondin type motif, member 13 (ADAMTS-13) and von Willebrand factor (vWF) multimer protease expression are decreased during inflammation (negative acute phase protein response similar to albumin), increasing the risk of vWF-mediated thrombosis seen in thrombotic microangiopathy (TMA).55 TMA is a well-recognized cause of disseminated 1314 S E C T I O N X I Pediatric Critical Care: Immunity and Infection organ dysfunction and seems to be frequently encountered in children with MODS under the TAMOF acronym (thrombocytopenia-associated multiorgan failure; see later discussion) Therapies targeted to microcirculatory dysfunction, shock, and I-R are mainly supportive, with hemodynamic optimization through the means of fluid resuscitation, vasoactive-inotropic support, and transfusion No specific therapies exist for thrombotic events unless overt vascular thrombosis or emboli occur Use of activated protein C has not shown any benefit Nevertheless, if TMA occurs, plasma exchange is indicated.56,57 More recently, use of C5a monoclonal antibody (eculizumab) has been suggested to treat TAMOF associated with atypical hemolytic uremic syndrome.58 Epithelial Dysfunction Epithelial disruption and injury play an under-recognized role in MODS Although immunologically inert, with limited immune effectors present during homeostatic state, injury to epithelia induce a rapid functional adaptation aimed at maintaining integrity of the host to the outer environment Inflammation and other triggers (e.g., viral infection, burns, mechanical ventilation) will rapidly recruit immunologic effectors and modify epithelial structures For example, gut and respiratory epithelia not normally express TLRs in order to limit responses to circulating pathogenassociated molecular patterns (PAMPs; e.g., endotoxin, flagellin, lipopeptides) It has been shown that cyclic stretching of lung epithelial cells induces the expression of TLRs and potentiates an innate response to bacteria.59 However, the most significant effect of epithelial injury is the loss of the mechanical barrier, exposure to external pathogens, and alteration of organ function (e.g., lungs, intestines) Although therapies targeted to restoring epithelial integrity not exist outside of skin grafting, effort should be focused on limiting epithelial injury through treatment of concurrent inflammation triggers, such as viral or fungal infection, and optimization of standard care, such as mechanical ventilation, renal replacement therapy, or digestive support (e.g., enteral nutrition) Potential optimization of the epithelial microbiome may play a significant role in the future.60,61 Neurohumoral Response Although central in all cardiovascular adaptive mechanisms, the autonomous (i.e., parasympathetic) nervous system has been recently recognized as an important modulator of the immune and inflammatory response of the host This neuro-immune interaction was termed the inflammatory reflex.62–64 It involves the afferent and efferent vagus nerve, nucleus tractus solitarius, and the reticuloendothelial system in various organs—such as the spleen, intestines, liver, lungs, and heart In these organs, terminal nerve fibers release acetylcholine, with resultant inhibition of proinflammatory cytokine production In addition, stimulation of the vagal nerve induces activation of the hypothalamus-pituitary-adrenal axis responsible for cortisol release from the adrenal cortex, as well as epinephrine, norepinephrine, and dopamine release from the adrenal medulla The gut is an important target of the inflammatory reflex, participating in the maintenance of gut barrier integrity after major burns and hemorrhagic shock Some experimental data suggest that the inflammatory reflex attenuates acute lung injury following I-R Experimental therapies targeting the inflammatory reflex are mostly focused on inhibiting acetylcholine esterase, enhancing cholinergic signaling, increasing levels of acetylcholine, and vagal stimulation Currently, vagal stimulation shows the greatest promise in modulating organ inflammation Multiple-Organ Dysfunction Syndrome Phenotypes MODS subtypes are related to the sequence of injury and focus of the primary insult Sepsis-induced MODS has a high mortality and systemic pathophysiology Kidney, heart, and lung failures are closely associated with negative outcomes and aggressive support is mandatory All aspects of MODS pathophysiology should be considered and therapies targeted toward recognizing infective causes, reversing shock, and administering antibiotics should be prioritized.65 Infection source control is of paramount importance Persisting or progressive MODS requires aggressive diagnosis and treatment of any residual infective nidus Special consideration should be given to patients with persistent immunodepression (see later discussion) Secondary hemochromatosis-associated cardiac hepatopancreatic MODS occurs in children who received multiple transfusions and developed iron overload with high ferritin level greater than 1000 mg/L and iron-binding capacity less than 50% Iron chelation can be considered Postoperative MODS is characterized by immediate MODS following surgery requiring prolonged ischemia and direct organ injury (e.g., liver transplantation, specific abdominal surgery, cardiac surgery) I-R injury is the mainstay and affects most organs Comprehensive perioperative management is crucial in postoperative MODS Hemodynamic and respiratory support need to be optimized and renal support/functional preservation is essential Mortality for postoperative MODS is low as most failing organs recover within 48 to 72 hours Among associated complications, severe cardiocirculatory instability (mostly related to I-R injury) and massive capillary leak can occur, impairing respiratory and renal function In trauma-induced MODS (inclusive or acute pancreatitis, major burns), organ injury can be direct or indirect and organ support remains the mainstay of therapy Secondary complications— such as sepsis, hemorrhage, and local complications—can occur In primary organ-related MODS (e.g., acute respiratory distress syndrome [ARDS], acute liver failure, hypertensive cardiomyopathy, uremic encephalopathy) mortality is variable and associated with progression to secondary organ dysfunction and complications Organ support and targeted therapy to the initiating event are necessary alongside prevention of MODS progression (Box 111.2) • BOX 111.2 Nonspecific Suggested Therapies to Prevent and Resolve Multiple-Organ Failure • Apply the 2020 Pediatric Surviving Sepsis Campaign recommendations if sepsis-induced multiple-organ dysfunction syndrome • Provide effective antibiotics and reverse shock in time-sensitive fashion • Remove nidus of infection • Use antitoxins for toxin-mediated disease • Remove fluid before fluid overload exceeds 10% of body weight • Use lung protection strategy as suggested in the Pediatric Acute Lung Injury Consensus Conference recommendations • Control hyperglycemia and nociceptive stimuli • Prevent drug toxicity by titrating drugs to liver/kidney function • Remove toxic drugs as indicated • Provide enteral nutrition • Prevent/stop systemic hemolysis CHAPTER 111 Multiple-Organ Dysfunction Syndrome Attempts to characterize sepsis-induced MODS based on inflammatory phenotypes are currently very popular In a recent multicenter observational study involving 401 children admitted to the PICU, Carcillo et al reported that 25% had more than two organ failures and prototypic inflammatory phenotypes.66 Those three overlapping phenotypes are (1) TAMOF, (2) immunoparalysisassociated 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 was associated with a threefold increase in mortality (23.8% vs 6.7%) in patients with one of these phenotypes and an increased relative risk of developing MAS Interestingly, significant overlap exists between all phenotypes Although debatable, this classification scheme addresses an important concept that holds therapeutic rationale, since all three phenotypes may respond to specific therapies IPAMOF is the most representative phenotype and may respond to immunostimulatory therapies (see earlier discussion) The incidence of IPAMOF is particularly elevated (.20%) in this population and may be biased by criteria used to define the immunodepressive state Setting appropriate and robust testing to define this clinical condition is central and should focus on patients with prolonged immunodepression, as transient immunodepression is known to be a physiologic response to stress/injury.67 TAMOF is well defined and clearly associated with thrombotic microangiopathy Plasma exchange is a recognized therapy for TAMOF and is aimed at removing thrombogenic ultra-large vWF multimers, restoring ADAMTS-13 activity, and reversing renal failure and MODS.68,69 SMOF had the highest mortality and extracorporeal organ support requirement and was associated with MAS Multiple-Organ Dysfunction Syndrome Definitions Pediatric MODS was defined in 1986 as the concomitant dysfunction of two or more organs or systems in critically ill children, using criteria proposed by Wilkinson et al.9,10 These criteria were subsequently updated by Proulx et al in 199670 and Goldstein et al in 2005.11 Several important differences exist among the definitions of pediatric MODS, including the number and type of organs and systems included, preconditions for evaluating singleorgan dysfunction, and different thresholds for scores and assessment tools used to define organ dysfunction.11,70 Consequently, the data on epidemiology, type and number of organs involved, and outcomes of pediatric MODS tend to vary in the literature contingent on the set of criteria used to define MODS A study comparing the Goldstein and Proulx criteria for pediatric MODS applied to a cohort of 842 consecutive pediatric patients admitted to a single PICU in 2009 to 2010 found statistically significant differences in the prevalence of MODS: 180 (21.4%) versus 314 (37.3%), respectively.3 Cardiovascular dysfunction was found to be less prevalent—15 (1.8%) versus 125 (14.9%)—using the Goldstein versus Proulx criteria owing to a precondition for intravenous fluid bolus administration of more than or equal to 40 mL/kg in hour in order for a patient to then undergo evaluation for criteria for cardiovascular dysfunction, such as hypotension, need for vasoactive medication, and rising arterial lactate Conversely, neurologic dysfunction was found to be more prevalent—428 (50.8%) versus 150 (17.8%) using the Goldstein versus Proulx criteria—as the changes in Glasgow Coma Score (GCS), an assessment tool used in both definitions, were less 1315 severe in the former definition (GCS #11 or acute change in GCS 3 points from baseline) compared with the latter (GCS ,5 or fixed, dilated pupils).3 Applying the two definitions yielded discordant 90-day mortality rates for patients with MODS at PICU admission (11.5% vs 17.8%; P 038), but similar 90-day survival of patients without MODS at PICU admission (98.9% vs 98.6%; P 73), using the Goldstein versus Proulx criteria, respectively.3 In addition, large multicenter database studies are limited to those components of MODS definitions that have been collected as part of an existing registry or multicenter study case report form, potentially under- or overestimating the prevalence of MODS and of MODS-related mortality.8 Given such modifications, meaningful comparisons across various pediatric critical care cohorts are difficult to conduct Multiple-Organ Dysfunction Syndrome Scoring Serial, usually daily, assessments of pediatric MODS scores have become an integral part of clinical studies in pediatric critical care in an effort to describe the clinical trajectory and severity of illness throughout the PICU admission Several pediatric MODS scores have been developed The most widely used score to date is the PEdiatric Logistic Organ Dysfunction (PELOD) score and its recently updated version, PELOD-2.13,71–73 PELOD-2 is composed of 10 measures within organ systems, including neurologic (GCS, pupillary reaction), cardiovascular (lactatemia, mean arterial pressure), respiratory (Pao2/Fio2, partial pressure of arterial carbon dioxide [Paco2], mechanical ventilation), renal (creatinine), and hematologic (white blood cell count, platelet count).13 Other pediatric organ dysfunction scores include the Pediatric-MODS (P-MODS),74 modified Sequential Organ Failure Assessment (mSOFA), and pediatric Sequential Organ Failure Assessment (pSOFA) scores.75–78 While used extensively in pediatric critical care studies, there are no current automated processes to integrate P-MODS scores into the clinical practice and routine workflow of the PICU However, data from adult applications of the SOFA score are encouraging and could potentially be applied in the pediatric population In an adult ICU study, Sandri et al modeled the sequence of organ dysfunctions using dynamic Bayesian networks, suggesting that MODS scores such as SOFA could be used to develop prognostic tools for therapeutic decisions at the bedside.79 Epidemiology From 14% to as many as 30% of children admitted to the PICU have MODS on PICU day 1.3,8,80 The incidence of new MODS during the PICU stay is estimated to be 22% to 39%.3 The leading cause of pediatric MODS is sepsis followed, in no particular order, by trauma, burns, pancreatitis, inborn errors of metabolism, transplantation, and others.81 A point prevalence study conducted between 2013 and 2014 in 128 PICUs from 26 countries showed that, among 567 children with severe sepsis, 68% developed MODS within days of recognition of severe sepsis.82 The incidence of MODS is lower but still significant in other populations, estimated at 12% to 27% in patients with trauma and burns,83–85 27% in patients with a liver transplant86 and 18% in patients with a bone marrow transplant.87 While data are not definitive, MODS appears to be more common in neonates 1316 S E C T I O N X I Pediatric Critical Care: Immunity and Infection compared with older children80,88 and in children with chronic illness compared with those without chronic illness, at least on PICU day 1.8 organ failure depicting all immunologic functions outside of homeostasis and adaptive responses Time Course and Outcomes Key References Of all MODS cases, 78% are noted on the first day of PICU admission.89 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.90 Over the last decade, as PICU mortality has decreased dramatically, NPMODS has been proposed as primary or secondary outcome in several completed and ongoing pediatric critical care observational and interventional studies, replacing mortality as an important outcome measure.82,90–92 A higher number of dysfunctional organs is associated with increased mortality, regardless of the patient population under study.84,93,94 In a study conducted in 1806 patients from PICUs between 1998 and 2000, mortality was reported in 0.6% of children with one organ dysfunction and 50% of children with organ dysfunctions NPMODS occurs in most patients who die and is significantly associated with worse functional outcomes in survivors.73,81,82,90,95 Carcillo JA, Berg RA, Wessel D, et al A multicenter network assessment of three inflammation phenotypes in pediatric sepsis-induced multiple organ failure Pediatr Crit Care Med 2019;20(12):1137-1146 Fortenberry JD, Nguyen T, Grunwell JR, et al Therapeutic plasma exchange in children with thrombocytopenia-associated multiple organ failure: The thrombocytopenia-associated multiple organ failure network prospective experience Crit Care Med 2019;47(3):e173-e181 Goldstein B, Giroir B, Randolph A, International Consensus Conference on Pediatric Sepsis International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics Pediatr Crit Care Med 2005;6(1):2-8 Hall MW, Knatz NL, Vetterly C, et al Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome Intensive Care Med 2011;37(3):525-532 Matics TJ, Sanchez-Pinto LN Adaptation and validation of a pediatric sequential organ failure assessment score and evaluation of the sepsis-3 definitions in critically ill children JAMA Pediatr 2017; 171(10):e172352 Proulx F, Gauthier M, Nadeau D, Lacroix J, Farrell CA Timing and predictors of death in pediatric patients with multiple organ system failure Crit Care Med 1994;22(6):1025-1031 Proulx F, Joyal JS, Mariscalco MM, Leteurtre S, Leclerc F, Lacroix J The pediatric multiple organ dysfunction syndrome Pediatr Crit Care Med 2009;10(1):12-22 Schlapbach LJ, Straney L, Bellomo R, MacLaren G, Pilcher D Prognostic accuracy of age-adapted SOFA, SIRS, PELOD-2, and qSOFA for in-hospital mortality among children with suspected infection admitted to the intensive care unit Intensive Care Med 2018;44(2):179-188 Tantalean JA, Leon RJ, Santos AA, Sanchez E Multiple organ dysfunction syndrome in children Pediatr Crit Care Med 2003;4(2): 181-185 Typpo K, Watson RS, Bennett TD, et al Outcomes of day multiple organ dysfunction syndrome in the PICU Pediatr Crit Care Med 2019;20(10):914-922 Villeneuve A, Joyal JS, Proulx F, Ducruet T, Poitras N, Lacroix J Multiple organ dysfunction syndrome in critically ill children: Clinical value of two lists of diagnostic criteria Ann Intensive Care 2016;6(1):40-46 Weiss SL, Fitzgerald JC, Pappachan J, et al Global epidemiology of pediatric severe sepsis: The sepsis prevalence, outcomes, and therapies study Am J Respir Crit Care Med 2015;191(10):1147-1157 Conclusions and Research Perspectives MODS remains a complex pathophysiologic and polymorphic syndrome encompassing all dynamic associations of organ failures Although a number of initial triggers exist that affect a variety of organs, MODS is a unifying concept that encompasses three axioms: Organ function and its residual functional capacity play significant physiologic roles in subsequent injury Nevertheless, little is known about the minimal residual function of various organs and the best criteria to better prognosticate progressive MODS Organ failure kinetics and the response of the host to an injury have not been sufficiently studied to allow the discrimination between a physiologic and pathophysiologic response Decompartmentalization of the response and interconnectivity between organs are not sufficiently understood All organs continuously interact with each other through numerous biological and immunologic mechanisms Interestingly, recent perspectives outline the rationale to consider inflammatory phenotypes in sepsis-induced MODS A larger perspective may extend this context-specific MODS to the concept of the immune The full reference list for this chapter is available at ExpertConsult.com ... anaerobic metabolism Depleted cellular ATP results in rapid hypoxanthine accumulation Upon reperfusion, hypoxanthine is converted into xanthine with simultaneous generation of superoxide anion and other... particularly elevated (.20%) in this population and may be biased by criteria used to define the immunodepressive state Setting appropriate and robust testing to define this clinical condition is... in sepsis-induced MODS A larger perspective may extend this context-specific MODS to the concept of the immune The full reference list for this chapter is available at ExpertConsult.com