Multiple-organ dysfunction syndrome









  • 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 1. 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.



  • 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). 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. Children with MODS have mortality rates of 10% to as high as 57% in selected populations. , First defined in 1986 as the simultaneous presence of two or more organ dysfunctions, , the definition, criteria, and monitoring of pediatric MODS have undergone several transformations over time. 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.


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:



  • 1.

    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 [Pa o 2 /F io 2 ratio], systemic blood pressure, etc.), or to tissue injury biomarkers (e.g., aspartate transaminase, troponins, cystatin C, 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.


  • 2.

    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.




    • Fig. 111.1


    Organ dysfunction kinetics following injury.


  • 3.

    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.” 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.



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. Recently recognized mitochondrial DNA (mtDNA) has been shown to be an important activator of innate immunity through (1) Toll-like receptor (TLR) 9 pathway and (2) NLRP3 inflammasome. Release of mtDNA into the circulation may trigger local and remote inflammatory responses, referred to as danger-associated 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. 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 9 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 cells. , 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. 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. , Recently, the combination of hydrocortisone, vitamin C, and thiamine in adult patients with septic shock suggested some potential hemodynamic benefit.


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-γ [IFN-γ], tumor necrosis factor-α [TNF-α]), 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. 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 .



• 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 μg/L



  • sCD25 ≥2400 U/mL




MAS affects all organ functions, but hepatobiliary consequences may be severe, as most children develop liver failure. , Similarly, cytokine release syndrome (CRS; see Chapter 92 ) can be seen following chimeric antigen receptor T-cell (CART) therapy. Prolonged cytokine-induced hyperinflammation, or persistent intractable inflammation syndrome (PICS), can occur and result in MODS and death. Conversely, cytokines also trigger transient or prolonged immunodepressive states. In most 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. Such physiologically transient immunodepression occurs after cardiopulmonary bypass, ventricular-assist device use, and trauma, spontaneously resolving within 5 to7 days. 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-α 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 ). ,



TABLE 111.1

Multiple-Organ Dysfunction Syndrome (MODS): Phenotypes, Diagnosis, and Therapies












































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-α response to LPS stimulation <200 pg/mL or mHLA-DR expression <8000/cell on day 3 and/or later a




  • Rapidly taper immunosuppressive drugs if present



  • Consider immunostimulatory therapies (GM-CSF, IFN-γ)



  • Give IVIG if low

SMOF


  • Respiratory and hepatic failure after day 3



  • Can be associated with PTLD–EBV



  • Diagnosis biomarkers: soluble Fas ligand >200 pg/mL after day 3




  • 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 recommendations b



  • 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 tocilizumab c


OFI definitions: cardiovascular, inotrope or vasopressors infusion requirement; pulmonary, PaO 2 /FiO 2 <300 mm Hg and mechanical ventilation; hepatic, ALT >100 U/L and either bilirubin >1.0 mg/dL or INR >1.5; renal, creatinine >1 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 1 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- γ, interferon-γ; 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; Pa o 2 /F io 2 , 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- α, tumor necrosis factor-α; TTP, thrombotic thrombocytopenic purpura.

a Immunodepression phenotypes may be observed: high regulatory T cells, myeloid-derived suppressor cells, immature neutrophils.


b 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.



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). , In addition, plasma exchange and high-flow continuous venovenous hemofiltration (see Chapter 75 ) have been associated with hemodynamic stabilization. , , Use of extracorporeal cytokine removal therapies (CytoSorb, oXiris) may show some selective efficacy in such patients. In patients with persistent immunodepression, immunostimulatory therapies (granulocyte-macrophage colony-stimulating factor [GM-CSF], IFN-γ) may prove to be of some benefit. , , Other immunostimulatory 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. Recently, the concept of hemodynamic coherence describing the relationship between changes in microcirculation and macrocirculation has emerged. 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 μm) 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 and alveolus. This capacity, called sieving , is also observed in the heart and brain and may participate in some specific pathophysiologic mechanisms, including malignant pertussis. ,


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 1 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). TMA is a well-recognized cause of disseminated 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. , More recently, use of C5a monoclonal antibody (eculizumab) has been suggested to treat TAMOF associated with atypical hemolytic uremic syndrome.


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 do not normally express TLRs in order to limit responses to circulating pathogen-associated 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. 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 do 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. ,


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 . 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. 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 μg/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 ).


Jun 26, 2021 | Posted by in CRITICAL CARE | Comments Off on Multiple-organ dysfunction syndrome

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