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Multiple organ dysfunction syndrome

Multiple organ dysfunction syndrome (MODS) is defined as the presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention, typically involving two or more organ systems and often leading to prolonged intensive care unit stays and high mortality rates.^[1] The incidence of MODS in adult ICU patients ranges from 10% to 40%, varying by population and setting.^[2] This syndrome represents a continuum of illness severity, progressing from systemic inflammatory response syndrome (SIRS) through sepsis to multiorgan failure, and is characterized by potentially reversible physiologic derangements rather than irreversible failure.^[3] MODS most commonly arises in critically ill patients following severe insults such as sepsis, major trauma, burns, or hypoperfusion, with sepsis being the leading trigger in up to 60% of cases.^[2] The pathophysiology involves a dysregulated host response, including excessive inflammation, endothelial dysfunction, microvascular thrombosis, and oxidative stress, which propagate organ injury through mechanisms like ischemia-reperfusion and cytokine storms.^[4] Commonly affected organs include the lungs (manifesting as acute respiratory distress syndrome), kidneys (acute kidney injury), liver (hepatocellular dysfunction), cardiovascular system (shock and myocardial depression), and central nervous system (encephalopathy), with respiratory involvement occurring in nearly all cases early in the course.^[2] Diagnosis relies on clinical assessment and scoring systems such as the Sequential Organ Failure Assessment (SOFA) score or the Multiple Organ Dysfunction (MOD) score, which evaluate dysfunction across six organ systems based on parameters like oxygenation, coagulation, liver function, cardiovascular hemodynamics, central nervous system status, and renal output.^[3] Mortality increases with the number and severity of failing organs, ranging from 27% for two-organ involvement to over 90% for five or more, underscoring the prognostic importance of early detection.^[2] Management is primarily supportive and multidisciplinary, focusing on treating the underlying cause (e.g., antibiotics for sepsis), optimizing hemodynamics with fluids and vasopressors, providing organ-specific support such as mechanical ventilation for respiratory failure or renal replacement therapy for kidney injury, and preventing secondary insults through nutrition and infection control.^[3] Recent insights emphasize early resuscitation and hemodynamic optimization, microcirculatory monitoring, and emerging interventions like extracorporeal therapies to mitigate inflammation, though no specific targeted therapies exist for MODS itself.^[5]^[2] Despite advances, MODS remains a leading cause of death in ICUs, highlighting the need for ongoing research into biomarkers and preventive strategies.^[6]

Introduction and Epidemiology

Definition and Classification

Multiple organ dysfunction syndrome (MODS) is characterized by the presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention, typically involving dysfunction of two or more organ systems following a severe systemic insult.^[7] This progressive yet potentially reversible process disrupts normal physiological balance across affected organs, distinguishing it as a continuum of escalating derangements rather than a static event.^[3] MODS is classified into patterns based on the timing of organ involvement: sequential, where organ dysfunction develops in a stepwise manner over days, often seen in trauma or subacute insults; or simultaneous, involving concurrent failure of multiple organs, more common in acute conditions like sepsis.^[8] Staging further categorizes MODS by the number of organs affected, such as two-organ or three-organ involvement, with greater organ counts associated with progressively higher mortality rates.^[9] Unlike systemic inflammatory response syndrome (SIRS), which denotes a widespread inflammatory reaction to various triggers without specifying organ impact, MODS focuses on the resultant physiological impairments in multiple systems.^[7] It also differs from multiple organ failure (MOF), an older term emphasizing irreversible end-stage collapse, by highlighting MODS as a dynamic, potentially treatable progression.^[3] The terminology evolved from earlier concepts like "multiple systems organ failure" (MSOF), used in the 1970s and 1980s to describe cascading failures in critically ill patients, to the current consensus definition established at the 1991 American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) conference, which shifted emphasis to dysfunction as a spectrum rather than absolute failure.^[7]

Incidence and Prevalence

Multiple organ dysfunction syndrome (MODS) affects a substantial proportion of critically ill patients, with estimates indicating that approximately 15% of intensive care unit (ICU) admissions develop organ failure, often progressing to MODS.^[10] In broader ICU cohorts, the incidence of MODS ranges from 10% to 30%, though it varies significantly by underlying condition; for instance, multiorgan failure occurs in about 22% of septic patients.^[11] A 2022 multicenter study in Iran involving 194 ICU patients reported a MODS prevalence of 56.2%, highlighting regional variations in critical care populations.^[12] In high-risk subgroups such as trauma or sepsis cases, the incidence rises markedly, reaching 28% to 88% among critically ill trauma patients and up to 27% in trauma patients with sepsis.^[2]^[13] Mortality associated with MODS is particularly elevated in sepsis-related cases, ranging from 40% to 75%, underscoring its role as a leading cause of death in these settings.^[9] Demographic factors influence MODS occurrence, with higher rates observed in males, who comprised 69.6% of cases in a large ICU cohort, and in elderly patients over 65 years, where age-related vulnerabilities exacerbate progression in trauma and critical illness.^[12] In pediatric populations, incidence is generally lower, with prevalence at ICU entry around 15.5% and new-onset MODS at 22.3%, though certain ethnic groups such as non-Hispanic Black children show elevated risk.^[14]^[15] Temporal trends reveal a surge in MODS during the COVID-19 pandemic from 2020 to 2023, driven by increased ICU admissions for severe respiratory and systemic complications, with multiple organ involvement common in up to 24% of severe cases and contributing to higher overall critical care burden.^[16]

Causes and Risk Factors

Primary Causes

Multiple organ dysfunction syndrome (MODS) is primarily triggered by acute insults that disrupt systemic homeostasis, leading to widespread organ failure. The most common initiating event is sepsis, which accounts for two-thirds of MODS cases in intensive care unit (ICU) settings, often through infection-induced bacteremia that overwhelms the immune system and causes systemic inflammation.^[2] Severe trauma represents another major cause, occurring in 28% to 88% of critically ill trauma patients, where hypovolemic shock from blood loss induces tissue ischemia and reperfusion injury.^[2] Major surgery, burns, and acute pancreatitis also serve as key triggers; for instance, extensive burns provoke a massive proinflammatory response due to tissue destruction, while pancreatitis initiates inflammatory cascades via pancreatic enzyme release into the bloodstream.^[2]^[17] These primary causes initiate MODS through distinct but overlapping mechanisms that ultimately converge on organ hypoperfusion and cellular stress. In sepsis, bacterial toxins and pathogens enter the circulation via bacteremia, activating endothelial cells and releasing cytokines that impair vascular integrity and microcirculation.^[9] Trauma and burns commonly lead to hypovolemic shock, reducing cardiac output and causing widespread ischemia that releases damage-associated molecular patterns (DAMPs), exacerbating the inflammatory response.^[2] Sterile insults like major surgery or pancreatitis trigger similar cascades without infection, involving the release of inflammatory mediators that promote endothelial dysfunction and coagulopathy.^[18] Non-infectious causes further contribute to MODS onset, particularly in scenarios without overt microbial invasion. Acute respiratory distress syndrome (ARDS), often from aspiration of gastric contents, directly impairs gas exchange and can precipitate hypoxic organ failure as a primary driver.^[2] Cardiogenic shock, resulting from acute myocardial infarction or heart failure, reduces systemic perfusion and mimics the hypovolemic effects seen in trauma.^[19] Drug toxicity, such as from overdoses of nephrotoxic or cardiotoxic agents, induces direct cellular damage and mitochondrial dysfunction, leading to multiorgan involvement.^[20] Recent reports indicate a rising incidence of MODS linked to sepsis, driven by increasing antimicrobial resistance (AMR); between 2018 and 2023, resistance rose in over 40% of monitored pathogen-antibiotic combinations, complicating sepsis management and elevating MODS risk.^[21] These acute triggers often culminate in organ hypoxia due to microvascular collapse, setting the stage for progressive dysfunction.^[9]

Predisposing Factors

Multiple organ dysfunction syndrome (MODS) susceptibility is heightened by various patient-specific factors that compromise physiological reserve and immune response prior to any acute insult. Advanced age, particularly over 65 years, significantly elevates the risk, with studies showing that elderly patients exhibit reduced organ resilience and higher mortality rates associated with MODS development.^[22] Comorbidities such as diabetes mellitus and chronic kidney disease further impair baseline organ function, independently predicting worse outcomes in critically ill individuals prone to MODS.^[2] Immunosuppression from conditions like HIV or treatments including chemotherapy weakens host defenses, increasing vulnerability through persistent lymphopenia and dysregulated inflammation.^[2] Genetic predispositions also play a role in modulating inflammatory responses that can precipitate MODS, especially in the context of sepsis. Polymorphisms in the TNF-alpha gene, such as the -308 G/A variant, are linked to heightened sepsis susceptibility and subsequent organ failure risk.^[23] Similarly, variations in IL-6 gene expression levels correlate with increased MODS incidence in septic patients, as these alterations amplify pro-inflammatory cascades.^[24] Environmental and lifestyle factors contribute to pre-existing vulnerabilities that exacerbate MODS risk. Malnutrition, often stemming from chronic illness or poor intake, diminishes nutritional reserves and impairs immune competence, serving as a key predisposing element in critical care settings.^[22] Chronic alcohol abuse induces direct organ damage and nutritional deficiencies, heightening susceptibility to multi-organ involvement during stress.^[25] Recent research highlights obesity as an independent risk factor for organ failure post-trauma, with obese patients showing altered inflammatory profiles that promote MODS progression.^[26] Moreover, frailty scores from 2023 studies have emerged as robust predictors of adverse outcomes including MODS in geriatric trauma populations, enabling earlier risk stratification.^[27]

Pathophysiology

Core Mechanisms

Multiple organ dysfunction syndrome (MODS) is fundamentally driven by systemic inflammation, characterized by a cytokine storm involving elevated levels of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). These cytokines are rapidly released in response to infection or injury, activating nuclear factor-kappa B (NF-κB) pathways in immune cells and endothelial cells, which amplifies the inflammatory cascade. TNF-α, detected within 30-90 minutes of lipopolysaccharide (LPS) exposure in experimental models, induces endothelial activation by upregulating adhesion molecules and procoagulant factors, leading to increased vascular permeability and capillary leak syndrome. Similarly, IL-1β, processed via the NLRP3 inflammasome, promotes endothelial dysfunction and microthrombosis, while IL-6 enhances capillary leakage through trans-signaling mechanisms, collectively contributing to widespread tissue edema and hypoperfusion across organ systems. This hyperinflammatory state correlates with sepsis severity and higher mortality rates in critically ill patients.^[28]^[29] Coagulation dysregulation plays a central role in MODS progression through the development of disseminated intravascular coagulation (DIC), an acquired disorder marked by systemic activation of the coagulation cascade, impaired fibrinolysis, and endothelial injury. In critical illnesses like sepsis, tissue factor expression on damaged endothelium and activated monocytes triggers thrombin generation, leading to widespread microthrombi formation in the microvasculature. These microthrombi obstruct small vessels, impairing organ perfusion and causing ischemic injury, as evidenced by autopsy findings of thrombosis in the lungs, kidneys, and brain. Neutrophil extracellular traps (NETs) and histones further exacerbate this by promoting platelet aggregation and inhibiting natural anticoagulants like thrombomodulin, resulting in a prothrombotic state that sustains organ hypoperfusion and dysfunction. Recent updates to DIC definitions emphasize its life-threatening nature, with severe cases directly linked to MODS and increased mortality.^[30]^[31] Oxidative stress, mediated by excessive reactive oxygen species (ROS) production, induces cellular injury and apoptosis, exacerbating MODS across multiple organs. In sepsis, activated neutrophils and macrophages generate ROS via NADPH oxidase and mitochondrial electron transport chain dysfunction, overwhelming antioxidant defenses such as superoxide dismutase and glutathione. This imbalance leads to lipid peroxidation, protein oxidation, and DNA damage, triggering intrinsic apoptotic pathways through mitochondrial outer membrane permeabilization and cytochrome c release. Cytokines like TNF-α and IL-6 further amplify ROS production, creating a vicious cycle of oxidative damage that impairs cellular energy metabolism and promotes cytopathic hypoxia. Studies in critically ill patients demonstrate elevated ROS markers correlating with organ failure severity, highlighting oxidative stress as a key mediator of tissue injury in MODS.^[29] Immunoparalysis represents a shift from hyperinflammation to immunosuppression in MODS, characterized by reduced immune cell function and increased susceptibility to secondary infections. This phase involves lymphocyte apoptosis, monocyte deactivation, and decreased HLA-DR expression on antigen-presenting cells, impairing pathogen clearance and prolonging critical illness. High-mobility group box 1 protein (HMGB1), a damage-associated molecular pattern released by necrotic cells and activated immune cells, sustains this hypo-inflammatory state by modulating toll-like receptor 4 (TLR4) signaling, promoting endothelial damage and coagulation abnormalities. Recent reviews underscore HMGB1's role as a mediator of persistent inflammation transitioning to immunoparalysis, with elevated levels associated with higher rates of nosocomial infections and worsened organ dysfunction in sepsis patients. This biphasic immune response contributes significantly to the high mortality observed in prolonged MODS cases.^[28]

Gut-Origin Hypothesis

The gut-origin hypothesis posits that the gastrointestinal tract serves as the primary "motor" driving multiple organ dysfunction syndrome (MODS), particularly following shock states where ischemia-reperfusion injury disrupts the intestinal mucosal barrier. This injury, often triggered by hypoperfusion in trauma or sepsis, leads to breakdown of the epithelial tight junctions and increased permeability, allowing luminal contents to escape into the systemic circulation.^[32] Bacterial translocation and the release of endotoxins, such as lipopolysaccharide (LPS), from the gut enter the portal venous system, where they amplify systemic inflammation by activating immune responses and promoting cytokine release. This process initiates a vicious cycle of remote organ injury, contributing to the progression of MODS. Supporting evidence from animal models demonstrates that selective gut decontamination—using antibiotics to target enteric pathogens—significantly attenuates MODS severity. For instance, in rodent models of hemorrhagic shock, decontamination reduced bacterial translocation, lowered inflammatory markers, and improved organ function scores compared to controls. Clinically, elevated plasma LPS levels correlate with MODS progression in critically ill patients; studies show that higher endotoxin activity (e.g., ≥0.6 units) in septic shock is associated with greater organ failure and mortality, as measured by SOFA or MODS scores.^[33]^[34] Recent evaluations, including 2023 analyses of ICU patients with septic shock, have questioned the hypothesis's primacy in non-septic MODS cases, where bacterial translocation did not consistently predict mortality despite gut dysbiosis. However, the role remains affirmed in trauma settings, where gut barrier dysfunction and microbial shifts directly exacerbate systemic inflammation and organ failure, as evidenced by persistent correlations in post-trauma cohorts. This translocation-driven inflammation links to broader cytokine storms observed in core MODS mechanisms.^[35]^[36]

Endotoxin and Macrophage Hypothesis

The Endotoxin and Macrophage Hypothesis proposes that lipopolysaccharide (LPS), a key endotoxin derived from the outer membrane of gram-negative bacteria, serves as a primary trigger for the systemic inflammatory cascade in multiple organ dysfunction syndrome (MODS) through its interaction with macrophages. LPS binds to Toll-like receptor 4 (TLR4) on the surface of macrophages, often in complex with CD14 and MD-2, activating intracellular signaling pathways such as NF-κB and MAPK, which culminate in the robust production and release of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6).^[37]^[38] This initial activation amplifies the immune response, transforming a localized infection into a widespread inflammatory storm that underlies the progressive organ failure characteristic of MODS.^[39] Central to this hypothesis is the hyperactivity of macrophages, particularly those resident in the spleen and liver, which act as sentinel cells that sequester and process circulating LPS. Upon LPS exposure, these macrophages undergo enhanced activation, releasing not only cytokines but also reactive oxygen species and other mediators that perpetuate inflammation in a phenomenon known as the "second hit," where the primed immune system overreacts to subsequent stimuli, leading to uncontrolled cytokine release and tissue damage across multiple organs.^[39]^[38] This macrophage-driven amplification is thought to sustain the inflammatory milieu, distinguishing it as a key driver of the hyperinflammatory phase in MODS pathogenesis.^[40] Clinical and experimental evidence strongly supports this mechanism, with studies showing markedly elevated serum levels of pro-inflammatory cytokines in MODS patients, directly correlating with detectable endotoxin concentrations and correlating with worse outcomes such as prolonged organ support needs.^[41]^[40] In preclinical models, interventions blocking LPS binding to TLR4 or neutralizing downstream cytokines have demonstrated significant reductions in organ injury, including decreased hepatic and pulmonary damage, highlighting the causal role of this pathway.^[42]^[43] As of 2025, narrative reviews continue to emphasize the endotoxin-macrophage axis in the persistent inflammation observed during the later stages of MODS, where ongoing low-grade LPS stimulation maintains macrophage dysfunction and cytokine dysregulation, informing emerging therapies like polymyxin B hemoperfusion for endotoxin adsorption in septic patients.^[44]^[45] This hypothesis also underscores the endotoxin pathway's contribution to associated microvascular permeability issues in MODS.^[39]

Hypoxia and Microvascular Dysfunction Hypothesis

The hypoxia and microvascular dysfunction hypothesis proposes that impaired tissue perfusion at the microcirculatory level, rather than solely macrohemodynamic instability, drives the progression of multiple organ dysfunction syndrome (MODS) by inducing regional tissue hypoxia and subsequent organ failure.^[46] This theory emphasizes how microvascular alterations persist even when systemic blood pressure is normalized through resuscitation, leading to heterogeneous oxygen delivery deficits that exacerbate cellular injury in critical illness such as sepsis.^[47] Central to this hypothesis is microcirculatory dysfunction, characterized by endothelial cell swelling and degradation of the endothelial glycocalyx, a protective gel-like layer on the vascular surface. Endothelial swelling narrows capillary lumens, while glycocalyx shedding—triggered by inflammatory mediators—exposes adhesion molecules, promotes leukocyte rolling and adhesion, and increases vascular permeability, collectively contributing to the no-reflow phenomenon where blood flow fails to restore adequately in microvessels despite reperfusion efforts.^[48]^[49] These changes result in shunting of blood away from nutrient-deprived capillary beds, fostering regional hypoxia in organs like the kidneys and liver even amid overall hemodynamic stability.^[50] This regional hypoperfusion shifts cellular metabolism toward anaerobic pathways, causing lactate accumulation as pyruvate is converted to lactate under oxygen scarcity, which further acidifies tissues and impairs mitochondrial function.^[51] Such metabolic derangements correlate with worsening organ dysfunction, independent of global perfusion metrics. Evidence from intravital microscopy in septic patients reveals heterogeneous microvascular flow, with stopped-flow capillaries and reduced perfused vessel density directly linked to impaired tissue oxygenation. These perfusion deficits show strong correlations with sequential organ failure assessment (SOFA) scores, where lower microvascular flow indices predict higher organ failure severity and mortality.^[52]^[53] Recent investigations highlight vasoplegia's role in perpetuating this microvascular failure during refractory shock, where profound vasodilation decouples macrocirculatory support from microcirculatory needs, sustaining hypoxia despite vasopressor therapy.^[54] This overlap with inflammatory cytokines underscores how endothelial activation amplifies perfusion heterogeneity in MODS.^[49]

Mitochondrial DNA Hypothesis

The mitochondrial DNA (mtDNA) hypothesis proposes that mtDNA released from injured or necrotic cells acts as a damage-associated molecular pattern (DAMP), initiating sterile inflammation that exacerbates multiple organ dysfunction syndrome (MODS). Unlike pathogen-associated molecular patterns, mtDNA triggers innate immune responses independently of infection, promoting systemic inflammatory cascades that disrupt organ homeostasis and intercellular signaling. This release occurs during cellular stress, such as ischemia or trauma, where mitochondrial integrity is compromised, allowing mtDNA to enter the cytosol or extracellular space.^[55] mtDNA, sharing structural similarities with bacterial DNA due to its unmethylated CpG motifs, primarily activates Toll-like receptor 9 (TLR9) on immune cells like macrophages, dendritic cells, and neutrophils. Upon binding, TLR9 recruits the adaptor protein MyD88, leading to nuclear factor-κB (NF-κB) activation and production of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). This pathway amplifies remote organ injury through endothelial dysfunction and impaired vascular communication, contributing to the progressive failure of organ crosstalk in MODS.^[56]^[57] Clinical evidence supports this mechanism, with elevated circulating mtDNA levels observed in critically ill patients developing MODS, directly correlating with disease severity as measured by organ failure scores. Patients exhibiting above-median plasma mtDNA DAMP concentrations faced a markedly increased relative risk of mortality, with several deaths attributed to severe MODS progression. Animal models further validate these findings; in polymicrobial sepsis induced by cecal ligation and puncture, TLR9 knockout mice showed attenuated renal mitochondrial oxidative stress, reduced vacuolization, preserved ATP levels, and improved survival compared to wild-type counterparts, demonstrating mtDNA-TLR9 signaling's causal role in organ dysfunction.^[55]^[58]^[56] Research from 2023 to 2025 has extended this hypothesis to long-term outcomes, revealing persistent mtDNA-mediated inflammation in MODS survivors that underlies bioenergetic failure. In post-sepsis cohorts, sustained mtDNA release from senescent mitochondria and neutrophil extracellular traps activates TLR9 and NLRP3 inflammasome pathways, fostering chronic low-grade inflammation, immune dysregulation, and neuromuscular weakness that impair physical recovery. This enduring mitochondrial inefficiency, characterized by reduced oxidative phosphorylation and elevated reactive oxygen species, highlights mtDNA's contribution to prolonged morbidity beyond acute MODS resolution.^[59]

Integrated Models

The "hit" model, particularly the two-hit hypothesis, posits that multiple organ dysfunction syndrome (MODS) often arises from an initial priming insult, such as trauma or major surgery, which activates a systemic inflammatory response, followed by a secondary hit, like infection or ischemia, that escalates organ failure.^[60] This sequential process explains the bimodal pattern of MODS, where early primary dysfunction from the first hit transitions to late secondary involvement through amplified cytokine release and immune dysregulation.^[2] For instance, in trauma patients, the initial injury primes neutrophils and endothelial cells, making subsequent events like nosocomial pneumonia more likely to trigger widespread microvascular damage.^[60] Organ crosstalk represents a critical integration in MODS pathogenesis, where dysfunction in one organ propagates failure in others via soluble mediators, extracellular vesicles, and metabolic signals, forming interconnected axes such as gut-liver, heart-lung-kidney, and brain-gut.^[61] In sepsis-induced MODS, hepatic impairment reduces cytokine clearance, exacerbating pulmonary and renal inflammation, while gut barrier breakdown releases bacterial products that fuel distant organ injury through lymphatic and vascular pathways.^[61] This bidirectional communication amplifies systemic inflammation, distinguishing MODS from isolated organ failure and underscoring the need to view it as a networked process rather than linear progression.^[2] Contemporary systems biology approaches frame MODS as a disruption of dynamic biological networks, incorporating epigenetics, microbiome alterations, and multi-omics data to map interactions across scales from molecules to organs.^[62] Recent reviews highlight multi-omics integration—combining transcriptomics, proteomics, and metabolomics—to identify hub genes like PRKAR1A, which regulate inflammatory pathways and offer therapeutic targets in sepsis-associated MODS.^[63] For example, weighted gene co-expression network analysis of patient datasets reveals modules linking microbial dysbiosis to epigenetic changes that perpetuate organ crosstalk, providing a holistic view beyond traditional hypotheses like gut-origin or mitochondrial DNA mechanisms.^[63]^[62] Isolated hypotheses, such as those focused on endotoxins or hypoxia, fail to capture MODS's heterogeneity and temporal dynamics, often overlooking patient-specific factors like genetic variability and comorbidities that influence progression.^[2] This limitation drives advocacy for personalized models, which leverage machine learning on multi-omics and clinical data to predict individual MODS trajectories and tailor interventions, as demonstrated in trauma cohorts where nomograms integrate biomarkers for risk stratification.^[64] Such approaches enhance prognostic accuracy, moving toward precision management in critical care.^[65]

Clinical Features

General Signs and Symptoms

Multiple organ dysfunction syndrome (MODS) manifests through nonspecific systemic signs that reflect broad physiological instability, often emerging in critically ill patients following severe insults such as sepsis or trauma. Prominent features include fever (typically >38°C) or hypothermia (<36°C), tachycardia (heart rate >90 beats per minute), altered mental status manifesting as encephalopathy or reduced Glasgow Coma Scale score, oliguria indicating early renal impairment, and jaundice due to hyperbilirubinemia.^[66]^[67]^[3] Laboratory indicators further underscore the systemic derangement, with common abnormalities encompassing leukocytosis (>12,000 cells/μL) or leukopenia (<4,000 cells/μL), thrombocytopenia (platelet count <100,000/μL), elevated serum lactate (>2 mmol/L), and metabolic acidosis (arterial pH <7.35).^[66]^[68] These findings signal an exaggerated inflammatory response and tissue hypoperfusion across multiple systems. MODS often evolves rapidly, progressing from single-organ dysfunction to multi-organ involvement within 24 to 72 hours post-insult, driven by unchecked systemic inflammation.^[69] In non-resolving cases, 2024 analyses of persistent inflammation, immunosuppression, and catabolism syndrome (PICS) reveal sustained elevations in C-reactive protein (>20 mg/L) and other acute-phase reactants, correlating with prolonged organ dysfunction and increased risk of recurrent infections.^[70] These global symptoms coexist with organ-specific effects, such as respiratory distress or hepatic failure.

Organ-Specific Manifestations

Multiple organ dysfunction syndrome (MODS) manifests through distinct patterns of failure in various organ systems, with clinical variability influenced by the underlying trigger such as sepsis or trauma. While systemic inflammation contributes to widespread effects, organ-specific signs emerge as critical indicators of progression, often requiring tailored monitoring in intensive care settings.^[2] Cardiovascular manifestations typically include hypotension refractory to fluid resuscitation, driven by vasodilation and myocardial depression, alongside arrhythmias such as atrial fibrillation or ventricular tachycardia. These features reflect reduced cardiac output and ejection fraction, with systolic and diastolic dysfunction observed in approximately 50% of patients with septic shock, associated with mortality rates up to 70%.^[2] Respiratory involvement commonly presents as acute respiratory distress syndrome (ARDS), characterized by severe hypoxemia with a PaO₂/FiO₂ ratio below 200 mmHg, bilateral pulmonary infiltrates, and prolonged ventilator dependence. This occurs in nearly all post-trauma MODS patients initially, often compounded by pulmonary hypertension and reduced lung compliance.^[2] Renal dysfunction is evidenced by acute kidney injury (AKI), defined by a serum creatinine level more than twofold the baseline or oliguria, occurring in 40–60% of critically ill patients with MODS. Progression frequently necessitates renal replacement therapy like dialysis due to impaired glomerular filtration and tubular damage.^[2] Hepatic manifestations feature hyperbilirubinemia exceeding 2 mg/dL and coagulopathy, indicated by prolonged prothrombin time and elevated international normalized ratio, stemming from impaired synthetic function and cholestasis. These signs, integral to scoring systems like SOFA, highlight liver failure as a marker of severe MODS.^[2] Additional organ systems show characteristic alterations: Central nervous system (CNS) effects include delirium and altered mental status, with Glasgow Coma Scale scores below 15 signaling encephalopathy from hypoperfusion and inflammation.^[2] Gastrointestinal (GI) involvement encompasses ileus, mucosal ischemia, and barrier dysfunction, leading to motility impairment and potential bacterial translocation.^[2] Hematologic complications manifest as disseminated intravascular coagulation (DIC), with thrombocytopenia below 50,000/μL, microthrombi formation, and bleeding tendencies.^[2] In pediatric patients, MODS exhibits nuances, with recent analyses indicating higher hepatic involvement, particularly in trauma-related cases due to hemorrhage-induced hypoperfusion, contrasting with lower frequency in adult cohorts.^[71]

Diagnosis

Clinical Assessment

Clinical assessment of multiple organ dysfunction syndrome (MODS) begins with a thorough history and physical examination to identify the inciting event and early signs of systemic instability in critically ill patients. The history typically reveals nonspecific symptoms such as fever, chills, fatigue, malaise, anxiety, or confusion, which may be subtle or absent in elderly patients, alongside localizing indicators like cough, dyspnea, abdominal pain, or focal tenderness suggestive of underlying infection or trauma as the trigger. Identifying the inciting event, such as sepsis, is crucial, as it often presents with abrupt fever, rigors, hyperventilation, and altered mental status due to a large infectious burden. On physical examination, the focus is on the patient's overall hemodynamic status, searching for a toxic appearance, focal signs of infection, and evidence of organ hypoperfusion, including cool extremities, delayed capillary refill time, and skin mottling, which indicate progressing microvascular dysfunction. Vital signs assessment reveals instability, such as tachycardia, tachypnea, widened pulse pressure, and hypotension refractory to initial fluid resuscitation, while organ-specific perfusion is evaluated through parameters like reduced urine output (oliguria) signaling renal involvement. Monitoring techniques for suspecting MODS emphasize both invasive and noninvasive methods to track organ perfusion and oxygenation at the bedside. Invasive tools, including arterial lines for continuous blood pressure monitoring and central venous pressure catheters to assess fluid status and right heart filling, provide precise hemodynamic data but carry risks of infection and complications in critically ill patients. Noninvasive alternatives, such as echocardiography for evaluating cardiac output and ventricular function, and near-infrared spectroscopy (NIRS) for measuring regional tissue oxygen saturation (StO2), offer safer, real-time insights into microvascular perfusion and tissue oxygenation without procedural risks; NIRS, in particular, detects early hypoperfusion by quantifying StO2 changes in peripheral tissues like the thenar eminence. These modalities enable serial evaluation of oxygen delivery impairment, with parameters like pressure-adjusted heart rate (heart rate multiplied by central venous pressure divided by mean arterial pressure) helping quantify cardiovascular derangements. Early warning systems facilitate rapid screening for patients at risk of progressing to MODS, particularly in non-ICU settings. The quick Sequential Organ Failure Assessment (qSOFA) score, using bedside variables—respiratory rate ≥22 breaths/min, altered mentation (Glasgow Coma Scale <15), and systolic blood pressure ≤100 mm Hg—identifies adults with suspected infection at higher risk of poor outcomes, including organ dysfunction, with a score ≥2 prompting escalation of care. Similarly, the Modified Early Warning Score (MEWS) incorporates vital signs and mental status for timely detection of deterioration in hospitalized patients. Guidelines emphasize dynamic assessments in intensive care units (ICUs), including serial bedside monitoring of perfusion parameters, fluid responsiveness, and evolving vital signs to guide individualized management. Biomarkers may be referenced briefly for confirmation once clinical suspicion is raised.

Scoring Systems and Biomarkers

The Sequential Organ Failure Assessment (SOFA) score is a widely used tool to quantify the extent of organ dysfunction in critically ill patients, including those with multiple organ dysfunction syndrome (MODS). It evaluates six organ systems—respiratory, cardiovascular, hepatic, coagulation, renal, and neurological—assigning a score from 0 (normal function) to 4 (most abnormal) for each, yielding a total score ranging from 0 to 24. An increase in the total SOFA score of 2 points or more from baseline is indicative of organ dysfunction, while scores exceeding 6 often signal the presence of MODS across multiple systems. The SOFA score was originally developed in 1994 to describe organ dysfunction objectively rather than predict outcomes directly, though it correlates with ICU mortality risk. The Multiple Organ Dysfunction (MOD) score, developed by Marshall et al. in 1995, provides another validated measure specifically tailored for MODS. It assesses the same six organ systems with scores of 0 to 4 each, resulting in a maximum total of 24, where higher scores reflect greater cumulative dysfunction and correlate with ICU mortality in a graded manner. This score emphasizes daily worst values during the ICU stay to track progression. The Logistic Organ Dysfunction (LOD) score, introduced in 1996, similarly evaluates six organ systems, including the hematologic system, on a 0-5 scale per system, with a total up to 22, and is designed for both description and mortality prediction using logistic regression-derived weights. The LOD score demonstrates strong discrimination for ICU outcomes, particularly when neurological failure is prominent. Biomarkers play a crucial role in aiding the diagnosis and staging of MODS by identifying underlying sepsis or specific organ injury. Procalcitonin levels are elevated in MODS linked to sepsis, with kinetics from day 1 to 5 correlating to severity and multiorgan involvement in pediatric cases, serving as an indicator of bacterial infection driving systemic inflammation. Neutrophil gelatinase-associated lipocalin (NGAL) is a sensitive marker for acute kidney injury (AKI) in MODS, often rising early in sepsis-associated renal dysfunction to predict progression. Cardiac troponin elevations signal myocardial injury in MODS, particularly in septic shock, where levels above the reference limit indicate dysfunction and add prognostic value beyond clinical scores. Emerging biomarkers and integrated approaches are enhancing MODS assessment, particularly for early detection. Cell-free DNA (cfDNA) levels are significantly higher in sepsis and severe infections leading to MODS, reflecting widespread cellular damage and serving as a noninvasive indicator of critical illness severity. Recent machine learning (ML)-integrated panels, incorporating cfDNA with other markers, are being explored for dynamic monitoring in 2024-2025 studies. Predictive models using ML nomograms have shown promise for forecasting MODS onset and recovery; for instance, 2024 trauma cohort analyses developed nomograms combining clinical variables to predict 1-week organ recovery with high accuracy (AUC >0.85), while 2022-2023 models for older ICU patients with MODS achieved robust external validation for short-term outcomes. Despite their utility, these scoring systems and biomarkers have limitations that affect clinical application. Inter-observer variability is notable in SOFA and MOD scores due to subjective elements in cardiovascular and neurological assessments, leading to reproducibility challenges in real-world settings. All systems, including LOD, require serial measurements over time to capture dynamic changes in organ function accurately, as single-point assessments underestimate progression in MODS.

Management

Supportive Care

Supportive care in multiple organ dysfunction syndrome (MODS) focuses on maintaining physiological homeostasis, preventing secondary injury, and supporting vital organ functions in the intensive care unit (ICU) setting. This approach involves a multidisciplinary strategy to address hemodynamic instability, metabolic derangements, infectious complications, and specific organ failures, guided by evidence-based protocols such as the Surviving Sepsis Campaign (SSC) guidelines, which are applicable to MODS often precipitated by sepsis.^[72] Hemodynamic support is a cornerstone of MODS management, beginning with fluid resuscitation to restore intravascular volume and perfusion. For patients with sepsis-associated MODS, an initial intravenous crystalloid fluid bolus of 30 mL/kg is recommended within the first 3 hours of recognition, using balanced solutions like lactated Ringer's to minimize risks such as hyperchloremic acidosis.^[72] If hypotension persists after adequate fluid administration (typically defined as a mean arterial pressure <65 mmHg), vasopressors should be initiated promptly, with norepinephrine as the first-line agent due to its potent vasoconstrictive effects and lower arrhythmia risk compared to alternatives like dopamine.^[72] In cases of acute respiratory distress syndrome (ARDS) complicating MODS, mechanical ventilation with low tidal volumes (4-8 mL/kg predicted body weight) is strongly recommended to reduce ventilator-induced lung injury and improve outcomes.^[73] Nutritional and metabolic support aims to mitigate catabolism and preserve organ integrity, particularly the gut barrier, which can exacerbate systemic inflammation in MODS. Early enteral nutrition (EN) is advised, initiated within 24-48 hours of ICU admission in hemodynamically stable patients, to provide calories (20-25 kcal/kg/day) and protein (1.2-2.0 g/kg/day) while avoiding parenteral nutrition unless EN is contraindicated.^[74] This approach helps maintain mucosal integrity and reduces translocation of gut bacteria, a key factor in preventing further organ dysfunction.^[74] Glycemic control is equally critical, with a target blood glucose range of 144-180 mg/dL recommended for critically ill patients to balance the risks of hyperglycemia-induced endothelial damage and hypoglycemia.^[5] Insulin therapy should be titrated using continuous infusion protocols, with frequent monitoring to avoid extremes.^[5] Infection control remains paramount, as uncontrolled infection drives MODS progression. Source control—encompassing drainage of abscesses, debridement of necrotic tissue, or removal of infected devices—should be achieved as rapidly as possible, ideally within 6-12 hours of diagnosis, to halt bacterial dissemination.^[72] Concurrently, broad-spectrum intravenous antibiotics covering likely pathogens (e.g., gram-positive, gram-negative, and anaerobic organisms) must be administered within 1 hour of sepsis recognition in MODS, with de-escalation based on culture results to minimize resistance.^[72] Organ-specific support modalities are tailored to the degree of dysfunction, with renal replacement therapy (RRT) indicated for severe acute kidney injury (AKI) in MODS, such as when oliguria persists despite optimization or in cases of refractory acidosis, hyperkalemia, or uremia. Continuous RRT (CRRT) is preferred over intermittent hemodialysis in hemodynamically unstable patients due to its gentler fluid and solute removal, targeting an effluent dose of 20-25 mL/kg/hour.^[75] For mechanically ventilated patients, sedation protocols emphasize analgesia-first strategies followed by light sedation to facilitate weaning and reduce delirium; daily interruption of sedatives and assessment using tools like the Richmond Agitation-Sedation Scale (RASS) target -1 to 0 (alert and calm) unless contraindicated.^[76] These measures align with the 2021 SSC Hour-1 bundle.^[5]

Targeted Therapies

Targeted therapies for multiple organ dysfunction syndrome (MODS) focus on addressing underlying pathophysiological mechanisms, particularly in sepsis-associated cases, which account for a significant proportion of MODS occurrences. Early administration of broad-spectrum antibiotics is a cornerstone intervention in sepsis-induced MODS, with guidelines recommending initiation within one hour of recognition to improve survival rates by targeting the infectious source and preventing progression of organ failure.^[77]^[78] For patients with refractory septic shock, low-dose hydrocortisone may accelerate shock reversal, with mixed evidence on mortality reduction from randomized trials; a weak recommendation exists in guidelines for use when relative adrenal insufficiency is suspected.^[79]^[80]^[5] Immunomodulatory agents represent another targeted approach to mitigate the dysregulated inflammatory response in MODS. Interleukin-1 (IL-1) receptor antagonists, such as anakinra, have shown promise in specific subsets of septic patients with hyperferritinemia or macrophage activation syndrome-like features, where phase II trials reported reduced mortality and faster resolution of organ dysfunction through blockade of IL-1β signaling.^[81] However, broader phase III trials in unselected severe sepsis populations have not consistently demonstrated overall mortality benefits, highlighting the need for biomarker-guided patient selection. As of 2025, ongoing phase II/III trials (e.g., TRIPS) are evaluating anakinra for reversal of inflammation in pediatric sepsis-induced MODS.^[82] Anti-inflammatory strategies also include endotoxin removal techniques for gram-negative sepsis contributing to MODS. Polymyxin B-immobilized fiber column hemoperfusion (PMX-HP) has been investigated to selectively adsorb circulating endotoxins, with some multicenter studies reporting improved hemodynamics and reduced organ dysfunction scores in patients with elevated endotoxin levels; however, large randomized trials have not shown consistent survival advantages, and major guidelines suggest against its routine use due to insufficient evidence.^[83]^[84]^[5] Experimental therapies targeting mitochondrial damage-associated molecular patterns (DAMPs), such as circulating mitochondrial DNA (mtDNA), are under investigation; preclinical and early-phase data suggest that mtDNA scavengers could attenuate systemic inflammation, though phase II trials from 2023 onward have yet to establish definitive efficacy in MODS.^[2] In cases of MODS complicated by disseminated intravascular coagulation (DIC), anticoagulation with low-molecular-weight heparin (LMWH) is employed to restore hemostatic balance and prevent microvascular thrombosis. Meta-analyses indicate that LMWH reduces 28-day mortality and shortens hospital stays in sepsis-associated DIC by modulating coagulopathy and inflammation, outperforming unfractionated heparin in safety profiles for non-bleeding patients; the 2025 ISTH DIC update includes phase-based scoring but maintains similar management principles.^[85]^[86]^[87] Looking toward future directions, precision medicine approaches in MODS emphasize biomarker-driven therapies to tailor interventions, such as using endotoxin activity assays or cytokine profiles to select candidates for PMX-HP or immunomodulators, potentially enhancing response rates in heterogeneous patient populations.^[88] Gene therapy for mitochondrial repair holds emerging potential, with preclinical models demonstrating correction of mtDNA mutations to restore cellular bioenergetics and mitigate organ failure in mitochondrial dysfunction-linked MODS; ongoing phase I/II trials target primary mitochondrial disorders but may extend to acquired insults like sepsis.^[89]^[90]

Prognosis and Outcomes

Short-Term Prognosis

The short-term prognosis of multiple organ dysfunction syndrome (MODS) is generally poor, with in-hospital mortality rates ranging from 30% to 50% in adult patients, primarily driven by the underlying etiology such as sepsis or trauma.^[91] Mortality escalates significantly with the involvement of more organ systems, reaching 50% to 90% when four or more organs are affected in adults with sepsis-induced MODS.^[9] Key predictive factors include advanced age and high Sequential Organ Failure Assessment (SOFA) scores; for instance, a SOFA score exceeding 15 is associated with mortality risks over 80%, as it reflects severe, widespread organ failure.^[92] Recovery patterns in the acute phase vary based on the extent of organ involvement, with approximately 50% of cases involving fewer than three organs resolving within 7 to 14 days through intensive supportive care, often marked by a median recovery time of 4 to 7 days in less severe clusters.^[93] However, persistent MODS beyond this window is frequently linked to secondary infections, which prolong ICU stays and worsen outcomes by exacerbating inflammatory responses.^[2] Early intervention using standardized sepsis bundles, such as timely antimicrobial administration and fluid resuscitation, has been shown to reduce short-term mortality by 20% to 30%, with recent implementations demonstrating a 22.6% decrease even in resource-limited settings.^[94] In pediatric patients, short-term mortality from MODS is somewhat lower, typically 20% to 40%, particularly in trauma-related cases where Day 1 MODS carries a 20.1% in-hospital death rate compared to 0.5% without dysfunction.^[15] Despite this, children experience higher rates of acute complications, including functional decline and the need for prolonged mechanical ventilation or renal support, which contribute to extended hospital stays and increased morbidity during the initial phase.^[14] Scoring systems like SOFA aid in predicting these outcomes by quantifying organ dysfunction severity at admission.^[95]

Long-Term Consequences

Survivors of multiple organ dysfunction syndrome (MODS) often experience post-MODS syndrome, a constellation of persistent physical, cognitive, and psychological impairments akin to post-intensive care syndrome observed in critical illness contexts such as sepsis-induced MODS.^[96] Cognitive impairments, affecting memory, attention, and executive function, occur in 30-50% of intensive care unit survivors, with severe sepsis cases showing up to 16.7% moderate-to-severe deficits persisting for years.^[96] Muscle weakness, particularly intensive care unit-acquired weakness, impacts approximately 50% of older survivors and contributes to reduced functional independence.^[96] Post-traumatic stress disorder (PTSD) develops in 19-22% of survivors, often compounded by pre-existing mental health conditions.^[96] These survivors also face elevated healthcare utilization, including rehospitalizations and emergency department visits; a 2025 cohort study of pediatric MODS patients found adjusted incidence rate ratios for readmissions up to 12.45 in infants at 30 days post-discharge compared to non-MODS peers, indicating substantially increased burden.^[97] Organ-specific sequelae further compound long-term morbidity in MODS survivors. Chronic kidney disease arises in nearly 20% of those with sepsis-associated acute kidney injury, progressing within one year even in non-severe cases.^[98] Pulmonary complications, including fibrosis-like changes from prior acute respiratory distress syndrome, lead to persistent lung dysfunction and reduced respiratory capacity.^[99] Cardiovascular events, such as heart failure and atherosclerosis, occur at elevated rates post-sepsis, with survivors facing a higher incidence of both atherosclerotic and nonatherosclerotic outcomes.^[100] Key risk factors for these long-term consequences include the duration of organ support, such as mechanical ventilation exceeding seven days, and episodes of delirium during acute illness, both of which independently predict cognitive and physical deficits.^[96] Recent cohort studies from 2023-2025 highlight reduced life expectancy among MODS survivors, with sepsis cases showing a 5- to 8-year decrement compared to age-matched controls, alongside substantial economic burdens from ongoing care.^[101] In pediatric populations, year-one healthcare costs for MODS survivors reached $80,133 for infants versus $5,183 for non-MODS controls, persisting through five years and underscoring the societal impact.^[97]

Historical Development

Early Descriptions

The recognition of multiple organ involvement in critically ill patients began with observations of organ failure clusters following severe trauma and shock in the mid-20th century. During World War II, British physician Eric Bywaters described cases of acute renal failure in patients with crush injuries sustained during the London Blitz, highlighting renal impairment as a direct consequence of hypovolemic shock and muscle necrosis, often leading to death despite survival of the initial injury.^[102] Similar patterns emerged in burn victims, where post-war studies noted acute kidney injury (AKI) as a frequent complication due to hypovolemia and toxin release, though these were viewed primarily as isolated renal events rather than part of a broader systemic process.^[103] In the 1960s, attention turned to pulmonary complications in trauma and sepsis patients, with reports of "shock lung"—a term coined for non-cardiogenic pulmonary edema and respiratory failure following shock states. This condition, later formalized as acute respiratory distress syndrome (ARDS), was detailed in a seminal 1967 paper by Ashbaugh and colleagues, who observed rapid-onset hypoxemia and reduced lung compliance in adults after diverse insults like trauma, sepsis, and aspiration, marking an early cluster of respiratory and often concurrent renal dysfunction but without a unified multi-organ framework.^[104] These post-World War II and 1960s accounts emphasized organ-specific syndromes in surgical and trauma contexts, such as AKI in burns or shock lung in hypovolemic states, reflecting a growing awareness of failure patterns in intensive care settings. The 1970s brought initial articulations of sequential or progressive multi-organ involvement. In 1973, Tilney et al. provided one of the first modern descriptions of "sequential system failure" in patients undergoing surgery for ruptured abdominal aortic aneurysms, noting a predictable progression starting with respiratory distress and renal failure in the context of hemorrhagic shock, where initial survival from the operation was undermined by cascading organ derangements.^[105] Building on this, Baue's 1975 editorial introduced the concept of "multiple, progressive, or sequential systems failure" as a distinct syndrome observed in postoperative and trauma patients, characterized by the stepwise involvement of lungs, kidneys, liver, and other systems, often triggered by shock or infection in surgical settings.^[106] Prior to the 1990s, medical literature predominantly focused on these isolated or pairwise organ syndromes—such as ARDS coupled with AKI—without a comprehensive systemic perspective, limiting interventions to organ-specific support like dialysis for renal failure or mechanical ventilation for pulmonary issues.^[3]

Key Milestones

In 1991, the American College of Chest Physicians (ACCP) and Society of Critical Care Medicine (SCCM) convened a consensus conference that formalized the definition of multiple organ dysfunction syndrome (MODS) as the presence of altered organ function in acutely ill patients, particularly in the intensive care unit (ICU), requiring intervention to maintain homeostasis, and distinguished it from the systemic inflammatory response syndrome (SIRS).^[107] This definition shifted focus from isolated organ failure to a progressive, interrelated dysfunction across multiple systems, often triggered by sepsis or trauma, and emphasized its role as a leading cause of ICU mortality.^[108] The mid-1990s marked the introduction of quantitative tools for assessing MODS severity, with the Sequential Organ Failure Assessment (SOFA) score developed in 1996 to quantify dysfunction in six organ systems—respiratory, cardiovascular, hepatic, coagulation, renal, and neurological—using readily available clinical variables.^[109] Refined in the 2001 International Sepsis Definitions Conference by SCCM, ESICM, ACCP, ATS, and SIS, the SOFA score was integrated into updated sepsis criteria, where an increase of 2 or more points indicated infection-associated organ dysfunction, facilitating standardized prognosis and research. Concurrently, the Surviving Sepsis Campaign, launched in 2002 and issuing its first guidelines in 2004, linked MODS prevention to early sepsis bundle interventions like fluid resuscitation and antibiotics, reducing organ failure incidence through global implementation. Therapeutic efforts in the 1990s, including anti-cytokine trials targeting tumor necrosis factor (TNF) and interleukin-1 (IL-1) in sepsis-induced MODS, largely failed to improve survival, as exemplified by the NORASEPT II trial's neutral results with monoclonal anti-TNF antibody despite preclinical promise. These setbacks, echoed in multiple phase III studies, underscored the complexity of inflammatory cascades and pivoted clinical practice toward supportive care strategies, such as mechanical ventilation and renal replacement therapy, rather than immunomodulation.^[110] From the 2010s onward, genomic studies illuminated MODS mechanisms, identifying key pathways like inflammation and apoptosis through bioinformatics analyses of differentially expressed genes in septic patients, revealing potential biomarkers such as upregulated cytokines and endothelial dysfunction genes. In the 2020s, research advanced with machine learning (ML) models for predicting MODS trajectories and long-term outcomes; for instance, a 2022 ML approach using electronic health records forecasted recovery from multi-organ failure up to one week ahead, while 2025 studies predicted 28-day survival in patients with sepsis and diabetes using interpretable machine learning models.^[111]^[112] These innovations, building on early case reports of organ interplay, enhance personalized risk stratification and highlight persistent challenges in mitigating prolonged morbidity.^[2]

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