Multiple organ failure remains one of the most challenging syndromes in acute care surgery and surgical intensive care, with a 2024 comprehensive review characterizing it as the concomitant dysfunction of two or more organ systems following severe physiologic insults such as sepsis, trauma, shock, or major surgery.
The review, published in Journal of Trauma and Acute Care Surgery, synthesized evidence on the etiology, pathophysiology, diagnosis, management, prognosis, prevention, and future directions for multiple organ failure (MOF) and the related syndrome of chronic critical illness (CCI) in critically ill surgical and trauma populations. The review synthesizes observational and translational data rather than randomized trial evidence and, as a narrative review, does not quantify treatment effects, establish causality, or demonstrate comparative effectiveness of specific interventions.
At its foundation, MOF involves an exacerbated systemic inflammatory response to an acute insult—a cascade encompassing cellular injury, immune dysregulation, endothelial dysfunction, microvascular disturbance, tissue hypoperfusion, and end-organ cellular injury driven by mitochondrial dysfunction, oxidative stress, and apoptosis. In sepsis, proinflammatory cytokines including tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 may contribute to systemic inflammation, endothelial activation, leukocyte recruitment, and thromboinflammatory pathways, a pattern described as a “cytokine storm.”
Organ manifestations vary by system. Respiratory failure may progress to acute respiratory distress syndrome (ARDS); cardiovascular dysfunction may include vasodilation, myocardial depression, hypotension, and mixed cardiogenic and distributive shock physiology; and acute kidney injury, hepatic dysfunction, neurologic impairment, gastrointestinal dysfunction, and hematologic abnormalities—including disseminated intravascular coagulation—may also occur. The researchers noted that acute mental status changes or delirium are often the first clinical sign of decreased end-organ perfusion and incipient MOF.
The review also detailed immune mechanisms that may link acute MOF to prolonged critical illness. Following injury or sepsis, emergency myelopoiesis—a rapid expansion of immature myeloid cells released into the systemic circulation—can drive nonresolving inflammation and dysfunctional adaptive immunity. As this immune dysregulation progresses, T-cell exhaustion and immunoparalysis may develop, increasing susceptibility to secondary infections and prolonging organ dysfunction. Disruption of the gut microbiome may further amplify systemic inflammation through bacterial translocation and endotoxin release.
The researchers emphasized an evolving morbidity trajectory. Advances in shock resuscitation and critical care have reduced early deaths from fulminant MOF, but patients who survive the acute phase may develop CCI, now described as a predominant phenotype of morbidity and mortality following MOF. CCI is characterized by persistent organ dysfunction, prolonged intensive care needs, and the persistent inflammation, immunosuppression, and catabolism syndrome (PICS), which may manifest as muscle wasting, impaired physical recovery, recurrent infections, and sepsis recidivism. Long-term complications, including physical disability, cognitive impairment, and psychological distress, often persist following intensive care unit discharge.
Prognosis depends on the underlying etiology, severity of organ dysfunction, response to treatment, age, comorbidities, and physiologic reserve. Sepsis-induced MOF was associated with a poorer prognosis compared with MOF related to trauma or major surgery. Higher Sequential Organ Failure Assessment (SOFA) scores correlate with increased mortality risk; the review also described the Multiple Organ Dysfunction Score, APACHE score, and Logistic Organ Dysfunction System as validated tools for risk stratification, each with distinct clinical tradeoffs.
Risk factors differ by clinical context. In severe trauma, total injury burden, shock severity, transfusion volume, comorbidity burden, and age were associated with MOF development. In sepsis, early physiologic derangement, vasopressor-refractory shock, comorbidities, and advanced age similarly increased risk.
Management remains primarily supportive and multidisciplinary. The review described early recognition and treatment of the inciting cause, including source control and antibiotics in sepsis and bleeding control with blood-based resuscitation in trauma. Additional strategies include lung-protective ventilation with low tidal volumes, prone positioning and neuromuscular blockade for severe ARDS, hemodynamic optimization, renal replacement therapy when indicated, nutritional support, and prevention of secondary injury. Pharmacologic approaches targeting inflammation or coagulation have not reliably prevented or reversed MOF; the researchers noted that the goal of immunomodulating therapies “remains elusive,” and corticosteroids remain controversial in selected settings.
The findings are primarily applicable to critically ill surgical and trauma populations, and generalizability to other patient groups may be limited.
Looking ahead, the researchers described a potential future landscape shaped by novel biomarker panels—including circulating cell-free DNA and inflammatory mediators beyond traditional markers such as C-reactive protein and procalcitonin—as well as artificial intelligence and machine learning models capable of integrating clinical, imaging, and genomic data to predict MOF and guide early intervention. Regenerative medicine approaches, including stem cell therapy and organ bioengineering, were also described as longer-term possibilities.
“Recognition of the patient at-risk, prompt resuscitation from shock, and protocolized intensive care that supports organ function while minimizing secondary injury remain the cornerstones of MOF care,” wrote lead researcher Scott Brakenridge, MD, of the University of Washington, Washington, DC, and colleagues.
Disclosures: Conflict of interest disclosure forms were supplied as Supplemental Digital Content. Specific conflicts were not detailed in the main article.
