There is perhaps no clinical entity that best epitomizes the discipline of critical care medicine as multiple organ dysfunction syndrome (MODS). The numerous pharmacologic and technologic advances reviewed in accompanying chapters have led to substantial improvements in the stabilization and support of the acutely presenting, critically ill patient such that the past decades have witnessed dramatic decreases in mortality rates from once almost universally lethal diseases. However, concomitant with the ability to alter the natural course of acute illness arose a new clinical dilemma characterized by the evolution of averted acute fatalities into protracted deaths marked by progressive dysfunction of multiple organs. Irrespective of the myriad of initial, life-threatening primary insults, the consequent progression through sequential organ dysfunction that has come to be called MODS has emerged as a final common pathogenic pathway that threatens the survival of critically ill children and challenges the clinical acumen of critical care teams. Despite readily recognizing the clinical manifestations of MODS and its associated epidemiologic causes and prognostic implications, our understanding of underlying pathophysiologic mechanisms remains incomplete and specific and targeted therapies remain limited. Numerous theories supported by both experimental and observational data have been espoused in an attempt to elucidate the mechanisms of MODS as well as to identify novel means for treating this too-oftenfatal syndrome. Herein, we provide a review of the definition and epidemiology of pediatric MODS, a discussion of some of the prevailing mechanistic theories regarding the pathogenesis and pathophysiology of MODS, and a brief description of therapeutic interventions that may impact on the clinical course of MODS.

The emergence of MODS as a clinical entity is one of the hallmark challenges of the modern era of critical care medicine. Establishment of modern intensive care units in the mid-1950s and the successful developments of contemporary life-support technologies have enabled patients afflicted with acute, lifethreatening critical illness to increasingly survive their primary injury. As further advances in surgery, anesthesiology, and medicine empowered physicians with life-saving interventions, intensivists recognized that their initial resuscitative efforts were later thwarted by the onset of numerous, secondary physiologic derangements in organs previously spared by the primary insult. Initial reports of this phenomenon often focused on single organ dysfunction, such as respiratory failure, as a complicating feature of the primary disease process or of the resuscitation itself. As early as 1950, Jenkins et al. (1) provided one of the earliest pathologic descriptions of what would later be recognized as acute respiratory distress syndrome (ARDS), which the authors identified as a complication of fluid resuscitation for shock. The notion that this clinical entity could involve multiple systems was suggested as early as 1963 by Burke et al. (2) who described “high output respiratory failure” as an important cause of death from peritonitis or ileus. While this study also focused primarily on respiratory derangements, the authors acknowledged the contributions
of hematologic, renal, and cardiovascular system dysfunction leading to patient demise.

That overwhelming infections could lead to MODS dates back to reports from the late 1960s. MacLean et al. (3) described the progression of septic shock in a large case series and detailed the sequential evolution of organ failure in this cohort. Shortly thereafter, Skillman et al. (4) described the clinical syndrome of serial respiratory, cardiovascular, and hepatic failure following hemorrhage from acute gastric stress ulcers complicated by gram-negative sepsis. Eventually, noninfectious triggers of MODS were observed, and in a related manner, Tilney et al. (5) described sequential failure of multiple organs in their seminal series of patients undergoing repair of ruptured aortic aneurysms. Shortly after these reports, Baue wrote what remains a landmark editorial in 1975 proposing that this observed “multiple, progressive, or sequential systems failure” represented a distinct clinical entity that was indeed more often difficult to combat and refractory to medical therapy than the triggering insult itself (6). Over the ensuing years, additional terms have been utilized to describe this clinical entity including “multiple organ failure” (MOF), “remote organ failure,” and “multiple organ system failure” (MOSF). Relevant to pediatric critical care medicine, Wilkinson et al. (7) provided the first description of MOSF in children after having derived age-adjusted criteria for organ failure.

Because of varying terminology, an American College of Chest Physicians (ACCP)/Society of Critical Care Medicine (SCCM) Consensus Conference was convened “to provide a conceptual and a practical framework to define the systemic inflammatory response to infection, which is a progressive injurious process that falls under the generalized term ‘sepsis’ and includes sepsis-associated organ dysfunction” (8). The participants emphasized that MODS reflected a continuum of dysfunction rather than a dichotomous state of normal function versus failure, that this condition was potentially reversible, and that the degree of organ dysfunction could change over time. The consensus group acknowledged that numerous host, pathogen, and treatment factors could impact the occurrence and course of MODS (8). Finally, conference delegates proposed the use of “multiple organ dysfunction syndrome” as the preferred term to describe this common clinical entity. Moreover, to reflect differences in pathophysiologic triggers leading to MODS, the concepts of primary versus secondary MODS were introduced. Primary MODS referred to its occurrence resulting from a well-defined insult in which organ failure occurred early and could be directly attributed to the insult itself (e.g., meningococcemia). In contrast, the concept of secondary MODS referred to its emergence after a latent period from the initial insult and likely as a consequence of a maladaptive host response to the injury, most commonly an infectious complication.