Organ Failure Remains an Unmet Global Challenge
Each year, more than 20 million people with organ failure (OF) are admitted to intensive care units around the world.1 With a 30% mortality rate, it remains the leading cause of death in intensive care units. OF is preceded by 2 syndromes, the systemic inflammatory response (SIRS) and multiple organ dysfunction (MODS), which can progress throughout days or weeks to single or multiple OF and death.2 This patterned sequence is the feared sequelae of many inciting acute and critical diseases (ACDs), which include severe sepsis, hemorrhage, trauma, burns, acute pancreatitis, and most recently, SARS-CoV-2 infection.3 The heart, lung, and kidney organ systems are most at risk of failing. The failure to translate multiple putative drug treatments to arrest OF is well documented.2 Current treatment standards for SIRS/MODS/OF are generic, including fluid resuscitation, inotropes, mechanical ventilation, and kidney replacement therapy. While optimizing physiology is a worthy goal,3 there is an urgent need for a new paradigm to introduce effective treatment strategies that go beyond organ support to target specific disease mechanisms to mitigate SIRS/MODS/OF and the risk of death.
The Gut-Lymph Model Is an Overlooked Treatment Paradigm for OF
The gut is acknowledged to be a major contributor to the pathogenesis of SIRS/MODS/OF.4,5 However, the various models that seek to explain its precise role have not yet provided the basis for effective treatments.2 This is also true for the gut-lymph model, which has been largely overlooked2 because no translational pathway has been forged. However, that is changing and there is a growing awareness that the lymph, and particularly the gut lymph, plays a critical role in homeostasis and the pathophysiology of many diseases.6 The gut-lymph model4 gives a treatment paradigm for SIRS/MODS/OF that is well placed for clinical translation (Figure).5 In health, the gut lymph transports fluid, lipids, protein, immune cells, hormones, and macromolecules from the intestines to the systemic circulation and plays an essential role in immune surveillance, lipid absorption, and fluid balance.6 In ACDs, reflex splanchnic vasoconstriction directs blood flow away from abdominal to vital organs. The resulting ischemia injures the gut wall, resulting in production of inflammatory and toxic factors and increased gut permeability to allow translocation of these factors. While small molecules are typically taken up by the portal venous system draining to the liver, larger molecules are preferentially taken up by the mesenteric lymphatics that coalesce at the cisterna chyli to become the thoracic lymph duct, which ascends through the chest.6,7 This pathway bypasses the liver and detoxification as thoracic lymph enters the systemic circulation directly in the left neck. Gut lymph can contribute up to two-thirds of the total thoracic duct lymph flow. Importantly, thoracic duct lymph enters the systemic circulation immediately upstream of the organs that fail most often in ACDs (ie, heart and lungs) before widespread distribution to other vulnerable organs (eg, kidney and liver).