Focus on host/organ unregulated response: a common cause of critical illness

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TL;DR

This article proposes that critical illness, regardless of the initial trigger (infection, trauma, cardiac arrest), converges on a common pathway termed the host/organ unregulated response (HOUR). The authors argue that a dysregulated host response, rather than the initial disease itself, is the primary driver of organ dysfunction and death. They advocate for therapeutic strategies that modulate HOUR rather than targeting the initiating cause alone, though they acknowledge that such management is not yet established in routine practice.

Full summary

3,379 CHARS

**Background:** Critical illnesses are highly heterogeneous in their initiating causes (e.g., infection, trauma, heart attack) but share a relatively homogeneous underlying pathophysiology. The authors introduce the concept of the host/organ unregulated response (HOUR) as a common co-pathophysiology that drives progression to critical illness. They propose a four-stage model of critical illness: pre-disease (chronic comorbidities, age, immunosuppression), initiating causes (acute injury or illness), common cause-HOUR (dysregulated host response as the 'second hit'), and critical illness (life-threatening organ dysfunction).

**Methods:** This is a narrative review and opinion piece. The authors synthesize existing literature on the pathophysiology of critical illness, focusing on the host response to various insults. They describe three categories of initiating causes: infective causes (e.g., sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection), non-infective causes (e.g., trauma, pancreatitis, where damage-associated molecular patterns [DAMPs] trigger inflammation), and traumatic brain injury (TBI), which directly insults the central nervous system and activates neural, hormonal, and immune responses from the outset.

**Key Results:** The authors identify several shared downstream pathways of HOUR. The stress response, mediated by the neuroendocrine system, plays a central role. Cytokine release syndrome (CRS) is described as a common pathway of immune and inflammatory responses that can induce secondary organ dysfunction (renal, hepatic, pulmonary). Mitochondria are identified as the 'final effector' in the host/organ response, generating ATP and performing cell signaling and death pathway activation. Endothelial dysfunction, including glycocalyx shedding, tight junction breakdown, capillary leakage, and procoagulant microvasculature, is another shared consequence. The authors note that clinical manifestations are diverse (e.g., cardiovascular with vasoplegia, acute respiratory distress syndrome [ARDS]) depending on the predominant phenotypic feature and final target organs.

**Clinical Implications:** The authors argue that therapeutic options remain restricted and that management of HOUR warrants greater attention. They recommend therapeutic principles based on recognition of HOUR, including: sedation and analgesia to attenuate stress response (opioids, NSAIDs, midazolam, propofol, dexmedetomidine, ketamine); antisympathetic drugs (beta-blockers, dexmedetomidine); anti-immune and anti-inflammatory therapies (citing studies in children with COVID-19 as beneficial); blood purification with adsorption for cytokine storm or endotoxin activity; targeted temperature management as the only recommended neuroprotective intervention after out-of-hospital cardiac arrest (per international guidelines); nutrition support, noting that high-calorie delivery in ARDS patients with high organ failure rates is associated with increased mortality; and mitochondrial-targeted antioxidants and agents that induce mitochondrial biogenesis or mitophagy as emerging therapies. The authors caution that interventions have both therapeutic and re-injury effects, and that identifying the optimal timepoint for intervention that does not interrupt the adaptive host response remains a challenge.