The usual suspects: a pragmatic framework to identify and address reversible contributors in apparent refractory septic shock

BACKGROUND: A subset of patients with septic shock remains hypoperfused or requires escalating vasopressor support despite initial resuscitation. Although this pattern may suggest progression toward refractory septic shock, early high vasopressor requirements or persistent hypoperfusion may still reflect potentially modifiable contributors, including unresolved infection, inadequate fluid administration, metabolic derangements, iatrogenic factors, or cardiac dysfunction. The recent SCCM/ESICM consensus provides expert-derived criteria for refractory septic shock, but the preceding bedside process of reassessing potentially reversible contributors remains less explicitly operationalized. MAIN BODY: This Perspective proposes a pragmatic framework for structured reassessment in apparent refractory septic shock. Refractoriness is approached as a multidimensional construct shaped by severity, time in shock, and prior optimization, in line with current consensus criteria. To operationalize the optimization dimension, we present the "usual suspects": a parallel, hypothesis-driven bedside reassessment of potentially reversible contributors during an apparent-refractory trajectory. Antimicrobial adequacy and source-control status provide the foundational substrate. In parallel, clinicians may reassess fluid responsiveness, tolerance, and efficiency; endocrine, metabolic, and iatrogenic contributors to vasoplegia, such as acidemia and sedation burden; and cardiac mechanisms, including ventricular performance, ventriculo-arterial coupling, and dynamic left ventricular outflow tract obstruction. The relative contribution of each domain is expected to vary across patients and over time, requiring reassessment guided by the dominant physiology rather than by a fixed sequence. CONCLUSIONS: This framework is intended as an operational companion to current consensus definitions of refractory septic shock. By organizing the bedside evaluation of potentially reversible contributors, it may help clinicians interpret persistent hypoperfusion and vasopressor escalation during the transition from apparent to established refractoriness.