Capillary refill time prolongation in sepsis and septic shock: supported and potential mechanisms from a pathophysiological perspective

Capillary refill time (CRT) has evolved from a bedside sign into a resuscitation target in septic shock. Although simple to measure, CRT reflects restoration of cutaneous microvascular blood flow after transient external compression and therefore integrates multiple physiological processes. This narrative review proposes a framework for understanding the principal pathophysiological mechanisms that may prolong CRT in sepsis and septic shock. Six non-mutually exclusive mechanisms are considered, broadly ordered according to the strength and directness of the supporting evidence. First, reduced effective tissue perfusion may trigger sympathetically mediated redistribution of blood flow away from the skin through precapillary vasoconstriction and closure of thermoregulatory arteriovenous shunts. Second, inadequate upstream flow generation may result from hypovolemia, ventricular dysfunction, adverse ventriculo-arterial coupling, arrhythmias, or excessive afterload. Third, inflammatory endothelial and microvascular injury may impair reactive hyperemia through glycocalyx degradation, edema, capillary derecruitment, microvascular obstruction, altered hemorheology, and flow heterogeneity. Fourth, loss of coordinated myogenic, neurogenic, and endothelial vasomotor regulation may uncouple systemic pressure from effective capillary recruitment. Fifth, severe vasoplegia may alter the arterial closing-pressure boundary and vascular-waterfall behavior, potentially increasing the pressure dependence of microvascular flow. CRT-specific observational associations support this proposal, but its causal contribution to CRT prolongation remains unproven. Sixth, elevated venous and interstitial pressures could impair microvascular perfusion; their proposed contribution to CRT prolongation remains hypothesis-generating because direct CRT-specific evidence is lacking. These mechanisms may coexist, with their relative contributions varying according to hemodynamic phenotype, disease severity, treatment, and timing of assessment. CRT should therefore be interpreted dynamically and integrated with preload responsiveness, cardiac output, arterial pressure, vasopressor exposure, skin temperature, mottling, venous congestion, and complementary perfusion markers. Responses to controlled hemodynamic interventions may help characterize peripheral perfusion responsiveness, although they cannot, by themselves, establish the underlying mechanism. This framework supports contextual interpretation of CRT and generates testable hypotheses about its prolongation, while distinguishing established physiology and observational associations from unproven causal mechanisms.