Background: To study effects of increasing vasopressor dosage and fluid resuscitation on ventriculoarterial (VA) coupling and venous return (VR)-related parameters in resuscitated normotensive septic shock patients with persistent hyperlactatemia. Methods: We performed a prospective experimental study in patients with septic shock who was admitted to medical intensive care unit and still had hyperlactatemia even received initial resuscitation to maintain mean arterial pressure (MAP) >65 mmHg. All patients received incremental dose of norepinephrine (NE) to increased MAP, then NE was titrated to baseline dosage and waited for 15 mins, then fluid bolus was given. VA coupling-related parameters [arterial elastance (Ea), left ventricular end-systolic elastance (Ees), left ventricular stroke work (SW), potential energy (PE), stroke volume (SV), and Ea/Ees], and VR-related parameters [central venous pressure (CVP), mean systemic pressure analogue (Pmsa), venous return pressure (Pvr)] were measured at 4 time points including pre-increased NE phase, post-increased NE phase, pre-fluid bolus phase, and post-fluid bolus phase. Primary outcome was average of Ea/Ees. Secondary outcomes were differences in VA coupling-related parameters and VR-related parameters between pre- vs. post- interventions.Results: All 20 patients were normotensive [MAP 74 (66-80) mmHg] with elevated blood lactate [2.7 (2.4-3.6) mmol/L] at enrollment. Average Ea/Ees was 0.89 (0.61-1.16). Compared to pre-increased NE phase, post-increased NE phase had significantly higher MAP, CVP, SV, SW, PE, Pmsa, and Pvr. Likewise, compared to pre-fluid bolus phase, post-fluid bolus raised MAP, CVP, SV, Ees, SW, Pmsa, and Pvr significantly. No difference in Ea/Ees compared between before- vs. after- received both interventions.Conclusions: In resuscitated normotensive septic shock patients with persistent hyperlactatemia, we found an average Ea/Ees of 0.89. Increasing NE dosage or fluid bolus increased most of VA coupling-related parameters and VR-related parameters, but not Ea/Ees. Further large study is warranted to validate these findings.