Effect of norepinephrine challenge on cardiovascular determinants assessed using a mathematical model in septic shock: a physiological study

Abstract

Background: The present study investigated the cardiovascular determinants of cardiac output (CO), mean systemic filling pressure analogue (Pmsa) derived by Geoffrey Parkin, efficiency of heart (Eh) and related parameters to a norepinephrine (NE) challenge [an increase of 10 mmHg mean arterial pressure (MAP) by NE] in septic shock patients using of a mathematical model.

Methods: Twenty-seven septic shock patients with pulse index continuous cardiac output (PiCCO) monitoring were enrolled. These patients required NE to maintain an individualized MAP for organ perfusion after early fluid resuscitation based on their clinical condition. NE was decreased to obtain a decrease of 10 mmHg from base MAP (MAP_-10mmHg), and the NE doses were adjusted to return MAP to baseline (MAP_base) and produce an increase of 10 mmHg from MAP_base (MAP_+10mmHg). Two NE challenge episodes were analyzed for each patient: from MAP_-10mmHg to MAP_base and from MAP_base to MAP_+10mmHg. The Pmsa, pressure gradient for venous return (PG_vr), and Eh (PGvr relative to Pmsa) were estimated using a mathematical model for the three MAP levels (MAP_-10mmHg, MAP_base and MAP_+10mmHg).

Results: A total of 54 episodes of NE challenges were obtained in 27 patients. Significant and consistent increases were observed in the central venous pressure (CVP), Pmsa, and PGvr in response during the NE titration. ΔCO negatively and significantly correlated with ΔCVP (r=-0.722, P<0.0001), ΔPmsa (r=-0.549, P<0.0001), ΔResistance of venous return (Rvr) (r=-0.597, P<0.0001), and ΔResistance of systemic vascular beds (Rsys) (r=-0.597, P<0.0001). Episodes of decreasing CO/Eh were associated with a higher ΔCVP than the CO/Eh-increasing episodes. The area under the curve (AUC) of ΔCVP to predict decreased CO by the incremental NE was 0.86, and the AUC of ΔCVP to predict decreased Eh was 0.94. A cutoff of ΔCVP >1.5 mmHg for detecting decreased CO resulted in a sensitivity of 75% and a specificity of 94.1%. A cutoff of ΔCVP >1.5 mmHg for detecting decreased Eh resulted in a sensitivity of 64.3% and a specificity of 100%.

Conclusions: There were a highly divergent response in Eh and CO to afterload challenge episodes of an NE-induced 10mmHg increase in MAP. An increase in CVP may be an early alarm to identify the reduction in CO/Eh during an NE-induced increase of MAP.

Keywords: Mean systemic pressure; cardiac efficiency; cardiac output; norepinephrine (NE); septic shock.

Figure 1

Estimated marginal means of CO, MAP, CVP and HR in 27 patients at three MAP levels. *, P<0.05 vs. MAP_−10mmHg; ^†, P<0.05 vs. MAP_base. MAP, mean arterial pressure; CO, cardiac output; CVP, central venous pressure; HR, heart rate.

Figure 2

Estimated marginal means of PGvr, Rvr, Rsys and Eh in 27 patients at three MAP levels. *, P<0.05 vs. MAP_−10mmHg; ^†, P<0.05 vs. MAP_base. PGvr, pressure gradient for venous return; Rvr, resistance of venous return; Rsys, resistance of systemic vasculature; Eh, efficiency of heart; MAP, mean arterial pressure (mmHg).

Figure 3

Linear regression analysis of the relationship between the Δ cardiac output (CO), the Δ heart rate (HR), the Δ central venous pressure (CVP) and the ΔPmsa in the 54 NE challenges. Pmsa, mean systemic pressure of model analog; Eh, efficiency of heart.

Figure 4

ROC curves using ΔCVP to predict CO-reducing and Eh-reducing responses to the increased NE. ROC, receiver operating characteristic; CVP, central venous pressure; CO, cardiac output (L/min); NE, norepinephrine (µg/kg/min); Eh, efficiency of heart; AUC, area under the curve.

Figure 5

Three types for cardiac output (CO) directional changes to a norepinephrine (NE) challenge based on the venous return curve and cardiac function curve. (A) “CO-increasing and efficiency of heart (Eh)-amplifying” response to NE; (B) “CO-little changed and Eh-reducing” response to NE; (C) “CO-decreasing and Eh-reducing” response to NE. The venous return (VR) curve and CO curve were constructed from central venous pressure (CVP), an analog model of mean systemic pressure (Pmsa), and CO. Line “a” indicates the baseline VR curve; line “b” indicates the volume effect of NE-induced generalized venoconstriction on CO; line “c” indicates the additional effect of venoconstriction on resistance to venous return (Rvr); line “d” indicates the baseline cardiac function curve; line “e” indicates the NE-induced impairment of cardiac function curve.