Cardiovascular determinants of resuscitation from sepsis and septic shock

To obtain a statistical power of 0.8 with alpha 0.5 and 95% confidence intervals for the first enrollment were calculated a priori that we would need 42 patients [12]. Thus, we recruited over 50 patients to overcome any a priori un-estimated biases. All data was tested for normality using Shapiro-Wilk analysis, and paired sample t test and Wilcoxon ranked sign test were carried out to assess differences induced by interventions. Independent sample t test for normally distributed data and Mann-Whitney U test for nonparametric measurements were used to test differences between variables grouped by MAP restored (> 65 mmHg), MAP increased, and CI increased at ≥ 15%. Pearson’s correlation analysis was used to find correlation between normally distributed data, Spearman’s correlation was used for nonparametric data, and chi-square test was used to find correlation between categorical data. Receiver operating characteristic analysis was used to test sensitivity and specificity of hemodynamic variables in predicting changes in categorical endpoints. Statistical studies were two-tailed, and p value of less than 0.05 was considered significant. Analyses were performed using SPSS (v23 for Mac, IBM USA). Unless otherwise stated, data are presented as mean ± SD.

Patient features on admission are described in Table 1. All were hypotensive (MAP 56.8 ± 3.1 mmHg) and tachycardic (113.1 ± 7.5 beats min⁻¹), with elevated lactate levels (lactate 5.0 ± 4.2) and had an increase in Ea relative to Ees consistent with ventriculo-arterial uncoupling. CI was variable, but in 74%, CI was > 2 L min⁻¹ M⁻². The mean admission SOFA score was 16.1, and the 30-day mortality rate was 47%. Thirty-day mortality was associated with higher admission lactate, BUN, and creatinine levels, but not with any other measured or derived hemodynamic variables. Specifically, 35 patients resolved their hypotension with VE alone but retained a 44% 30-day mortality rate, whereas those in septic shock had a 52% 30-day mortality rate of which was not significantly different. Additional file 2: Table S1 lists individual patient sepsis etiologies, SOFA and SAP II scores, and maximal doses of norepinephrine and dobutamine given.

Table 2 summarizes the cardiovascular parameters prior to and after the three sequential interventions, and Fig. 2a and b diagrams the associated mean ventriculo-arterial coupling and venous return-LV output changes while Additional file 3: Figure S1-S9 shows individual variables over each step per patient. In all subjects with all treatments, changes in CO co-varied in proportion to changes in Pvr (Fig. 3).

The effects of VE on hemodynamic parameters are reported in Table 3. In all patients, both MAP and CI improved following VE, as well as cardiac contractility (Ees). Regarding Guytonian physiological parameters, fluid administration improved Pra, Pmsa, and Pvr in all patients. Moreover, both HR and Ea decreased, causing VAC to improve toward normal values, thus improving both LVeff and Eh. However, these hemodynamic changes were not uniformly observed across patients. Table 3 shows predefined subgroup analyses for CI and MAP responders and non-responders to each step of the protocol. Additional file 3: Figure S10 and S11 displays the CI responders (increase in CI > 15%) versus non-responders to a VE of 30 mL/kg of crystalloids, NE and dobutamine, respectively; Fig. 4 displays the Ees and Ea lines; and Fig. 5 displays the venous return differences between subgroups of responders and non-responders. CI increased by > 15% in 49 of 55 patients. The CI and MAP increases in response to VE and NE were proportional to the pre-treatment PPV and Ea_dyn values (Additional file 3: Figure S12, S13, S14). As expected, VE-induced CI increases were associated with decreases in both PPV and SVV. Similarly, CI responders had higher baseline Ea_dyn, Ea, and Ees than CI non-responders. Importantly, a VE of 30 mL/kg of crystalloid also increased MAP > 65 mmHg in 35 patients (MAP responders). CI responders > 15% (Fig. 4) increased SV, arterial pressure, and Ees, whereas non-responders only increased LV end-diastolic volume and SV. MAP responders had higher PPV, SVV, and Ea_dyn than MAP non-responders. An Ea_dyn < 0.76 predicted MAP non-responders (Fig. 6), whereas baseline Ea > 1.9 mL mmHg⁻¹ was a weak though also significant predictor of MAP responders. Finally, patients with more normal baseline Ea/Ees had greater increases in CI and MAP. Additional subgroup analyses are given in Additional file 1: Results.

NE was given to the 20 of 55 patients who remained hypotensive post VE. NE increased MAP in 12 patients by 10 ± 2 mmHg and decreased MAP slightly in 8 by 2 ± 2 mmHg. NE was also associated with a decreased HR, PPV, and SVV, while Pra, Ea, Ea_dyn, and Pmsa increased. VAC worsened to decoupled values like those seen at baseline, whereas both Eh and LVeff were unchanged. Those 12 patients in whom MAP increased > 65 mmHg (MAP responders) had higher pre-NE Ees and Ea values and lower HR than the MAP non-responders (Fig. 4c). An Ea_dyn > 0.83 and Ea > 1.75 predicted a MAP increase > 15% (Fig. 6). Not surprisingly, the CI response to NE was also variable, increasing in 5 and minimally decreasing in 4 patients. Interestingly, NE CO responders increased Ees improving VAC whereas non-responders did not (Fig. 4c).

Dobutamine was given to 6 of the 8 patients whose MAP remained hypotensive following NE and VE. Dobutamine increased MAP, CI, and Ees causing VAC and Eh to improve. Both HR and Pra decreased, causing Pvr to increase, whereas neither PPV, SVV, Pmsa, nor LVeff changed. Pre-dobutamine Ea was higher in those whose MAP increased (Ea 2.73 ± 0.12 vs. 2.16 ± 0.37 mL mmHg⁻¹, p = 0.02). Four of the 6 patients increased CO > 15%, and in those patients, Ees improved more than in the other 2 CO non-responders (Fig. 4d).

The study has several limitations. First, we did not personalize resuscitation therapy but used a defined SSG resuscitation protocol. Still, our findings agree with previous studies on VE responders [27] and support the use of dynamic parameters to predict CO and MAP responsiveness to VE [14, 15, 25]. Second, we only measured these cardiovascular variables during the initial 5-h resuscitation interval. Although we hypothesize that these parameters would continue to be predictive of cardiovascular response, other processes might decrease the predictive value of these measures. Still, during the initial rescue phase of septic shock [28], these parameters appear robust. Third, Ea, Ees, and Pmsa were calculated using formulae rather than measuring them directly using more invasive means. Thus, to the extent that the assumptions made to create these measures are inaccurate in severe sepsis, our measurement accuracy will degrade. For example, Ea is highly dependent on heart rate. Still, in our subjects, though tachycardic were unchanged during resuscitation. We doubt that other calculation inaccuracies exist because all these measures have been validated against more definitive measures in animal models of septic shock [29], and in humans during both septic shock [25] and post-cardiopulmonary bypass vasoplegia [30]. End-systolic pressure was estimated as 0.9∙systolic arterial pressure measured at the radial artery. Systolic arterial pressure may be altered in sepsis as the measuring cite moves distal from the aorta. Still, in animal models, the subsequent change in systolic arterial pressure with resuscitation was similar across all measuring sites, meaning that the directional changes in calculated Ees and Ea would remain accurate independent of monitoring loci. Although we calculated Pmsa using formulae based on both CO and Pra [8], the computational components for Pra were an order of magnitude less than the observed changes in Pvr. Furthermore, we validated our Pmsa measures on endotoxic dogs using direct measures of Pms by transient stop flow during step-wise volume infusion and withdrawal, demonstrating an excellent correlation [29]. Furthermore, our Ea and Ees values compare to those of other studies [11, 12, 18]. Finally, we estimated CO and SV using an uncalibrated arterial pressure waveform analysis algorithm (Mostcare®). To the extent that its assumptions become inaccurate during NE and dobutamine infusion, then the accuracy of these data will degrade. However, others have shown that the Mostcare® device follows CO in septic shock patients given NE [31, 32]. Furthermore, as listed in the methods, we checked the accuracy of the Mostcare® CO estimates with echocardiographic estimates at each step and found the two methods consistent.

From the clinical perspective, several points become clear. First, it is impossible to know a priori if a septic patient who presents with hypotension fits the Sepsis-3 criteria for septic shock [33] without first performing VE, as fully two thirds of our patients reversed their hypotension with the initial fluid resuscitation alone. Second, it is not clear if separating patients into either sepsis or septic shock is clinically relevant because the mortality rate in our cohort and their levels of end-organ injury was unaffected by this separation. Third, individualized fluid resuscitation based on the use of dynamic markers of fluid responsiveness allow for both accurate prediction of subsequent absolute change in cardiac output and, if followed continually, the actual changes in cardiac output over time. Fourth, although norepinephrine restores or sustained arterial pressure in septic shock patients, it does so at the expense of the heart, by selectively increasing Ea and decoupling LV ejection power from afterload. Thus, these data argue for limiting use of NE to initially restoring MAP and organ perfusion and then tapering it off once stable.