Physiologic cardiovascular studies in resuscitated normotensive septic shock with persistent hyperlactatemia.

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.

Comparison of mean systemic pressure in patients with acute circulatory failure receiving passive leg raising vs. pneumatic leg compression

Background: Driving pressure of venous return (VR) is determined by a pressure gradient between mean systemic pressure (Pms) and central venous pressure (CVP). While passive leg raising (PLR) and pneumatic leg compression PC (PC) can increase VR, no study has explored the effects of these two procedures on Pms and VR-related hemodynamic variables. Methods: Forty patients with acute circulatory failure were enrolled in this analysis. All patients obtained both PLR and PC, and were measured for Pms, CVP, mean arterial pressure (MAP), cardiac output (CO), VR resistance (RVR), and systemic vascular resistance (SVR) at baseline and immediately after procedures. To minimize carry over effect, the patients were divided in 2 groups based on procedure sequence which were 1) patients receiving PLR first then PC (PLR-first), and 2) patients receiving PC first then PLR (PC-first). Both groups waited for a washout period before performing the 2 second procedure. Primary outcome was difference in Pms between PLR and PC procedures. Secondary outcome were differences in CVP, MAP, CO, RVR, and SVR between PLR and PC procedures. Results: No difference was found in baseline characteristics and no carry over effect was observed between the 2 groups of patients. Compared with baseline, both PLR and PC significantly increased Pms, CVP, MAP, and CO. PLR increased Pms (9.0±2.3 vs 4.8±1.7 mmHg, p<0.001), CVP (4.5±1.2 vs. 1.6±0.7 mmHg, p<0.001), MAP (22.5±5.6 vs. 14.4±5.0 mmHg, p<0.001), and CO (1.5±0.5 vs. 0.5±0.2 L/min, p<0.001) more than PC. However, PC, also significantly increased RVR (16 ± 27.2 dyn.s/cm5, p=0.001) and SVR (78.4 ± 7.2 dyn.s/cm5, p<0.001) but no difference in PLR group. Conclusion: Among patients with acute circulatory failure, PLR increased Pms, CVP, MAP, and CO more than PC.

Comparison of mean systemic pressure in patients with acute circulatory failure receiving passive leg raising vs. pneumatic leg compression

Background: Driving pressure of venous return (VR) is determined by a pressure gradient between mean systemic pressure (Pms) and central venous pressure (CVP). While passive leg raising (PLR) and pneumatic leg compression PC (PC) can increase VR, no study has explored the effects of these two procedures on Pms and VR-related hemodynamic variables. Methods: Forty patients with acute circulatory failure were enrolled in this analysis. All patients obtained both PLR and PC, and were measured for Pms, CVP, mean arterial pressure (MAP), cardiac output (CO), VR resistance (RVR), and systemic vascular resistance (SVR) at baseline and immediately after procedures. To minimize carry over effect, the patients were divided in 2 groups based on procedure sequence which were 1) patients receiving PLR first then PC (PLR-first), and 2) patients receiving PC first then PLR (PC-first). Both groups waited for a washout period before performing the 2 second procedure. Primary outcome was difference in Pms between PLR and PC procedures. Secondary outcome were differences in CVP, MAP, CO, RVR, and SVR between PLR and PC procedures. Results: No difference was found in baseline characteristics and no carry over effect was observed between the 2 groups of patients. Compared with baseline, both PLR and PC significantly increased Pms, CVP, MAP, and CO. PLR increased Pms (9.0±2.3 vs 4.8±1.7 mmHg, p<0.001), CVP (4.5±1.2 vs. 1.6±0.7 mmHg, p<0.001), MAP (22.5±5.6 vs. 14.4±5.0 mmHg, p<0.001), and CO (1.5±0.5 vs. 0.5±0.2 L/min, p<0.001) more than PC. However, PC, also significantly increased RVR (16 ± 27.2 dyn.s/cm5, p=0.001) and SVR (78.4 ± 7.2 dyn.s/cm5, p<0.001) but no difference in PLR group. Conclusion: Among patients with acute circulatory failure, PLR increased Pms, CVP, MAP, and CO more than PC.

Norepinephrine potentiates the efficacy of volume expansion on mean systemic pressure in septic shock

Background Through venous contraction, norepinephrine (NE) increases stressed blood volume and mean systemic pressure (Pms) and exerts a “fluid-like” effect. When both fluid and NE are administered, Pms may not only result from the sum of the effects of both drugs. Indeed, norepinephrine may enhance the effects of volume expansion: because fluid dilutes into a more constricted, smaller, venous network, fluid may increase Pms to a larger extent at a higher than at a lower dose of NE. We tested this hypothesis, by mimicking the effects of fluid by passive leg raising (PLR). Methods In 30 septic shock patients, norepinephrine was decreased to reach a predefined target of mean arterial pressure (65–70 mmHg by default, 80–85 mmHg in previously hypertensive patients). We measured the PLR-induced increase in Pms (heart–lung interactions method) under high and low doses of norepinephrine. Preload responsiveness was defined by a PLR-induced increase in cardiac index ≥ 10%. Results Norepinephrine was decreased from 0.32 [0.18–0.62] to 0.26 [0.13–0.50] µg/kg/min (p < 0.0001). This significantly decreased the mean arterial pressure by 10 [7–20]% and Pms by 9 [4–19]%. The increase in Pms (∆Pms) induced by PLR was 13 [9–19]% at the higher dose of norepinephrine and 11 [6–16]% at the lower dose (p < 0.0001). Pms reached during PLR at the high dose of NE was higher than expected by the sum of Pms at baseline at low dose, ∆Pms induced by changing the norepinephrine dose and ∆Pms induced by PLR at low dose of NE (35.6 [11.2] mmHg vs. 33.6 [10.9] mmHg, respectively, p < 0.01). The number of preload responders was 8 (27%) at the high dose of NE and 15 (50%) at the low dose. Conclusions Norepinephrine enhances the Pms increase induced by PLR. These results suggest that a bolus of fluid of the same volume has a greater haemodynamic effect at a high dose than at a low dose of norepinephrine during septic shock.

Physiologic Cardiovascular Studies in Resuscitated Normotensive Septic Shock with Persistent Hyperlactatemia.

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.

Comparison of Mean Systemic Pressure in Patients with Acute Circulatory Failure Receiving Passive Leg Raising vs. Pneumatic Leg Compression.

Background: Driving pressure of venous return (VR) is determined by mean systemic pressure (Pms) and central venous pressure (CVP). While passive leg raising (PLR) and pneumatic leg compression PC (PC) can increase VR, there is no study explore the effects of these two procedures on Pms and VR-related hemodynamic variables.Methods: Forty patients with acute circulatory failure were included in this analysis. All patients were performed both PLR and PC, and were measured for Pms, CVP, mean arterial pressure (MAP), cardiac output (CO), VR resistance (RVR), and systemic vascular resistance (SVR) at baseline and immediately after procedures. To minimized carry-on effect, the patients were divided into 2 groups based on procedure sequence which were 1) the patients who received PLR first then PC (PLR-first), and 2) the patients who received PC first then PLR (PC-first). Both groups were waited for washing period before performed 2nd procedure. Primary outcome was difference in Pms between PLR and PC procedure. Secondary outcome were differences in CVP, MAP, CO, RVR, and SVR between PLR and PC procedure.Results: There was no difference in baseline characteristics and no carry-on effect between 2 groups of patients. Compared to baseline, both PLR and PC significantly increased Pms, CVP, MAP, and CO. Compared to PC, PLR more increased Pms (9.0±2.3 vs 4.8±1.7 mmHg, p<0.001), CVP (4.5±1.2 vs. 1.6±0.7 mmHg, p<0.001), MAP (22.5±5.6 vs. 14.4±5.0 mmHg, p<0.001), and CO (1.5±0.5 vs. 0.5±0.2 L/min, p<0.001). PC, but not PLR also significantly increased RVR (16 ± 27.2 dyn.s/cm5, p=0.001) and SVR (78.4 ± 7.2 dyn.s/cm5, p<0.001) .Conclusion: In patients with acute circulatory failure, PLR more increased Pms, CVP, MAP, and CO than PC.

The Guytonian Equation: Established Physiological Law?

The present collection of papers is meant to focus on old and new concepts about venous return. This essay argues that one widely held old concept is wrong. The misconception would be perpetuated by those who speak of “repurposing the systemic venous return model”. The model in question describes systemic venous return as driven through a “resistance to venous return” in proportion to the difference between mean systemic pressure and right atrial pressure. It arose from experiments in which right atrial pressure (Pra) was recorded while flow was forced through the peripheral vasculature by a pump, with data points taken after pressures equilibrated to each new level of flow. The steady-state flow (F) set by the pump could be taken interchangeably as cardiac output (CO) or venous return (VR). Pra at the zero-flow level settled at what is defined as “mean systemic pressure” (Pms), understood as the pressure at which all the elastic segments of the peripheral vasculature equilibrate in the absence of pressure differences associated with flow. Total circulating volume was kept constant, independent of flow level. The data were approximated by the equation Pra = Pms – F*RVR, alternatively written as F = (Pms – Pra)/RVR. From the point of view of the first formulation, we see Pra falling in proportion to F, starting from Pms at zero flow, a concise statement of the actual experimental procedure and findings. The second formulation has been seen from a different perspective; that F is proportional to the net driving pressure, i.e., (Pms – Pra), in which Pra is seen as a back pressure opposing venous return. From this point of view, adopted by a leading researcher of his time, A.C. Guyton, comes the idea that, to increase VR, the heart must somehow reduce Pra. Re-examining the model that Guyton and his coworkers developed reveals that the appearance of Pms in their equation does not identify this variable as a pressure that exists physically at the upstream end of the pathway for venous return. At best, the model offers a way of looking at the factors that determine the equilibrium between the Pra that results in the peripheral vasculature at a particular steady-state level of flow that is consistent with the influence of Pra on the output of the heart. It has nothing to offer for the advancement of understanding of the pathophysiology of real, dynamic flow within vascular segments.

Venous return and the physical connection between distribution of segmental pressures and volumes

More than sixty years ago, Guyton and coworkers related their observations of venous return to a mathematical model. Showing steady-state flow (F) as proportional to the difference between mean systemic pressure (Pms) and right atrial pressure (Pra), the model fit their data. The parameter defined by the ratio (Pms − Pra)/F, first called an “impedance,” came to be called the “resistance to venous return.” The interpretation that Pra opposes Pms and that, to increase output, the heart must act to reduce back pressure at the right atrium was widely accepted. Today, the perceived importance of Pms is evident in the efforts to find reliable ways to estimate it in patients. This article reviews concepts about venous return, criticizing some as inconsistent with elementary physical principles. After review of basic background topics—the steady-state vascular compliance; stressed versus unstressed volume—simulations from a multicompartment model based on data and definitions from Rothe’s classical review of the venous system are presented. They illustrate the obligatory connection between flow-dependent compartment pressures and the distribution of volume among vascular compartments. An appendix shows that the pressure profile can be expressed either as decrements relative to arterial pressure or as increments relative to Pra (the option taken in the original model). Conclusion: The (Pms − Pra)/F formulation was never about Pms physically driving venous return; it was about how intravascular volume distributes among compliant compartments in accordance with their flow-dependent distending pressures, arbitrarily expressed relative to Pra rather than arterial pressure.