Table 3 shows hemoglobin and blood chemistries during hemorrhage and resuscitation. By protocol design, serum hemoglobin remains relatively constant, and all values are within 1 g/dL of each other, although serum hemoglobin was lower at PAOP 10 versus PAOP 5 mm Hg (P = 0.004). Glucose concentrations during the experimental protocol did not change significantly. Venous oxygenation increased from hemorrhage to PAOP 5 (P < 0.0005), but thereafter did not change. Ionized calcium remains constant throughout the experimental procedure. Serum pH increased from hemorrhage to PAOP 5 (P = 0.002), thereafter did not change.
We found that, with progressive fluid volume administration in hemorrhaged animals, the slope of rise in RAP exceeds the slope of rise in PVP, causing the net pressure gradient for venous return to decrease. LV diastolic compliance, as reflected by mitral valve E/e′ and E/A ratios, changes significantly, which indicates the onset of impaired LV relaxation and reduced myocardial compliance (diastolic dysfunction) during fluid resuscitation, particularly in nonresponders. Accordingly, IVC blood flow fails to sequentially improve after PAOP 10 mm Hg. There is a significant curvilinear relationship between PVP and SVV, suggesting that the measurement of PVP may be a useful static index to predict fluid responsiveness. All fluid responders have PVP < 15 mm Hg.
The curvilinearity of the traditional Starling relationship comparing SV with LV end-diastolic pressure (LVEDP) has been used to define and predict a patient’s response to volume administration.3,21,22 Responders are thought to be functioning on the steep portion of this curve, where SV increases more than LVEDP after a fluid challenge. In contrast, nonresponders are thought to function on the flatter plateau portion of the curve, where filling pressure increases more than SV after parenteral volume expansion. Data from this study confirm this concept as seen in Figure 1.
If, however, SV is plotted against left ventricular end-diastolic volume (LVEDV) instead of LVEDP, the relationship appears linear in normal patients,23,24 as well as in patients with dilated cardiomyopathy,25,26 and may reflect recruitment of unaligned sarcomeres with greater LVEDV and stretch-induced calcium activation of myocytes.25,27 Our data support these findings with the linearity of the SV-LV EDD relationship and equal distribution of fluid responders and nonresponders (Fig. 2). These findings suggest that SV should improve in every patient after a fluid challenge if LVEDV increases. However, in practice, fluid responsiveness to a volume challenge is found in only 50% of patients.21,28 Consequently, other factors need to be considered to interpret these findings.
The curvilinearity of the SV-LVEDP relationship can be explained by the curvilinearity of the diastolic LVEDP-LVEDV relationship,23,24 which indicates that myocardial diastolic compliance may be instrumental in determining fluid responsiveness. The lower flat portion of the diastolic compliance curve represents sarcomere stretch with filling, whereas the steep upper portion reflects imposed restraining influences from the pericardium, cardiac cytoskeleton, and intramyocardial collagen.2,11,13 Because of this configuration, filling pressure in the heart during fluid resuscitation could rise more than PVP, thereby decreasing the pressure gradient for venous return. Data from the current study confirm this concept, as the position on the diastolic compliance curve shifts rightward with fluid resuscitation (Fig. 3) with progressively impaired relaxation causing the pressure gradient for venous return to decrease (Fig. 4). Most fluid responders are located on the lower portion of the diastolic compliance curve, whereas nonresponders are centered on the steep upper portion of the curve (Fig. 3). Furthermore, our results agree with other studies in which large amounts of infused fluid restricted diastolic filling of the heart and reduced LV compliance.18 Consequently, the hemodynamic response to volume administration not only represents systolic function, as determined by the position on the traditional Starling function curve (Fig. 1), but also whether the administered fluid is actually translocated to the heart during diastole to increase end-diastolic volume.
These data are consistent with the concept of imposed pericardial restraint during fluid administration. It is known that the pericardium causes an upward shift in the diastolic compliance curve of the heart and, with volume expansion, the pericardium contributes to elevated diastolic pressures and limits cardiac filling of both ventricles.11–13 Our measurements of E/A and E/e′ during fluid resuscitation indicate that the onset of impaired LV relaxation with pseudonormalization and reduced diastolic compliance occurs during fluid resuscitation from hemorrhagic shock within clinically accepted end points of therapy. Consequently, the slope of RAP change is greater than the slope of PVP change with higher filling pressures. Furthermore, our data are compatible with and help interpret the reported findings of Kumar et al.,29,30 where normovolemic volunteers received 3 L of IV saline. In those studies, SV increased not by an increase in LVEDV but from hypervolemic hemodilution with an accompanying reduction in left ventricular end-systolic volume. The crystalloid infusion caused significant reductions in hematocrit, viscosity, and SVR but failed to increase cardiac filling, presumably because of a reduction in diastolic ventricular compliance. Although our data support the concept of progressive pericardial restraint during fluid resuscitation, a definitive study will require direct measurement of pericardial pressure.
After a significant increase in heart rate with hemorrhage, heart rate remained stable throughout the resuscitation period (Table 2). Because heart rate inversely affects right ventricular filling,31 any confounding effect from tachycardia on SV was minimized. Despite a progressive reduction in the venous return filling pressure gradient with fluid volume expansion, IVC blood flow continues a trend to increase, which may represent a progressive reduction in the resistance to venous return throughout volume resuscitation. Multiple factors affect venous return other than the filling pressure gradient, including sympathetic activation which, although not directly affecting venous compliance, may reduce the unstressed venous capacitance causing an increase in blood volume.2,3,5 During resuscitation, part of the administered fluid may redistribute within the splanchnic venous bed from the stressed volume to replenish the unstressed volume. Last, blood viscosity can affect venous resistance.3 In our study, we minimized any effect of hemodilution and reduced viscosity by alternating albumin with whole blood or albumin mixed with high-hematocrit blood collected from spleen.
In laboratory and clinical studies, dynamic indices have repeatedly proven to be better predictors of fluid volume responsiveness than static indices, such as filling pressures.28 Static central filling pressures such RAP and PAOP reflect end-diastolic volumes of the heart, as well as unquantifiable influences from myocardial compliance. However, dynamic indices reflect the heart-lung interactions occurring during positive pressure ventilation, causing preload-afterload mismatch in the right ventricle. Our data indicate that PVP may represent a sensitive static index of preload responsiveness during fluid resuscitation of hemorrhagic shock. With the inherent limitations imposed on the acquisition and interpretation of dynamic indices,32 the measurement of PVP may be simpler and applicable in other cases where the use of dynamic indices is limited such as during spontaneous ventilation.
There are several limitations to the present study that require further discussion. Strictly speaking, the net pressure gradient for venous return equals RAP – mean circulatory filling pressure (MCFP), where the latter is the pressure in the venous system during circulatory standstill at zero blood flow and determined by the stressed venous volume. Because of inherent complexities obtaining the MCFP measurement at repeated intervals in an intact animal, we substituted PVP for MCFP, and baseline values of PVP in our animals appear comparable with the MCFP values reported in other studies.1,3,33 Next, we did not directly measure pericardial pressure, and a definitive study would require this measurement in addition to opening the chest and pericardium after fluid resuscitation to conclusively demonstrate pericardial restraint. However, the steep portion of the diastolic compliance curve has already been shown to be significantly influenced by an intact pericardium,11 and all fluid nonresponders in this study were located on this steep portion (Fig. 3). This was a carefully conducted, well-controlled, study in healthy normal animals with normal diastolic compliance, which could explain the high AUC obtained by our ROC curves for PVP, SVV, and PAOP. Our data need to be validated in patients with and without diastolic dysfunction. The presence of diastolic dysfunction may cause greater filling pressures in response to fluid infusion than normal patients,34 which could significantly affect the patient’s response to fluid administration. We also measured left- and right-sided pressures and LV diameters but did not quantify intracardiac volumes. Although LVEDD can accurately approximate LVEDV assessed by more invasive means,35 we used transthoracic echocardiography so as not to alter chest wall or pericardial integrity. Volumetric studies of the heart at elevated pericardial pressures show that the atria increase in size more than the ventricles during fluid administration,36 which could account for a further increase in end-diastolic pressure without an increase in LVEDV and SV. Finally, we did not examine the venous pressure waveform during the venous filling phase, such as venous pulse pressure and slope, which could provide further insight into venous capacitance and compliance.37
In conclusion, with progressive fluid resuscitation in hemorrhaged animals, the slope of rise in RAP exceeds the slope of rise in PVP causing the venous return pressure gradient to decrease. Accordingly, IVC blood flow increases with the initial fluid bolus after hemorrhage but fails to sequentially improve when PAOP exceeds 10 mm Hg. There is a significant curvilinear relationship between PVP and SVV, suggesting that the measurement of PVP may be a useful static index to predict fluid responsiveness. Significant changes in LV diastolic compliance, as reflected by mitral valve E/e′ and E/A ratios, indicate the onset of impaired relaxation and pseudonormalization during fluid resuscitation. These data indicate that the hemodynamic response to fluid administration during resuscitation from hemorrhagic shock can be significantly influenced by the diastolic properties of the heart and whether the fluid is actually translocated from the periphery to increase end-diastolic volume. Diastolic properties of the heart may limit the systolic response to fluid administration after hypovolemic shock, and greater emphasis should be placed on the clinical assessment of diastolic function during resuscitation.
Name: Michael Kinsky, MD.
Contribution: This author helped design, develop, and conduct the study; acquire, collect, and analyze the data; and prepare the manuscript.
Attestation: Michael Kinsky attests to having approved the final manuscript and level of participation and also attests to having reviewed the original study data and data analysis, and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Nicole Ribeiro, MD.
Contribution: This author participated in the study and analyzed the data.
Attestation: Nicole Ribeiro attests to this level of participation.
Name: Maxime Cannesson, MD, PhD.
Contribution: This author analyzed and interpreted the data.
Attestation: Maxime Cannesson attests to this level of participation.
Name: Donald Deyo, DVM.
Contribution: This author helped develop the study and participated in the study.
Attestation: Donald Deyo attests to this level of participation.
Name: George Kramer, PhD.
Contribution: This author helped develop the study and interpret the data.
Attestation: George Kramer attests to this level of participation.
Name: Michael Salter, MS.
Contribution: This author helped participate in study and analyze the data.
Attestation: Michael Salter attests to this level of participation.
Name: Muzna Khan, MS, RT.
Contribution: This author helped participate in study and analyze the data.
Attestation: Muzna Khan attests to this level of participation.
Name: Hyunsu Ju, PhD.
Contribution: This author helped participate in study and analyze the statistics.
Attestation: Hyunsu Ju attests to this level of participation.
Name: William E. Johnston, MD.
Contribution: This author helped design and develop the study; analyze and interpret the data; and prepare the manuscript.
Attestation: William E. Johnston attests to having approved the final manuscript and level of participation, also attests to having reviewed the original study data, data analysis, and attests to the integrity of the original data and the analysis reported in this manuscript.
Dr. Maxime Cannesson is the Section Editor for Technology, Computing and Simulation for Anesthesia & Analgesia. This manuscript was handled by Dr. Steven L. Shafer, Editor-in-Chief, and Dr. Cannesson was not involved in any way with the editorial process or decision.
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© 2016 International Anesthesia Research Society
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