High Central Venous Pressure and Right Ventricle Size are Related to Increased Stroke Volume to Negative Fluid Balance in Critically Ill Patients

Background This study aimed to determine whether a negative uid balance can increase stroke volume (SV) and the relationship between changes in hemodynamics variables. This prospective study included patients with high central venous pressure (CVP) ( ≥ 8 mmHg) treated in the Critical Medicine Department of Peking Union Medical College Hospital. Patients were classied into two groups based on their right to left ventricle diastolic dimension (RV D /LV D ) ratio using a cutoff value of 0.6. The hemodynamic and echo parameters of the two groups were recorded at baseline and after negative uid balance.


Abstract Background
This study aimed to determine whether a negative uid balance can increase stroke volume (SV) and the relationship between changes in hemodynamics variables.

Methods
This prospective study included patients with high central venous pressure (CVP) (≥8 mmHg) treated in the Critical Medicine Department of Peking Union Medical College Hospital. Patients were classi ed into two groups based on their right to left ventricle diastolic dimension (RV D /LV D ) ratio using a cutoff value of 0.6. The hemodynamic and echo parameters of the two groups were recorded at baseline and after negative uid balance.

Results
This study included 71 patients: 35 in Group 1 (RV D /LV D ≥ 0.6) and 36 in Group 2 (RV D /LV D <0.6). Of all patients, 56.3% showed increased SV after negative uid balance. Cox logistic regression analysis suggested that a high CVP and RV D /LV D ratio were signi cant independent risk factors for SV increase after negative uid balance in critically patients without underlying cardiac disease. The AUC of CVP was 0.894. A CVP> 10.5 mmHg provided a sensitivity of 87.5% and a speci city of 77.4%. The AUC of CVP combined with the RV D /LV D ratio was 0.926 ,which provided a sensitivity of 92.6% and a speci city of 80.4%.

Conclusion
High CVP and RV D /LV D ratio were identi ed as independent risk factors for RV volume overload in critically patients without underlying cardiac disease. A reduced intravascular volume may increase SV for these patients.

Background
In the management of hemodynamic instability, optimal adjustment of cardiac preload is essential for improving stroke volume (SV) and tissue perfusion. Fluid management in critical patients is crucial for prognosis, as both inadequate uid or uid overload can lead to negative outcomes [2]. In particular, uid overload and high CVP are associated with poor outcomes [3]. Traditionally, uid responsiveness is de ned as the ability of the left ventricle (LV) to increase SV by 10-15% in response to uid infusion [4].
However, we found that negative uid balance can also increase SV under certain conditions in clinical practice. This is because the left and right ventricles (RV) are interdependent and interactive; thus, a change in volume and pressure load or a change in myocardial stiffness and contractility on one side may affect the ventricle on the other side [5]. Several studies have reported that uid overload can increase RV size [6]. RV size is known to modify the response to uid challenge, such that higher RV dilatation is associated with a lower likelihood of uid responsiveness. If RV size further increases and the right to left ventricular end-diastolic dimensions (RV D /LV D ) ratio is ≥ 0.6, the ventricular septum and pericardium may lead to a signi cant decrease in LV end-diastolic area and SV.
According to the understanding of uid responsiveness, assessing the lling state of the RV is key to judging the volume status. However, evaluation of the lling state remains a challenge. Dynamic monitoring of right end-diastolic pressure and assessment of RV size via echocardiography are currently used as indices of RV lling state [7][8][9][10]. However, it is unknown whether a negative uid balance can increase SV in patients with high CVP. Furthermore, the relationship between hemodynamic parameters and therapy outcomes are unclear. In the present study, we use our clinical database to address these questions.

Study design and patient enrollment
The primary aim of this study was to evaluate the relationship between hemodynamic parameters and VTI changes after negative uid management in patients with high CVP. The study was designed as a prospective observational cohort study. All patients with abnormally high CVP (i.e., outside the normal range of 0-7 mmHg) treated at the Critical Medicine Department of Peking Union Medical College Hospital from May 2017 to October 2017 were included in the study sample. This study was approved by the ethics committee of Peking Union Medical College Hospital (S-617) and written informed consent was provided by the next of kin of all participants.

Inclusion and exclusion criteria
The inclusion criteria were (i) CVP ≥ 8 mmHg and (ii) age > 18 years. The exclusion criteria were (i) noncurative goals of therapy, (ii) a history of cardiac disease, and (iii) pulmonary hypertension or precaval malformations. Patients were divided into two groups according to RV D /LV D ratio: Group 1 comprised patients exhibiting RV dilatation (RV D /LV D ratio ≥ 0.6) and Group 2 comprised patients without RV dilatation (RV/LV ratio < 0.6).

Study protocol
All patients were treated as follows: (1) All enrolled patients underwent the routine procedures of the Critical Care Department of Peking Union Medical College Hospital. Arterial and venous lines were inserted. Time 0(T0)was recorded at ICU admission, and T1 was recorded after a negative uid balance of 500 mL within 30-60 minutes. Central venous and arterial blood gases analysis were performed at T0 and T1.
(2) Critical ultrasound was also performed at T0 and T1 by competent attending physicians or fellows using an ultrasound system equipped with an array probe(X-Porte,Sonosite, Bothell WA USA). At least ve standard views (acoustic windows) were obtained and recorded for each scan: parasternal long axis, parasternal short axis, apical four-chamber, subcostal, and inferior vena cava (IVC). The following parameters were analyzed Figure 1 : RV D /LV D ratio, tricuspid annular plane systolic excursion (TAPSE), diameter of the inferior vena cava (DIVC), left ventricular eject fraction (LVEF), and left ventricular stroke volume (LVSV). LVSV was calculated by combining the averaged left ventricular out ow tract velocity time integral (LVOT VTI) by pulsed wave Doppler for the whole respiratory cycle with 2D measurement of the related diameter [11]. RV size was also evaluated at end-expiration by the RV D /LV D ratio. RV D and LV D were measured in the apical 4-CH view by identifying the maximal distance between the ventricular endocardium and the interventricular septum perpendicular to the long axis at the beginning of the QRS complex [12]. All results were con rmed by two competent attending physicians.
(3) The method of negative uid balance (application of diuretic drugs or continuous renal replacement therapy) was determined by the physician. No changes were made to mechanical ventilation, the set of vasoactive drugs, or the sedation level (Δ Richmond Agitation-Sedation Scale score < 1 point). Furthermore, no changes were made to the thoracic/abdominal pressure that may cause changes in CVP.
In the case of patient hypoxia, the inhaled oxygen concentration was adjusted to ensure SP02 > 95%, Pa02 > 60 mmHg.

Data collection
Clinical data were extracted from the ICU computerized database and medical records, including patients' socio-demographic data, biometric parameters, comorbidities, respiratory support mode, and Acute Physiology and Chronic Health Evaluation II scores. Hemodynamic parameters (heart rate, mean arterial blood pressure, and CVP) and echo parameters (such as DIVC, RV D /LV D ratio, LVEF, LVOT VTI, and TAPSE) were recorded at T0 and T1. Central venous oxygen saturation (ScVO2), central venous-arterial carbon dioxide difference (GAP), and serum lactate levels (lac) were also recorded at the same time. The primary outcome of the study was to clarify VTI change after negative uid management in patients with high CVP. The secondary outcome was to evaluate the relationship between hemodynamic parameters and VTI change after negative uid management.

Statistical analysis
Statistical analysis was performed using SPSS software version 20.0 for Windows (IBM, Armonk, NY).
Results for continuous variables with a normal distribution (e.g., age, Acute Physiology and Chronic Health Evaluation II score) are reported as the mean ± standard deviation. Student's t-test was used to compare means between two groups. Results for continuous variables that were not normally distributed are reported as the median (25th and 75th percentiles) and compared using nonparametric tests. The paired sample t-test was used for comparisons between groups before and after treatment. Cox regression models were used to measure the relative risk (RR) and 95% CI for each factor to discover how SV can increase after negative uid balance. The correlation between RV and ∆VTI/T0VTI variables was analyzed using Pearson correlation analysis. Receiver operating characteristic (ROC) curves were used to determine the ability of the indices to predict LVOT VTI increase > 10% after negative uid balance. The areas under the ROC curves (AUCs) were compared using DeLong's test. The AUC, sensitivity, and speci city are expressed as values with 95% con dence intervals (CIs). A P value < 0.05 was considered to be statistically signi cant.

Demographic and clinical characteristics of patients
During the study period, a total of 154 patients were admitted with CVP ≥ 8 mmHg. Of these, 65 did not meet the study criteria. In addition, nine patients were excluded due to poor TT image quality or incomplete image acquisition; six patients were excluded due to inconsistent judgments of the ultrasound results by the two physicians; and three patients were excluded due to new tachyarrhythmia during the trial. Thus, the nal sample for analysis comprised 71 patients ( Table 1. In terms of hemodynamic parameters, patients in Group 1 had a higher CVP and GAP and lower ScV02 relative to Group 2 (all p < 0.05). No group differences were observed for HR, MAP, or lactate levels.
Regarding the echo parameters, the RV D /LV D ratio, DIVC, ∆VTI,and ∆VTI /T0VTI were higher, while T0 VTI was lower, in Group 1 patients (all p < 0.05). There were no group differences in LVEF or TAPSE. Furthermore, there were no signi cant differences in demographic characteristics between the two groups.

Comparison of hemodynamic parameters at T0 and T1 between groups
As shown in Fig. 3, CVP, DIVC, and RV D /LV D ratio decreased signi cantly in both groups after negative uid management (p < 0.05). None of the patients in our study experienced cardiac and/or tissue perfusion insu ciency. Cardiac output related parameters (LVOT VTI, GAP, ScV02) improved in Group 1 (p < 0.05), and the lactate level decreased in Group 2 ( p < 0.05). In addition, the P/F ratio increased signi cantly in both groups (p < 0.05). Figure 4 presents the individual parameter values for RV and ∆VTI/T0VTI among all patients. CVP, RV D /LV D ratio, and DIVC were signi cantly correlated with ∆VTI/T0VTI (r = 0.64 (p < 0.05), 0.64(p < 0.053), and 0.59 (p < 0.05), respectively). By contrast, no relationship was observed between TAPSE and ∆VTI/T0VTI.

Risk factors for a LVOT VTI increase > 10% at T1
Cox regression analysis was used to examine possible risk factors for the outcomes of negative uid management. Each of the hemodynamics variables was taken into account. The results revealed that CVP and RV D /LV D ratio were the most signi cant predictors (p < 0.05). The RRs of CVP and RV D /LV D ratio were 2.425 (95% CI, 1.458-4.003) and 8.588 (95% CI, 1.947-37.887), respectively. ( Table 2)  The AUC of CVP for predicting a LVOT VTI increase > 10% at T1 was 0.883 (95% CI 0.804-0.902) The best diagnostic threshold was 10.5 mmHg, which provided a sensitivity of 87.5% and a speci city of 77.4%. (Fig. 5) The regression equation for all of the risk parameters is: Logit (P) =-10.474 + CVP *0.886 + RV D /LV D ratio *2.854 (≥ 0.6 = 1,<0.6 = 0).
The AUC of CVP combined with RV D /LV D ratio for predicting a LVOT VTI increase > 10% at T1 was 0.926 (95% CI 0.866-0.96). The best diagnostic threshold was 0.3689, which provided a sensitivity of 92.5% and a speci city of 80.6%. (Fig. 5)

Discussion
In the steady state, venous return is equal to cardiac output [13]; thus, right ventricular function is essential for venous return [14,15]. The challenge of uid management is to nd the ideal preload to avoid the negative effect of ventricular interdependence on LV function and cardiac output. The right half of the heart behaves very differently from the left. Tyberg et al. [11] measured pericardial pressure and right atrial pressure in patients with acute excessive uid loading before cardiopulmonary bypass. They found that these two types of pressure increased at the same rate, while the right atrial transmural pressure was unchanged. Previous studies have reported no relationship between right transmural pressure and right ventricular end-diastolic volume and stroke volume [16][17][18]. The healthy human RV lls at or below its unstressed volume, such that RV end-diastolic volume changes occur without any changes in RV diastolic wall stretch. Presumably, conformational changes in RV shape rather than stretch allow such volume changes to occur without measurable changes in the transmural right atrial pressure. With increased volume loading of the RV, right ventricular end-diastolic pressure and SV both increased. The relation of SV to venous return has a plateau: once this plateau is reached, any further increases in lling pressure will not augment cardiac output [19]. As a result, when RV reaches the at part of the pressurevolume curve, the left heart no longer determines cardiac output. If the RV further increases in size and the right ventricular end-diastolic pressure rapidly increases, this can cause leftward ventricular septal (VS) shift. VS shift can result in decreased SV, leading to a phenomenon colloquially termed "falling off the Starling curve" [14] 14141414 [14][14] [14].
The present study is a prospective study about the relationship between hemodynamic parameters during negative uid management. The intervention was performed in a short period of time (39±17 minutes), while other factors affecting CVP were unchanged. Notably, 56.3% of our patients showed increased VTI after negative uid balance, which is not exactly the same as the comment cognition. As the Starling curve does not have descending branches, it cannot explain the increase in SV after reducing the intravascular volume. Thus, we assume that patients experienced RV volume overload. A negative uid balance can reduce RV volume, resulting in a rightward VS shift, an increase in left ventricular enddiastolic volume, and an increase in CO. However, it remains unclear if determining RV volume overload is key to therapy. In terms of the hemodynamic and echo parameters in our cohort, CVP, GAP, ScVO2, RV/LV diastolic area ratio, LVOT VTI, and DIVC differed signi cantly between the two groups. A high RV D /LV D ratio and CVP value were identi ed as risk factors for RV volume overload. Due to its geometrical complexity, assessment of RV volume is a very di cult task. Although quantitative validation is lacking, the correlation of RV linear dimensions with RV end-diastolic volumes appears to worsen with increased preload [20][21][22]. RV D /LV D ratio has been shown to be an indicator of RV size, and can thus provide reliable information about RV shape and size. A ratio ≥0.6, regardless of whether RV is within the normal reference limits, may relate to certain conditions such as RV volume overload [20]. In our study, we found that a R/V ratio ≥0.6 was a risk factor for VTI increase after negative uid balance. Our results are similar to those of previous studies [23]. However, our measurement method is more clinically operable and repeatable. Wiesenack et al. measured RV volume in patients with mechanical ventilation to help guide uid resuscitation. However, in patients with pulmonary embolism and chronic pulmonary hypertension, only RVEDA/LVEDA>1 indicates RV volume overload [24,25]. When R/V ratio is applied clinically, it should be considered in combination with the patient's underlying disease and ventricular septal morphology.
We also identi ed high CVP as a signi cant risk factor for RV volume overload. The gold standard for evaluating RV lling pressure is invasive monitoring using a centrally placed venous catheter [26]. CVP can be used as a surrogate of intravascular volume, and is often applied at the bedside to guide uid administration in critically ill patients. Since the lling pressure and SV of the RV do not have a linear relationship, it has recently been acknowledged that CVP is ineffective for evaluating a patient's uid responsiveness [27][28][29]. While the absolute value of CVP alone cannot predict uid responsiveness, it is necessary to understand that CVP is a marker of pressure and a regulating factor of venous return. Thus, an increase in CVP can be used as a clinical safety mechanism to avoid uid overload and high RV lling pressure. We consider CVP to be a safety-related indicator rather than a cardiac preload indicator in clinical settings [30]. In the present study, we found that a high CVP may re ect that the RV volume load has exceeded the normal range; failure to appreciate this limit may result in a VS rightward shift and reduced SV. It has been proposed that, once CVP has exceeded 10-14 mm Hg in non-intubated patients with acute RV myocardial infarction, further volume loading is detrimental. A mean CVP > 14 mmHg is almost always associated with a reduced RVSWI [31,32]. Garcia-Montilla et al. [33] reported that the optimal RV lling pressure in patients with acute respiratory distress syndrome (ARDS) is 13±2 mm Hg. Furthermore, they demonstrated that once CVP reaches 15 mmHg, further increments in lling pressure did not increase RVSPG; rather, due to overstretching of myocardial bers, RVSPG decreased. These values may be considered the optimal RV lling pressure in patients with acute RV infarction or ARDS.
Our results suggest that CVP > 10.5 mmHg can predict whether VTI increases after a negative uid balance in patients without underlying cardiac disease with high sensitivity but low speci city. When we combined the two risk factors, the predictive ability improved.
Notably, none of our patients experienced CO and tissue perfusion insu ciency after negative uid management. However, the oxygenation index improved in both groups-especially Group 1. It is well known that uid overload may lead to pulmonary edema and failure of weaning from mechanical ventilation. A milestone study by Wiederman et al. [34] showed that a conservative uid management protocol aimed to lower CVP resulted in a major reduction in net uid balance, improving lung function and shortening the duration of mechanical ventilation. Clinicians should be alert to high CVP as it may indicate increased RV tension and leftward VS, potentially leading to increased left ventricular lling pressure and pulmonary edema. Accurate uid therapy for patients with high CVP will not lead to hypoperfusion, but will be bene cial for other organs.
Lastly, this study is subject to several limitations. Firstly, our study included a convenience sample of participants from a single institution, and may have thus systematically excluded some participant groups. As a pragmatic study, this population had similar characteristics to previous clinical audits using the same inclusion criteria. Nevertheless, additional clinical research is needed to con rm our ndings. Secondly, although we excluded patients with any pre-existing heart disease based on clinical records or echocardiography, some patients might have developed subclinical heart disease after their last echocardiography. Thirdly, the determination of RV volume load may be imperfect. In our experience, estimation of RV/LV size ratio is fairly accurate, even when assessed by trainees relative to an experienced clinicians.

Conclusion
Traditionally, RV function is thought to be of minimal relevance to overall cardiovascular homeostasis. Patients with normal cardiac function require precise uid management to prevent a decrease in CO resulting from inappropriate RV lling. In the present study, we identi ed a high CVP value and RV D /LV D ratio as risk factors for RV volume overload. Further studies of whether precise uid management can improve patients' 28-day mortality, shorten ICU stay, or shorten the duration of mechanical ventilation are required.

Declarations -Ethical Approval and Consent to participate
Ethics approval and consent to participate: This study was approved by the ethics committee of the Peking Union Medical College Hospital (S-617), and written informed consent was provided by the next of kin of all subjects .
-Consent for publication Not applicable.
-Availability of supporting data Not applicable.

-Competing interests
The authors declare that they have no con icts of interest.
-Funding Not applicable.
-Authors' contributions X. Wang and D. Liu conceived and designed the study. H. Zhao and X. Ding were performed the ultrasound test. H. Zhao wrote the draft manuscript. D. Liu gave nal approval of the version to be published. All of the authors read and approved the nal manuscript.
-Acknowledgements Not applicable.