The Feasibility of Applying Inferior Vena Cava Collapse Index to Guide the Use of Fluid Therapy in Neonates with Pulmonary Hemorrhage on Mechanical Ventilation

Purpose. Explore the feasibility of applying Inferior Vena Cava Collapse Index (IVC-CI) in guiding the use of uid therapy in neonates with Pulmonary Hemorrhage (PH) on mechanical ventilation. Construct a novel and non-invasive technique in accurately and dynamically assess the uid volume of neonates. Methods. Cases met the diagnostical criteria of Pulmonary Hemorrhage (PH) admitted between July 2016 to June 2018 were reviewed and included into the Control Group for this study. Cases met the same said criteria between July 2018 and June 2020 were included into the Experimental Group. PHILIPS Bedside color Doppler ultrasound system was used in detecting and calculating the IVC-CI, which was later used for patients in experimental group to guide the practice of uid therapy. A total of 54 cases were reviewed with 8 cases excluded for death during hospitalization. 24 cases were included into the control group, 22 cases were included into the experimental group. of respectively respectively. The of the two the same suggesting the differences between the two groups the and following after statistical signicance.


Introduction
Pulmonary hemorrhage in neonates is a massive hemorrhage involving at least 2 lobes of the lungs, resulting in high morbidity and mortality rate. The particularly high incidence of pulmonary hemorrhage in neonates can be ascribed to their anatomical and developmental characteristics [1] . Timely mechanical ventilation and hemostatic treatment play a decisive role, while uid therapy is also particularly critical. Reasonable and effective uid therapy can provide the body with a stable internal environment, reduce further tissue injury, alter the course of the disease and produce more favorable outcome [2] .
Perspective approaches were applied in conducting this study. Routine and conventional treatments including mechanical ventilation and hemostasis were performed while calculating the Inferior Vena Cava Collapse Index (IVC-CI) [(Maximum diameter of I.VC -Minimum diameter of I.VC)/Maximum diameter of I.VC] [3] [4] to assess the effectiveness of uid therapy.

Patients And Methods
2.1 Case Collection. This study was conducted at the Neonatal Intensive Care Unit (NICU) of Children's Hospital of Fudan University Xiamen Branch (Xiamen Children's Hospital), one of the regional's medical centers for neonatal diseases. Cases met the diagnostical criteria of Pulmonary Hemorrhage (PH) [5][6] admitted between July 2016 to June 2018 were reviewed and included into the Control Group for this study. Cases met the same said criteria between July 2018 and June 2020 were reviewed and included into the Experimental Group. Exclusion criteria included: 1. PH occurred more than 1 week after birth; 2. Patients with severe liver failure, idiopathic pulmonary hemosiderosis, intracranial hemorrhage; 3.
congenital fatal malformations, hypoplasia of the trachea or chest/abdominal wall, severe congenital heart diseases, hemophilia and other coagulation abnormalities; 4. patients dies during hospitalization.
PHILIPS bedside color Doppler ultrasound system was used in detecting and calculating the IVC-CI, which was later used for patients in experimental group to guide the practice of uid therapy. A total of 54 cases were reviewed with 8 cases excluded for death during hospitalization. 24 cases were included into the control group, 22 cases were included into the experimental group.
This study was approved by the Ethics Committee of the Children's Hospital of Fudan University Xiamen Branch (Xiamen Children's Hospital) and was performed in compliance with the Declaration of Helsinki. Written consent form from all patients' legal guardians were received.
2.2 Methods. Bedside ultrasound system was used to assess the IVC-CI of patients in experimental group to evaluate the effectiveness of uid therapy. Ultrasound assessment was performed by the same group of experienced physicians.
2.2.1 Ultrasound Data Collection. The patients were placed supine and sedated, ultrasound probe was placed to the right of the subxiphoid process to show the long-axis view of the inferior vena cava. 0.5-1 cm below where the hepatic vein meets the inferior vena cava was selected as the measurement point.

Therapeutic
Approaches. All cases included into the study were on mechanical ventilation support, most of the patients were clinically diagnosed basing on the observation of intratracheal hemorrhage. Immediately after the onset of PH, the IVC-CI was acquired with the said method. Therapeutic principles include correction of acidosis and plasma transfusion. IVC-CI was assessed again both before and after the transfusion. Considering there were no commonly acknowledged practice of using IVC-CI to guide uid therapy in neonates, we referred to the guidelines published for adults, which indicate for limited uid intake when IVC-CI is below 15% and rather aggressive uid therapy when IVCC reached above 50%.
Once the active hemorrhage stopped and vitals including blood oxygen saturation, blood pressure, heart rate stabilized, IVC-CI was monitored every 4 hours with the observation cut-off point at 72 hours after the onset of PH.

Observational
Index. pH, partial pressure of carbon dioxide (pCO 2 ), partial pressure of arterial oxygen (pO 2 ), blood lactate concentration, oxygenation index [(FiO 2 ×Mean Arterial Pressure)/PaO 2 ], and heart rate and the time intervals for the improvement of said indexes were recorded. The correlation of IVC-CI and changes of mean plasma hemoglobin concentration (Hb) was monitored. The uid intake of the patients during the observation period was recorded.

Statistical
Analysis. Measurement data were expressed in mean ± standard manners (x±s), and ttest was used for comparison between groups, and categorical data were presented as number of cases or ratio, and chi-square test was used for comparison between groups. All tests of statistical hypotheses were two-sided, and p ≤ 0.05 was considered statistically signi cant. All data were analyzed using SPSS 22.0 (SPSS Inc., Chicago, IL, USA).

Results
3.1 Demographic Data. All 54 cases were included into the study, 8 cases were excluded because of death during hospitalization. 22 cases were included into the experimental group and 24 cases in control group. Basic demographic data included gestational ages, birth weight, gender, time of the onset of PH.
The differences were not statistically signi cant. Basic demographic data was compiled in the Table 1. 3.2 Major Arterial Blood Gas Index at the Onset of PH. Indexes included pH, partial pressure of carbon dioxide (pCO 2 ), partial pressure of arterial oxygen (pO 2 ), blood lactate concentration, oxygenation index (OI). Heart rate as an important vital was also included for analysis. Data in Table 2 suggested the differences were of no statistical signi cance.

Correlation between IVC-CI and changes of hemoglobin concentration.
In clinical practice, hemoglobin concentration is used widely to assess whether or not there is an active bleeding. This index usually drops when internal hemorrhaging is underway. To establish that IVC-CI can re ect on the changes of uid volume, the baseline hemoglobin concentration (Hb B ) and the concentration (Hb H ) after diagnosed with PH were recorded. As indicated in Table 3 and Figure 1, the greater changes hemoglobin concentration Hb exhibited, the greater IVC-CI elevated, suggesting a strong correlation between these two indexes, also proving that IVC-CI can dynamically re ect on the body's uid volume status. Table 4, a comparison between the uid intake of 2 groups was drawn, the differences of intake uid volume in the rst 6 hours and the 6th to 24th hours after the onset of PH were of statistical signi cance, while the intake uid volume between the 24th to the 48th hours after the onset of PH was considered statistically insigni cant.

As demonstrated in
3.5 During the pathophysiological process of Hb, blood lactate concentration is elevated because of the cellular anaerobic respiration process. Oxygenation Index [(FiO2×MAP)/PaO 2 ] is also signi cantly elevated [7] . Hence, there two indexes can re ect on the body's circulatory and respiratory conditions. During the observation period, the time interval took for blood lactate concentration to drop back to normal range were recorded (T Lactate ) and compared between different groups. A lactate concentration below 4 mg/dl was considered normal. The period of time took for Oxygenation Index (P/F) to drop by 50% was also recorded (T OI ). Compiled data in Table 5 suggested that the differences between two groups were of statistical signi cance.

Discussion
Pulmonary hemorrhage in neonates is mostly hemorrhagic, the pathophysiological changes this time is mostly about increase vascular ltration pressure, increased ventricular preload [5] . Hemorrhaging thus leads to hypovolemia, and if there is a lack of relatively aggressive uid resuscitation during this period and an untimely response to hypovolemia, dramatic circulatory volume uctuations and inadequate perfusion of vital organs such as the heart and brain may lead to rapid progression of the conditions [8] .
Empirical and stereotyped correction of acidosis and transfusion may cause uid overload. Increased secretion of Endothelin-1 (ET-1) of the vascular endothelial cells is triggered in response to PH. Contraction of smooth muscle and aggravated pulmonary edema can result in elevated pulmonary arterial pressure. Hypoxemia resulted from PH may cause hypoxic myocardial injury and cardiac dysfunction. All these factors lead to increased circulatory burden, causing tissue edema, organ dysfunctions and circulatory failure. Consequently, relatively limited uid intake to alleviate the circulatory burden and thus reverse the process of pulmonary edema may avoid the development of cardiac failure, eventually reduces mortality [9] .
Therefore, the introduction of volume assessment to guide uid therapy in neonatal PH is crucial. In contrast, preterm infants are inherently characterized by unclosed ductus arteriosus, unclosed foramen ovale, immature lung development, relative pulmonary hypertension, right ventricular predominance, and unstable circulatory status [1] . Moreover, indicators more frequently used in clinical practice such as heart rate, blood pressure, urine volume, and lactate concentration are easily affected by many factors such as stimulation, body temperature and respiration, making it di cult to assess volume status accurately. In order to obtain dynamic indicators such as central venous pressure, pulmonary capillary wedge pressure, per beat variability and pulse pressure variability, invasive operations are required with complications associated with infection, thrombosis, hematoma, pneumothorax, and operation failure, making it even more di cult to obtain in preterm infants.
Recent years' clinical practice and scienti c research revealed the effectiveness of applying IVC-CI in dynamically assessing the volume status, making it a comprehensive evaluation index of cardiac functional status. Because of the fact that IVC-CI can be acquired in a non-invasive manner, repeated assessment can be performed to evaluate the effectiveness of uid therapy [10] . Zhu Weihua et al. found that compared with patients breathing spontaneously, IVC-CI can more accurately evaluate uid load and uid responsiveness in patients on mechanical ventilation, producing timely report on the effectiveness of the therapeutic approaches [11] . The fast respiratory rate and the short distance from the inferior vena cava to the atrium in preterm infants make accurate measurement of IVC-CI relatively di cult. In contrast, children with pulmonary hemorrhage are critically ill and poorly responsive, or are passively ventilatordependent due to sedation, which is suitable for the application of IVC-CI to assess volume status. In this study, hypoxia, hypercapnia, elevated lactate concentration, and increased heart rate were found in all patients with PH, with no signi cant difference between the two groups. The inferior vena cava collapse index was found to be between 50% and 75% in the early stage of PH in 22 patients in the experimental group, and Figure 1 re ects a positive correlation between the IVC-CI and the degree of hemoglobin concentration decline in the early stage of PH. Similar to the ndings of E Wilkman et al. who reported that IVC-CI can accurately assess volume status at positive end-expiratory pressure ventilation mode [12] .
The study on the relation between IVC-CI and uid status is relatively scarce. A foreign study with crosssectional analysis of neonates found that IVC-CI correlated well with central venous pressure, but not with either gestational age or birth weight. Evidently, IVC-CI was not in uenced by birth weight or gestational age [13] . The results of this study were similar to those of adult studies in that the IVC-CI correlated well with CVP [14] [15] .
In the experimental group of this study, patient's urine volume, heart rate, blood pressure, capillary lling time, lactate, and left ventricular ejection fraction (LVEF) were taken into overall evaluation, while referring to the IVC-CI practices in adult patient in making therapeutic attempts (Limited uid resuscitation when IVC-CI < 15%, active uid resuscitation when IVC-CI > 50%) [16] [17] . Our study revealed that IVC-CI usually drop by 10-15% 6 hours after the onset of PH. This result was thus used to limit the uid intake of patients in experimental group. We retrospectively reviewed the cases in control group and discovered that the volume intake in the rst 6 hours and between the 6th to 24th hour after the onset of PH was 60±4ml/Kg and 93±4ml/Kg respectively, suggesting the experimental group received more uid during the rst 6 hours than the control group, fewer uid in the following 18 hours, both with statistical signi cance. The following day witnessed no particular difference in terms of uid intake. When comparing the time taken for improvement of lactate concentration and oxygenation index in both groups, the experimental group was shorter than the control group, and the difference was signi cant.
This study showed that ultrasound-guided measurement of IVC-CI can promptly assess the volume status, provide targeted guidance for uid therapy, shorten the improvement time of lactate concentration and oxygenation index, and facilitate the recovery of the disease. It is similar to the ndings of Clive N May et al [18] who reported that ultrasound-guided uid therapy shortened the duration of ICU stay and the duration of mechanical ventilation in patients with severe sepsis.
It is worth noticing that we selected a different ultrasound probing point for measuring the IVC-CI compared to adult patients. A routine measuring point is in between the con uence of the hepatic vein into the inferior vena cava and the con uence inferior vena cava into the right atrium [19] . while we select 0.5-1 cm below where the hepatic vein meets the inferior vena cava was selected as the measurement point. This alteration was made because of the anatomical short distance between the con uence of hepatic vein into the inferior vena cava and the con uence of inferior vena cava into the right atrium in neonates, and the routine measuring point is subject to the in uence of heart beat, consequently affecting the accuracy of the measurement. Moreover, the measurement should not be performed when patients experience respiratory distress, which may lead to an abnormally elevated IVC-CI, thus causing misdiagnosis and unnecessary treatment.
Due to the small number of cases included into the study and an untraditional measurement point of the IVC-CI, there may be certain limitations about the conclusion of the study. Hopefully such limitation can be alleviated through future studies which include more samples, leading to a more robust, timely and accurate assessment of the effectiveness of uid therapy in neonates.    Figure 1 Linear relation between IVC-CI and Hb(data from Table 3) Supplementary Files This is a list of supplementary les associated with this preprint. Click to download.