IMPACT OF 6% HYDROXYETHYLSTARCH 130/0.42 ON BRAIN PERFUSION IN TERM NEONATES WITH HYPOXIC-ISCHEMIC ENCEPHALOPATHY

Introduction Perinatal hypoxic ischemic encephalopathy (HIE) is associated with approximately one-quarter of global neonatal deaths. In 2010, there were an estimated 1.15 million cases of neonatal encephalopathy, of which 96% of were from lowand middle-income countries [23]. More than a million children who survive birth asphyxia develop problems such as cerebral palsy, mental retardation, learning difficulties, and other disabilities [25]. The main strategies of intensive care remain: mild therapeutic hypothermia of 33-35 ̊C for 72 hours; positive pressure ventilation; volume resuscitation; cardiac output support; glucose control; anticonvulsant therapy [26]. Dysregulated cerebral blood flow may be a key component for secondary neurologic injury in HIE. Cerebrovascular autoregulation maintains relatively constant cerebral blood flow across changes in perfusion pressure. Cerebral vasoreactivity describes the vasodilatory and vasoconstrictive responses to changes in blood pressure that mediate cerebral blood flow autoregulation [2, 3]. The load of fluids to increase intravascular volume is the point of carein infants becauseunlike adults the cerebral blood flow in neonates depends mainly on the cardiac output than blood pressure [11] but the choice of fluids is still debatable.However, the safety of HES 6% in newborns seems quite proven [16, 22], its efficacy as a fluid for volume replacement in the acute period of severe hypoxic-ischemic encephalopathy remains discussible.

Basing on cerebral perfusion Doppler indices and systemic circulation the hemodynamic support included volume resuscitation and control of blood pressure and cardiac output with the following inotropic and vasopressor administration if needed. Dobutamine and/or dopamine were administered in routinely recommended dosage. The intensive therapy was focused on normovolemia, support of mean blood pressure above 35-40 mm Hg and adequate cardiac output [26].
Depending on fluids for volume resuscitation, all infants were randomly divided into HES and control groups. In HES group 45 term infants with moderate to severe hypoxic-ischemic encephalopathy were treated at the 1st DOL with 6% hydroxyethylstarch (HES) 130/0.42 in a balanced crystalloid solution at a dose of 10 ml/kg. The control group included 160term neonates with hypoxic-ischemic encephalopathy undergoing routine intensive care with normal saline at a dose of 20 ml/kg as the loading volume if needed.The issues of safety of HES 6% 130/0.42 in newborns we considered in a previous publication [22]. To assess the efficacy of 6% HES we selected such criteria as mean blood pressure (MBP) and transfontanel Doppler indices RI, PI and CPP [1].
Statistical analysis was performed with JASP 0.9.0.1 software (Amsterdam, The Netherlands, 2018) in accordance with generally accepted standards for mathematical statistics. Before the statistical processing, all data were checked for normal distribution using the Shapiro-Wilk's W-test. For non-parametric data primary statistical analysis included the calculation of the median, 25thand 75thpercentiles. The Mann-Whitney U-test was used for statistical comparison of the studied groups. Kendall's Tau and Spearman's rank correlation coefficient used to measure the strength of the relationship between variables. The unidirectional analysis of variance (ANOVA test) performed to determine the significant influence of each factor on subject effects in the dynamics. A p-value less than 0.05 was considered as significant in all of the tests.
At the first step, we figured out benchmarks for the HES 6% efficacy evaluation. Depending on short-term end-point as cerebral leukomalacia rate,we conducted acomparative analysis between central and cerebral hemodynamics indices and leukomalacia diagnosed by US/MRI criteria (Tab. 1).

Note. HES -Hydroxyethyl starch, MBP -Mean Blood Pressure, RI -Resistive Index, PI -Pulsatile Index, CPP -Cerebral Perfusion Pressure
The data presented in Table 1 shows that newborns, who subsequently were diagnosed with cerebral leukomalacia, had statistically lower RI and PI rates on the 1st and 3rd days of intensive care. The correlation between these variables is also confirmed by the correlation analysis of Kendall-Tau. The RI value on Day 1 negatively correlated with the development of leukomalacia (r = -0.12; p = 0.018), as well as RI on Day 3 (p = -0.13; p = 0.016). The weakness of the described correlation could be explained by the unpredictable state of autoregulation of cerebral blood flow in newborns with HIE during therapeutic hypothermia and the presence of ante-/intranatal factors that influence the development of leukomalacia.
Understanding that hemodynamics and cerebral Doppler indices on Day 1 are mostly baseline characteristics, we used mean blood pressure, Pourcelot Resistive Index (RI) and Gosling Pulsatility Index (PI) on Day 3 as benchmarks for the HES 6% efficacy evaluation. Exactly the same, Day 3 RI predictable value coincides with data by Elstad  Next step we conducted the comparative analysis between central and cerebral hemodynamics indices on Day 2 and Day 3 in neonates with HES 6% administration / no HES 6% on Day 1 (Tab. 2).
Evaluating data from Table 2, no statistically significant differences in RI and PI values on Days 2 and 3 between two groups found excepting slight but significant distinction in mean blood pressure (MBP).
Considering of the above, we provided the ANOVA test to decisively figure out if the administration of HES 6% 130/0.42 fluid on Day 1 for volume resuscitation affects cerebral blood flow patterns the nearest days after. Impact of HES 6% administration at Day 1 on RI dynamics on Day 1 and Day 2 presented in Table 3 and Figure 1.
The results from ANOVA test in the Table 4 show, that there is a significant difference between RI measured on the Day 1 and Day 2 (p=0.020) inside the groups of patients who received and did not receive HES 6% at Day 1. However, administration of HES 6% at Day 1 resulted in similar changes in RI level on both Day 1 and Day 2 of treatment (p=0.418),exactly RI increased in both days. RI level was significantly higher in patients who received HES 6% comparing to no-HES 6% group (p=0.025).
The graph on Figure 1 represents the dynamics confirming that administration of HES 6% resulted in significant improvement of RI level on Day 1 and Day 2 (p=0.025).
Impact of HES 6% administration at Day 1 on RI dynamics on Day 2 and Day 3 presented in Table 4 and Figure 2.
The results from ANOVA test in the Table 4 show, that there is a significant difference between RI measured on the Day 2 and Day 3 (p=0.019) inside the groups of patients received and did not receive HES 6% at Day 1. However, administration of HES 6% on Day 1 resulted in similar changes in RI values on both Day 2 and Day 3 of treatment (p=0.330), exactly RI increased in both days. RI level was significantly higher in infants who received HES 6% comparing to no-HES 6% group (p=0.023).

Figure 1. The descriptive plot for effect of HES 6% administration at Day 1 on RI dynamics on Day 1 and Day 2. HES -Hydroxyethyl starch, RI -Resistive Index
The graph on Figure 2 represents the dynamics confirming that administration of HES 6% resulted in significant improvement of RI level on Day 2 and Day 3 (p=0.023).
The ideal fluid for neonates should have a composition as similar as possible to the extracellular fluid, to support cellular metabolism and avoid organ dysfunction, and should increase intravascular volume and persist over time, to optimize cardiac output. Unfortunately, no ideal fluid exists, and the available fluid options are roughly divided in three groups: crystalloids, colloids, and blood products. Crystalloid and colloid solutions are discussed, emphasizing advantages and disadvantages of each [18].
Crystalloids are the fluids most commonly used in neonates as well as in pediatric and adult population [6]. Comparing to colloids crystalloids are low-cost, thenoted side effect such as tissue edema can develop when large volumes are used.However, the volumereplacement ratio for crystalloids is quite low and crystalloids only have a short-lived effect on the systemic perfusion. According to Starling's "Threecompartment model", four-times more crystalloids have the same volume effect as colloids [12].
Colloids are composed of large molecules designed to remain in the intravascular space for several hours, increasing plasma osmotic pressure and reducing the need for further fluids. The use of albumin is associated with improved mean arterial pressure and cardiac output with an infusion of a lower volume, but the increased blood-brain barrier permeability restricts it's using in neonates with severe HIE because of the relative risk of brain edema [4].
Systematic reviews regarding use of starches in children have shown that there are not enough evidence as to influence on the risk of death using crystalloid vs colloid in pediatric intensive care [20,21]. Applying of 6% hydroxyethylstarch (HES) 130/0.42 in a balanced crystalloid solution approved for use in the neonatal period, but there is limited data on its benefit/risk ratio in hypoxic-ischemic encephalopathyof newborns [8].
Unlike adult population [13,14], there are no strict evidences in neonatal patients regarding serious adverse events as coagulopathy or renal impairment related to administration of HES 6% 130/0.42 in routine dosage 10 ml/kg IV [8,17,19] as well as in children [24]. Considering that fluid restriction is typically recommended for infants with HIE [26], 6% HES 130/0.42could be used for volume replacement in this group of patients in standard dosage not exceeding 10-15 ml/kg of body weight to avoid potential side effects.

Conclusion
Administration of 6% HES 130/0.42 in a balanced crystalloid solution at the dose of 10 ml/ kg of body weight in term newborns with severe hypoxic-ischemic encephalopathy isan effective tool for volume resuscitation resulting in improvement of cerebral blood flow, specifically increasing of Doppler Resistive Index in front cerebral arteries. Having regard toits influence on central and cerebral hemodynamics, preventing of secondary postischemic brain injury is quite feasible, but additional data needs to be collected before any further conclusions can be drawn.

The perspectives of future studies
Compliance with Ethical Standards. The study was approved by Biomedical Ethical Commission of the Regional Children's Hospital, Dnipro, Ukraine. Protocol #5, 2011 Feb 21.

Disclosure
The author has no conflict of interest to declare. Acknowledgements. No external funding source.