Relationship between Hypernatremia and Intraventricular Hemorrhage in very and extremely preterm neonates: A

Literature Review

Abstract:

The purpose of this study is to identify the important risk factors that contribute to intraventricular hemorrhage (IVH) and hypernatremia in the early postnatal life of the preterm neonates having extremely low birth weight. The study seeks to find a relationship between the two pathologies in neonates born before term and its relevance in this era and age. Intracerebral hemorrhage results in the destruction of the hypothalamic nuclei, a reduction in the secretion of antidiuretic hormones, and hypernatremia; hence, hypernatremia in preterm neonates with severe IVH may be the result of severe brain damage. Contrary to this, hypernatremia had been shown to cause brain shrinkage. A chronological study would be used to compare both and the goal is thus, to analyze and form an opinion about the topic on the basis of research in chronological order.

Introduction:

Intraventricular hemorrhage (IVH) has been identified as a frequent consequence in preterm neonates having extremely low birth weight and with the gestational age (GA) matching appropriately with their birth body weight (BBW). A number of studies suggest that hypernatremia contributes to this mix, especially. The scope of this review is to delve thoroughly through a set of researches from the last ten years to discern the relationship between both, intraventricular hemorrhage and hypernatremia in premature neonates.

Intraventricular hemorrhage (IVH) is quite often observed as a source of neonatal morbidity among extraordinarily premature preterm neonates. It leads to adverse sequelae on the development of neurons. Some of the factors that related to IVH were male gender, rupture of brain membranes at a premature stage, delivery method, postnatal resuscitation, onset of sepsis at a very early stage, hypoxemia, syndrome of respiratory distress, pneumothorax, hypercarbia, and hypocarbia. (Villamor- Martinez et al., 2018). Furthermore, it was reported that IVHs were observed to be very more common among preterm neonates with hypernatremia. The IVH pathogenesis is multifactorial; it includes, broadly, the germinal fragility matrix vasculature, blood flow fluctuation in cerebral, and platelet and coagulation disturbances.

However, the association between intracranial hemorrhage and hypernatremic dehydration has been well-defined among pediatric patients and newborn preterm neonates. However, initially, it was uncertain whether the early fluid change or level of serum sodium would affect the severe IVH occurrence in preterm neonates. Therefore, the review of a few studies revealed a possible association between IVH and hypernatremia. The purpose of this study was to examine and investigate the association between severe IVH and concentration of serum sodium as well as the impact of sodium intake in the early days of extremely preterm neonates with low birth weight preterm neonates. (Kluckow & Evans, 2000; Lim et al., 2011; Riskin et al., 2008). Sodium is a vital source of muscle function and nerves. The body keeps balanced sodium with a variety of mechanisms. The Sodium level in preterm neonates is determined by the food and drink of the mother. However, high levels of sodium can cause an increase in the blood pressure resulting in intraventricular hemorrhage of neonates (Biomarkers Branch & Pirkle, 2019). Also, according to (Guo et al., 2019) the sugar level (very low or very high) leads to hypernatremia & intraventricular hemorrhage in preterm neonates.

In this literature review, most of the material was available easily on PubMed/MedLine and EMBase in the age group pertaining to the review within the last ten years, with additional studies that focused on the contributing risk factors as well.

Review of the literature:

Introduction: IVH vs. Hypernatremia

Intraventricular hemorrhage (IVH), which was previously undetectable has now with the help of CT (Computed Tomography) scans been able to provide brain imaging in not only neonates but also extremely preterm neonates. As a result, intraventricular hemorrhage along with its extensions can be viewed promptly on a CT scan. It was further revealed that predisposing factors to intraventricular hemorrhage include respiratory distress syndrome, acidosis, hypercapnia, etc. (M. Levene & L De Vries, 1984). Therefore, during the last decade, the incidence has declined but still, IVH is considered a highly significant risk factor for morbidity and mortality among extraordinarily premature preterm neonates. The literature revealed that in approximately 90% of the cases, IVH has occurred during the first three days of postnatal life. Intraventricular hemorrhage (IVH) is considered the most important element that causes mortality amongst those who had developmental impairment during long run in preterm neonates.

Another literature revealed that in a retrospective analysis, neonates having completed less than a twenty-seven-week gestation period developed plasma sodium greater than 145mmol/L (hypernatremia) within the first five days of life. Birthweight, gender, and increased insensible water loss seemed to be of no significance and yet neonates that had developed CLD, PDA, and IVH had died (Gawlowski, Aladangady & Coen, 2006).

In fact, the incidence of developmental disability in extremely preterm babies with very low birth rate has been identified to cause intraventricular hemorrhage and even germinal matrix intraventricular hemorrhage as a result of infarcts caused by turbulent blood flow of the brain since this region contains vessels that lack some components of a completely formed blood-brain barrier (BBB), like BM deposition, tight junctions, and glial end foot investiture. As a result, the ventricles distend, and the rate of blood flow decreases which causes stasis and activates cyclooxygenase 2 (COX-2) system and prostaglandins stimulated by hypoxia and hypotension. This results in the production of VEGF (vascular endothelial growth factor), a factor that serves as a potent stimulator for the formation of new blood vessels. This sets into motion the disruption of the blood-brain barrier within the periventricular white matter. Thus, the microglia release the hazardous reactive oxygen species that contribute to more damage in the preterm brain than they do in the adult brain by causing damage to the endothelium, altering the hemostasis and increasing anaerobic metabolism. In addition to this, ROS stimulates the activation of the cyclooxygenase 2 system. The multifactorial effect of all of these in turn leads to infarctions in the brain. Genetics might also play a vital role in the pathogenesis of intraventricular hemorrhage but more important than that is to take into account the relation between gestational age and IVH. About 90% of cases of hemorrhage are discovered by the end of the first week of the postnatal life of a neonate regardless of their gestational age. This goes to show that gestational age (GA) does not pose as a risk factor for intraventricular hemorrhage in preterm neonates. The literature revealed that prevention for IVH must focus on its environmental and genetic causes. (McCrea & Ment, 2008)

The basic definition of hypernatremia would be when the level of serum sodium is above 145mmol/L. Hypernatremia is not a rare occurrence in the general population and so is of little, if at all, risk if given prompt treatment. If proper management is not provided, hypernatremia can be the cause of mortality. Vasopressin and thirst maintain a normal osmolality in the body in a range of 280 to 295 mOsm/kg. Dysfunction in the aforementioned factors can lead to hypernatremia. In neonates, however, this phenomenon is still being researched upon. The main cause in preterm neonates that leads to abnormal sodium levels in the blood is more often due to excess or loss of fluid intake, rather than the excess intake of sodium. Insensible water loss (IWL) is very common in preterm infants in contrast to infants that have completed term because of a greater ratio of surface area to body weight and the presence of non-keratinized skin in extremely preterm neonates which allows great loss of water from the body since this process speeds up in the last trimester of antenatal life. Average water loss in term infants is 20-40 mL/kg/day but in infants with gestation age of fewer than twenty-six weeks, this loss can be over or equal to 200 mL/kg/day. Another factor that contributes towards hypernatremia is nephrogenesis in the neonate which is achieved completely in the neonate at the 34-36 weeks of gestation. In preterm neonates, this means that the kidneys are not fully functional and correlate to a glomerular filtration rate that is pretty low and nephrons that are still immature. This further leads to a decrease in the excretion of extra fluid and electrolytes from the body and decreased production of urea due to the high anabolic state in the body. Complications of hypernatremia in a preterm infant include intraventricular hemorrhage, thrombosis, and edema of the brain, CVS collapse, and severe hyperbilirubinemia. The literature confirmed that out of all the predisposing factors that correlated to hypernatremia, low birth weight contributed the most, and babies that were more immature were more likely to develop hypernatremia. The extracellular compartment causes the postnatal weight loss due to isotonic dehydration as a result of water balance that is negative and diuresis. Changes in the concentration of sodium can cause shifts of water inside and outside the ECF which may prove fatal in extremely preterm neonates. (Gawlowski, Aladangady & Coen, 2006)

Hypernatremia of the neonate is a serious condition that manifests as dehydration due to abnormally increased levels of sodium in the breast milk and is usually secondary to lactation that is insufficient. Neonatal hypernatremia is a dangerous condition because of the consequences like IVH, cerebral edema, hydrocephalus, and gangrene. Neonates lose some of their birth weight through the first week of their life, normally and regain it back by the tenth day of their postnatal life. However, if there is a constant decrease in birth weight, even after the first two weeks of postnatal life, it should ring alarm bells because this is the first sign of neonatal hypernatremia. There are a few causes that lead to increased levels of blood glucose galactopoiesis because of a sick neonate and less frequency of breast stimulation and drainage and the other factor was the low birth weight of gestational age of the neonate (Mujawir & Jaiswal, 2017)

Sodium & Fluid Intake and its effect and association with Intraventricular Hemorrhage

Most of the literature reviewed suggested that hypernatremic dehydration and intraventricular hemorrhage (IVH) go hand in hand, especially their associations in infants that are born preterm and with low birth weight. As previously stated, IVH is one of the most rising causes of mortality and developmental abnormalities in preterm neonates. The more severe the IVH, the greater the developmental abnormality. That is to say, Grade III and Grade IV IVH are prone to more neurological sequelae than Grade I and Grade II IVH, according to the Papile classification. The severity of IVH, in turn, depends mostly upon low birth weight.In relation to intake of sodium and balance of fluid, it has been discovered that the risk of severe IVH increases with increased sodium intake within the first for days of postnatal life, especially in neonates with extremely low birth weight. Lupton et al. revealed that a high serum sodium concentration during the initial four days of life, when defined by serum sodium > 145 mM/L or > 152 mM/L, was not associated with an increased risk of IVH in VLBW infants. A study by Perrott et al demonstrated the association of high blood sodium levels with major disabilities of the brain development in infants with a gestational age of fewer than thirty weeks although no strong association with IVH was proved. The hypernatremic dehydration caused a hemorrhage in a preterm neonate shows diffuse lines of lesions, especially in the junction between the gray and white matter of the brain and in multiple parenchymal sites which may further lead to encephalomalacia. Hence, the literature reveals that sodium imbalance may have several outcomes on the neonate, the most important of which is IVH, while others also include, PDA, RDS, sensory hearing loss or impairment, and developmental disabilities, most of the motor origin. (Moritz, 2009; Oh, 2012). ‘Preterm neonates are at the greatest risk of hypernatremia (Gawlowski 2006; Jones 1976; Rees 1984; Wilkins 1992b) and later of hyponatremia (Al-Dahhan 1983; Day 1976; Mannan 2012; Rees 1984). Hypernatraemia has been variably defined as a serum sodium > 145 mmol/L (Balasubramanian 2012) or ≥ 150 mmol/L (Baraton 2009; Harkavy 1983; Takahashi 1994); and hyponatraemia as a serum sodium < 135 mmol/L (Kloiber 1996) or < 130 mmol/L (Baraton 2009; Day 1976; Takahashi 1994).’ Water and sodium balance is showcased in the serum sodium level and this changes a lot after postnatal life, especially due to ECF because it contracts after birth as a result of negative water and sodium balance and proceeds to cause loss of water. The rest of the water loss is because of transepidermal loss of water, especially in extremely low birth weight neonates. Higher excretion of sodium by the kidney increases the tendency for high levels of serum sodium in the body even though there is a low glomerular filtration rate initially. Thus, in the first few weeks of postnatal life, water intake of a neonate is modified to balance the changes in sodium serum or other causes of hydration. Preterm infants have high fractional excretion of sodium (FENa) secondary to impaired tubular sodium reabsorption (Al-Dahhan 1983; Aperia 1981; Mannan 2012; Wilkins 1992b). Despite a relatively low GFR, it is thought the increase in GFR overtime frequently exceeds the limited tubular sodium reabsorption capacity in very preterm infants (Al-Dahhan 1983; Aperia 1981). Reported risk factors for hyponatremia include increasing prematurity (Mannan 2012), birth weight of fewer than 1000 grams, feedings of fortified human milk, and the occurrence of intraventricular hemorrhage (Kloiber 1996). Intake of sodium in preterm infants is from a combination of both, parenteral and enteral sources. The European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) however, suggests the usage of parenteral sodium intake in neonates that are preterm in order for them to adapt more easily to it.

In the initial phase of transition, it is suggested for the net negative sodium balance to reach a range of 2 to 5 mmol/kg and during the next phase, that is, the intermediate phase, to allow the body to counter the losses of electrolytes and replace them. In the third and final phase, that is the growth phase 3-5mmol/kg/day must be provided for two things; to deplete the body for losses and to build new tissue to increase growth rate. ESPGHAN recommendations for enteral intakes are 3 to 5 mmol/kg/day (Agostoni 2010). Thus, for easier understanding, early higher sodium supplementation is defined intake of parenteral or enteral dosage of ≥ 2 mmol/kg/day; and later higher sodium supplementation is defined as intake of parenteral or enteral dosage of ≥ 5 mmol/kg/day, and lower sodium supplementation as < 3 mmol/kg/day. Restriction of sodium especially in fluids that are parenteral reduces the chances and severity of the hyponatremia that may follow and sodium requirements may easily be fulfilled by intake of water but only in the early cases of hyponatremia because later cases of hyponatremia are more often than not benign conditions. Sodium is vital for electrolyte and fluid therapy in extremely preterm neonates. Postnatal growth failure is of common incidence to them as well so it is important to reduce their morbidity and mortality levels by optimizing their sodium intake.

So, in a nutshell, it is important to provide early management and treatment to preterm neonates having hypernatremic dehydration because its consequences are extremely severe as it causes shrinkage of the neonatal brain which is followed by a huge influx of solutes into the brain cells to allow restoration of normal brain volume as an adaptive response. This rapid response can for the correction of hypernatremia can cause cerebral edema that can lead to the rupture of the vessels in the cerebral space and cause subarachnoid hemorrhage, intraventricular hemorrhage, or permanent brain death. There has been an increasing body of literature reporting an association between hypernatremia and IVH in preterm neonates. Apart from this, the risk of severe neurological complications can increase in extremely preterm neonates as a result of the rapid correction of serum sodium. That is why a serum sodium correction rate of less than 0.5 mmol/L/h or 10 mmol/L/d provides better outcomes and it has been emphasized that the maximum rate of decrease of the serum sodium level in term neonates with hypernatremic dehydration should not exceed 0.6 mmol/L/h or 15 mmol/L/d17. In conclusion, hypernatremia is independently associated with any IVH or severe IVH or death during the first 10 days of life. It, therefore, seems appropriate to follow the same guidelines that have been used in term neonates and older infants to treat hypernatremia in ELBW preterm infants as well. (Lee et al, 2015; Dalton, Dechert & Sarkar, 2014; Chan et al, 2017)

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