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Periventricular leukomalacia: pathophysiological concerns due to immature development of the brain.

Abstract: Periventricular leukomalacia (PVL) is a result of injury and necrosis of myelinated fibers around the lateral ventricles. PVL is now considered the principal form of brain injury in preterm infants. This injury can have long-term effects on physical, motor, sensory, cognitive, and social development. Some proposed pharmacological treatments being considered to aid in prevention of this injury are raising concerns because they have failed to show evidence of efficacy or have potential for deleterious long-term effects. Current treatment is aimed at injury prevention; therefore, nurses play a critical role. Awareness of the pathophysiologic concerns about preterm neonates can help nurses focus their assessments to identify patients at risk.

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Periventricular leukomalacia (PVL) is now found to be the principal form of brain injury in preterm infants (Volpe, 2001). The incidence has been reported to range from 15% to 20% in this population (Perlman, 1998). Lesions of PVL are bilateral and nonhemorrhagic but not necessarily symmetrical. These lesions result in focal or diffuse necrosis of white matter surrounding the lateral ventricles, which results in a reduction of myelinated neurons and ventriculomegaly (Perlman, 1998; Porton-Deterne, Bloch, & Lacert, 2000; Volpe, 1989, 2001); see Fig 1 and 2. Although PVL can occur in utero or in the early days after preterm or term birth, 75% of infants with PVL are preterm (Blackburn, 1998). PVL is proposed to be the result of multiple factors that cause hypoxic-ischemic injury. This injury typically occurs in premature infants between 26 and 34 weeks of gestation (Jelinski, Yager, & Juurlink, 1998). Despite the fact that this injury occurs early in development, evidence of the extent of injury may not be apparent until some time later in the child's maturity (Hack et al., 2002; McCormick & Richardson, 2002).

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This article reviews particular aspects of the developing brain and presents research that may explain its vulnerability. Research on proposed treatment options, the role of nursing in identifying neonates at risk, implications for nursing management, and future implications for research also are discussed.

Background

Preterm birth is defined as live birth that occurs before 37 weeks of gestation. In 1996, 9.7% of all births in the United States were preterm (Centers for Disease Control and Prevention [CDC], 1999). This was an increase of 0.3% from 1989 (CDC). According to the CDC, significant disparities exist among non-multiple-birth preterm infants of different ethnicities. Black neonates are two times more likely to be born preterm than white non-Hispanic neonates (16.3% versus 8.1%, respectively). American Indian and Alaskan native neonates are 11.0% more likely to be born premature, Hispanic 10.1%, and Asian/Pacific Islander 9.3%.

Preterm infants are placed at further risk when they are born weighing less than 2.5 kg. Low-birth-weight neonates account for 11% of all births in the United States, and of those who survive, the combined risk factors of prematurity and low birth weight place them at a 32% higher probability of developing PVL. These preterm and low-birth-weight infants are 40% more likely to have long-term sequelae, usually due to brain injury (Greene, 2002; Olsen, Paakko, Vainionpaa, Pyhtinen, & Jarvelin, 1997; Wood, Marlow, Costeloe, Gibson, & Wilkinson, 2000).

Brain injury in preterm infants is of critical concern because the brain is still developing. PVL can have long-term effects on all aspects of physical, motor, sensory, cognitive, and social development (Greene, 2002; Hack et al., 2002; McCormick & Richardson, 2002). The propensity for injury to the brain in preterm infants is due to the oxidative stress placed on all neonates during the birthing process, the immaturity of the developing nervous system, and the immaturity of the cerebrovascular supply. This places preterm neonates at risk for ischemic episodes that can lead to free-radical production, which can then damage the precursors of myelinating cells (Grinspan, 1998; Lou, Lassen, & Friis-Hansen, 1979; Lou, Lassen, Skov, & Pederson, 1979; Robles, Palomino, & Robles, 2001; Takashima & Tanaka, 1978; Yoshida-Shuto, Yasuhara, & Kobayashi, 1992).

Pathophysiology

Oxidative Stress

Robles et al. (2001) studied 10 healthy full-term neonates and 10 preterm neonates and found that the birthing process places all neonates under oxidative stress. They reported that the full-term neonates had levels of hydroperoxides, which are measures of oxidative stress, that dropped sharply in the first few hours following birth and dropped by as much as 50% by day 3 after birth. However, in premature infants these hydroperoxides were present at near birth levels for as long as a week and at dangerously high levels for even longer. Therefore, preterm neonates are at risk for free-radical injury during this initial period. Markers for free-radical scavengers also were measured, and the researchers reported that the levels in both term and preterm neonates were low right after birth, which demonstrates that the stress of birth overpowers all neonates' ability to compensate. However, the younger the gestational age, the lower the levels for markers of free radicals. Therefore, premature infants were at risk for brain injury because of the high levels of free radicals and their decreased antioxidant defenses that lasted at least a week after birth.

Myelination

Brain development begins as early as 3 weeks after the fertilization of an ovum. However, even after a 40-week gestation period brain development is not complete. Many of its axons are not yet myelinated. It is not until after birth that the primary sensory and motor axons begin myelination. The myelination of these axons is finished shortly thereafter. However, axons implicated in cognitive and associative functions do not complete myelination until the first 6-8 years of life (Scheibel, 1997). Further, axons involved in executive functions from the prefrontal lobes continue the myelination process well into the second decade of life (Klingberg, Vaidya, Gabrieli, Moseley, & Hedehus, 1999).

Oligodendrocytes are the cells responsible for the myelination of the central nervous system. Neuroblasts, the precursors to these cells, arise from the germinal matrix zones in the brain. The neuroblasts must multiply, migrate to the proper location, and differentiate during neurogenesis (Grinspan, 1998; Shen, Xueming, Capela, & Temple, 1998). However, in rat pups these precursors have been identified as susceptible to apoptosis caused by oxidative stress (Grinspan; Jelinski et al., 1998). Further, neuroblasts seem to be susceptible to injury because of their reduced peroxide-scavenging abilities (Juurlink, Thorburne, & Hertz, 1998). This means these cells are particularly vulnerable to free-radical attack, which is a common element of ischemic-reperfusion injuries and oxidative stress (Robles et al., 2001; Volpe, 2001). Because oligodendrocytes are responsible for myelinating an average of 15 axons each, damage to one can affect many neurons (Kandel, Schwartz, & Jessel, 2000).

Cerebrovascular Supply and Hemodynamics

Takashima and Tanaka (1978) identified key factors in the development of the vascular structure of the developing brain that may explain the tendency for injury in preterm infants. They reported that cerebrovascular development at 28 weeks gestation is very simplistic, with less tortuous vessels and minimal branching especially in the periventricular white matter, which is supplied by the ventriculofugal branches of the striate arteries. They found that as age of gestation increased, so did branches in the periventricular white matter. They further reported that in infants 1 month after birth (in a 40-week gestation) branches were well developed.

Miyawaki, Masui, and Takashima (1998) further reported that vessel density in the deep white matter was high at 16-24 weeks of gestation, and then transiently low at 28-36 weeks of gestation, followed by an increase after 39 weeks of gestation. This finding could explain why PVL typically occurs between 26 and 34 weeks of gestation (Jelinski et al., 1998).

Cerebral blood vessels in the premature infant also may have an immature contraction mechanism that may render them vulnerable to ischemia. Wagerle, Moliken, and Russo (1995) studied ovine fetal and newborn cerebral arterial contraction responses and found that contractile reactivity of middle cerebral arteries to norepinephrine was highest in early gestation and significantly (p [less than or equal to] .05) decreased as the fetus matured. Therefore, when the immature sympathetic nervous system causes contraction of the cerebral blood vessels, they may lack the ability to counteract this. This reduced vessel size can decrease or completely abolish blood flow to areas that have an already limited number of blood vessels, such as the periventricular region, thus exposing them to ischemic injury (Miyawaki et al., 1998; Takashima & Tanaka, 1978).

Another related factor in this population is autoregulation, which is not fully functional in preterm neonates. If autoregulation is impaired, then cerebral perfusion pressure is not maintained and cerebral blood flow can become pressure passive. Because preterm neonates also are vulnerable to hypotension, they may be at risk for further ischemic events (Lou, Lassen, & Friis-Hansen, 1979; Lou, Lassen, Skov, & Pedersen, 1979; Volpe, 2001).

However, Weindling and Kissack (2001) proposed that cerebral blood flow in the preterm neonate is not always subjective to blood pressure as had been thought. They proposed that cerebral blood flow is sometimes influenced by cardiac output. They studied 26 preterm neonates who were less than 32 weeks gestation and weighed less than 1,500 g. Using the principles of the Fick equation, which calculates the tissue oxygen consumption based on the cardiac output times the difference between the arterial and venous levels of oxygen (V[O.sub.2] = Q x (Ca[O.sub.2] - Cv[O.sub.2]), the authors calculated the amount of oxygen consumed by tissues during the first 12 hours after birth. They found an inverse relationship between cardiac output and the amount of oxygen extracted in cerebral tissues in 100% of their participants (N = 26). They argued that blood pressure had no correlation to cerebral oxygen extraction and its measurement did not warn researchers of these neonates' low cardiac output, which increased cerebral aerobic demands and cellular metabolism. An explanation for these results is that autoregulation remained intact in all these participants; however, failure of autoregulation is common in this population.

Free-Radical Injury

When cells have been under ischemic conditions and then experience a reperfusion of blood, free radicals are produced, which in turn cause a cascade of events that damage or kill cells. Free radicals cause cell membrane destruction, which in turn causes the release of lipid metabolites and glutamate. Release of lipid metabolites initiates the arachadonic acid cascade, while release of glutamate initiates neurotransmitter excitation. Neurotransmitter excitation allows the influx of [Ca.sup.2+] and [Na.sup.+] into cells while water and [Cl.sup.-] follow passively. This sudden swelling of the intracellular environment, coupled with [Ca.sup.2+] overload in the mitochondria, leads to cell dysfunction, eventually necrosis, and in some cases apoptosis (Fiskum, 2000; Verma, 2000; Zipfel, Babcock, Lee, & Choi, 2000).

Treatment Concerns

An important treatment consideration of neonates involves prevention of a primary or secondary brain injury. Current approaches include maintaining mean arterial pressure within a safe range, which may in turn help to maintain cerebral blood flow. However, regulation of cerebral blood flow in this population is confounding to researchers.

It is still not clear what minimal amount of cerebral blood flow is required to perfuse white matter in preterm infants. Studies have shown that very low volumes (1.6-3.0 ml per 100 g per min) of cerebral blood flow are found in surviving preterm neonates who have normal to near-normal neurologic outcomes (Altman et al., 1988; Greisen & Borch, 2001; Greisen & Trojaborg, 1987 [as cited in Volpe, 2001]). However, both preterm and full-term infants are shown to have poor neurologic outcomes from both low and high cerebral blood flow. This is due to the immaturity and fragility of the germinal matrix. Therefore, the range of cerebral blood flow needed to per fuse brain tissue in the preterm neonate is very narrow (Lou, Lassen, & Friis-Hansen, 1979; Lou, Lassen, Skov, & Pedersen, 1979; Rosenbaum, Almli, Yundt, Altman, & Powers, 1997; Skov, Lou, & Pedersen, 1984).

Pharmacological treatments being considered for prevention of ischemic injury are also raising concerns, because their effects in vitro are not always reproducible in neonates. Researchers propose that some of these treatments may also pose additional risks for injury within this vulnerable population.

Vitamin E

Understanding that the precursors to oligodendroglia are particularly vulnerable to free-radical attacks leads to the question, can this injury be prevented by using free-radical scavengers? Oka, Belliveau, Rosenberg, and Volpe (1993) studied the use of vitamin E as a free-radical scavenger in vitro and reported promising results in prevention of injury to immature oligodendroglia. They reported that even when added many hours after the onset of injury, vitamin E was able to rescue these immature cells from free-radical death. Conversely, studies involving the administration of vitamin E intramuscularly to preterm neonates for their first 3 days after birth did report a reduction of periventricular hemorrhage, yet they failed to show a decrease in overall morbidity and mortality (Chiswick, Gladman, Sinha, Toner, & Davies, 1991; Sinha, Davies, Toner, Bogle, & Chiswick, 1987). Although this medication itself is not believed to have caused any damage, the evidence is not conclusive that this medication is effective as a preventive treatment for PVL.

Dexamethasone

Initially, it was thought that dexamethasone, known to assist in the prevention of secondary brain injury, would be beneficial in preventing PVL. However, its use for prevention of chronic lung disease in preterm infants also has revealed that dexamethasone can be responsible for harmful neurologic effects in this population.

Shinwell et al. (2000) studied 248 premature neonates after birth. Participants received either a 3-day course of intravenous (IV) dexamethasone or a control of saline for treatment of respiratory distress syndrome. On follow-up after discharge, 190 neonates survived, with 159 available for follow-up evaluation. The mean age was 53 months with a range of 24-71 months. They reported that of those who had received dexamethasone (n = 80), there was a 49% frequency of cerebral palsy (CP, n = 39). These findings were compared with the control group (n = 79), which had a 15% frequency of CP (n = 12). Therefore, other factors may have contributed to the neurologic injury reported in both the treatment and control group, but dexamethasone may have placed them at an increased risk.

Magnesium Sulfate

There has also been a growing enthusiasm for the use of magnesium sulfate to prevent brain injury because of its vasodilator, antioxidant, and anticytokine effects (Volpe, 2001). However, studies of women who received magnesium sulfate as a tocolytic agent antenatally showed a higher incidence of morbidity and mortality in preterm neonates (Grether, Hoogstrate, Walsh-Green, & Nelson, 2000; Mittendorf et al., 1997). The morbidity associated with antenatal magnesium sulfate might be explained by one study's results. Rantonen et al. (2001) reported that use of magnesium sulfate as a tocolytic was associated with decreased cerebral per fusion pressure and blood flow in the anterior cerebral artery and internal carotid artery during the first day of life (p < .05). They also reported that during the entire study period systolic blood pressures and pulse pressure in the neonates exposed to magnesium sulfate were lower than those in the controls. However, other studies have not been able to reproduce these findings (Pezzati et al., 2001). Hence, magnesium sulfate may not be a neuroprotectant in this population as was hypothesized.

These studies show that careful consideration must be given to all treatments and interventions implemented with this population because so little is known about their immediate and long-term effects. Further, in vitro studies have not always been able to replicate the complicated interactions of the human body systems. Therefore, these studies are not always predictive of a treatment's human success.

Nursing Considerations

In light of the fact that no treatments exist without possibility of consequence, current treatment is still aimed at injury prevention. Maintenance of cerebral blood flow and protection of cerebral oxygenation are important in the prevention of PVL (Weindling & Kissack, 2001). This is why nurses play such a pivotal role in the care of this vulnerable population. Awareness of complex physiological interactions that affect cerebral blood flow and oxygenation can help nurses to refine their assessment on these important factors and identify those individuals who may be at risk for this injury. Three key questions can be asked to help identify factors that can place an individual at risk: Can this directly or indirectly affect oxygenation? Can this increase metabolic demand of oxygen? Can this prevent or decrease blood supply to the brain?

Nurses should monitor for adequate aeration, assessed by auscultation. This is an indication of the amount of lung surface that is available to diffuse oxygen. Increased secretions and pooling in the lungs also can decrease the diffusion of gases and should be suctioned (Willis, 1997). However, suctioning can be responsible for episodes of hypoxemia and increased intracranial pressure, blood pressure, and cerebral perfusion pressure in preterm infants (Durand, Sangha, Cabal Hoppenbrouwers, & Hodgman, 1989; Norris, Campbell, & Brenkert, 1982). Suctioning in this population should not be performed routinely, but based on need. Patients should be pre-oxygenated before suctioning and suctioning should be limited to 15 seconds and a maximum of two passes (Pritchard, Flenady, & Woodgate, 2002; Young, 1995). Arterial oxygenation (Sa[O.sub.2]) should be maintained at higher than 90% because below this there is a significant decrease in oxygen delivered to tissues (Willis, 1997).

Monitoring laboratory values is an important nursing role. Arterial blood gases are important to examine because these values can have a direct effect on cerebral blood flow and oxygenation. An increased PaC[O.sub.2] is significant because this is a powerful vasodilator and can lead to increased intracranial pressure (Willis, 1997). Severe decreases in PaC[O.sub.2] (hypocapnia) also can cause cerebral vasoconstriction, reducing cerebral blood flow and severely reducing tissue P[O.sub.2] by approximately one-third (Greisen & Vannucci, 2001). Alterations in pH level in either direction can affect the amount of oxygen that is supplied to tissues. A decreased pH (acidosis) causes hemoglobin to dissociate from oxygen readily while an increased pH (alkalosis) causes hemoglobin to conserve oxygen (Willis, 1997). Observation for a decrease in hemoglobin or hematocrit is important because decreases in either can reduce the blood's ability to carry enough oxygen to the brain. Electrolyte imbalances can indirectly affect cerebral blood flow and oxygen consumption. Therefore, electrolytes should be carefully maintained in a normal range (Hickey, 1997).

With frequent assessments, nurses can prevent and initiate treatment for fever, hypothermia, infection, hypoglycemia, and pain. These factors can increase the metabolic demand for oxygen at the cellular level (Willis, 1997). Greisen and Borch (2001) recommend maintaining a minimum mean arterial pressure of 30 mm Hg in preterm infants between 26 and 32 weeks gestation, because this has been shown to maintain cerebral perfusion in areas more sensitive to low blood flow such as the periventricular white matter. Conversely, hypertension can be associated with periventricular or intraventricular hemorrhage, which can then interrupt blood supply to adjacent areas (Gronlund, Korvenranta, Kero, Jalonen, & Valimaki, 1994).

For neonates who maintain autoregulation, cardiac output may be a better indicator of cellular oxygen needs because it has been shown to be inversely related to oxygen extraction at the cellular level (Weindling & Kissack, 2001). Cardiac output is a function of stroke volume and heart rate (CO = SV x HR). Stroke volume is influenced by preload, afterload, and contractility. If heart rate is elevated, its cause should be deciphered. If it is due to a decrease in vascular volume, then fluid resuscitation should be initiated. A decrease in vascular volume will decrease preload, which is the amount of stretch during diastole. This will decrease stroke volume, which can decrease cardiac output and increase extraction of oxygen at the tissue level (Vitello-Cicciu & O'Sullivan, 1993; Weindling & Kissack, 2001). A decreased PaC[O.sub.2] (hypocapnia) is usually due to controlled ventilation and can cause peripheral vasoconstriction. This peripheral vasoconstriction causes an increase in systemic vascular resistance, which increases afterload. Increased afterload can cause a decrease in cardiac output. Heart rate also will influence cardiac output and therefore should be monitored (Vitello-Cicciu & O'Sullivan).

Maintaining position of the head in supine midline has been shown to support cerebral venous drainage and prevent elevation of cerebral blood volume (Pellicer, Gaya, Madero, Quero, & Cabanas, 2002). Decreasing the number of interventions and unnecessary stimuli that these neonates receive will decrease stress. This stress is known to have detrimental effects on preterm infants (Appleton, 1997).

Nurses also play an important role with parents by providing teaching and anticipatory guidance in neonates who may be affected by or at risk for PVL. By modeling developmentally appropriate interaction and encouraging parental involvement in their child's care, nurses can promote parent-infant interaction (Blackburn, 1998).

Conversant care of these patients will help to identify factors that may place individuals at risk. After identifying at-risk individuals, nurses can initiate more frequent assessments and treatment regimes aimed at further preventing decreased cerebral blood flow and cerebral oxygenation.

Outcomes

Some neonates will die from the initial hypoxic or hemorrhagic injury (Blackburn, 1998). However, of those who survive the initial injury, the long-term outcomes for neonates with PVL have been shown to vary. Some develop visual, motor, and cognitive impairments, attention problems, and visual-spatial deficits. For those neonates who develop cystic lesions, the most typical sequelae are spastic diplegia of the legs possibly with coexisting hydrocephalus. However, not all children develop the same neurologic deficits or have the same degree of deficit (Blackburn, 1998; Han, Bang, Lim, Yoon, & Kim, 2002; Porton-Deterne et al., 2000). Olsen et al. (1997) studied 84 children at 8 years. Of these children, 42 were born preterm, and 42 full term. Of the preterm children who also had CP, 100% had magnetic resonance imaging (MRI) findings that were consistent with PVL. They also reported that of the children with minor neurologic dysfunction, MRI findings for 25% were consistent with PVL. However, they also reported that of the children with no neurologic dysfunction, the MRI findings for 25% were consistent with PVL. This demonstrates that a diagnosis of PVL does not always mean poor neurological outcome. It also demonstrates that MRI is a good diagnostic tool but may not be predictive of outcome. These authors suggest that neurologic examinations are better predictors of future outcomes. Serial ultrasound or computed tomography (CT) scans also can be used as a diagnostic tool to trail the succession of the lesion or monitor neonates at risk (Blackburn, 1998).

Future Considerations

Volpe (2001) advocated for the use of near-infrared spectroscopy to measure real-time concentrations of oxygenated and deoxygenated hemoglobin as an indirect measure of cerebral blood flow. Although this non-invasive device is not yet available for clinical application, preliminary studies show that it may identify abnormalities in pressure-passive cerebral circulation, which can then be treated (Soul, Taylor, Wypij, Du Plessis, & Volpe, 2000; Tsuji, Du Plessis, Taylor, Crocker, & Volpe, 1998). This type of monitoring would be ideal to help nurses identify neonates at risk.

Randomized and controlled clinical trials with larger populations of preterm infants need to be performed to clarify which treatments have a future. Also needed is a better understanding of what constitutes a safe range of cerebral blood flow in this population and how to best monitor and influence it without causing deleterious effects. With the large number of preterm deliveries and increased survival at younger gestational ages, these questions have an imminent importance.

Summary

PVL is a potentially preventable brain injury in preterm neonates who do not have prenatal lesions. Nurses have the ability to influence the care of this vulnerable population through their thorough and frequent assessments, interventions, and evaluations. Understanding the pathophysiologic concerns in this population can help nurses systematically monitor preterm neonates for key factors that can affect cerebral blood flow and cerebral oxygenation.

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Questions or comments about this article may be directed to: Cecelia I. Roscigno, BSN RN CNRN, by e-mail at graymt@u.washington.edu. She is a predoctoral research fellow in biobehavorial nursing and a student in the Doctor of Philosophy in nursing program at the University of Washington, Seattle.
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Author:Roscigno, Cecelia I.
Publication:Journal of Neuroscience Nursing
Geographic Code:1USA
Date:Dec 1, 2002
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