Acute Diffusion-Weighted Imaging Signaling Severe Periventricular Leukomalacia in Preterm Infants: Case Report and Review of Literature.

Introduction: Periventricular leukomalacia occurs in up to 25% of very preterm infants resulting in adverse neurodevelopmental outcomes. In its acute phase, periventricular leukomalacia is clinically silent. Although ultrasonography is widely available, its sensitivity in the early detection of periventricular leukomalacia is low. Case Report and Published Literature: We identified a preterm infant with early diffusion-weighted imaging changes that later evolved to periventricular leukomalacia. Thirty-two cases of abnormal diffusion-weighted imaging reliably heralding severe periventricular leukomalacia in the preterm infant have been published in the literature. Notable features include the following: (1) infants were more mature preterm infants (29-36 weeks' gestation); (2) findings were often serendipitous with benign clinical courses; (3) diffusion-weighted imaging changes only were evident in the first weeks of life with later evolution to more classical abnormalities on conventional magnetic resonance imaging (MRI) or ultrasonography. Conclusion: Diffusion-weighted imaging in the first week of life may be a reliable early marker of severe periventricular leukomalacia injury in more mature preterm infants.

A quality improvement initiative to reduce acid-suppressing medication exposure in the NICU.

BACKGROUND: Acid-suppressing medications (ASMs) are commonly prescribed in the neonatal intensive care unit (NICU), in particular among preterm infants, despite well-established adverse effects and little evidence to support efficacy. LOCAL PROBLEM: We sought to develop an initiative to reduce ASM exposure in our predominantly inborn level III NICU. Our specific aim was to reduce the number of nonindicated ASM prescriptions by 50% within a 12-month period. METHODS: Our multidisciplinary team developed an evidence-based guideline defining indications for ASM prescription in a level III NICU. Plan-do-study-act cycles included staff education, formal clinical practice guideline implementation, and implementation of standardized documentation tools in the electronic health record (EHR). Outcome measures were the number of nonindicated and total inpatient prescriptions started per month, duration of ASM prescription, and number of prescriptions continued after NICU discharge. Balancing measures were the number of patients started on thickened feeds and number of patients discharged home on nasogastric tube feeds. We used statistical process control and Pareto charts to assess these measures over a 12-month baseline period, 9-month implementation period, and 19-month post-implementation period spanning September 2017-December 2020. RESULTS: Nonindicated ASM prescriptions decreased from median 3 to 0 per month from the baseline to post-implementation period. Simultaneously, the median number of ASM prescriptions at discharge declined from 2 to 0 per month. The median duration of inpatient prescriptions declined from 23 to 7 days. Rates of patients started on thickened feeds and patients discharged home on nasogastric tube feeds remained stable throughout the study. CONCLUSION: Enactment of an evidence-based guideline was associated with a substantial decline in nonindicated ASM use in our NICU and a decline in duration of exposure to ASM's when prescribed. Our interventions proved effective in altering clinical practice and could be applied to other NICUs with similar patient populations aiming to reduce ASM use.

Protection of melatonin in experimental models of newborn hypoxic-ischemic brain injury through MT1 receptor.

The function of melatonin as a protective agent against newborn hypoxic-ischemic (H-I) brain injury is not yet well studied, and the mechanisms by which melatonin causes neuroprotection in neurological diseases are still evolving. This study was designed to investigate whether expression of MT1 receptors is reduced in newborn H-I brain injury and whether the protective action of melatonin is by alterations of the MT1 receptors. We demonstrated that there was significant reduction in MT1 receptors in ischemic brain of mouse pups in vivo following H-I brain injury and that melatonin offers neuroprotection through upregulation of MT1 receptors. The role of MT1 receptors was further supported by observation of increased mortality in MT1 knockout mice following H-I brain injury and the reversal of the inhibitory role of melatonin on mitochondrial cell death pathways by the melatonin receptor antagonist, luzindole. These data demonstrate that melatonin mediates its neuroprotective effect in mouse models of newborn H-I brain injury, at least in part, by the restoration of MT1 receptors, the inhibition of mitochondrial cell death pathways and the suppression of astrocytic and microglial activation.

Bumetanide enhances phenobarbital efficacy in a rat model of hypoxic neonatal seizures.

Neonatal seizures can be refractory to conventional anticonvulsants, and this may in part be due to a developmental increase in expression of the neuronal Na(+)-K(+)-2 Cl(-) cotransporter, NKCC1, and consequent paradoxical excitatory actions of GABAA receptors in the perinatal period. The most common cause of neonatal seizures is hypoxic encephalopathy, and here we show in an established model of neonatal hypoxia-induced seizures that the NKCC1 inhibitor, bumetanide, in combination with phenobarbital is significantly more effective than phenobarbital alone. A sensitive mass spectrometry assay revealed that bumetanide concentrations in serum and brain were dose-dependent, and the expression of NKCC1 protein transiently increased in cortex and hippocampus after hypoxic seizures. Importantly, the low doses of phenobarbital and bumetanide used in the study did not increase constitutive apoptosis, alone or in combination. Perforated patch clamp recordings from ex vivo hippocampal slices removed following seizures revealed that phenobarbital and bumetanide largely reversed seizure-induced changes in EGABA. Taken together, these data provide preclinical support for clinical trials of bumetanide in human neonates at risk for hypoxic encephalopathy and seizures.

The clinically available NMDA receptor antagonist, memantine, exhibits relative safety in the developing rat brain.

The N-methyl-d-aspartate glutamate receptor (NMDAR) has been implicated in preterm brain injury (periventricular leukomalacia (PVL)) and represents a potential therapeutic target. However, the antagonist dizocilpine (MK-801) has been reported to increase constitutive neuronal apoptosis in the developing rat brain, limiting its clinical use in the developing brain. Memantine is another use-dependent NMDAR antagonist with shorter binding kinetics and has been demonstrated to be protective in a rat model of PVL, without effects on normal myelination or cortical growth. To further evaluate the safety of memantine in the developing brain, we demonstrate here that, in contrast to MK-801, memantine at neuroprotective doses does not increase neuronal constitutive apoptosis. In addition, there are no long-term alterations in the expression of NMDAR subunits, AMPAR subunits, and two markers of synaptogenesis, Synapsin-1 and PSD95. Evaluating clinically approved drugs in preclinical neonatal animal models of early brain development is an important prerequisite to considering them for clinical trial in preterm infants and early childhood.

NMDA receptor blockade with memantine attenuates white matter injury in a rat model of periventricular leukomalacia.

Hypoxia-ischemia (H/I) in the premature infant leads to white matter injury termed periventricular leukomalacia (PVL), the leading cause of subsequent neurological deficits. Glutamatergic excitotoxicity in white matter oligodendrocytes (OLs) mediated by cell surface glutamate receptors (GluRs) of the AMPA subtype has been demonstrated as one factor in this injury. Recently, it has been shown that rodent OLs also express functional NMDA GluRs (NMDARs), and overactivation of these receptors can mediate excitotoxic OL injury. Here we show that preterm human developing OLs express NMDARs during the PVL period of susceptibility, presenting a potential therapeutic target. The expression pattern mirrors that seen in the immature rat. Furthermore, the uncompetitive NMDAR antagonist memantine attenuates NMDA-evoked currents in developing OLs in situ in cerebral white matter of immature rats. Using an H/I rat model of white matter injury, we show in vivo that post-H/I treatment with memantine attenuates acute loss of the developing OL cell surface marker O1 and the mature OL marker MBP (myelin basic protein), and also prevents the long-term reduction in cerebral mantle thickness seen at postnatal day 21 in this model. These protective doses of memantine do not affect normal myelination or cortical growth. Together, these data suggest that NMDAR blockade with memantine may provide an effective pharmacological prevention of PVL in the premature infant.