Cerebroprotective actions of hydrogen sulfide in the epileptic brain in newborn pigs.

BACKGROUND: Neonatal epileptic seizures cause postictal dysregulation of cerebral blood flow. Hydrogen sulfide (H2S), a mediator with vasodilator and antioxidant properties, is produced in the brain by astrocyte cystathionine ß-synthase (CBS). This study investigated whether H2S improves the cerebral vascular outcome of seizures. METHODS: Epileptic seizures were induced in newborn pigs using bicuculline. The effects of the CBS inhibitor aminooxyacetate (AOA) and the H2S donor NaHS on cerebral vascular outcome of seizures were examined in live pigs, cerebral endothelial cells, and cortical astrocytes. RESULTS: Brain H2S was elevated during seizures. AOA blocked H2S and reduced functional hyperemia in the epileptic brain. The endothelium- and astrocyte-dependent vasodilation of pial arterioles was impaired 48 h after seizures suggesting cerebral vascular dysfunction. Systemic NaHS elevated brain H2S and blocked reactive oxygen species in the epileptic brain and in primary endothelial cells and astrocytes during inflammatory and excitotoxic conditions. Postictal cerebrovascular dysfunction was exaggerated in H2S-inhibited pigs and minimized in NaHS-treated pigs. CONCLUSIONS: H2S elevation in the epileptic brain via activation of CBS contributes to functional hyperemia and exhibits cerebroprotective properties. The H2S donor NaHS enhances brain antioxidant defense and provides a therapeutic approach for preventing adverse cerebral vascular outcome of neonatal epileptic seizures. IMPACT: Epileptic seizures in neonates lead to prolonged postictal cerebral vascular dysregulation. The role of hydrogen sulfide (H2S), a mediator with vasodilator and antioxidant properties, in the epileptic brain has been explored. Astrocytes are major sites of enzymatic H2S production in the epileptic brain. Postictal cerebral vascular dysfunction is exaggerated when astrocyte H2S production is pharmacologically inhibited during seizures. Postictal cerebral vascular dysfunction is minimized when the brain H2S is elevated by systemic administration of NaHS during seizures. NaHS provides a therapeutic approach for improving cerebrovascular outcome of epileptic seizures via a mechanism that involves the antioxidant potential of H2S.

Assessing Neonatal Opioid Withdrawal Syndrome Severity as a Function of Maternal Buprenorphine Dose and Umbilical Cord Tissue Concentrations.

BACKGROUND: Infants born to mothers with opioid use disorder (OUD) and prenatally treated with buprenorphine have a significantly lower incidence of neonatal opioid withdrawal syndrome (NOWS), its treatment duration, and hospital length of stay compared with methadone. However, risk of NOWS remains and clinicians continue to lack an objective methodology to predict NOWS severity among these infants. OBJECTIVE: The purpose of this study was to assess the relationship between buprenorphine exposure, umbilical cord tissue (UCT) concentrations, and NOWS development and severity. METHODS: A single-center retrospective observational cohort study from March 2018 through June 2020 of newborns exposed to buprenorphine in utero. Associations between quantified buprenorphine exposure, neonatal UCT concentrations, NOWS diagnosis, and severity were made using regression analyses. RESULTS: A total of 24 mothers and 25 neonates were included. Length of maternal buprenorphine therapy (months) positively correlated to norbuprenorphine (r2 = 0.234, P = 0.019) and buprenorphine + norbuprenorphine UCT concentrations (r2 = 0.203, P = 0.031). A positive relationship was seen between active metabolite concentrations and cumulative morphine dose (mg/kg) for treatment of severe NOWS (r2 = 0.471, P = 0.007). A 0.36 ng/g buprenorphine + norbuprenorphine UCT (CI = 0.002-0.72, P = 0.049) equated in a 1-point increase in modified peak Finnegan score. CONCLUSION AND RELEVANCE: Buprenorphine and norbuprenorphine UCT concentrations can allow for quantification of in utero fetal exposure and demonstrate an association with a longer duration of exposure with the severity and treatment of NOWS in exposed infants.

A Newborn Infant with Congenital Central Hypoventilation Syndrome and Pupillary Abnormalities: A Literature Review.

We present a neonate with early onset apnea and bradycardia in the absence of primary cardiorespiratory and central nervous system disorders that eventually required chronic ventilator support starting at 6 hours of life. Molecular testing of paired-like homeobox 2b (PHOX2B) gene mutation confirmed the diagnosis of congenital central hypoventilation syndrome (CCHS). CCHS is a rare genetic disorder characterized by impaired central respiratory control with or without broad spectrum of autonomic nervous system (ANS) dysregulations. Ocular ANS dysregulation is a rare finding in CCHS individuals, and it is usually discovered later in life. However, the ophthalmic evaluation of this neonate on first day of life revealed persistent mild dilated oval pupils with limited light reactivity.

Early-Onset Fulminant Sepsis in a Preterm Neonate due to Streptococcus gallolyticus : A Case Report and Literature Review.

Streptococcus gallolyticus is an uncommon cause of neonatal infections. We describe the first case of fulminant lethal neonatal sepsis due to S. gallolyticus reported in literature. Our patient was an extremely low birth weight premature infant born to a mother with prolonged rupture of amniotic membranes and chorioamnionitis. We also review the cases of neonatal S. gallolyticus infections reported in literature. Fifty-eight percent neonatal S. gallolyticus infections presented in the first week of life. Importantly, S. gallolyticus meningitis is more commonly reported with early-onset infections compared with group B streptococcal meningitis, which is more common with late-onset infections. Streptococcus gallolyticus should be included in differential for neonatal sepsis, particularly in the presence of meningitis in the first week of life. Most cases are sensitive to penicillin; however, cases of reduced sensitivity to penicillin have also been reported.

The effects of sodium bicarbonate infusion on cerebrovascular function in newborn pigs.

BACKGROUND: Sodium bicarbonate (NaHCO3) is no longer recommended by the Neonatal Resuscitation Program (NRP), but is still being used by some neonatologists. The effects of NaHCO3 on cerebral hemodynamics are unclear. Therefore, we investigated the effects of NaHCO3 on cerebral blood flow (CBF) and cerebrovascular function using a newborn piglet model. METHODS: Newborn pigs were anesthetized, intubated, and ventilated. Cranial windows were implanted to evaluate changes in pial arteriolar diameters (PADs) as a surrogate for CBF during a 4-h intravenous infusion of 3% NaHCO3. Cerebrovascular reactivity to vasodilators and vasoconstrictors was investigated during vehicle control and during NaHCO3 infusion. RESULTS: NaHCO3 infusion caused significant and progressive pial arteriolar vasoconstrictions. During NaHCO3 infusion, cerebrovascular reactivity was preserved. Adding vasodilators decreased cerebral vasoconstriction, while adding vasoconstrictors exaggerated cerebral vasoconstriction. CONCLUSIONS: Intravenous infusion of NaHCO3 over 4 h caused progressive vasoconstriction of pial arterioles. Cerebrovascular function evaluated by the responses of pial arterioles to physiologically relevant vasoconstrictors and vasodilators was preserved during NaHCO3 infusion. A notable additional reduction of PADs was observed during NaHCO3 infusion in the presence of vasoconstrictors. Extrapolating our findings to human neonates should alarm the clinicians that using NaHCO3 in neonates may cause cerebral hypoperfusion. IMPACT: Cerebral vasoconstriction occurs during slow infusion of 3% diluted NaHCO3. Cerebral vasoconstriction is exaggerated when another vasoconstrictor is added during NaHCO3 infusion. Cerebrovascular function is preserved during NaHCO3 infusion. Clinicians should be aware of the risk of cerebral hypoperfusion with NaHCO3 infusion in vulnerable neonates.

The cold receptor TRPM8 activation leads to attenuation of endothelium-dependent cerebral vascular functions during head cooling.

Using the cranial window technique, we investigated acute effects of head cooling on cerebral vascular functions in newborn pigs. Head cooling lowered the rectal and extradural brain temperatures to 34.3 ± 0.6°C and 26.1 ± 0.6°C, respectively. During the 3-h hypothermia period, responses of pial arterioles to endothelium-dependent dilators bradykinin and glutamate were reduced, whereas the responses to hypercapnia and an endothelium-independent dilator sodium nitroprusside (SNP) remained intact. All vasodilator responses were restored after rewarming, suggesting that head cooling did not produce endothelial injury. We tested the hypothesis that the cold-sensitive TRPM8 channel is involved in attenuation of cerebrovascular functions. TRPM8 is immunodetected in cerebral vessels and in the brain parenchyma. During normothermia, the TRPM8 agonist icilin produced constriction of pial arterioles that was antagonized by the channel blocker AMTB. Icilin reduced dilation of pial arterioles to bradykinin and glutamate but not to hypercapnia and SNP, thus mimicking the effects of head cooling on vascular functions. AMTB counteracted the impairment of endothelium-dependent vasodilation caused by hypothermia or icilin. Overall, mild hypothermia produced by head cooling leads to acute reversible reduction of selected endothelium-dependent cerebral vasodilator functions via TRPM8 activation, whereas cerebral arteriolar smooth muscle functions are largely preserved.

Congenital Perineal Groove Defect in Monozygotic Twin Infants: A Literature Review.

Perineal groove is a rare benign congenital anomaly with lesion that resembles perforation of mid-perineum or perineal raphe area. Most reported cases of congenital perineal groove presented as an isolated defect in term or early-term singleton female infants. Thus far, there is no reported case of this anomaly in monozygotic twins. Embryo pathogenesis of this female predominance congenital defect remains controversial. Many clinicians are unfamiliar with this congenital anomaly. This congenital defect tends to get self-resolved at around 2 year of age. Nevertheless, the exposed nonepithelized mucous membrane can carry risk of local infection or irritation with the possibility of requiring early surgical correction. The defect can be infrequently associated with other ano-urogenital malformations that required immediate surgical intervention. Most isolated cases tend to be asymptomatic and self-healed with expectant management. Surgical correction may be considered if not healed after 2 years of age. Early diagnosis at birth is important to avoid misdiagnoses at later age for trauma, dermatitis, sexual abuse, and risk of unnecessary aggressive intervention. Early parental counseling for providing good hygiene and close follow-up is important to prevent infection or inflammation. Presentation of this anomaly in both monozygotic twins may support the hypothesis of potential disruption during embryo morphogenesis stages.

Racial differences in opioid withdrawal syndrome among neonates with intrauterine opioid exposure.

BACKGROUND: The aim of this study was to investigate the association between race and severe neonatal opioid withdrawal syndrome (NOWS) in infants exposed to intrauterine opioids. METHODS: This is a prospective observational study on intrauterine opioid-exposed term infants. Exposure to opioids was based on maternal disclosure, urine, or umbilical cord drug screening. Severe NOWS was defined based on modified Finnegan scoring and the need for pharmacological intervention. RESULTS: One hundred and fifty mother-infant pairs, 60 Black and 90 White with history of opioid exposure during pregnancy, were included. More White than Black infants developed NOWS that required pharmacological treatment, 70 vs. 40%: RR = 1.75 (1.25-2.45). In adjusted analysis, there was no significant association between race and the development of severe NOWS in mothers who attended opioid maintenance treatment program (OMTP). However, in mothers who did not attend OMTP, White race remained a significant factor associated with the development of severe NAS, RR = 1.69 (1.06, 2.69). CONCLUSIONS: Severe NOWS that required pharmacological intervention was significantly higher in White than in Black infants born to mothers who did not attend OMTP. Larger studies are needed to evaluate the association between social as well as genetic factors and the development of NOWS. IMPACT: There is a significant association between race and development of severe NOWS.

Amplitude-integrated EEG in infants with neonatal abstinence syndrome.

BACKGROUND: To describe amplitude-integrated encephalogram (aEEG) characteristics of neonates with neonatal abstinence syndrome (NAS). METHODS: This is a prospective observational study. Newborns exposed to prenatal opioids and their gestational matched controls were included. A single-channel aEEG was obtained using Olympic 6000 CFM monitor. The background activity (continuous/discontinuous), the amplitudes (µV) and the presence of sleep-wake cycle (SWC) were documented. RESULTS: A total of 59 infants, 23 with NAS and 36 controls were enrolled. All aEEG were completed within 48 hours of life prior to initiation of treatment. Birth weight and gestational age were similar in both groups. An aEEG was abnormal (discontinuous pattern and/or absent SWC) in 78 % (18/23) of infants with NAS versus only 25% in control group (9/36), [OR 10.8, CI (2.7-46.5) P < 0.001]. 61% of infants with NAS had discontinuous pattern [OR 7.8, CI (2-32) P = 0.001] and 39% had absence of sleep-wake cycle [OR 7.1, CI (1.4-39.4) P = 0.007]. CONCLUSIONS: A majority of infants with NAS have abnormal aEEG activity.

H2S mediates the vasodilator effect of endothelin-1 in the cerebral circulation.

H2S is an endogenous gasotransmitter that increases cerebral blood flow. In the cerebral vascular endothelium, H2S is produced by cystathionine δ-lyase (CSE). Endothelin-1 (ET-1) has constrictor and dilator influences on the cerebral circulation. The mechanism of the vasodilation caused by ET-1 may involve endothelium-derived factors. We hypothesize that ET-1-elicited dilation of pial arterioles requires an elevation of H2S production in the cerebral vascular endothelium. We investigated the effects of ET-1 on CSE-catalyzed brain H2S production and pial arteriolar diameter using cranial windows in newborn pigs in vivo. H2S was measured in periarachnoid cerebrospinal fluid. ET-1 (10-12-10-8 M) caused an elevation of H2S that was reduced by the CSE inhibitors propargylglycine (PPG) and ß-cyano-l-alanine (BCA). Low doses of ET-1 (10-12-10-11 M) produced vasodilation of pial arterioles that was blocked PPG and BCA, suggesting the importance of H2S influences. The vasodilator effects of H2S may require activation of smooth muscle cell membrane ATP-sensitive K+ (KATP) channels and large-conductance Ca2+-activated K+ (BK) channels. The KATP inhibitor glibenclamide and the BK inhibitor paxilline blocked CSE/H2S-dependent dilation of pial arterioles to ET-1. In contrast, the vasoconstrictor response of pial arterioles to 10-8 M ET-1 was not modulated by PPG, BCA, glibenclamide, or paxilline and, therefore, was independent of CSE/H2S influences. Pial arteriolar constriction response to higher levels of ET-1 was independent of CSE/H2S and KATP/BKCa channel activation. These data suggest that H2S is an endothelium-derived factor that mediates the vasodilator effects of ET-1 in the cerebral circulation via a mechanism that involves activation of KATP and BK channels in vascular smooth muscle. NEW & NOTEWORTHY Disorders of the cerebral circulation in newborn infants may lead to lifelong neurological disabilities. We report that vasoactive peptide endothelin-1 exhibits vasodilator properties in the neonatal cerebral circulation by stimulating production of H2S, an endothelium-derived messenger with vasodilator properties. The ability of endothelin-1 to stimulate brain production of H2S may counteract the reduction in cerebral blood flow and prevent the cerebral vascular dysfunction caused by stroke, asphyxia, cerebral hypoxia, ischemia, and vasospasm.

Astrocyte-produced carbon monoxide and the carbon monoxide donor CORM-A1 protect against cerebrovascular dysfunction caused by prolonged neonatal asphyxia.

Neonatal asphyxia leads to cerebrovascular disease and neurological complications via a mechanism that may involve oxidative stress. Carbon monoxide (CO) is an antioxidant messenger produced via a heme oxygenase (HO)-catalyzed reaction. Cortical astrocytes are the major cells in the brain that express constitutive HO-2 isoform. We tested the hypothesis that CO, produced by astrocytes, has cerebroprotective properties during neonatal asphyxia. We developed a survival model of prolonged asphyxia in newborn pigs that combines insults of severe hypoxia, hypercapnia, and acidosis while avoiding extreme hypotension and cerebral blood flow reduction. During the 60-min asphyxia, CO production by brain and astrocytes was continuously elevated. Excessive formation of reactive oxygen species during asphyxia/reventilation was potentiated by the HO inhibitor tin protoporphyrin, suggesting that endogenous CO has antioxidant effects. Cerebral vascular outcomes tested 24 and 48 h after asphyxia demonstrated the sustained impairment of cerebral vascular responses to astrocyte- and endothelium-specific vasodilators. Postasphyxia cerebral vascular dysfunction was aggravated in newborn pigs pretreated with tin protoporphyrin to inhibit brain HO/CO. The CO donor CO-releasing molecule-A1 (CORM-A1) reduced brain oxidative stress during asphyxia/reventilation and prevented postasphyxia cerebrovascular dysfunction. The antioxidant and antiapoptotic effects of HO/CO and CORM-A1 were confirmed in primary cultures of astrocytes from the neonatal pig brain exposed to glutamate excitotoxicity. Overall, prolonged neonatal asphyxia leads to neurovascular injury via an oxidative stress-mediated mechanism that is counteracted by an astrocyte-based constitutive antioxidant HO/CO system. We propose that gaseous CO or CO donors can be used as novel approaches for prevention of neonatal brain injury caused by prolonged asphyxia. NEW & NOTEWORTHY Asphyxia in newborn infants may lead to lifelong neurological disabilities. Using the model of prolonged asphyxia in newborn piglets, we propose novel antioxidant therapy based on systemic administration of low doses of a carbon monoxide donor that prevent loss of cerebral blood flow regulation and may improve the neurological outcome of asphyxia.

Does prolonged severe hypercapnia interfere with normal cerebrovascular function in piglets?

BACKGROUND: Hypercapnia causes cerebral vasodilation and increased cerebral blood flow (CBF). During prolonged hypercapnia it is unknown whether cerebral vasodilation persists and whether cerebrovascular function is preserved. We investigated the effects of prolonged severe hypercapnia on pial arteriolar diameters (PAD) and cerebrovascular reactivity to vasodilators and vasoconstrictors. METHODS: Piglets were anesthetized, intubated and ventilated. Closed cranial windows were implanted to measure PAD. Changes in PAD were documented during hypercapnia (PaCO2 75-80 mm Hg). Cerebrovascular reactivity was documented during normocapnia and at 30, 60, and 120 min of hypercapnia. RESULTS: Cerebral vasodilation to hypercapnia was sustained over 120 min. Cerebrovascular responses to vasodilators and vasoconstrictors were preserved during hypercapnia. During hypercapnia, vasodilatory responses to second vasodilators were similar to normocapnia, while exposure to vasoconstrictors caused significant vasoconstriction. CONCLUSIONS: Prolonged severe hypercapnia causes sustained vasodilation of pial arteriolar diameters indicative of hyperperfusion. During hypercapnia, cerebral vascular responses to vasodilators and vasoconstrictors were preserved, suggesting that cerebral vascular function remained intact. Of note, cerebral vessels during hypercapnia were capable of further dilation when exposed to additional cerebral vasodilators and, significant vasoconstriction when exposed to vasoconstrictors. Extrapolating these findings to infants, we suggest that severe hypercapnia should be avoided, because it could cause/increase cerebrovascular injury.

Preventing harmful effects of epileptic seizures on cerebrovascular functions in newborn pigs: does sex matter?

BackgroundThe potential contribution of sex-related variables to cerebrovascular functions in neonates remains elusive. Newborn piglets provide a translationally relevant model for studying the effects of seizures in the neonatal brain. The present study investigated whether sex differences contribute to cerebrovascular functions in healthy and epileptic newborn pigs.MethodsEpileptic seizures were induced in female and male newborn pigs by bicuculline. An antioxidant drug, the carbon monoxide-releasing molecule CORM-A1, was administered enterally before or during seizures. The responses of pial arterioles to endothelium-, astrocyte-, and vascular smooth muscle-dependent vasodilators were tested in intact and 48-h postictal piglets using the cranial window technique.ResultsIn intact newborn pigs, we did not observe any sex-related differences in cerebrovascular functions. In the postictal male and female newborn pigs, a marked reduction in responses of pial arterioles to endothelium- and astrocyte-dependent vasodilators was detected. CORM-A1, administered before or during seizures, greatly improved the outcome of seizures on cerebrovascular functions in both male and female piglets.ConclusionWe found no evidence of sex-related differences in cerebral vasodilator functions in control and epileptic newborn pigs. In both male and female newborns, epileptic seizures lead to prolonged cerebral vascular dysfunction that is effectively prevented by CORM-A1 therapy.

Selective head cooling during neonatal seizures prevents postictal cerebral vascular dysfunction without reducing epileptiform activity.

Epileptic seizures in neonates cause cerebrovascular injury and impairment of cerebral blood flow (CBF) regulation. In the bicuculline model of seizures in newborn pigs, we tested the hypothesis that selective head cooling prevents deleterious effects of seizures on cerebral vascular functions. Preventive or therapeutic ictal head cooling was achieved by placing two head ice packs during the preictal and/or ictal states, respectively, for the ∼2-h period of seizures. Head cooling lowered the brain and core temperatures to 25.6 ± 0.3 and 33.5 ± 0.1°C, respectively. Head cooling had no anticonvulsant effects, as it did not affect the bicuculline-evoked electroencephalogram parameters, including amplitude, duration, spectral power, and spike frequency distribution. Acute and long-term cerebral vascular effects of seizures in the normothermic and head-cooled groups were tested during the immediate (2-4 h) and delayed (48 h) postictal periods. Seizure-induced cerebral vascular injury during the immediate postictal period was detected as terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive staining of cerebral arterioles and a surge of brain-derived circulating endothelial cells in peripheral blood in the normothermic group, but not in the head-cooled groups. During the delayed postictal period, endothelium-dependent cerebral vasodilator responses were greatly reduced in the normothermic group, indicating impaired CBF regulation. Preventive or therapeutic ictal head cooling mitigated the endothelial injury and greatly reduced loss of postictal cerebral vasodilator functions. Overall, head cooling during seizures is a clinically relevant approach to protecting the neonatal brain by preventing cerebrovascular injury and the loss of the endothelium-dependent control of CBF without reducing epileptiform activity.

Perineal Groove: A Rare Congenital Midline Defect of Perineum.

Perineal groove is a rare congenital malformation that is characterized by an exposed wet sulcus with nonkeratinized mucous membrane that extends from the posterior vaginal fourchette to the anterior ridge of the anal orifice. This condition is one of the uncommon anomalies of urogenital/anogenital region that is unknown to many clinicians. Although, this condition may be self-resolved before the age of 2 years, this nonepithelized mucous membrane can pose the risk of local irritation and infection, urinary tract infection, and the possibility of nonself-resolved condition that eventually needs surgical correction. Only a few reported cases (n = 23) were found in current medical literatures. This lesion could be misdiagnosed as contact dermatitis, trauma, or even sexual abuse. Therefore, recognition of the congenital perineal groove at birth is important for the health care providers to deliver an appropriate parental counseling and appropriate follow-up.

Preterm Infants Can Mount Appropriate C-Reactive Protein Responses to Early Onset Sepsis.

OBJECTIVE: This study aims to evaluate whether infants born at ≤ 32 weeks' gestational age (GA) can mount C-reactive protein (CRP) responses during early onset bacterial sepsis that are comparable to infants born at > 32 weeks' GA. METHODS: Retrospectively (2003-2012) infants with a positive bacterial culture during the first 72 hours of life were identified and grouped into two categories based on their GA: ≤ 32 weeks (group A) and > 32 weeks (group B). RESULTS: Group A included 25 and group B included 122 infants. Both groups responded similarly to sepsis with an increase in CRP (p = 0.59). Each group had a significant change in intragroup CRP levels over time (p < 0.0001). However, in both groups, the degree of this change was at the same rate over time (p = 0.74). CONCLUSION: CRP responses to bacterial sepsis during the first 72 hours of life in infants born at ≤ 32 weeks' GA are comparable to infants born at > 32 weeks' GA.

Brain-derived circulating endothelial cells in peripheral blood of newborn infants with seizures: a potential biomarker for cerebrovascular injury.

Neonatal seizures have been associated with cerebrovascular endothelial injury and neurological disabilities. In a piglet model, the long-term loss of endothelial regulation of cerebral blood flow coincides with the surge of brain-derived circulating endothelial cells (BCECs) in blood. We hypothesized that BCECs could serve as a noninvasive biomarker of cerebrovascular injury in neonates with seizures. In a prospective pilot feasibility study, we enrolled newborn infants with confirmed diagnoses of perinatal asphyxia and intraventricular hemorrhage (IVH); both are commonly associated with seizures. Infants without clinical evidence of cerebrovascular injuries were representative of the control group. BCECs were detected in the CD45-negative fraction of peripheral blood mononuclear cells by coexpression of CD31 (common endothelial antigen) and GLUT1 (blood-brain barrier antigen) via automated flow cytometry method. In Infants with asphyxia (n = 12) and those with IVH grade III/IV (n = 5), the BCEC levels were 9.9 ± 0.9% and 19.0 ± 2.0%, respectively. These levels were significantly higher than the control group (n = 27), 0.9 ± 0.2%, P < 0.001. BCECs in infants with cerebrovascular insults with documented clinical seizures (n = 10; 16.8 ± 1.3%) were significantly higher than infants with cerebrovascular insults with subclinical or no seizures (n = 7; 9.5 ± 1.2%); P < 0.001. BCEC levels decreased with seizure control. BCECs levels were elevated in infants with seizures caused by severe IVH and perinatal asphyxia. We suggest that monitoring BCEC levels in peripheral blood can potentially offer a biological marker that reflects cerebrovascular insult and recovery. Further studies with a larger number of patients are required to support these findings.

Ethanol lock therapy: a pilot infusion study in infants.

BACKGROUND: Ethanol lock therapy (ELT) has emerged as an effective method for the prevention and treatment of central line-associated bloodstream infections (CLABSIs), but the safety of ELT in infants has not been established. OBJECTIVE: The objective of this study was to determine blood alcohol concentration (BAC) and evidence of hepatic injury in infants after infusing a small one-time dose of ethanol, equivalent to the volume that would be flushed through the central venous catheter (CVC) after ELT is completed. METHODS: This was a prospective pilot study in infants weighing ≤6 kg with and without liver dysfunction who had a CVC. The primary end points were 5-minute and 1-hour BACs after a 0.4-mL dose of 70% ethanol was flushed through the CVC. Acceptable BACs were defined as <0.025% at 5 minutes and <0.01% at 1 hour. The secondary end point was evidence of hepatic injury, defined as a change of greater than 2 times the upper limit of normal of any component in the hepatic panel in patients with a normal baseline panel or doubling of any component in the hepatic panel in patients with an abnormal baseline panel (aspartate aminotransferase, alanine transaminase, total or direct bilirubin, gamma-glutamyl transferase, or alkaline phosphatase). RESULTS: A total of 10 patients were included for analysis, with a mean age and weight of 3.5 ± 2.4 months and 4.5 ± 0.9 kg, respectively. All patients had acceptable BACs and no evidence of hepatic injury. In 8 patients, 5-minute BACs were undetectable; BACs of the other 2 patients were 0.011%. One-hour BACs in all patients were undetectable. CONCLUSIONS: Flushing ELT resulted in acceptable BACs and no evidence of hepatic injury in this patient cohort. Further studies are needed to investigate the long-term safety and efficacy of ethanol infusion after ELT in this patient population for the prevention and treatment of CLABSIs.

Contributions of KATP and KCa channels to cerebral arteriolar dilation to hypercapnia in neonatal brain.

Mechanisms by which Pco2 controls cerebral vascular tone remain uncertain. We hypothesize that potassium channel activation contributes to the neonatal cerebrovascular dilation in response to increases in Paco2. To test this hypothesis, experiments were performed on newborn pigs with surgically implanted, closed cranial windows. Hypercapnia was induced by ventilation with elevated Pco2 gas in the absence and presence of the KATP channel inhibitor, glibenclamide and/or the KCa channel inhibitor, paxillin. Dilations to pinacidil, a selective KATP channel activator, without and with glibenclamide, were used to evaluate the efficacy of KATP channel inhibition. Dilations to NS1619, a selective KCa channel activator, without and with paxillin, were used to evaluate the efficacy of KCa channel inhibition. Cerebrovascular responses to the KATP and KCa channel activators, pinacidil and NS1619, respectively, cAMP-dependent dilator, isoproterenol, and cGMP-dependent dilator, sodium nitroprusside (SNP), were used to evaluate the selectivity of glibenclamide and paxillin. Glibenclamide blocked dilation to pinacidil, but did not inhibit dilations to NS1619, isoproterenol, or SNP. Glibenclamide prior to hypercapnia decreased mean pial arteriole dilation ~60%. Glibenclamide treatment during hypercapnia constricted arterioles ~35%. The level of hypercapnia, Paco2 between 50 and 75 mmHg, did not appear to be involved in efficacy of glibenclamide in blocking dilation to Paco2. Similarly to glibenclamide and KATP channel inhibition, paxillin blocked dilation to the KCa channel agonist, NS1619, and attenuated, but did not block, arteriolar dilation to hypercapnia. Treatment with both glibenclamide and paxillin abolished dilation to hypercapnia. Therefore, either glibenclamide or paxillin that block dilation to their channel agonists, pinacidil or NS1619, respectively, only partially inhibit dilation to hypercapnia. Block of both KATP and KCa channels completely prevent dilation hypercapnia. These data suggest hypercapnia activates both KATP and KCa channels leading to cerebral arteriolar dilation in newborn pigs.

Adjusting for bias in C-reactive protein levels when using a vitros slide method in infants.

OBJECTIVE: Low total serum protein levels may cause a positive bias on C-reactive protein (CRP) detected by the Vitros 250 Chemistry System (Ortho-Clinical Diagnostics, Inc., Johnson & Johnson Co., Raritan, NJ). Low total serum protein levels are observed in some infants. Our objective was to define a cutoff value for normal levels of CRP measured on the Vitros System that is comparable to the cutoff value of 1.0 mg/dL measured by rate nephelometry on a Beckman Array System (Beckman Instruments Inc., Fullerton, CA). STUDY DESIGN: CRP was prospectively measured on the same serum sample on Vitros and Beckman systems. Using a result of ≥1.0 as the "gold standard" definition of an abnormal CRP, measures of association were calculated. RESULTS: CRP was measured in 981 blood samples that were collected from 361 infants. A cutoff CRP level using the Vitros system at 1.5 mg/dL had the highest sensitivity and negative predictive value comparable to 1.0 mg/dL measured by nephelometry. By regression analysis, each increase by 1 mg/dL by nephelometry caused an increase by 1.5 mg/dL on the Vitros system (R(2) = 0.94; p < 0.001; slope = 0.66; 95% confidence intervals, 0.65, 0.67). CONCLUSION: In infants, when measuring CRP levels by Vitros CRP slide system, a normal reference level of 1.5 mg/dL instead of 1 mg/dL should be used.