NAC and Vitamin D Improve CNS and Plasma Oxidative Stress in Neonatal HIE and Are Associated with Favorable Long-Term Outcomes.

N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) + 1,25(OH)2D (calcitriol 0.05 mg/kg q12h, 0.03 mg/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate (n = 14) or severe HIE (n = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases in these PD markers were titrated by neural demand. Hypothermia and normothermia altered NAC PK estimates. NVD was well tolerated. Excluding genetic syndromes (2), prolonged ECMO (2), lost-to-follow-up (1) and SIDS death (1), 24 NVD treated HIE infants have no evidence of cerebral palsy, autism or cognitive delay at 24-48 months. These data confirm that low, safe doses of NVD in HIE neonates decreased oxidative stress in plasma and CNS, improved CNS energetics, and are associated with favorable developmental outcomes at two to four years.

NAC and Vitamin D Restore CNS Glutathione in Endotoxin-Sensitized Neonatal Hypoxic-Ischemic Rats.

Therapeutic hypothermia does not improve outcomes in neonatal hypoxia ischemia (HI) complicated by perinatal infection, due to well-described, pre-existing oxidative stress and neuroinflammation that shorten the therapeutic window. For effective neuroprotection post-injury, we must first define and then target CNS metabolomic changes immediately after endotoxin-sensitized HI (LPS-HI). We hypothesized that LPS-HI would acutely deplete reduced glutathione (GSH), indicating overwhelming oxidative stress in spite of hypothermia treatment in neonatal rats. Post-natal day 7 rats were randomized to sham ligation, or severe LPS-HI (0.5 mg/kg 4 h before right carotid artery ligation, 90 min 8% O2), followed by hypothermia alone or with N-acetylcysteine (25 mg/kg) and vitamin D (1,25(OH)2D3, 0.05 µg/kg) (NVD). We quantified in vivo CNS metabolites by serial 7T MR Spectroscopy before, immediately after LPS-HI, and after treatment, along with terminal plasma drug concentrations. GSH was significantly decreased in all LPS-HI rats compared with baseline and sham controls. Two hours of hypothermia alone did not improve GSH and allowed glutamate + glutamine (GLX) to increase. Within 1 h of administration, NVD increased GSH close to baseline and suppressed GLX. The combination of NVD with hypothermia rapidly improved cellular redox status after LPS-HI, potentially inhibiting important secondary injury cascades and allowing more time for hypothermic neuroprotection.

N-Acetylcysteine rapidly replenishes central nervous system glutathione measured via magnetic resonance spectroscopy in human neonates with hypoxic-ischemic encephalopathy.

Persistent oxidative stress depletes reduced glutathione (GSH), an intracellular antioxidant and an important determinant of CNS injury after hypoxia ischemia. We used standard, short echo time Stimulated Echo Acquisition Mode (STEAM) to detect GSH by magnetic resonance spectroscopy (MRS) in 24 term neonates with hypoxic-ischemic encephalopathy (HIE), on day of life 5-6, after rewarming from therapeutic hypothermia. MRS demonstrated reliable, consistent GSH of 1·64 ± 0·20 mM in the basal ganglia immediately before intravenous infusion of N-acetylcysteine. N-acetylcysteine resulted in a rapid and significant GSH increase to 1·93 ± 0.23 mM within 12-30 min after completion of infusion ( n = 21, p < 0.0001, paired t-test), compared with those who did not receive N-acetylcysteine ( n = 3, GSH = 1.66 ± 0.06 mM and 1.64 ± 0.09 mM). In one perinatal stroke patient, GSH in the diffusion-restricted stroke area was 1.0 mM, indicating significant compromise of intracellular redox potential, which also improved after N-acetylcysteine. For comparison, GSH in healthy term neonates has been reported at 2.5 ± 0.9 mM in the thalamus. This is the first report to show persistent oxidative stress reflected in GSH during the subacute phase in neonates with HIE and rapid response to N-acetylcysteine, using a short echo MRS sequence that is available on all clinical scanners without spectral editing.

Fetal and Neonatal Effects of N-Acetylcysteine When Used for Neuroprotection in Maternal Chorioamnionitis.

OBJECTIVE: To evaluate the clinical safety of antenatal and postnatal N-acetylcysteine (NAC) as a neuroprotective agent in maternal chorioamnionitis in a randomized, controlled, double-blinded trial. STUDY DESIGN: Twenty-two mothers >24 weeks gestation presenting within 4 hours of diagnosis of clinical chorioamnionitis were randomized with their 24 infants to NAC or saline treatment. Antenatal NAC (100 mg/kg/dose) or saline was given intravenously every 6 hours until delivery. Postnatally, NAC (12.5-25 mg/kg/dose, n = 12) or saline (n = 12) was given every 12 hours for 5 doses. Doppler studies of fetal umbilical and fetal and infant cerebral blood flow, cranial ultrasounds, echocardiograms, cerebral oxygenation, electroencephalograms, and serum cytokines were evaluated before and after treatment, and 12, 24, and 48 hours after birth. Magnetic resonance spectroscopy and diffusion imaging were performed at term age equivalent. Development was followed for cerebral palsy or autism to 4 years of age. RESULTS: Cardiovascular measures, cerebral blood flow velocity and vascular resistance, and cerebral oxygenation did not differ between treatment groups. Cerebrovascular coupling was disrupted in infants with chorioamnionitis treated with saline but preserved in infants treated with NAC, suggesting improved vascular regulation in the presence of neuroinflammation. Infants treated with NAC had higher serum anti-inflammatory interleukin-1 receptor antagonist and lower proinflammatory vascular endothelial growth factor over time vs controls. No adverse events related to NAC administration were noted. CONCLUSIONS: In this cohort of newborns exposed to chorioamnionitis, antenatal and postnatal NAC was safe, preserved cerebrovascular regulation, and increased an anti-inflammatory neuroprotective protein. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00724594.

Antenatal pharmacokinetics and placental transfer of N-acetylcysteine in chorioamnionitis for fetal neuroprotection.

OBJECTIVE: To determine the pharmacokinetics (PK) and placental transfer of intravenous (i.v.) N-acetylcysteine (NAC) in mothers with a clinical diagnosis of chorioamnionitis (CA) and determine the PK of i.v. NAC in their infants. STUDY DESIGN: In this prospective, double-blind study i.v. NAC 100 mg/kg/dose or saline was administered within 4 hours of CA diagnosis to pregnant women ≥24 weeks' gestation and then every 6 hours until delivery. Maternal PK and placental transfer were determined with maternal blood and matched maternal and cord venous blood. Neonatal PK estimates were determined from i.v. NAC (12.5-25 mg/kg/dose) administered every 12 hours for 5 doses. Noncompartmental analyses were performed for maternal and neonatal PK estimates. RESULTS: Eleven mothers (5 preterm, 6 near-term) and 12 infants (1 set of twins) received NAC. Maternal clearance (CL) of NAC was faster than in nonpregnant adults, with a terminal elimination half-life of 1.2 ± 0.2 hours. The NAC cord to maternal ratio was 1.4 ± 0.8, suggesting rapid placental transfer and slower rate of fetal CL. Neonatal PK estimates for near-term compared with preterm infants showed a significantly shorter terminal elimination half-life (5.1 vs 7.5 hours, respectively) and greater CL (53.7 vs 45.0 mL/h/kg, respectively). CONCLUSIONS: Maternal CL and placental transfer of NAC was rapid, with umbilical cord concentrations frequently exceeding maternal concentrations. The administration of NAC to mothers with CA achieves predictable NAC plasma concentrations in the fetus, indicating that antenatal neuroprotection may be possible for these newborns at high risk for neuroinflammation.

Chloramphenicol toxicity revisited: a 12-year-old patient with a brain abscess.

Chloramphenicol, a broad-spectrum antibiotic, is rarely used in the United States due to its well-described adverse effects. Because of its limited use, many clinicians are unfamiliar with its indications, spectrum of activity, and potential adverse drug effects. We describe a 12-year-old patient who presented after two craniotomies for a persistent brain abscess complicated by long-term chloramphenicol administration. Findings for this patient were consistent with many of the adverse drug effects associated with chloramphenicol, including elevated chloramphenicol serum concentrations, anemia, thrombocytopenia, reticulocytopenia, and severe metabolic acidosis. Rare manifestations of chloramphenicol toxicity that developed in this patient included neutropenia, visual field changes, and peripheral neuropathy. Chloramphenicol administration was discontinued, and hemodialysis was initiated for severe metabolic acidosis. The patient recovered with severe visual field deficits. Although chloramphenicol is rarely indicated, it remains an effective antibiotic. Healthcare providers should become familiar with the pharmacology, toxicology, and monitoring parameters for appropriate use of this antibiotic.

Clinical pharmacokinetics and therapeutic efficacy of esmolol.

Esmolol is a unique cardioselective ß(1)-receptor blocking agent with a rapid onset and short duration of action. Since our previous review in 1995, the pharmacokinetics and efficacy of esmolol have been investigated in a number of acute care settings. Three studies investigated the pharmacokinetics and safety of esmolol in the paediatric population. The disposition of esmolol in children was found to be linear with plasma concentrations increasing in proportion to dose over the ranges studied. The pharmacokinetic estimates for esmolol showed a shorter elimination half-life (t(½)) [2.7-4.8 minutes] and a higher clearance (281 mL/kg/min) in newborns and infants than that found in children (>2 years old) and adults. Dosing requirements to achieve targeted blood pressure in post-coarctectomy patients were substantially higher (mean 700 µg/kg/min) than that used in adults. Esmolol was effective in controlling hypertension following cardiac surgery and terminating supraventricular arrhythmias in children. The efficacy of esmolol has been established in a variety of patients, including those with unstable angina, myocardial ischaemia, supraventricular arrhythmias, peri- and postoperative tachycardia and hypertension, and electroconvulsive therapy. With careful titration and monitoring, esmolol can be used effectively in patients with congestive heart failure and chronic obstructive lung disease because of its unique short t(½) and ß(1)-selectivity. Different dosage schedules have been developed depending on clinical setting and diagnosis. Generally, a loading dose of ≤500 µg/kg/min over 1 minute is administered followed by a continuous infusion of 25-300 µg/kg/min. Hypotension, being the primary adverse effect, can be minimized by careful dosage titration and patient monitoring. In the perioperative setting involving tracheal intubation and extubation, a number of recent studies have suggested that titration of esmolol to a haemodynamic endpoint can be safe and effective, resulting in a decreased incidence of myocardial ischaemia. The most effective regimen in attenuating the response to heart rate and blood pressure after laryngeal tracheal intubation was a loading dose of 500 µg/kg/min for 4 minutes followed by a continuous infusion of 200-300 µg/kg/min. In cardiac and non-cardiac surgical patients esmolol has been shown to decrease episodes of myocardial ischaemia and arrhythmias. In the perioperative period for non-cardiac surgery routine use of ß-blockers (ß-adrenoceptor antagonists) is no longer recommended. However, in patients at high risk for myocardial ischaemia or undergoing high-risk surgery where a ß-blocker is indicated, esmolol is the ideal perioperative agent to minimize the risk of hypotension and bradycardia based on its pharmacodynamic and pharmacokinetic characteristics. For postoperative patients in atrial fibrillation, esmolol achieves rapid ventricular rate control. However, for the prevention of postoperative atrial fibrillation esmolol provides no advantage over oral ß-blockers. In other situations where emergent ß-blockade is required, such as electroconvulsive therapy, esmolol has been shown to effectively control haemodynamic response. After more than 2 decades of use esmolol continues to provide an important therapeutic option in the acute care setting.

Effect of heliox on albuterol delivery by metered-dose inhaler in pediatric in vitro models of mechanical ventilation.

STUDY OBJECTIVE: To determine the effect of varying concentrations of heliox, a mixture of helium and oxygen, on albuterol delivery administered by metered-dose inhaler (MDI) in pediatric mechanically ventilated models. DESIGN: Prospective in vitro laboratory study. SETTING: University-affiliated research laboratory. MODELS: The lungs of a 10-kg infant and 30-kg child receiving humidified pressure-regulated volume-controlled ventilation were simulated. The infant settings were an endotracheal tube (ETT) of 4.0 mm, tidal volume of 150 ml, positive end-expiratory pressure of 2 cm H(2)O, rate of 20 breaths/minute, inspiratory time of 0.7 second; the child settings were an ETT of 6.0 mm, tidal volume of 450 ml, positive end-expiratory pressure of 2 cm H(2)O, rate of 16 breaths/minute, and inspiratory time of 0.8 second. MEASUREMENTS AND MAIN RESULTS: Ten albuterol MDI canisters with chlorofluorocarbon propellants were each actuated once sequentially (total dose 1000 mug) with a commercially available aerosol holding chamber. Albuterol was collected onto a filter proximal to a lung simulator. The filter was rinsed, and concentrations were determined by high-performance liquid chromatography. In the infant model, heliox mixtures of 70:30, 60:40, and 50:50 were compared with nitrogen:oxygen (N(2):O(2)) mixtures in the same ratios. The effect of the 70:30 mixtures was also explored in a child model. Each gas mixture was tested 5 times. At all three ratios, albuterol delivery to the end of the ETT was improved with heliox compared with N(2):O(2) (approximately 7% vs 3-4%, p<0.0001, one-way analysis of variance [ANOVA] with a Bonferroni correction for multiple comparisons). No significant difference was noted in mean percentage albuterol delivery among the varying ratios of heliox studied. By two-way ANOVA, significantly greater albuterol delivery was noted with 70:30 heliox compared with 70:30 N(2):O(2) (7-8% vs 3%, p<0.0001), with no significant difference between the infant and child model (p=0.21). The gas mixture, model, and interaction of the two explained 88% of the variability in mean percentage albuterol delivery. CONCLUSION: Heliox increased albuterol delivery administered by MDI to the end of the ETT in these in vitro pediatric models of mechanical ventilation. Further studies are needed to determine if the improved albuterol delivery with heliox enhances clinical response in infants and children needing mechanical ventilation.

Albuterol delivery with conventional and synchronous ventilation in a neonatal lung model.

OBJECTIVE: To compare the percentage of nebulized albuterol delivered with conventional (intermittent mandatory ventilation) vs. synchronous (assist-control and assist-control with flow synchronization) ventilation in a neonatal lung model. DESIGN: Prospective in vitro laboratory study. SETTING: Research laboratory. SUBJECT: Neonatal lung model. INTERVENTIONS: The model simulated an intubated neonate with a spontaneous respiratory rate of 40, 60, or 80 breaths per minute and compliance and resistance values of bronchopulmonary dysplasia. A VIP Bird ventilator was used for all ventilator modes. Albuterol 2.5 mg was administered with a T Up-Draft II Neb-U-Mist nebulizer attached to a 12.75-cm (10-mL) reservoir of circuit tubing. Albuterol was collected onto a filter (particle retention .05, two-factor analysis of variance). CONCLUSIONS: The percentage of nebulized albuterol delivered to the end of the endotracheal tube in a mechanically ventilated neonatal model was not affected by mode of ventilation under the conditions studied. Further clinical studies are needed to determine whether lung deposition and distribution or clinical efficacy of albuterol is influenced by synchronous ventilation in this patient population.