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.

Esmolol is a unique cardioselective β(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 β(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 β-blockers (β-adrenoceptor antagonists) is no longer recommended. However, in patients at high risk for myocardial ischaemia or undergoing high-risk surgery where a β-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 β-blockers. I...

Objective To determine the pharmacokinetics (PK) and placental transfer of intravenous (IV) N-acetylcysteine (NAC) in mothers with a clinical diagnosis of chorioamnionitis and determine the PK of IV NAC in their infants. Study design In this prospective, double blind study IV 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 IV 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 non-pregnant adults, with a t1/2 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 t1/2 (5.1 vs.7.5 hours, respectively) and higher CL (53.7 vs. 45.0 mL/hr/kg, respectively). Conclusions Maternal CL and placental transfer of NAC was rapid with umbilical cord concentrations frequently exceeding maternal concentrations. NAC administration 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, 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.

ObjectiveTo 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 designTwenty-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.ResultsCardiovascular 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.ConclusionsIn this cohort of newborns exposed to chorioamnionitis, antenatal and postnatal NAC was safe, preserved cerebrovascular regulation, and increased an anti-inflammatory neuroprotective protein.Trial registrationClinicalTrials.gov: NCT00724594.