Dexmedetomidine versus standard therapy with fentanyl for sedation in mechanically ventilated premature neonates.

OBJECTIVE: To compare the efficacy and safety of dexmedetomidine and fentanyl for sedation in mechanically ventilated premature neonates. METHODS: This was a retrospective, observational case-control study in a level III neonatal intensive care unit. Forty-eight premature neonates requiring mechanical ventilation were included. Patients received fentanyl (n=24) or dexmedetomidine (n=24) for pain or sedation. Each group also received fentanyl and lorazepam boluses as needed for agitation. The primary outcomes were efficacy and frequency of acute adverse events associated with each drug. Days on mechanical ventilation, stooling patterns, feeding tolerance, and neurologic outcomes were also evaluated. RESULTS: There were no significant differences in baseline demographics between the dexmedetomidine and fentanyl patients. Patients in the dexmedetomidine group required less adjunctive sedation and had more days free of additional sedation in comparison to fentanyl (54.1% vs. 16.5%, p<0.0001). There were no differences in hemodynamic parameters between the 2 groups. Duration of mechanical ventilation was shorter in the dexmedetomidine group (14.4 vs. 28.4 days, p<0.001). Meconium passage (7.5 vs. 22.4 days, p<0.0002) and time from initiation to achievement of full enteral feeds (26.8 vs. 50.8 days, p<0.0001) were shorter in the dexmedetomidine group. Incidence of culture-positive sepsis was lower in the dexmedetomidine group (48% vs. 88%). The incidence of either severe intraventricular hemorrhage or periventricular leukomalacia was not statistically significantly reduced (2% vs. 7%). CONCLUSIONS: Dexmedetomidine was safe and effective for sedation in the premature neonates included in this study. Prospective randomized-controlled trials are needed before routine use of dexmedetomidine can be recommended.

Indomethacin pharmacodynamics are altered by surfactant: a possible challenge to current indomethacin dosing guidelines created before surfactant availability.

The effect of surfactant administration for respiratory distress syndrome (RDS) on indomethacin (INDO) pharmacodynamics and dosing requirements for patent ductus arteriosus (PDA) closure and renal toxicity was evaluated. A 22-year prospective cohort study including 442 INDO-treated patients given 466 INDO treatment courses. The database included demographic information, medical problems, and medications. Neonates with a PDA confirmed by echocardiography were treated with INDO, 0.25-0.3 mg/kg. Subsequent INDO dosing was based on a combined pharmacokinetic/pharmacodynamic (PK/PD) approach. Data were fit to an Emax model and ANOVA was used to compare mean closure levels between groups. PDA closure was successful in 405 of 442 patients (91.6%) and in 434 of 466 treatment courses (93.1%) using an individualized PK/PD dosing approach. Renal toxicity was documented in 56 of 442 patients (12.7%) or 56 of 466 treatment courses (12.0%). Patients not treated with synthetic surfactant trended toward lower mean INDO concentrations at PDA closure compared to patients treated with synthetic surfactant (1.65 vs. 2.01 mg/l; P > 0.05) and significantly lower mean INDO concentrations at PDA closure compared to patients treated with natural surfactant (1.65 vs. 2.15 mg/l; P < 0.002). This requires an increased total dose of ~0.3 mg/kg or an individual dose increase of 0.1 mg/kg. Administration of natural or synthetic surfactant for RDS may increase the INDO concentrations and doses needed for PDA closure in premature infants.

Treatment of Citrobacter koseri infection with ciprofloxacin and cefotaxime in a preterm infant.

OBJECTIVE: To report a case of successful treatment of Citrobacter koseri infection in a preterm infant as a means of challenging the current treatment recommendations on the basis of pharmacodynamic and pharmacokinetic considerations. CASE SUMMARY: A premature infant was diagnosed with C. koseri sepsis after 3 weeks in intensive care. Concern for meningitis was based on the propensity for central nervous system (CNS) involvement with Citrobacter infection along with new findings of ventriculomegaly and hydrocephalus shown on cranial ultrasound (CUS). The infant was treated with ciprofloxacin 10-20 mg/day and cefotaxime 100 mg/day for 21 days. After treatment, lumbar puncture was normal, follow-up CUS returned to baseline, and the infant passed a hearing screen after discharge. A favorable outcome was achieved in this case. DISCUSSION: Approximately 76% of neonatal patients infected with C. koseri develop brain abscesses. The mortality rate for meningitis due to Citrobacter spp. is approximately 30%, and of the infants who survive, more than 80% have some degree of mental retardation. Third-generation cephalosporins and aminoglycosides are traditional therapies against this infection. The current antibiotic strategies have failed to prevent the high rates of morbidity and mortality associated with Citrobacter infections. A possible basis for these poor outcomes is failure to apply appropriate pharmacokinetic and pharmacodynamic principles in selecting antibiotics that will achieve adequate concentrations to kill the bacteria in granulocytes within the CNS. Based on favorable sensitivity data, penetration into neutrophils and the CNS, and favorable toxicity profiles, ciprofloxacin and meropenem would appear to be the most appropriate antibiotic treatment options for systemic infection or meningitis caused by C. koseri. CONCLUSIONS: Ciprofloxacin and meropenem should be considered antibiotic treatment options for systemic infection or meningitis caused by C. koseri.

Low-dose aminophylline for the treatment of neonatal non-oliguric renal failure-case series and review of the literature.

OBJECTIVE: Aminophylline is a methylxanthine with multiple physiologic actions. At low doses, aminophylline can antagonize adenosine and improve renal function via increased glomerular filtration rate. Despite its clinical use, little data exists in neonates for this indication. Therefore, the objective of this report is to describe the impact of aminophylline on renal function indices in a series of neonates with acute renal failure. MATERIALS AND METHODS: This was a retrospective chart review of 13 neonates with acute renal failure who received aminophylline during a 15-month study period. Aminophylline was administered at 1 mg/kg intravenously or orally every twelve hours. Forty-six percent (n = 6) of the patients received a 5 mg/kg loading dose before initiation of maintenance therapy. Most patients had already received other treatments for renal failure, including diuretics and dopamine. RESULTS: Resolution of acute renal failure (with normalization of serum creatinine and blood urea nitrogen) was documented in 10 patients (77%). Four of the thirteen patients died from complications due to their prematurity. Failure of low-dose aminophylline was observed in 3 of the 4 patients who died. CONCLUSIONS: Low-dose aminophylline in neonates with acute renal failure is associated with an improvement in renal function indices.

Possible Ibuprofen-induced kernicterus in a near-term infant with moderate hyperbilirubinemia.

A 36-week gestation newborn was admitted to the neonatal intensive care unit for treatment of primary pulmonary hypertension and possible sepsis. The infant developed hyperbilirubinemia on day 4 of life and peaked on day 5 at a total serum bilirubin of 19 mg/dL. Phototherapy was started on day 4 and continued for 5 days. On day 8 of life, ibuprofen was started for fever; a concurrent total serum bilirubin was 15.7 mg/dL. The subsequent hospital course was uneventful, and discharge occurred on day 22 of life. Because the patient failed a hearing screen at discharge, he was referred for a diagnostic audiology workup. He subsequently failed formal audiometric testing on two occasions one week apart, and was given a diagnosis of auditory dys-synchrony and/or auditory neuropathy, consistent with kernicterus. At 5½ months of age, he was reported to be hypotonic and to have frequent arching movements. Since the total serum bilirubin did not exceed 19 mg/dL, concern was raised that ibuprofen may have caused displacement of bilirubin from its albumin binding site, resulting in kernicterus due to excessive unbound bilirubin concentrations. Ibuprofen should be administered with caution in preterm infants at risk for kernicterus.

Efficacy of sucrose to reduce pain in premature infants during eye examinations for retinopathy of prematurity.

BACKGROUND: Eye examinations for retinopathy of prematurity (ROP) are painful to the neonate. The use of topical anesthetic for eye examinations to evaluate ROP is routine in our neonatal intensive care unit (NICU), but does not completely suppress painful responses. Sweet solutions have been shown to reduce procedural pain in newborns. OBJECTIVE: To examine whether the addition of sucrose 24% to topical anesthetic improves procedural pain control during the ROP eye examination. METHODS: Neonates born at < or = 30 weeks' gestation were included in this placebo-controlled, double-blind, crossover study. Patients were randomly assigned to receive treatment with either proparacaine HCl ophthalmic solution 0.5% plus 2 mL of sucrose 24% or proparacaine HCl ophthalmic solution 0.5% plus 2 mL of sterile water (placebo) prior to an eye examination. In a subsequent eye examination, each patient received the alternate treatment. Oral sucrose and sterile water were prepared in the pharmacy in identical syringes, and physicians, nurses, and pharmacists in the NICU were blinded to the treatment given. Pain was measured using the Premature Infant Pain Profile (PIPP) scoring system, which measures both physical and physiologic measures of pain, and the scores were simultaneously assessed by 2 study nurses. PIPP scores were recorded 1 and 5 minutes before and after the eye examination and during initial placement of the eye speculum. The same ophthalmologist performed all eye examinations. Several different definitions of a pain response were investigated. RESULTS: Twenty-three infants were studied, with 12 receiving sucrose and 11 receiving placebo as the first treatment. For 3 of the 5 definitions of pain response, patients experienced significantly less pain at speculum insertion with sucrose than with placebo. After the ROP examination, pain responses were similar with either sucrose or placebo. CONCLUSIONS: Oral sucrose may reduce the immediate pain response in premature infants undergoing eye examination for ROP.

Efficacy of topical anesthetics to reduce pain in premature infants during eye examinations for retinopathy of prematurity.

BACKGROUND: Eye examinations for retinopathy of prematurity (ROP) are stressful and probably painful, but many ophthalmologists do not apply topical anesthetics because their efficacy in reducing pain has not been established. OBJECTIVE: To evaluate the potential benefits of topical anesthetic eye drops in reducing pain during neonatal eye examination for ROP. METHODS: Neonates born at < or =30 weeks' gestation and expected to have at least 2 examinations for ROP were included. Patients were randomly assigned to receive either proparacaine HCl ophthalmic solution 0.5% or NaCl 0.9% (saline) eye drops prior to an eye examination. In a subsequent examination, each patient received the alternate treatment. Eye drops were prepared in the pharmacy in identical tuberculin syringes, and physicians, nurses, and pharmacists were blinded to the treatment given. Pain was measured using a scoring system with both physical and physiologic measures of pain (Premature Infant Pain Profile [PIPP], possible range 1-21), which has been validated in preterm infants. PIPP scoring was performed simultaneously by 2 nurses: 1 and 5 minutes before and after the eye examination and during initial placement of the eye speculum. The same ophthalmologist performed all examinations. RESULTS: Twenty-two patients were studied, with 11 infants receiving proparacaine and 11 receiving saline as the first treatment. Crossover was performed with a median of 17.5 days between treatments. Patients experienced significantly less pain at speculum insertion with proparacaine than with saline (paired difference -2.5 +/- 3.4; p = 0.001). CONCLUSIONS: Topical anesthetic pretreatment reduces the pain response to eye examination for ROP and should become routine practice. Because this is not effective in all infants, additional measures to reduce pain should be taken.

Lepirudin use in a neonate with heparin-induced thrombocytopenia.

OBJECTIVE: To describe a case of heparin-induced thrombocytopenia (HIT) in a premature infant and the doses of danaparoid and lepirudin needed to achieve appropriate therapeutic endpoints. CASE SUMMARY: A 30-week gestational age infant was diagnosed with HIT with heparin antibodies. Danaparoid 2.0-2.4 units/kg/h achieved anti-Xa levels of 0.2-0.4 U/mL, but thrombocytopenia failed to resolve. Lepirudin was started in place of danaparoid. Lepirudin doses of 0.03-0.05 mg/kg/h achieved target activated partial thromboplastin time values of 1.5-2.0 times baseline. DISCUSSION: Dosing information for danaparoid in neonates is limited, and information for lepirudin appears only in German literature at this time. HIT is well documented in newborns, and lepirudin use in these situations is likely to increase. This report provides some guidance for optimal dosing. It also provides some guidance for HIT evaluation in preterm infants, in whom blood volume for laboratory tests is a major issue. CONCLUSIONS: HIT is an important and potentially fatal problem in neonates. Lepirudin may be the drug of choice, especially since danaparoid is now unavailable. Initial lepirudin dosing should not exceed 0.05 mg/kg/h.

Infasurf and curosurf: theoretical and practical considerations with new surfactants.

Type II pneumocytes, normally responsible for surfactant production and release, are insufficiently formed and differentiated in the premature infant born before 34 weeks' gestation. Without an adequate amount of pulmonary surfactant, alveolar surface tension increases, leading to collapse and decreased lung compliance. Pulmonary surfactants are naturally occurring substances made of lipids and proteins. They lower surface tension at the interface between the air in the lungs, specifically at the alveoli, and the blood in the capillaries. This review examines the relative benefits of the two most recently marketed surfactants, calfactan (Infasurf) and poractant alfa (Curosurf).

Effect of age and birth weight on indomethacin pharmacodynamics in neonates treated for patent ductus arteriosus.

OBJECTIVES: To determine patent ductus arteriosus (PDA) closure rates, and indomethacin (INDO) toxicity rates in neonates dosed with INDO using an individualized pharmacokinetic/pharmacodynamic (PK/PD) dosing approach. In addition, develop PD curves evaluating dose-response and concentration-response relationships for closure and renal toxicity, especially in select subgroups historically known as "poor responders" (<1000 g and > or = 10 days postnatal age). DESIGN: Prospective, cohort study. SETTING: Level III neonatal intensive care unit. SUBJECTS: One hundred thirty-nine patients receiving 151 courses of INDO for PDA closure were evaluated. INTERVENTIONS: Patients initially received 0.25 mg/kg of INDO, followed immediately by 1 mg/kg of furosemide. INDO concentrations were obtained 2 hrs and 8 hrs after the dose and were assayed using high-performance liquid chromatography. Individualized PK parameters were calculated with subsequent INDO dosing based on the individualized PK variables to increase trough serum concentrations by 0.3-0.5 mg/L. MEASUREMENTS AND MAIN RESULTS: Ductal closure was successful in 127 patients (91%). Renal toxicity occurred in 21 (15%) patients and was temporary and reversible. No significant differences in response rates based on treatment weight or postnatal age were observed. PD curves were similar for neonates <1000 g vs. > or = 1000 g. PD curves were also similar for neonates with postnatal age <10 days vs. > or = 10 days. Statistically significant differences were noted between neonates categorized for postnatal age <10 days vs. > or = 10 days in total days of therapy (1.8 vs. 2.3 days), total number of doses required to close PDA (3.5 vs. 5.6 doses), critical INDO dose (0.9 vs. 1.4 mg/kg), critical INDO concentration (1.9 vs. 1.4 mg/L), and critical dose/critical concentration ratio (0.52 vs. 2.2). CONCLUSIONS: These findings support the hypothesis that the poor PDA closure rates with INDO for neonates >10 days postnatal age are the result of pharmacokinetic differences only and that weight does not impact response rates. Individualized pharmacokinetic/pharmacodynamic dosing of INDO continues to achieve higher closure rate than current dosing standards. Patients historically known as poor responders significantly benefit from this dosing approach.