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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.

Objective: To describe a case of dexmedetomidine use for sedation in a 24-week gestational age premature neonate. Case Summary: A 9-day-old, 24-week gestational age male neonate on high-frequency oscillatory mechanical ventilation was experiencing severe agitation refractory to high-dose intravenous narcotics and benzodiazepines. Since the infant's respiratory stability was reliant on adequate sedation, he was given dexmedetomidine after several days of suboptimal response to escalation of standard agents. Treatment prior to dexmedetomidine included continuous-infusion fentanyl 10 μg/kg/h, intravenous lorazepam 0.6 mg/kg every 4 hours, intermittent doses of both lorazepam and midazolam as needed, and a single bolus dose of phenobarbital. The patient calmed markedly during the dexmedetomidine loading dose infusion and remained adequately sedated while the drug was continued. The dexmedetomidine infusion allowed weaning of mechanical ventilation settings and eventual extubation of the infant, as well as rapid tapering of other sedative medications. The maximum dexmedetomidine infusion rate was 0.7 μg/kg/h, and total duration of therapy was 19 days. No significant adverse effects were directly attributed to dexmedetomidine use during this time. Discussion: Dexmedetomidine is a novel α2-agonist approved for short-term sedation in mechanically ventilated adults. Data describing its use in pediatric and neonatal patients continue to emerge. The prolonged use of dexmedetomidine in very-low-birth-weight neonates has not been described in the literature. Conclusions: Dexmedetomidine was an effective sedative and analgesic in a 24-week gestational age neonate treated for refractory agitation while on mechanical ventilation. Based on its documented efficacy for pain and sedation and its favorable adverse effect profile, dexmedetomidine warrants further study as first-line or adjunct therapy with narcotics for sedation in ventilated newborns.

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.

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.

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 ⩽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.

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 ⩽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.

Study Objective. To evaluate traditional nomogram (TN) versus individualized pharmacokinetic gentamicin dosing practices in neonatal intensive care units, focusing on achieving target therapeutic concentrations (peak > 8 μg/ml, trough < 2 μg/ml), number of dosing changes, number of concentrations obtained, and evidence of nephrotoxicity. Design. Retrospective chart review. Setting. Three neonatal intensive care units. Patients. Three hundred nine infants prescribed gentamicin. Intervention. None. Measurements and Main Results. Sixty-seven percent of patients receiving pharmacokinetic dosing had initial peak concentrations of 8 μ/ml or greater compared with 7% of patients receiving TN dosing (p

Objective: To describe a case of tramadol withdrawal in a neonate and treatment with clonidine after exposure to long-term maternal use of high-dose tramadol. Case Summary: A 34-week gestational age neonate displayed symptoms of tramadol withdrawal within 48 hours of delivery. Due to a confusing initial clinical picture, including presumed congenital Chlamydia, questionable seizures, and an original report of maternal use of ketorolac (Toradol), diagnosis was delayed until day of life 5. Symptoms included jitteriness, myoclonic movements, and irritability. Upon further questioning of the mother, it was revealed that she was actually taking tramadol 600–800 mg daily. The infant was placed on maintenance therapy with oral clonidine (from 1 to 3 μg/kg orally every 3 hours) until discontinuation on day of life 11. After 3 days off treatment, he began to display symptoms of withdrawal again. Clonidine was restarted at 1 μg/kg orally every 8 hours and he was discharged home on maintenance clonidine therapy at 18 days postnatal age. A 7-day tapering regimen was initiated 2 weeks after discharge, and no further withdrawal symptoms occurred. Discussion: Few published articles are available to guide clinicians on the clinical course and treatment strategies for tramadol dependence and withdrawal. In neonates, the reports are particularly sparse. Traditional agents used in neonatal opioid withdrawal are narcotics (morphine, tincture of opium, methadone), benzodiazepines (diazepam, lorazepam), and phenobarbital. Clonidine use for neonatal abstinence syndrome from narcotics has been shown to be effective alone or in combination with agents such as other opiates and chloral hydrate. Potential benefits of clonidine therapy include shorter duration of therapy, reduced withdrawal symptoms, and decreased length of hospital stay. Conclusions: Withdrawal can be prolonged in infants exposed to maternal tramadol use. Clonidine may be a safe and effective option for managing symptoms of neonatal tramadol abstinence.

OBJECTIVES Aminophylline has proven useful for treating renal failure in preterm infants. Previous reports state that aminophylline is incompatible with some neonatal total parenteral nutrition (TPN) solutions. If this is correct, administration of aminophylline doses would be complicated by the need to hold TPN and provide flush solution after each aminophylline dose. Our experience with administering aminophylline over 30 minutes concurrently with TPN was that this was not problematic. We therefore examined the in vitro compatibility of aminophylline and TPN solutions used in our neonates over a 30-minute interval to see if our policy of allowing concurrent mixing of these products was appropriate. METHODS TPN solutions (2.5 mL) were mixed with 1 mL of intravenous aminophylline 2.5 mg/mL in a glass vial. Three different TPN solutions used in our NICU were collected for the study, and five samples of each combination were prepared. Samples were watched for 60 minutes to see if precipitation occurred. RESULTS Although the aminophylline and TPN solutions were not miscible, no turbidity or precipitation was observed. CONCLUSIONS This study supports that aminophylline is physically compatible with neonatal TPN for 60 minutes.

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 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.

OBJECTIVE: To compare heparin dosage adjustment using only activated partial thromboplastin time (APTT) with a method using non-steady-state heparin concentrations (HCs) to rapidly achieve and maintain an APTT ratio greater than or equal to 1.5 times baseline throughout the first 24 hours of therapy. DESIGN: Randomized, blind, parallel comparison of an empiric dosing method based only on APTT with a dosing method based on the calculation of heparin clearance using non-steady-state HCs. SETTING: A private community teaching hospital. The patient, physician, nurses, and investigators were blinded to the dosing method. Only the clinical staff pharmacist, who received the consult and made all dosage adjustments, was not blinded. PATIENTS: All patients requiring heparin for the treatment of thromboembolic disease were evaluated for potential inclusion in the study. Patients were enrolled in the study if they had a clinical diagnosis of deep venous thrombosis confirmed by objective means such as venography or ultrasonography. Patients were excluded if they had active bleeding, platelet dysfunction, thrombocytopenia, severe hepatic disease (total bilirubin >25.7 μmol/L), renal disease, or evidence of stroke. Patients were also excluded if they were receiving heparin prior to enrollment. MAIN OUTCOME MEASURE: Maintenance of an APTT ratio greater than or equal to 1.5 times baseline throughout the first 24 hours of heparin therapy. RESULTS: Thirty-four patients were enrolled in the study; 17 in each group. The groups were not significantly different with regard to gender, age, baseline APTT, or mean loading dose (p>0.5). Mean initial infusion rates for the control and HC groups were 1042 ± 194 and 1071 ± 143 units/h, respectively (p>0.5). After the first rate adjustment at 4 hours, the difference achieved significance at 1032 ± 232 and 1367 ± 317 units/h for the control and HC groups, respectively (pCONCLUSIONS: This study demonstrates that, in contrast to standard heparin dosing methods, the use of non-steady-state HCs allows patients with deep venous thrombosis to rapidly achieve and maintain therapeutic APTT ratios throughout the critical first 24 hours of therapy.

OBJECTIVE:To review the literature on the physiologic changes created by neonatal patent ductus arteriosus (PDA) and the potential impact on drug disposition in these infants.DATA SOURCES:An Index Medicus and bibliographic search of the English-language literature pertaining to neonatal PDA and drug usage in newborns.DATA SYNTHESIS:PDA in premature infants is associated with a variety of physiologic changes that could alter drug disposition. Perfusion of drug-elimination organs (i.e., liver and kidney) may be diminished, resulting in decreased drug elimination. Further, the general fluid overload state associated with PDA may result in larger volumes of distribution (Vd), and dilutional effects for many drugs. Drug absorption, Vd, tissue penetration, and clearance may be affected by the physiologic changes incurred by a PDA. Although the pharmacokinetics of several categories of therapeutic agents may be affected by a PDA, disposition changes with the aminoglycosides and indomethacin have been the best documented. The most reliable pharmacokinetic change appears to be related to drug Vd. The interpretation of many of these studies is confounded by a potential drug interaction with the concurrent administration of indomethacin for PDA closure.CONCLUSIONS:Close therapeutic drug monitoring is indicated in newborns with PDAs as abrupt changes in drug disposition can occur with PDA closure. PDA-induced changes in specific pharmacokinetic parameters of agents such as the aminoglycosides, indomethacin, and perhaps vancomycin may prove to be a valuable diagnostic adjunct for the identification of babies with undiagnosed PDA. More research into this pharmacophysiologic aspect of pharmacokinetics is warranted.

Heparin clearance and pharmacodynamic response were examined in 12 patients being treated for deep venous thrombosis (DVT, 6 patients) or pulmonary embolism (PE, 6 patients). A loading dose of 70 units/kg was administered to DVT patients and 100 units/kg to PE patients followed by an initial infusion rate of 15 or 25 units/kg/h for DVT or PE patients, respectively. Heparin clearance was determined at 4, 12, and 24 h after initiating heparin therapy. The mean heparin clearance in the DVT group was 2,164 +/- 1,024 ml/h at 4 h, 2,591 +/- 1,239 ml/h at 12 h, and 2,795 +/- 1,863 m/h at 24 h. The PE patients had clearances of 1,775 +/- 494, 2,004 +/- 321, and 2,843 +/- 1,000 ml/h at 4, 12, and 24 h, respectively. The difference between the two groups was not statistically significant (p greater than 0.50). The activated partial thromboplastin time (aPTT) was used as a measure of heparin effect. The maximum effect (EMAX) and concentration required to attain 50% of the maximum effect (EC50) were determined for each group using the Lineweaver-Burke linearization method. The mean EMAX and EC50 for the DVT patients were 130 +/- 40.99 s and 1.01 +/- 0.70 units/ml, respectively. For the PE patients, the mean EMAX was 418 +/- 200 s and the mean EC50 was 4.32 +/- 2.81 units/ml. The difference between both groups for each parameter was statistically significant (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Thrombotic events are a serious and potentially fatal complication during the neonatal period. Despite clinically serious thromboses in up to one percent of neonates and less severe complications (e.g., catheter malfunction secondary to clots) in a much higher percentage, well-designed studies on prevention and treatment of thromboses are lacking. Treatment approaches are largely anecdotal and involve the use of heparin and, occasionally, thrombolytics. Proper monitoring of anticoagulant and thrombolytic effects is difficult because of the limited blood volumes available from neonates and the relatively large sample volumes needed for most coagulation studies. Activated clotting times (ACTs) are preferred because they use low blood volume and are a rapid bedside test. Heparin should be administered with an initial loading dose of 50–100 units/kg followed by a continuous infusion of 20 units/kg/h. Further doses should then be adjusted based on the ACT, targeting a value of 1.5–2.5 times the control. Thrombolytics also have been used in several case reports and are guided by both clinical response and serial D-dimer values. We prefer urokinase 100 units/kg/h for local infusion to the thrombus and urokinase 1000–10 000 units/kg/h for systemic therapy.

SummaryIndomethacin (INDO) pharmacokinetics were examined in 18 neonates on 19 occasions, before and after patent ductus arteriosus (PDA) closure, Patients received INDO as an initial dose of 0.25 mg/kg intravenously, and INDO serum concentrations were measured 2 and 8 h after the dose. Subsequent d

OBJECTIVE: To compare the delivery of an albuterol metered-dose inhaler (MDI) (Ventolin) via an Aerochamber (Monaghan) with an inline adapter (Medicomp Straight Swivel) in an in vitro infant lung model. METHODS: An in vitro infant lung model was modified to compare the delivery of albuterol MDI 10 inhalations via an Aerochamber with an inline adapter. The adapter and Aerochamber were placed at the endotracheal tube. A 1000 mL intravenous bag filled with 500 mL deionized water was attached to a 3.5 mm endotracheal tube (10 cm length). An Infant Bear Cub ventilator was used at the following settings: positive inspiratory pressure 20 cm H2O, intermittent mandatory ventilation 40 breaths/min, positive end expiratory pressure 4 cm H2O, and inspiratory time 0.5 second. Each device was run at least 10 times and assayed in duplicate by HPLC. An unpaired Student's t-test was used to analyze the statistical significance of the data. RESULTS: There was significantly greater delivery of albuterol with the Aerochamber (19.49 ± 7.23 μg; 2.17% ± 0.8%) as compared with an inline adapter (1.0625 ± 1.36 μg; 0.12% ± 0.15%) (p = 0.001). CONCLUSIONS: The Aerochamber provides a greater delivery of albuterol metered-dose inhalations to the lung than the inline adapter in an in vitro infant lung model.

One hundred eighty-four neonates had gentamicin serum concentrations measured twice after an initial loading dose of 5 mg/kg infused over 1 hour. Gentamicin concentrations immediately postinfusion were calculated using a one-compartment pharmacokinetic model. The extrapolated peak gentamicin concentrations achieved with the 5 mg/kg loading dose was optimal (between 5 and 12 micrograms/ml) in 94% of cases. Had an initial dose of 2.5 mg/kg been given as suggested in most references, peak concentrations 5 mg/kg or higher would only have been achieved in 5% of neonates less than 28 weeks' gestation, 10% of neonates 28 to 30 weeks' gestation, 11% of neonates 31 to 34 weeks' gestation, and 36% of neonates more than 34 weeks' gestation. Our data support the need for greater loading doses of gentamicin in newborns. Our recommendation of 5 mg/kg achieves gentamicin concentrations known to be safe and effective.

To determine the effect of patent ductus arteriosus on the pharmacokinetics of gentamicin in neonates and to examine whether any particular pharmacokinetic parameter is of value as a marker of patent ductus arteriosus.Cohort study of neonates treated with gentamicin, according to a standard dosing protocol.A 24-bed, Level III, neonatal intensive care unit.Neonates treated with gentamicin at the time of admission to the neonatal intensive care unit, using a standard protocol, and who were36 wks of gestational age.All patients received a gentamicin loading dose, and had gentamicin concentrations measured at 2 and 12 hrs after this dose, in order to determine pharmacokinetic parameters and calculate the optimum maintenance dose. Those neonates subsequently diagnosed to have patent ductus arteriosus, based on clinical suspicion and echocardiographic confirmation, were compared with those neonates without clinically suspected patent ductus arteriosus. Gentamicin pharmacokinetic parameters were calculated using a one-compartment model.A total of 322 courses of gentamicin were administered (patent ductus arteriosus, n = 106; control, n = 216). Gentamicin clearance was decreased in the patent ductus arteriosus group vs. the control group (40.02 vs. 44.73 mL/kg/hr; p.0108). Volume of distribution was greater for patent ductus arteriosus patients (0.61 L/kg) than for controls (0.54 L/kg) (p.0002). Also, volume of distribution was a useful marker for presence of patent ductus arteriosus, with a 92% specificity for patent ductus arteriosus.Gentamicin dosing should be altered in neonates with patent ductus arteriosus to reflect the impact of higher volume of distribution and lower clearance. When the gentamicin volume of distribution exceeds 0.7 L/kg, it may be of predictive value for the presence of patent ductus arteriosus.

A 25-week gestational age newborn, birthweight 650 grams, has several complications in the first 3 days of life including respiratory distress syndrome treated with surfactant, clinical signs of patent ductus arteriosus which is being evaluated to confirm diagnosis and consideration for ligation, and intraventricular hemorrhage diagnosed on the morning of day 3 of life. On the afternoon of day 3, the patient develops seizure-like activities. Symptoms consist of jerking of the right shoulder followed by chewing motions, and are associated with oxygen desaturation and tachycardia. These symptoms occur about 5 times over a one-hour period. An electroencephalogram (EEG) is ordered and three events are noted during a 30 minute recording. A debate about initiating anticonvulsant therapy ensues; the neurologist wants to wait until the EEG is interpreted to initiate an anticonvulsant, while the pharmacotherapy specialist argues for initiating phenobarbital during the EEG, timed to be given during any observed clinical seizure activity or obvious electrographic seizure activity on the EEG. Based on the neurologist’s recommendaTreatment of seizures in Newborns: The Dilemma of starting the Right Drug, at the Right Time, in the Right Doses, and Monitoring the Right endpoints

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.

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 andor = 10 days postnatal age).Prospective, cohort study.Level III neonatal intensive care unit.One hundred thirty-nine patients receiving 151 courses of INDO for PDA closure were evaluated.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.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 neonates1000 g vs.or = 1000 g. PD curves were also similar for neonates with postnatal age10 days vs.or = 10 days. Statistically significant differences were noted between neonates categorized for postnatal age10 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).These findings support the hypothesis that the poor PDA closure rates with INDO for neonates10 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.

OBJECTIVE: To describe the use of enoxaparin to treat suspected thrombosis in a preterm neonate. CASE DESCRIPTION: A 29-week-gestation white infant with a family history of protein S deficiency lost color and blood flow to the right hand several hours after removal of the umbilical artery catheter. Although normal color returned to all except the distal first, second, and third fingers after warming, Doppler flow showed a radial artery defect, indicating a lack of blood flow. Enoxaparin 1 mg/kg intravenously every eight hours was then started. Heparin concentrations measured via anti-Xa assay drawn four and eight hours after a dose were 0.78 and 0.39 units/mL, respectively. Pharmacokinetic parameters calculated from these concentrations using a one-compartment model were elimination half-life four hours, volume of distribution 0.13 L/kg, and clearance 0.022 L/kg/h. No adverse effects were noted. Blood flow eventually returned, leaving only the third fingertip chronically injured. DISCUSSION: Differences between the neonatal and adult hemostatic systems contribute to an increased risk of thromboembolic events and an altered sensitivity to heparin anticoagulation in the neonate. Although heparin is currently the anticoagulant of choice, it may produce several adverse effects, such as hemorrhage and thrombocytopenia, which may be avoided by use of low-molecular-weight heparins (LMWHs). However, despite the efficacy and improved safety profile of LMWHs in adults, data regarding their use in children and neonates are scarce. This case demonstrates that enoxaparin can be used safely and effectively in a preterm infant through appropriate monitoring of heparin concentrations to adjust dosages. A larger volume of distribution of enoxaparin was noted in this neonate than in adults. CONCLUSIONS: Enoxaparin 1 mg/kg intravenously every eight hours was used safely in this preterm infant with suspected thrombosis, suggesting that more than one dosing regimen may be appropriate in this population.

OBJECTIVE: To evaluate drug delivery to the lungs of nebulized and metered-dose inhalers (MDIs) in an in vitro infant lung model. METHODS: An in vitro lung model was modified to study drug delivery. A 1000 mL intravenous bag filled with 500 mL deionized water was attached to a 3.5 mm (12 cm length) endotracheal tube. An inline Marquest Whisper Jet infant circuit nebulizer system delivered 2.5 mg/3 mL albuterol sulfate inhalation solution (Ventolin nebules) at a flow rate of 5 L/min. An Aerochamber (Monaghan) was placed at the endotracheal tube for the delivery of the MDIs. Albuterol MDI (Ventolin) 10 inhalations and beclomethasone MDI (Beclovent) 20 inhalations were delivered. A Servo 900C (Siemens-Elma) was used at the following ventilator settings: positive inspiratory pressure 30 cm H2O), intermittent mandatory ventilation 40 breaths/min, positive end expiratory pressure 4 cm H2O, inspiratory time 0.4 sec. Each formulation was run at least 10 times and assayed in duplicate by HPLC. An unpaired Student's t-test was used to analyze the statistical significance of the data. RESULTS: There was a significantly greater percentage of drug delivery with MDI albuterol (1.96 ± 0.50) as compared with nebulized albuterol (1.26 ± 0.37) (p = 0.002) or beclomethasone diproprionate (0.51 ± 0.24) (p = 0.001). CONCLUSIONS: Albuterol MDI provides a more efficient delivery of drug to the lung as compared with nebulized albuterol and MDI beclomethasone diproprionate.

An in vitro model was developed to assess nebulized drug delivery. The model simulated the intubated neonate and examined the effect of changes in a variety of parameters commonly confronted in the clinical setting. Theophylline was nebulized for 15 minutes and captured in an artificial lung system (a 1000-mL intravenous bag). Variables were: Peak pressure (20, 24, 28 cm H2O), ventilator rate (40, 60, 80 breaths/min), nebulizer flow rate (5, 7, 10 L/min), endotracheal tube size (2.5, 3.0, 3.5 mm), and ventilator type (Servo 900C, Bourns BP 200, Bear Cub BP 2001). The amount of drug actually captured in the bag ranged from 0.009 to 12.59 percent (mean 2.08). A multivariate analysis showed that only nebulizer flow rate had a statistically significant effect on drug delivery with 10 L/min delivering the most drug. All factors combined only accounted for 11.5 percent of the variability in drug delivery. In light of the wide and unpredictable amounts of drug delivered through ventilators, dosing to pharmacologic effect rather than staying within narrow dosing guidelines may be more rational in patients responding poorly to standard doses.

The effect of phenobarbital administration on theophylline clearance was studied in 24 premature neonates. Aminophylline was administered according to a standard protocol of 6 mg/kg loading dose followed by a maintenance dose of 2.5-5 mg/kg/12 h. Of the 24 neonates studied, 12 received a mean phenobarbital dose of 26.34 mg/kg/d (ranging from 2 mg every 24 h to 25 mg every 12 h) and the mean phenobarbital concentration was 56.12 micrograms/ml (range 22-112 micrograms/ml). The remaining 12 patients did not require phenobarbital therapy but did receive aminophylline alone. The two groups were closely matched for gestational age, 5-min Apgar scores, and sex (p greater than 0.2). Steady-state theophylline clearance was determined at least once a week for four or more separate weeks. The study lasted a minimum of 8 wk and if more than one theophylline clearance was determined in any given week, the mean of these clearances was used. Both groups demonstrated an increase in mean theophylline clearance over time (from 15.75 and 16.67 ml/h/kg to 30.33 and 35.42 ml/h/kg for the aminophylline and aminophylline plus phenobarbital groups, respectively). The mean slope, an indicator of the average change in theophylline clearance, was 2.19 for the aminophylline group and 3.27 for the aminophylline plus phenobarbital group (p greater than 0.2), indicating that the theophylline clearance for neonates receiving phenobarbital was not significantly different from that for neonates receiving aminophylline alone. Based on this information, aminophylline does not need to be adjusted solely based on concomitant phenobarbital administration; however, theophylline concentrations should be monitored since theophylline clearance can change rapidly and unpredictably in neonates.

The efficacy of the FDA guidelines for theophylline dosing in newborns was evaluated retrospectively in 224 patients who had clearance data available. Mean projected post loading dose serum concentration was 4.1 +/- 1.0 mg/L in 160 patients. Mean projected steady-state concentration was 4.8 +/- 1.6 mg/L in 189 patients receiving intravenous aminophylline and 4.2 +/- 1.3 mg/L in 35 patients on oral therapy. Projected serum concentrations were subtherapeutic (less than 6.0 mg/L) in 181 of the 224 patients analyzed. There was a statistically significant difference in serum concentrations between asphyxiated and nonasphyxiated patients (p less than 0.001). There was no significant difference in mean projected serum concentrations between patients age 26-41 weeks (postconceptional age). This study suggests that the FDA dosing guidelines for theophylline in infants is inadequate and results in subtherapeutic (less than 6.0 mg/L) serum concentrations in the majority of newborns.

phenobarbital dosing requirements and plasma clearance were examined for asphyxiated and nonasphyxiated neonates. The gestational age, postnatal age, duration of phenobarbital therapy and plasma phenobarbital concentrations were similar for the two groups. The plasma phenobarbital clearance was 4.1 +/- 1.0 (SD) and 8.7 +/- 3.9 (SD) ml/kg/h for asphyxiated and nonasphyxiated neonates, respectively. Asphyxiated neonates only require about half the maintenance dose of nonasphyxiated neonates to achieve similar plasma concentrations.

The effect of asphyxia on theophylline clearance was studied in 30 newborns who were matched for gestational age, postnatal age, and the presence or absence of asphyxia. Asphyxiated newborns cleared theophylline at approximately half the rate of nonasphyxiated newborns. We found that, in order to achieve a steady-state plasma concentration of 8 mg/L of theophylline, asphyxiated neonates should receive 2.1 mg/kg/day, while nonasphyxiated neonates should receive 3.9 mg/kg/day.

Theophylline-induced seizures are reported in two neonates. The serum theophylline concentrations during seizures were 51.0 mg/liter and 54.0 mg/liter. Toxic symptoms prior to seizures may be absent or undetected, supporting the necessity of blood level monitoring during theophylline therapy.

The effect of total parenteral nutrition (TPN) induced cholestasis on theophylline clearance was examined in premature neonates. Thirty-six neonates receiving TPN and theophylline concurrently were reviewed. Aminophylline was administered according to a standard protocol of 6 mg/kg loading dose, followed by a maintenance dose of 2.5-5 mg/kg every 12 h. Of the 36 neonates reviewed, 18 developed cholestasis (direct bilirubin greater than or equal to 1 mg/100 ml and direct bilirubin greater than or equal to 60% of total bilirubin). The remaining 18 did not develop cholestasis. The two groups were closely matched for gestational age, 5-min apgar score, and sex. The neonates with cholestasis had a mean maximum direct bilirubin of 5.19 mg/100 ml (range 1-13.8 mg/100 ml) as compared to the patients without cholestasis who had a mean maximum direct bilirubin of 0.54 mg/100 ml (range 0.3-0.8 mg/100 ml). Steady-state theophylline clearance was determined at least once a week for at least 4 separate weeks. The study lasted a minimum of 8 weeks, and if more than one theophylline clearance was determined in any given week, the mean of these clearances was used. Both groups demonstrated a significant increase in mean theophylline clearance over time (from 16.09 and 18.60 ml/h/kg to 28.65 and 24.73 ml/h/kg for the cholestatic and noncholestatic groups, respectively). The mean slope, an indicator of the average rate of change of theophylline clearance, was 1.4 for the noncholestatic group and 2.5 for the cholestatic group, indicating that the theophylline clearance for neonates with cholestasis was not significantly different from that for neonates with normal liver function (p = 0.61) over time.

Six neonates with prolonged, intractable seizures were treated with valproic acid (VPA). Each patient had received maximum doses of phenobarbital (greater than 40 micrograms/ml), and five patients received at least two additional anticonvulsants, without success. Seizure activity was controlled in five of six (83%) cases. In four cases, all other anticonvulsants could be withdrawn, and seizures were controlled on VPA monotherapy. VPA was discontinued in three patients because of VPA-induced hyperammonemia. VPA pharmacokinetic measurements were as follows: for total VPA, volume of distribution (V) = 0.40 l/kg (range, 0.36 to 0.47 l/kg), serum clearance (Cl) = 14.4 ml/h/kg (5.5 to 18.2 ml/h/kg), half-life (T1/2) = 26.4 hours (8.6 to 48.5); for unbound VPA, V = 2.02 l/kg (1.14 to 2.44 l/kg), Cl = 108.9 ml/h/kg (42.0 to 252.0 ml/h/kg). T1/2 = 17.6 hours (6.7 to 34.2). VPA free fraction ranged from 11.3 to 31.6% (mean, 19.2%).

HEMODIALYSIS 1 or charcoal hemoperfusion 2 is often thought to be required when patients overdose with a near-lethal quantity of toxic drugs. 2 Recently, however, oral charcoal has been investigated as a noninvasive means of enhancing drug removal from the blood, 3-8 referred to by Levy 3 as "gastrointestinal dialysis." We report a case of theophylline overdose in which oral activated charcoal was used to promote theophylline removal from the body. Report of a Case A 23-year-old woman complained of symptoms of nausea, vomiting, diarrhea, tachycardia, and extreme tremulousness; allegedly she had taken twenty 5-mg tablets of terbutaline sulfate and twenty 200-mg tablets of theophylline (Theo-dur) in a suicide gesture earlier that day. In the emergency room, several theophylline and terbutaline tablets were found in the vomitus. Her serum theophylline concentration at the time of admission was 32.5 mg/L, rising to a peak of 98.7 mg/L shortly thereafter. Eighteen hours

A 47–year-old woman with endstage renal disease and dialysis-induced encephalopathy was being treated with carbamazepine for myoclonus. Her carbamazepine serum concentration appeared to be therapeutic at 5.1 μg/ml. She experienced a seizure while on hemodialysis/hemoperfusion that was possibly related to the removal of carbamazepine during dialysis. The elimination of carbamazepine on a dialysis day was compared with elimination on a nondialysis day. The half-life and apparent clearance were the same for each day, indicating that hemodialysis/hemoperfusion had little effect on the overall removal of carbamazepine from the body. The possible reasons for this lack of effect are discussed.

In this study, we prospectively evaluated the effect of oral cimetidine on serum lidocaine concentrations in 6 patients with suspected myocardial infarction. Compared to baseline lidocaine levels, total lidocaine concentrations increased by 8.2 +/- 7.8% at 6 hours, 16.4 +/- 9.0% at 12 hours and 27.9 +/- 9.4% at 24 hours after two doses of oral cimetidine. Unbound lidocaine concentrations increased by 14.3 +/- 4.1% at 6 hours, and 18.3 +/- 10.3% at 24 hours after cimetidine. In patients with myocardial infarction (3), total lidocaine concentrations increased by 24.2 +/- 10.4%, whereas unbound lidocaine increased by 8.9 +/- 10.2% at 24 hours. Therefore, increases in total lidocaine concentrations after cimetidine administration were considerably less than those previously reported and empiric dosage reductions of lidocaine in patients receiving cimetidine may not be appropriate.

Sir .—We read with interest the article by Naqvi et al 1 regarding vancomycin pharmacokinetics in neonates. We would like to focus on the important effect of indomethacin use on vancomycin disposition in neonates. We have treated numerous neonates with vancomycin for Staphylococcus epidermidis infections. Each neonate receives a vancomycin loading dose of 15 to 20 mg/kg administered intravenously over one hour. A postloading dose peak and trough serum concentration value are obtained before the first maintenance dose is given. Pharmacokinetic variables, volume of distribution, and half-life are then calculated using a one-compartment pharmacokinetic model. Eleven neonates with postconceptional ages of less than 35 weeks are the subject of this letter. The group was subdivided into six neonates with patent ductus arteriosus (PDA) treated with indomethacin and five control neonates without PDA who did not receive indomethacin. The characteristics of the neonates and their vancomycin pharmacokinetic variables are summarized in

During pregnancy, most studies of medications given have centered around urban centers. Most of these studies emphasize teratogenetic effects or CNS depression. Few studies have looked at over-the-counter (OTC) drugs and none at medications taken by women in rural settings. OTC drugs used by 60 women during pregnancy in Guilford County, N.C. were assessed. Although the area is not strictly rural, it is far less urban than other areas where pregnant women's drug histories were studied. Histories were obtained through a patient interview. An average of five (5) were ingested by each patient. The most common drugs consumed were vitamins 92%, caffeine 80%, iron 73%, acetaminophen 62.5%. Few teratogenic agents were found. Acetaminophen 62.5% replaced aspirin as the leading analgesic. Drugs of abuse were not emphasized so few were reported. Significance of the study appears threefold. One, most of the OTC drugs taken by rural women appear similar to that taken by urban women in other studies. Two, acetaminophen, a drug about which little is known of its effects on the fetus, has replaced aspirin as the leading analgesic and may post a significant threat to the fetus and newborn infant. Finally, caffeine continues to be consumed by many pregnant women. If animal studies where large amounts are consumed are valid, the drug can cause teratogenic effects and may prove a significant risk to the human fetus.