Peter Gal

Theophylline disposition in obesity

Theophylline disposition was examined in 14 obese subjects and 57 normal subjects. A single oral dose of aminophylline solution was given and serum and saliva samples were collected over several hours and assayed by high‐pressure liquid chromatography. The apparent volume of distribution (Vd) and body clearance (ClB) were analyzed for total body weight (TBW) and ideal body weight (IBW). The Vd averaged 0.482 (SD = 0.084) L/kg TBW in normals vs 0.382 (0.069) L/kg TBW and 0.77 (0.189) L/kg IBW in obese subjects. The ClB averaged 63.0 (28.5) ml/hr/kg IBW in normals compared to 32.8 (11.1) ml/hr/kg TBW and 64.1 (20.8) ml/hr/kg IBW in obese subjects. Similar Vd values between the two groups when TBW is used indicates that loading dose is best calculated based on TBW. Similar ClB based on lBW in normal and obese subjects indicates that lBW should be used to calculate maintenance doses for theophylline. Mean half‐lives were longer in obese subjects than in normals, 8.6 (2.0) and 6.0 (2.1) hr, respectively, suggesting that obese patients may need less frequent dosing.

Effect of Food on the Bioavailability and Pattern of Release of a Sustained-Release Theophylline Tablet

Abstract: The effect of food on the bioavailability, time to peak level, and pattern of release of a sustained‐release theophylline preparation was examined in six normal volunteers. The average bioavailability for the 100‐ and 300‐mg tablets was 98 ± 0.03% (S.E.M.). This is consistent with previously published data. Food decreased measured theophylline concentration during the first 4 hours for the 100‐mg tablets and at the fourth‐hour sample following the 300‐mg tablets. The decreased rate of absorption resulted in a shift of the absorption curve to the right with a delay in the time to peak level. Peak serum concentrations for tablets given with a meal occurred 6 hours after the 100‐mg tablets and 8 hours after the 300‐mg tablets, as opposed to 4 and 6 hours, respectively, for tablets in the fasting state. The release pattern of the theophylline preparation approximated zero‐order kinetics for all fasting and food treatments.

Oseltamivir Dosing for Influenza Infection in Premature Neonates

Under the Emergency Use Authorization issued in April 2009, oseltamivir can be used to treat 2009 influenza A (H1N1) virus infection in children aged <1 year. No data exist on the dosing of oseltamivir in premature babies. A hospital health care worker inadvertently exposed 32 neonatal intensive care unit babies to 2009 influenza A (H1N1); a protocol was expeditiously implemented to collect samples for pharmacokinetics and dosage evaluation. Results suggest 1.0 mg/kg/dose twice daily in premature babies produces oseltamivir carboxylate exposures similar to that in older children receiving 3.0 mg/kg/dose twice daily. These results provide initial guidance on dosing oseltamivir in this vulnerable population.

Efficacy of phenobarbital monotherapy in treatment of neonatal seizures—relationship to blood levels

Seventy-one neonates were observed for the relationship between phenobarbital plasma concentrations and elimination of seizures. Sixty neonates (85%) had seizures controlled by phenobarbital alone. Effective plasma concentrations were 10.1 to 46.4 mg per liter. Although 36 neonates had seizures controlled by phenobarbital concentrations below 20 mg per liter, 7 neonates required levels above 30 mg per liter. We recommend that plasma phenobarbital concentrations should equal or surpass 40 mg per liter before additional anticonvulsants are used for neonates with seizures.

Effect of routine probiotic, Lactobacillus reuteri DSM 17938, use on rates of necrotizing enterocolitis in neonates with birthweight < 1000 grams: a sequential analysis

BackgroundNecrotizing enterocolitis (NEC) is a disease in neonates, often resulting in death or serious medical or neurodevelopmental complications. The rate of NEC is highest in the smallest babies and many efforts have been tried to reduce the rate of NEC. In neonates born below 1500 grams, the rate of NEC has been significantly reduced with the use of various probiotics. This study examines the impact of routine use of a probiotic, Lactobacillus reuteri DSM 17938 (BioGaia®), on the rate of NEC in neonates at highest risk for developing NEC, those with birth weight ≤1000 grams.MethodsThis is a retrospective cohort study comparing the rates of NEC in neonates with birth weight ≤ 1000 grams. The groups are separated into those neonates born from January 2004 to June 30, 2009, before introduction of L. reuteri , and neonates born July 2009 through April 2011 who received routine L. reuteri prophylaxis. The chart review study was approved by our institutional review board and exempted from informed consent.Neonates were excluded if they died or were transferred within the first week of life. The remainder were categorized as having no NEC, medical NEC, surgical NEC, or NEC associated death. Since no major changes occurred in our NICU practice in recent years, and the introduction of L. reuteri as routine prophylaxis was abrupt, we attributed the post-probiotic changes to the introduction of this new therapy. Rates of NEC were compared using Chi square analysis with Fisher exact t-test.ResultsMedical records for 311 neonates were reviewed, 232 before- and 79 after-introduction of L. reuteri prophylaxis. The incidence of NEC was significantly lower in the neonates who received L. reuteri (2 of 79 neonates [2.5%] versus 35 of 232 untreated neonates [15.1%]). Rates of late-onset gram-negative or fungal infections (22.8 versus 31%) were not statistically different between treated and untreated groups. No adverse events related to use of L reuteri were noted.ConclusionsProphylactic initiation of L. reuteri as a probiotic for prevention of necrotizing enterocolitis resulted in a statistically significant benefit, with avoidance of 1 NEC case for every 8 patients given prophylaxis.

Valproic acid efficacy, toxicity, and pharmacokinetics in neonates with intractable seizures

Six neonates with prolonged, intractable seizures were treated with valproic acid (VPA). Each patient had received maximum doses of phenobarbital (>40 μg/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 (T½) = 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). T½ = 17.6 hours (6.7 to 34.2). VPA free fraction ranged from 11.3 to 31.6% (mean, 19.2%).

Neonatal Seizures A Survey of Current Practice

A nationwide survey of neonatologists and pediatric neurologists was conducted to ascertain their methods of evaluating and managing neonatal seizures. Of the sampled 750 physicians, 284 (38%) responded to the single mailing. Most respondents use a routine for seizure workup which includes glucose, calcium and electrolyte determinations, and a lumbar puncture. On the other hand, there was a great variation in the use of an EEG, CT scan, skull x-ray, and a drug and metabolic screen. Phenobarbital was the initial drug of choice and phenytoin usually the second drug. Neurologists used higher loading doses for phenobarbital and phenytoin. Most physicians monitored blood levels to adjust maintenance doses. Drug therapy was usually continued for two months to one year after seizure control. Criteria for discontinuation were often arbitrary but included a normal electroencephalogram and the absence of seizures. The results demonstrate a lack of consensus in the evaluation and management of neonates with seizures.

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.

Factors influencing theophylline disposition in 179 newborns

The pharmacokinetics of intravenous theophylline were prospectively studied in 179 premature babies. Interrelated variables were analyzed for their influence on theophylline serum clearance. Gestational age, gender, duration of treatment, body weight, and Apgar scores were not found to correlate significantly with theophylline clearance. Weak but statistically significant correlations were found between serum clearance and postnatal (p less than 0.005) and postconceptional age (p less than 0.01). No significant difference in mean serum clearance (Cls) values was found between small-for-gestational-age (SGA) patients (Cls = 17.9 +/- 5.3 ml/kg/h) and appropriate-for-gestational-age (AGA) patients (Cls = 18.8 +/- 5.8 ml/kg/h). Conversely, asphyxiated patients had significantly lower mean clearance values than nonasphyxiated patients (16.4 +/- 5.3 ml/kg/h vs. 20.2 +/- 5.4 ml/kg/h, respectively, p less than 0.001). Volume of distribution for theophylline (n = 147) was 0.77 +/- 0.17 L/kg; there was no significant difference in distribution volumes between asphyxiated and nonasphyxiated patients or between SGA and AGA patients. Step-wise multiple regression analysis revealed postnatal age as the most important determinant of theophylline clearance among the variables analyzed (p less than 0.01). Postconceptional age had a statistically significant association with theophylline clearance in the entire group (n = 179, p less than 0.05). Duration of treatment had a small and statistically borderline effect (p less than 0.10) on theophylline clearance among nonasphyxiated infants when age factors were considered. Analysis of covariance confirmed the statistical effects of both postnatal age and asphyxia on theophylline serum clearance.

Use of Enoxaparin in a Preterm Infant

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.