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Introduction Assess the cost-effectiveness (US healthcare payer perspective) of sarilumab subcutaneous (SC) 200 mg + methotrexate versus conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) or targeted DMARD + methotrexate for moderate-to-severe rheumatoid arthritis (RA) in adults with inadequate response to methotrexate. Methods Microsimulation based on patient profiles from MOBILITY (NCT01061736) was conducted via a 6-month decision tree and lifetime Markov model with 6-monthly cycles. Treatment response at 6 months was informed by a network meta-analysis and based on American College of Rheumatology (ACR) response. Responders: patients with ACR20 response who continued with therapy; non-responders: ACR20 non-responders who transitioned to the subsequent treatment. Utilities and quality-adjusted life-years (QALYs) were estimated via mapping 6-month ACR20/50/70 response to relative change in Health Assessment Questionnaire Disability Index score (short term) and based on published algorithms (long term). Direct costs considered drugs (wholesale acquisition costs), administration and routine care. Results Lifetime QALYs and costs for treatment sequences on the efficiency frontier were 3.43 and $115,019 for active csDMARD, 5.79 and $430,918 for sarilumab, and 5.94 and $524,832 for etanercept (all others dominated). Sarilumab was cost-effective versus tocilizumab and csDMARD (incremental cost-effectiveness ratios of $84,079/QALY and $134,286/QALY). Probabilistic sensitivity analysis suggested comparable costs and slightly improved health benefits for sarilumab versus tocilizumab, irrespective of threshold. Conclusion In patients with moderate-to-severe RA, sarilumab 200 mg SC every 2 weeks + methotrexate can be considered a cost-effective treatment option, with lower costs and greater health benefits than alternative treatment sequences (+ methotrexate) beginning with adalimumab, certolizumab, golimumab and tofacitinib and below commonly accepted cost-effectiveness thresholds against tocilizumab + methotrexate or csDMARD active treatment. Funding Sanofi and Regeneron Pharmaceuticals, Inc. Electronic supplementary material The online version of this article (10.1007/s12325-019-00946-1) contains supplementary material, which is available to authorized users.

Although the benefit of first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) over chemotherapy in EGFR mutation-positive (EGFRm) non-small-cell lung cancer (NSCLC) has been demonstrated in clinical trials, the optimal treatment sequence remains unclear. The objective of our study was to evaluate the cost-effectiveness of dacomitinib in Sweden vs afatinib and osimertinib in first-line treatment of EGFRm NSCLC. A partitioned survival model was developed with three health states: progression-free, post-progression, and death. Progression-free and overall survival curves were used to inform movements between states. Clinical data were taken from randomized trials, compared via a network meta-analysis (NMA). Utility data were taken from published studies and costs from national Swedish sources. The model used a 15-year time horizon and a Swedish healthcare payer perspective. Sensitivity and scenario analyses were performed. The base-case analysis showed that dacomitinib accrued a total of 2.10 quality-adjusted life-years (QALYs) at a total cost of Swedish krona (SEK) 874,615. The incremental cost-effectiveness ratio (ICER) for dacomitinib vs afatinib was SEK 461,556 per QALY gained. The ICER of osimertinib vs dacomitinib, where the small QALY gains of the former came at a high additional cost, was SEK 11,444,709. Deterministic and probabilistic sensitivity analyses confirmed the robustness of these results; changes to drug and medical resource use costs and overall survival had the greatest impact on ICER estimates. This model is subject to uncertainty associated with extrapolating long-term treatment effects from shorter trial follow-up periods, although this would also be a limitation when using direct comparison or time-dependent hazard ratios. The NMA was limited by the use of indirect comparison, although sensitivity analyses supported the robustness of our findings. Our model demonstrated that dacomitinib is cost-effective for first-line EGFRm NSCLC treatment in Sweden vs afatinib and osimertinib.

Introduction As clinical roles for pharmacists expand, effective physical assessment training for pharmacy students is essential. The study objective was to determine whether doctor of pharmacy students taught physical assessment using mid-fidelity manikins improved in confidence and accuracy. Long-term retention of skills was also measured. Methods First-year (P1) pharmacy students were enrolled in a case-based course over two semesters between August 2018 and May 2019. Manikins were incorporated into the fall semester course for students to perform physical assessment as part of the individual case workup process. Students completed surveys before and after the course to evaluate differences in their confidence and accuracy with detecting normal vs. abnormal vital signs. After 21 weeks of no manikin exposure, students were again surveyed and assessed to evaluate long-term retention of physical assessment skills. Results Fifty-six students were included. Student confidence in assessing heart rate, blood pressure (BP), and lung sounds improved significantly between pre-exposure and post-exposure (34%, 39%, and 71% improvement, respectively), and accuracy in assessing BP and lung sounds improved significantly between pre-exposure and post-exposure (28% and 23% improvement, respectively). Confidence and accuracy were maintained throughout the study including follow-up. Conclusions Early introduction of mid-fidelity manikins to P1 pharmacy students in a case-based, spaced learning strategy provided a successful approach to teach physical assessment skills.

Despite a substantial number of treatment options in rheumatoid arthritis (RA) following tumor necrosis factor inhibitor (TNFi) inadequate response or intolerance (TNF-IR), a lack of clarity on the optimal approach remains. Sarilumab, a human monoclonal anti-interleukin-6 receptor alpha antibody, can be used as monotherapy or in combination with methotrexate or other conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) in TNF-IR patients.To conduct a cost-utility analysis from a U.S. health care system perspective for sarilumab subcutaneous 200 mg + methotrexate versus abatacept + methotrexate or a bundle of TNFi + methotrexate for treatment of adult patients with moderately to severely active RA and TNF-IR.Analysis was conducted via individual patient simulation based on patient profiles from the TARGET trial (NCT01709578); a 6-month decision tree was followed by lifetime semi-Markov model with 6-month cycles. Treatment response at 6 months, informed by network meta-analysis, was based on American College of Rheumatology (ACR) 20/50/70 criteria; patients achieving ≥ ACR20 continued with current therapy, and other patients moved to the next line of biologic DMARD therapy or conventional synthetic DMARD palliative treatment. Direct costs included wholesale acquisition drug costs and administration and routine care costs. Routine care costs and quality-adjusted life-years (QALYs) were estimated by predicting the Health Assessment Questionnaire Disability Index score based on treatment response and were imputed from published equations.Sarilumab + methotrexate dominated the TNFi bundle + methotrexate, achieving lower costs ($319,324 vs. $356,096) and greater effectiveness (4.27 vs. 4.15 QALYs), and was on the cost-efficiency frontier with abatacept + methotrexate ($360,211 and 4.29 QALYs). Abatacept + methotrexate was not cost-effective versus sarilumab + methotrexate. Scenario analyses indicated the results were robust; sarilumab + methotrexate became dominant against abatacept + methotrexate after reduced model horizon, minimum response based on ACR50 or ACR70, or time to discontinuation per treatment class. Sarilumab + methotrexate was also dominant versus the TNFi bundle; when class-specific time to treatment discontinuation was specified, sarilumab remained cost-effective with an incremental cost-effectiveness ratio of $36,894.Sarilumab + methotrexate can be considered an economically dominant (more effective, less costly) option versus a second TNFi + methotrexate; compared with abatacept + methotrexate, it is a less costly but less effective option for patients with moderately to severely active RA who have previously failed TNFi.This study was funded by Sanofi and Regeneron Pharmaceuticals. Kiss and Gal are employees of Evidera, which received consulting fees from Sanofi/Regeneron for conducting this study. Muszbek was employed by Evidera at the time of this study. Kuznik and Chen are current employees of and stockholders in Regeneron Pharmaceuticals. Fournier is an employee of and stockholder in Sanofi. Proudfoot is a former employee of and current stockholder in Sanofi and current employee and stockholder in ViiV Healthcare/GlaxoSmithKline. Michaud has received grant funding from Pfizer and the Rheumatology Research Foundation. The sponsors were involved in the study design, collection, analysis, and interpretation of data as well as data checking of information provided in the manuscript. The authors had unrestricted access to study data, were responsible for all content and editorial decisions, and received no honoraria related to the development of this publication.

Introduction A skills laboratory session was created to train students to perform basic pulmonary function test (PFT) assessments. The objective of this study was to evaluate whether pharmacy student confidence changed after conducting a PFT in a laboratory session and if this was enhanced by adding a second session. Methods A two-week educational activity was designed. For week one, each student completed a PFT with an instructor coaching to assure proper performance. Week two occurred one week later, and in pairs, students again completed an individual PFT, but the paired student served as the coach rather than the instructor. Students completed three surveys, a baseline before training, and after completing the sessions in week 1 and week 2, to assess confidence in PFT procedures on a 10-point scale. Survey results were analyzed using the sign test. A summary of instructor time and supply costs was also estimated. Results Forty-five students consented to all surveys (78.9 percent inclusion rate). There was a significant increase in confidence for all items between the first and second surveys. Between the second and third surveys, only two items increased significantly. Conclusions The educational intervention was successful in improving student self-confidence in performing PFTs. However, limited additional confidence was gained by adding a second week of training, especially in context of resource allocation. These findings informed instructors that a one week PFT training may be sufficient and that resources needed for a second PFT training week may be better invested in another teaching opportunity.

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.

Therapeutic drug monitoring is increasingly giving way to dosing drugs based on population-based pharmacokinetic parameters, even when pharmacokinetic values vary quite a bit in individual patients. Further, drug concentrations are often considered appropriate if they are within a defined therapeutic range, even if the patient response is suboptimal. This lecture discusses the limitations of therapeutic ranges in neonates, and proposes greater emphasis on pharmacodynamic curves to individualize drug therapy. Examples are provided using methylxanthines, indomethacin, antiepileptic drugs and aminoglycosides. The potential to use pharmacokinetic findings to describe physiologic changes and occasionally assist with diagnosis is also discussed.

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.

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).

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.

Gastroesophageal reflux is a common disorder found in infants and children. Treatment modalities include conservative measures, medications, and surgery. Histamine2 receptor antagonists alone or in combination with prokinetic agents are the first-line medical options, but the addition of prokinetic agents or a change to proton pump inhibitors is reasonable. Corrective fundoplication is reserved as the last-line treatment strategy. The use of proton pump inhibitors such as omeprazole for acid suppression has been studied in children, and a stable, extemporaneous formulation can be prepared. Despite limited data in pediatrics, omeprazole appears to be safe and effective for treating reflux and for decreasing the need for fundoplication.

Mary Ann VT Dimaguila,1,2 Peter Gal,1,3,4 Tiffany Wilson,1 John E Wimmer Jr,1,2 McCrae Smith,1,2 Rita Q Carlos,1,2 Christie C Davanzo,1,2 J Laurence Ransom1,2 1Women's Hospital of Greensboro, Cone Health, Greensboro, NC, USA; 2Piedmont Neonatology, Greensboro, NC, USA; 3Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 4Greensboro Area Health Education Center, Greensboro, NC, USA Background: A recent study showed that use of Lactobacillus reuteri as probiotic prophylaxis decreased the necrotizing enterocolitis (NEC) rate from 15.1% to 2.5% in neonates with birth weight below 1000 g. Given the controversies surrounding use of probiotics in neonatal intensive care units, we address one additional aspect of routine implementation of probiotics for NEC prophylaxis – the pharmacoeconomic impact. Methods: Using data from our initial published experience, and continuing data collection after instituting a higher dose of L. reuteri, we measured the reduction in NEC in neonates with birth weight below 1000 g. Cost savings from prior studies examining the cost and outcomes of medical and surgical NEC were used to calculate the financial impact of routine L. reuteri DSM 17938 prophylaxis. Results: Medical records for 354 neonates were reviewed, 232 in the years before introduction of L. reuteri prophylaxis and 79 who received L. reuteri prophylaxis dosed at 0.1 mL daily and 43 neonates given a total daily dose of 0.2 mL as one or two doses. The incidence of NEC was significantly lower in the neonates who received L. reuteri (two of 122 neonates [1.6%] versus 35 of 232 neonates [15.1%]). The expected benefits for our neonatal intensive care unit per 100 extremely low-birth-weight neonates treated were four fewer deaths, five fewer cases of medical NEC, eight fewer cases of surgical NEC, one less patient with short-bowel syndrome, and a cost saving of approximately $2.2 million. Conclusion: Prophylactic initiation of L. reuteri as a probiotic for prevention of NEC in neonates with birth weight ≤ 1000 g is a cost-effective strategy during their stay in neonatal intensive care. Keywords: necrotizing enterocolitis, probiotic, extremely low birth weight, Lactobacillus reuteri, pharmacoeconomics

Background: Preterm infants are at high risk for late-onset infections due to gram-negative or fungal organisms. Evidence supports that a common source for these organisms may be the gastrointestinal tract. One theoretical way to change the infection rate is to alter the bacterial flora inhabiting the newborn gastrointestinal tract using probiotics. This study examines the impact of routine use of a probiotic, Lactobacillus reuteri DSM 17938 (BioGaia®), on the rate of late-onset gram-negative and fungal infection in neonates with birth weight ≤ 1000 grams. Methods: This is a retrospective cohort study comparing the rates of gram-negative bacterial and fungal infections 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 July 2012 who received routine L. reuteri prophylaxis. Neonates were excluded if they died or were transferred within the fi rst week of life. The remainder were included in the study and recorded as either having late onset infection related to gram negative organisms or fungi, or not having late onset infection. 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 infection were compared using Chi square analysis with Fisher exact t-test. Results: Medical records for 354 neonates were reviewed, 232 before- and 122 after-introduction of L. reuteri prophylaxis. Despite a marked reduction in necrotizing enterocolitis and mortality, the incidence of late-onset infection varied from year-to-year, but was not signifi cantly altered by the introduction of routine L. reuteri. No adverse events related to use of L. reuteri were noted. Conclusions: Prophylactic initiation of L. reuteri as a probiotic does not decrease late-onset infection.

The challenging issues in pediatric pharmacotherapy are both profound and exciting. Microtechnologies for evaluating the impact of genetics in disease (e.g., using polymerase chain reactions) and the possibilities of therapeutic interventions create major clinical and ethical dilemmas that remain to be resolved. Inclusion of pediatric patients in drug development and marketing trials also remains a point of contention. Finally, well-established therapies should not be overlooked in favor of new but unestablished treatment approaches. Future columns will continue to use the current format, in which a few selected topics of high therapeutic importance are discussed. The research technologies, discussion of new drug therapy interventions, and preventive strategies most likely to benefit the health care of infants, children, and adolescents will remain the scope of this column.

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.

Background Necrotizing 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. Methods This 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. Results Medical 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. Conclusions Prophylactic 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.

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.

Under the Emergency Use Authorization issued in April 2009, oseltamivir can be used to treat 2009 influenza A (H1N1) virus infection in children aged

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.

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 sop 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 G koseri.

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.