Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams.

Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly. Fluconazole plasma concentrations from samples obtained by either scheduled or scavenged sampling were measured using a liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using NONMEM 7.2. Population PK parameters were allometrically scaled by body weight. Covariates were evaluated by univariable screening followed by multivariable assessment. Fluconazole exposures were simulated in premature infants using the final PK model. A population PK model was developed from 141 infants using 604 plasma samples. Plasma fluconazole PK were best described by a one-compartment model with first-order elimination. Only serum creatinine was an independent predictor for clearance in the final model. The typical population parameter estimate for oral bioavailability in the final model was 99.5%. Scavenged samples did not bias the parameter estimates and were as informative as scheduled samples. Simulations indicated that the study dose maintained fluconazole troughs of >2,000 ng/ml in 80% of simulated infants at week 1 and 59% at week 4 of treatment. Developmental changes in fluconazole clearance are best predicted by serum creatinine in this population. A twice-weekly dose of 6 mg/kg achieves appropriate levels for prevention of invasive candidiasis in extremely premature infants.

Assessment of adherence to guidelines for using progesterone to prevent recurrent preterm birth.

OBJECTIVE: To assess if women with recurrent preterm birth had been offered, received, and adhered to progesterone supplementation guidelines and to ascertain reasons for failure to follow guidelines. METHODS: Charts of infants who were products of recurrent spontaneous preterm birth were reviewed at four neonatal intensive care units of Akron Children's Hospital. Mothers of identified infants were interviewed and charts abstracted to determine: if progesterone was offered; acceptance of progesterone; compliance with progesterone; and reasons why progesterone was declined. RESULTS: One hundred twenty-eight mothers with a recurrent spontaneous preterm birth were identified and 98 consented to participate. 62.2% (61/98) of the interviewed mothers reported that they were offered progesterone. Of the women offered progesterone, 82% (50/61) accepted treatment and 18.0% (11/61) declined. One woman who accepted progesterone did not receive it. Of the women who received progesterone, 18.4% (9/49) reported compliance failure. Of the women who did not receive progesterone, 75.5% (37/49) reported that they were not offered progesterone and 89.2% (33/37) of the women not offered progesterone reported that their care providers were aware of their prior preterm delivery. CONCLUSIONS: Only 50% (49/98) of women who were candidates for progesterone received treatment. The main reason for women not receiving treatment was not being offered progesterone by their caregiver.

Standardizing documentation and the clinical approach to apnea of prematurity reduces length of stay, improves staff satisfaction, and decreases hospital cost.

BACKGROUND: Apnea of prematurity, a common disorder, can severely compromise an infant's condition unless correctly diagnosed and treated. Infants with a history of apnea of prematurity can be discharged home but then be rehospitalized for an apneic event, an apparent life-threatening event, or sudden infant death syndrome. The definition of a clinically significant cardiopulmonary event, such events' documentation, and the treatment approach were standardized, and discharge criteria were refined. METHODS: A prospective, single-center comparison was conducted between a group of premature infants before and after implementation of the standard approach. Data were collected prospectively from August 1, 2005, through July 21, 2006, for the prestandard-approach group and from August 1, 2006, through September 16, 2007, for the standard-approach group. RESULTS: Twenty-two (35%) of the 63 infants in the prestandard-approach group experienced discharge delays because of poor documentation, whereby the clinician could not determine the safety of discharge. This resulted in 59 additional hospital days (mean length-of-stay [LOS] increase, 5.7 days). The standard-approach group of 72 infants experienced no discharge delays and no additional hospital days, and LOS decreased (all p < .0001). Annual charges were reduced by more than $58,000 in avoiding unnecessary hospital days. Readmission to the hospital for apnea of prematurity occurred for 5 (7.9%) of the prestandard-approach group but none of the standard-approach group (p = .0203). Overall compliance with the standardization process has been maintained at > or = 96%. CONCLUSION: Implementation of a standard approach to the definition of apnea of prematurity and its treatment and documentation decreases LOS and reduces cost.

The impact of postintubation chest radiograph during pediatric and neonatal critical care transport.

OBJECTIVES: Tracheal intubation is necessary in the setting of pediatric/neonatal critical care transport but information regarding usefulness and efficiency of a confirmatory postintubation chest radiograph is limited. We hypothesize that routine postintubation chest radiograph to confirm tracheal tube position is not informative and can be eliminated to improve efficiency without compromising safety in transport. DESIGN: This was a prospective observational study. The primary study outcome was the rate of tracheal tube repositioning after postintubation chest radiograph and the secondary outcome was the on-scene time. Additional data obtained included the initial accuracy of tracheal tube depth based on Pediatric Advanced Life Support and Neonatal Resuscitation Program guidelines. SETTING: A children's hospital-based pediatric/neonatal critical care transport team in northeastern Ohio. PATIENTS: All pediatric/neonatal patients intubated by the transport team during the 18-month study period (January 2009-July 2010). MEASUREMENTS AND MAIN RESULTS: There were 77 patients enrolled (43 pediatric, 34 neonatal). A postintubation chest radiograph was obtained 85.7% of the time and showed tracheal tube malposition in 47% of cases. No difference was seen in the rate of malpositioned tracheal tubes in the neonatal group compared with pediatric group (51.7% vs. 43.2%, p = 0.54). The calculated tracheal tube depth based on the Neonatal Resuscitation Program and Pediatric Advanced Life Support guidelines was correct in 50% of the neonates and 41.9% of the pediatric patients. In patients with appropriate initial tracheal tube depth by calculations, the tracheal tube was repositioned at similar rates after postintubation chest radiograph in both neonatal and pediatric patients (50% vs. 41.9%, p = 0.48). When comparing mean onscene times for patients with/without a postintubation chest radiograph, the neonatal patients saved 33 minutes on average when no chest radiograph was obtained (mean ± sd: 60.6 ± 35.8 min vs. 93.8 ± 23.8 min, p = 0.01). There was no statistical difference in on-scene time for pediatric patients whether they did or did not receive a postintubation chest radiograph. CONCLUSIONS: Although postintubation chest radiographs may extend the overall on-scene transport times in select patients, our data show that the postintubation chest radiographs remain informative in pediatric/neonatal critical care specialty transport and should be obtained when feasible.

Safety and effectiveness of meropenem in infants with suspected or complicated intra-abdominal infections.

BACKGROUND: Intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial with excellent activity against pathogens associated with intra-abdominal infections. The purpose of this study was to determine the safety and effectiveness of meropenem in young infants with suspected or complicated intra-abdominal infections. METHODS: Preterm and term infants <91 days of age with suspected or confirmed intra-abdominal infections hospitalized in 24 neonatal intensive care units were studied in an open-label, multiple-dose study. Adverse events and serious adverse events were collected through 3 and 30 days following the last meropenem dose, respectively. Effectiveness was assessed by 3 criteria: death, bacterial cultures, and presumptive clinical cure score. RESULTS: Of 200 subjects enrolled in the study, 99 (50%) experienced an adverse event, and 34 (17%) had serious adverse events; no adverse events were probably or definitely related to meropenem. The most commonly reported adverse events were sepsis (6%), seizures (5%), elevated conjugated bilirubin (5%), and hypokalemia (5%). Only 2 of the serious adverse events were determined to be possibly related to meropenem (isolated ileal perforation and an episode of fungal sepsis). Effectiveness was evaluable in 192 (96%) subjects, and overall treatment success was 84%. CONCLUSIONS: Meropenem was well tolerated in this cohort of critically ill infants, and the majority of infants treated with meropenem met the definition of therapeutic success. CLINICAL TRIALS REGISTRATION: NCT00621192.

Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra-abdominal infections.

BACKGROUND: Suspected or complicated intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial agent with excellent activity against pathogens associated with intra-abdominal infections in this population. The purpose of this study was to determine the pharmacokinetics (PK) of meropenem in young infants as a basis for optimizing dosing and minimizing adverse events. METHODS: Premature and term infants <91 days old hospitalized in 24 neonatal intensive care units were studied. Limited PK sampling was performed following single and multiple doses of meropenem 20 to 30 mg/kg of body weight every 8 to 12 hours based on postnatal and gestational age at birth. Population and individual patient (Bayesian) PK parameters were estimated using NONMEM. RESULTS: In this study, 200 infants were enrolled and received the study drug. Of them, 188 infants with 780 plasma meropenem concentrations were analyzed. Their median (range) gestational age at birth and postnatal age at PK evaluation were 28 (23-40) weeks and 21 (1-92) days, respectively. In the final PK model, meropenem clearance was strongly associated with serum creatinine and postmenstrual age (clearance [L/h/kg] = 0.12*[(0.5/serum creatinine)**0.27]*[(postmenstrual age/32.7)**1.46]). Meropenem concentrations remained >4 µg/mL for 50% of the dose interval and >2 µg/mL for 75% of the dose interval in 96% and 92% of patients, respectively. The estimated penetration of meropenem into the cerebrospinal fluid was 70% (5-148). CONCLUSIONS: Meropenem dosing strategies based on postnatal and gestational age achieved therapeutic drug exposure in almost all infants.

Evaluation and development of potentially better practices for perinatal and neonatal communication and collaboration.

OBJECTIVE: The obstetric and neonatal exploratory focus group of the Vermont Oxford Network Neonatal Intensive Care Quality Improvement Collaborative 2002 set out to improve collaboration, communication, and coordination between maternal and neonatal caregivers in 3 areas: the pregnancy at 22 to 26 weeks, measurement of maternal outcomes that are linked with neonatal outcomes, and team performance during high-risk delivery. Antepartum and intrapartum maternal attributes and interventions also were considered important measurements to identify practice variations and their relationship to neonatal outcomes for ongoing obstetric and neonatal collaboration. METHODS: Potentially better practices were developed on the basis of evidence in the literature, expert opinion, and internal analysis at the participating perinatal centers. The potentially better practices include development of local guidelines at each center for the care and counseling of pregnant women who are at risk for delivering at the margin of viability; communication strategies for obstetric and neonatology providers relating to high-risk pregnancy treatment plans; team communication and performance at high-risk deliveries; design of organizational structures and processes that facilitate obstetric and neonatal collaboration; and development of perinatal data to evaluate effects of perinatal practices on maternal, fetal, and neonatal outcomes. RESULTS: As a result of the project, participating centers developed local guidelines for pregnancies between 22 and 26 weeks, created a cross-center maternal database that currently is being linked to neonatal outcomes, and completed a pilot study on video simulation of neonatal-perinatal team communication. CONCLUSIONS: Increased understanding of practice variation in the management of care for infants who are at the margins of viability, locally developed guidelines, and a focus on improved team communication during delivery can be accomplished with a multicenter collaborative approach.

Management of high-order multiple births: application of lessons learned because of participation in Vermont Oxford Network collaboratives.

OBJECTIVES: The delivery and care of sextuplets is complex. Potentially better practices that were developed as part of the Vermont Oxford Network improvement collaboratives were used to prepare for a sextuplet delivery at Akron Children's Hospital. METHODS: The team used potentially better practices that were learned from the Neonatal Intensive Care Quality Improvement Collaborative 2002 using multidisciplinary teams. There was extensive media coverage of the delivery. RESULTS: The goal was to use nearly all potentially better practices that focused on the goals of reducing nosocomial infection, reducing chronic lung disease, reducing radiograph use, reducing length of stay, reducing blood gas use, promoting nutrition, reducing intraventricular hemorrhage, and enriching family-centered care. The center aimed to use these 97 potentially better practices. Of the 97 possible potential better practices as set by the Neonatal Intensive Care Quality Improvement Collaborative 2002, 96 (99%) were used. CONCLUSIONS: This is a blueprint that any center that is faced with high-order multiple births could use as a reference point to begin planning. The team created a benchmark to achieve in every birth of very low birth weight infants and not just a special situation of high-order multiple births.

Attitudes of obstetric and pediatric health care providers toward resuscitation of infants who are born at the margins of viability.

OBJECTIVES: The objective of this study was to determine the attitudes of a variety of health care providers toward the recommendations that should be made to parents regarding the resuscitation of infants who are born at the margins of viability. METHODS: A written questionnaire was distributed to the medical and nursing staff at 4 tertiary perinatal centers. For each of 5 weekly gestational age intervals from 22 weeks to 26 weeks, 6 days, the health care providers were asked to describe on a scale from 1 to 5 whether they would strongly discourage through strongly encourage resuscitation. They also were queried regarding their comfort with counseling regarding these issues. The attitudes of various groups of providers were compared across weekly intervals. RESULTS: A total of 204 physicians and 539 nurses completed the survey. The majority would strongly discourage, either discourage or strongly discourage, be neutral or recommend, recommend or strongly recommend, and strongly recommend resuscitation during the 23rd, 24th, 25th, 26th, and 27th weeks of gestation, respectively. Obstetric caregivers were slightly less likely than pediatric caregivers to strongly discourage resuscitation from 22 weeks to 22 weeks, 6 days and 23 weeks to 23 weeks, 6 days. There were no significant differences in the recommendations of obstetricians and pediatricians. Pediatric nurses were more likely to strongly recommend resuscitation from 26 weeks to 26 weeks, 6 days and more likely either to discourage or to strongly discourage resuscitation from 23 weeks to 23 weeks, 6 days and to strongly discourage resuscitation from the 22 weeks to 22 weeks, 6 days than their obstetric counterparts. Obstetric nurses were slightly less likely than obstetricians to strongly recommend resuscitation at 26 weeks to 26 weeks, 6 days and less likely to strongly discourage resuscitation from 22 weeks to 22 weeks, 6 days. CONCLUSIONS: The caregivers' recommendations seem to be based logically on the current literature regarding survival and morbidity that is experienced by infants who are born at the threshold of viability. Although there are minor differences, there was a relatively consistent approach among professional groups.