Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants.

Clindamycin may be active against methicillin-resistant Staphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials. Intravenous data were collected from 62 infants (135 plasma PK samples) with postnatal ages of <121 days (median [range] gestational age of 28 weeks [23 to 42] and postnatal age of 17 days [1 to 115]). In addition to body weight, postmenstrual age (PMA) and plasma protein concentrations (albumin and alpha-1 acid glycoprotein) were found to be significantly associated with clearance and volume of distribution, respectively. Clearance reached 50% of the adult value at PMA of 39.5 weeks. Simulated PMA-based intravenous dosing regimens administered every 8 h (≤32 weeks PMA, 5 mg/kg; 32 to 40 weeks PMA, 7 mg/kg; >40 to 60 weeks PMA, 9 mg/kg) resulted in an unbound, steady-state concentration at half the dosing interval greater than a MIC for S. aureus of 0.12 µg/ml in >90% of infants. There were no adverse events related to clindamycin use. (This study has been registered at ClinicalTrials.gov under registration no. NCT01728363.).

Developmental pharmacokinetics of piperacillin and tazobactam using plasma and dried blood spots from infants.

Piperacillin-tazobactam is often given to infants with severe infection in spite of limited pharmacokinetics (PK) data. We evaluated piperacillin-tazobactam PK in premature and term infants of ages <61 days with suspected systemic infection. Infants received intravenous piperacillin-tazobactam (80 to 100 mg/kg of body weight every 8 h [q 8 h]) based on gestational and postnatal age. Sparse plasma samples were obtained after first and multiple doses. Drug concentrations were measured by tandem mass spectrometry. PK data were analyzed using population nonlinear mixed-effect modeling. Target attainment rates for the time unbound piperacillin concentrations remained above the MIC for 50% and 75% of the dosing interval at steady state were evaluated. Bias in population PK parameter estimates was assessed for dried blood spot (DBS) samples, and a comparability analysis was performed for DBS and plasma drug concentrations using linear regression. We obtained 128 plasma samples from 32 infants, median gestational age of 30 weeks (range, 23 to 40 weeks) and postnatal age of 8 days (range, 1 to 60). Piperacillin and tazobactam PK models included body weight (WT) and postmenstrual age (PMA) as covariates for clearance and WT for volume of distribution and were used to optimize dosing in infants. DBS drug concentrations were 50 to 60% lower than those in plasma, but when combined with plasma concentrations and a matrix effect, the data generated PK model parameters similar to those for plasma alone. With PMA-based dosing (100 mg/kg q 8 h, 80 mg/kg q 6 h, and 80 mg/kg q 4 h for PMA of ≤30, 30 to 35, and 35 to 49 weeks, respectively), 90% of simulated infants achieved the surrogate therapeutic target of time above the MIC (≤32 mg/liter) for 75% of the dosing interval.

Antibiotic Safety and Effectiveness in Premature Infants With Complicated Intraabdominal Infections.

BACKGROUND: In premature infants, complicated intraabdominal infections (cIAIs) are a leading cause of morbidity and mortality. Although universally prescribed, the safety and effectiveness of commonly used antibiotic regimens have not been established in this population. METHODS: Infants ≤33 weeks gestational age and <121 days postnatal age with cIAI were randomized to ≤10 days of ampicillin, gentamicin, and metronidazole (group 1); ampicillin, gentamicin, and clindamycin (group 2); or piperacillin-tazobactam and gentamicin (group 3) at doses stratified by postmenstrual age. Due to slow enrollment, a protocol amendment allowed eligible infants already receiving study regimens to enroll without randomization. The primary outcome was mortality within 30 days of study drug completion. Secondary outcomes included adverse events, outcomes of special interest, and therapeutic success (absence of death, negative cultures, and clinical cure score >4) 30 days after study drug completion. RESULTS: One hundred eighty infants [128 randomized (R), 52 nonrandomized (NR)] were enrolled: 63 in group 1 (45 R, 18 NR), 47 in group 2 (41 R, 6 NR), and 70 in group 3 (42 R, 28 NR). Thirty-day mortality was 8%, 7%, and 9% in groups 1, 2, and 3, respectively. There were no differences in safety outcomes between antibiotic regimens. After adjusting for treatment group and gestational age, mortality rates through end of follow-up were 4.22 [95% confidence interval (CI): 1.39-12.13], 4.53 (95% CI: 1.21-15.50), and 4.07 (95% CI: 1.22-12.70) for groups 1, 2, and 3, respectively. CONCLUSIONS: Each of the antibiotic regimens are safe in premature infants with cIAI. CLINICAL TRIAL REGISTRATION: NCT0199499.

Development of Parenteral Nutrition-Associated Liver Disease and Other Adverse Effects in Neonates Receiving SMOFlipid or Intralipid.

BACKGROUND: Intravenous lipid emulsions (ILEs) are a risk factor for parenteral nutrition-associated liver disease (PNALD) in the neonatal population. Current literature supports the use of SMOFlipid (4-oil ILE), a fish oil-containing lipid emulsion, for the reversal of PNALD. However, there is little information about the use of 4-oil ILEs for preventing PNALD. The purpose of this study is to examine the safety of a 4-oil ILE in neonates and its effectiveness in preventing PNALD among neonates compared with Intralipid (a soybean-oil, SO-ILE). METHODS: This is an observational, cohort, comparative safety study, conducted in a level III neonatal intensive care unit. Participants include neonates who received a 4-oil ILE in their parenteral nutrition (PN) formula, who were matched with historical data of patients who received an SO-ILE, in a 1:3 fashion (4-oil ILE:SO-ILE). The primary outcome of this study is the presence of PNALD (defined as direct bilirubin > 2 mg/dL) after initiation of PN. RESULTS: A total of 1332 participants (333 4-oil ILE vs 999 SO-ILE) were included in the data analysis, and PNALD was found to occur in 1.8% of patients in the 4-oil ILE group and 3.6% of patients in the SO-ILE group (Relative risk (RR) 0.5; 95% CI, 0.21-1.18). CONCLUSION: The decrease in the incidence of PNALD among the 4-oil ILE group compared with the SO-ILE group indicates a 4-oil ILE may have a hepatoprotective effect.

Safety of donor milk: a brief report.

OBJECTIVE: To review the standard processing and testing of human donors and donor milk and to report the frequency of detected markers of potential harm. STUDY DESIGN: This was a retrospective analysis of the data gathered by a donor and human milk screening and monitoring process over a period of 3 years. RESULTS: Screening results from 2011 to the end of 2015 demonstrated that careful history taking resulted in rejection or hold of 29.7% of willing donor candidates. Individual infection screening tests rejected an additional 0.3-2.9 per 1000 donations. DNA fingerprinting of donations eliminated 2 out of 13 491. Drug testing rejected 42 out of 12 408 and dilution or adulteration eliminated 73 out of 4935 donations. Only the dilution rejection rate was significantly higher in the remunerated donors. The details of these results are presented. CONCLUSIONS: There are significant risks involved in the collection, processing and distribution of donor milk-based products. The behaviors of the donors, biochemical and genetic screening and milk processing are critical to mitigation of these recognized risks. Testing at this level of rigor appears to be justified.

Technique for intrapartum administration of surfactant without requirement for an endotracheal tube.

OBJECTIVE: To evaluate the feasibility and safety of administering surfactant into the nasopharynx during delivery, thus permitting the baby to aspirate the solution into the fluid-filled airway as an air-fluid interface is established. This process avoids the endotracheal intubation (ETI) and positive pressure ventilation (PPV) usually associated with prophylaxis, thus avoiding the pulmonary barotrauma associated with the conventional method of surfactant administration. STUDY DESIGN: In all, 23 neonates weighing 560 to 1804 g and born at 27 to 30 weeks had their nasopharyngeal airways suctioned and then 3.0-4.5 ml Infasurf instilled into the nasopharynx before delivery of the shoulders. Continuous positive airway pressure (CPAP) of 10 cmH(2)O was administered by mask as the babies initiated breathing. Nasal CPAP at 6 cmH(2)O was then continued for a minimum of 48 hours. RESULTS: In all, 13 of 15 babies delivered vaginally were weaned quickly to room air and required no further surfactant or endotracheal intubation for RDS. Five of eight babies delivered by C-section required subsequent endotracheal intubation soon after birth and two received subsequent endotracheal tube surfactant. CONCLUSION: Nasopharyngeal surfactant instillation at birth appears to be relatively safe and simple to accomplish, especially for vaginal births. A large randomized clinical trial will be required to determine the efficacy of this technique when compared to prophylaxis by endotracheal intubation and to nCPAP alone.

Nutrition in the neonatal intensive care unit: how do we reduce the incidence of extrauterine growth restriction?

Extrauterine growth restriction is a major clinical problem for prematurely born neonates, especially critically ill preterm neonates, and malnutrition in the neonatal intensive-care unit remains common. There are numerous perceived risks to initiation of adequate nutritional support. How many of these factors pose a real risk to health outcomes is less clear. Current nutritional support does not prevent extrauterine growth restriction and the consequences of malnutrition are both acute and delayed. Our clinical approach to providing nutritional support impacts neonatal morbidity and long-term neuro developmental outcomes. While more and better evidence is needed to help guide best practices, this gap should not prevent neonatologists from using the observations in this review to improve their current practice. There is evidence that changes in nutritional support can have a positive influence on growth. These include early administration of intravenous amino acids and lipids, minimal enteral nutrition, and supplemented formula and human milk. Simply recognizing the degree of growth failure by monitoring weight and focusing on the accruing deficit should encourage clinicians to increase nutritional support to enhance recovery growth. Continued research is needed to define the efficiency of early feeding, more rapid advancements in nutritional support, protein needs, the optimal composition of breast-milk supplements, the etiology of necrotizing enterocolitis, and perhaps most importantly, the health consequences of extrauterine growth restriction.

Reducing acquired infections in the NICU: observing and implementing meaningful differences in process between high and low acquired infection rate centers.

BACKGROUND: Acquired infection is one of the most prevalent sources of concern in neonatal intensive care units (NICUs). Center-to-center variation has been noted by both the National Nosocomial Infection Surveillance System and the Vermont Oxford Network suggesting that site of care influences outcomes including acquired infection. OBJECTIVE: To reduce the acquired infection rate by isolating and then implementing meaningful process differences between high and low infection rate centers. DESIGN/METHOD: A multistaged observation and intervention study. The primary outcome measure was defined as a positive blood culture, collected more than 3 days after birth. Hospital patient days along with infection episodes were collected for all NICU admissions in the network during the baseline and post-implementation periods. A detailed observation guide was used during site visits to high and low infection rate centers. The observations recorded in the guide allowed the team to isolate meaningful differences, which were shared with the network. Individual NICUs decided which of the meaningful differences, if any, to implement. To estimate the impact on costs, additional data were gathered in a case-matched series of infants in one demonstration site. RESULTS: In all, 15 meaningful differences were isolated and shared with the network. The network rate for acquired infection dropped from 3.8 to 2.9 episodes per 1000 patient days. In the demonstration site, the infection rate dropped from 7.4 to 4.0 per 1000 patient days. CONCLUSION: Isolation of process level differences between high and low performing centers followed by implementation of these meaningful differences may reduce acquired infections. Other targeted areas of care may benefit from this quality improvement methodology.

Population pharmacokinetics of intravenous acyclovir in preterm and term infants.

BACKGROUND: Acyclovir is used to treat herpes infections in preterm and term infants; however, the influence of maturation on drug disposition and dosing requirements is poorly characterized in this population. METHODS: We administered intravenous acyclovir to preterm and term infants <31 days postnatal age and collected plasma samples. We performed a population pharmacokinetic analysis. The primary pharmacodynamic target was acyclovir concentration ≥3 mg/L for ≥50% of the dosing interval. The final model was simulated using infant data from a clinical database. RESULTS: The analysis included 28 infants (median 30 weeks gestation). Acyclovir pharmacokinetics was described by a 1-compartment model: clearance (L/h/kg) = 0.305 × [postmenstrual age (PMA)/31.3 weeks]. This equation predicts a 4.5-fold increase in clearance from 25 to 41 weeks PMA. With proposed dosing, the pharmacodynamic target was achieved in 91% of infants: 20 mg/kg every 12 hours in infants <30 weeks PMA; 20 mg/kg every 8 hours in infants 30 to <36 weeks PMA and 20 mg/kg every 6 hours in infants 36-41 weeks PMA. CONCLUSIONS: Acyclovir clearance increased with infant maturation. A dosing strategy based on PMA accounted for developmental changes in acyclovir disposition to achieve the surrogate pharmacodynamic target in many infants.

Determining population and developmental pharmacokinetics of metronidazole using plasma and dried blood spot samples from premature infants.

BACKGROUND: Limited pharmacokinetic (PK) data of metronidazole in premature infants have led to various dosing recommendations. Surrogate efficacy targets for metronidazole are ill-defined and therefore aimed to exceed minimum inhibitory concentration of organisms responsible for intra-abdominal infections. METHODS: We evaluated the PK of metronidazole using plasma and dried blood spot samples from infants ≤32 weeks gestational age in an open-label, PK, multicenter (N = 3) study using population PK modeling (NONMEM). Monte Carlo simulations (N = 1000 virtual subjects) were used to evaluate the surrogate efficacy target. Metabolic ratios of parent and metabolite were calculated. RESULTS: Twenty-four premature infants (111 plasma and 51 dried blood spot samples) were enrolled: median (range) gestational age at birth 25 (23-31) weeks, postnatal age 27 (1-82) days, postmenstrual age 31 (24-39) weeks and weight 740 (431-1466) g. Population clearance (L/h/kg) was 0.038 × (postmenstrual age/30) and volume of distribution (L/kg) of 0.93. PK parameter estimates and precision were similar between plasma and dried blood spot samples. Metabolic ratios correlated with clearance. CONCLUSION: Simulations suggested the majority of infants in the neonatal intensive care unit (>80%) would meet the surrogate efficacy target using postmenstrual age-based dosing.

A paradigm shift in the prevention of retinopathy of prematurity.

For more than 50 years it has been known that oxygen therapy can lead to retinopathy of prematurity (ROP). Recent clinical research has led many neonatologists to lower the target oxygen saturation alarm limits to 85-93% and to titrate the inspired oxygen in small increments. Despite efforts to optimize oxygen therapy, the number of cases of severe ROP remains high as more extremely low birth weight infants survive. Based on new insights into the pathogenesis of ROP, there are multiple interventions, in addition to optimizing oxygen therapy that may help decrease severe ROP. Interventions that have the potential to prevent phase I ROP (birth to ≤32 weeks PMA) include increasing retinal erythropoietin (exogenous rHuEPO) and serum IGF-1 (breast milk and/or exogenous IGF-1), maintaining serum glucose below 120 mg, and providing omega-3 supplements. Interventions with potential to prevent proliferative ROP in phase II (infants >32-34 weeks PMA) include treating anemia with a liberal policy of transfusion in premature infants with stage III ROP, photopic adaptation, vitamin E supplements (>34 weeks PMA), and omega-3 supplements. The WINROP algorithm has shown promise as a biomarker in the early identification of extremely low birth weight infants at high risk for proliferative ROP. As there is interplay of multiple factors in the causation of ROP, we suggest that the simultaneous application of some combination of multiple interventions, mentioned above, may reduce the burden of ROP in the most vulnerable infants. These concepts need study in well-designed randomized clinical trials before being incorporated into clinical practice.

INH-A21: a donor-selected Staphylococcal human immune globulin for the prevention of late-onset neonatal Staphylococcal infection.

INH-A21 is an experimental human immune globulin for intravenous infusion (IGIV) derived from donors specifically selected for elevated levels of antibodies against the Staphylococcal fibrinogen-binding proteins, serine aspartate dipeptide repeat G and clumping factor A. Phase II results demonstrated that infusions of INH-A21 were well tolerated and there were no trends for increasing adverse events, or the common morbidities associated with prematurity. Enrollment has been completed in (but no results have been released from) a Phase III human trial testing INH-A21 as a prophylactic agent against staphylococcal infection in very low birth weight infants (500-1250 g).

Empiric use of ampicillin and cefotaxime, compared with ampicillin and gentamicin, for neonates at risk for sepsis is associated with an increased risk of neonatal death.

BACKGROUND: We reported previously that the use of cephalosporin among premature neonates increased the risk of subsequent fungal sepsis. As a result, we recommended that ampicillin and gentamicin be used as empiric coverage for early-onset neonatal sepsis while culture results are awaited. OBJECTIVES: To describe antibiotic use during the first 3 days after birth for neonates admitted to the NICU and to evaluate the outcomes for neonates treated with 2 different antibiotic regimens. METHODS: We assembled a cohort of inborn neonates, from our deidentified administrative database, who had documented exposure to ampicillin during the first 3 days after birth. Infants treated concurrently with cefotaxime or gentamicin were evaluated, to identify the factors that were associated independently with death before discharge, with both univariate and multivariate analyses. RESULTS: There were 128,914 neonates selected as the study cohort; 24,111 were treated concurrently with ampicillin and cefotaxime and 104,803 were treated concurrently with ampicillin and gentamicin. Logistic modeling showed that neonates treated with ampicillin/cefotaxime were more likely to die (adjusted odds ratio: 1.5; 95% confidence interval: 1.4-1.7) and were less likely to be discharged to home or foster care than were neonates treated with ampicillin/gentamicin. This observation was true across all estimated gestational ages. Other factors that were associated independently with death included immature gestational age, need for assisted ventilation on the day of admission to the NICU, indications of perinatal asphyxia or major congenital anomaly, and reported use of ampicillin/cefotaxime. CONCLUSIONS: For patients receiving ampicillin, the concurrent use of cefotaxime during the first 3 days after birth either is a surrogate for an unrecognized factor or is itself associated with an increased risk of death, compared with the concurrent use of gentamicin.

Reported medication use in the neonatal intensive care unit: data from a large national data set.

OBJECTIVES: The objectives were (1) to identify the drugs reported most commonly during NICU care, (2) to examine how different methods of documenting drug use could influence prioritization of drugs for future research aimed at evaluating safety and efficacy, (3) to describe the demographic differences in the population samples for some specific medications, (4) to identify which reported medications are used for patient populations with >20% mortality rates, and (5) to examine how reports of drug use change over time. METHODS: A retrospective review of a large national data set was performed. RESULTS: The 10 medications reported most commonly for the NICU were ampicillin, gentamicin, ferrous sulfate, multivitamins, cefotaxime, caffeine citrate, furosemide, vancomycin, surfactant, and metoclopramide. Medications used for patient populations with >20% mortality rates included amphotericin, clonazepam, dobutamine, epinephrine, ethacrynic acid, insulin, lidocaine, metolazone, milrinone, inhaled nitric oxide, nitroglycerin, octreotide, pancuronium, phenytoin, sodium nitroprusside, sodium polystyrene sulfonate (Kayexalate), tris-hydroxymethylaminomethane acetate buffer, and tolazoline. Several of these drugs (eg, amphotericin B and bumetanide) were used primarily for extremely premature neonates, and this usage might explain the high mortality rates for the population of neonates treated with these medications. Other medications (clonazepam, milrinone, inhaled nitric oxide, and phenytoin) were used primarily for near-term and term infants. The explanation for the high mortality rates for these neonates is less clear and may be related primarily to the severity of illness for which the medications are used. Utilization rates for several different medications (eg, cisapride, metoclopramide, and dexamethasone) changed by >50% during the past 5 years. CONCLUSIONS: Data reported here are the first from a large national data set on the use of different medications for neonates admitted for intensive care and should be helpful in establishing priority agendas for future drug studies in this population.

Comparison of Infasurf (calfactant) and Survanta (beractant) in the prevention and treatment of respiratory distress syndrome.

BACKGROUND: In biophysical and animal testing, Infasurf develops lower surface tension and restores total surfactant activity better than Survanta. METHODS: We performed 2 prospective, randomized, masked clinical trials; 1 trial used a prophylactic strategy aimed at prevention of respiratory distress syndrome (prophylaxis trial) for infants who were born between 23 weeks, 0 days and 29 weeks, 6 days of gestation, and the second trial used a treatment strategy (treatment trial) for intubated infants with a birth weight of 401 to 2000 g who required fractional inspired oxygen of >0.4 to maintain an arterial oxygen saturation of >90% (or an arterial/alveolar oxygen ratio of <0.2) at any time before 36 hours of age. Our purpose was to determine if Infasurf (calfactant) was more effective than Survanta (beractant) at increasing the proportion of patients alive and not receiving supplemental oxygen at 36 weeks' postmenstrual age. Informed, written, parental consent was required, and protocols were approved by the institutional review boards of all participating institutions. The dose of surfactant was 4 mL/kg (100 mg/kg) for Survanta and 3 mL/kg (105 mg/kg) for Infasurf for both trials. The assigned drug was drawn into 2 masked syringes and administered by a health care professional who, in most cases, was not directly responsible for caring for the patient. A maximum of 3 repeat treatments, at least 6 hours apart, were permitted if the neonate required fractional inspired oxygen of >0.30 to maintain an arterial oxygen saturation of >90% (or an arterial/alveolar oxygen ratio of 0.33) and the infant remained intubated for respiratory distress syndrome. RESULTS: Both trials were halted for not meeting enrollment targets after a 32-month recruitment period. The decision to end recruitment was made after the interim analysis of the treatment trial. We enrolled 749 infants in the prophylaxis trial and 1361 infants in the treatment trial. The primary outcome (alive and not receiving supplemental oxygen at 36 weeks' postmenstrual age) rate in the prophylaxis trial was 52.1% for group 1 and 52.4% for group 2. In the treatment trial, the primary outcome rate was 58.7% in group 1 and 56.8% in group 2. Based on sample-size requirements for a conclusion of similarity, and the lack of statistical significance to the differences noted in the primary outcome, we have chosen not to break the investigator blind but to report the results as groups 1 and 2. CONCLUSION: Early trial closure prevents us from either accepting or rejecting our null hypothesis.

Multicenter study to determine antibody concentrations and assess the safety of administration of INH-A21, a donor-selected human Staphylococcal immune globulin, in low-birth-weight infants.

Nosocomial or late-onset sepsis is a common complication among premature infants, with a frequency inversely correlated with birth weight. Increased susceptibility to infection is due in part to an immature humoral (antibody-mediated) immune response. This study investigated the pharmacokinetics (PKs) and safety of a donor-selected specific intravenous immune globulin (IVIG) preparation, INH-A21 (Veronate), for prevention of sepsis in premature infants. Thirty-six infants weighing between 500 and 1,250 g during the first postnatal week were eligible to begin a series of up to four intravenous infusions of 500 or 750 mg/kg of body weight INH-A21. Blood samples were analyzed for antibodies against the Ser-Asp dipeptide repeat G (SdrG) and clumping factor A (ClfA) surface proteins of staphylococci. Sparse sampling and population PK analyses were performed to derive PK parameters. Following administration of the 500- and 750-mg/kg doses, the estimated average steady-state levels of anti-ClfA were 6.1 U/ml and 9.2 U/ml, respectively, and those of anti-SdrG were 5.2 U/ml and 7.7 U/ml, respectively. The elimination half-lives for anti-ClfA and anti-SdrG were 719 h and 701 h, respectively, and the clearances were 0.18 ml/h and 0.21 ml/h, respectively. In the final model, the values of the PK parameters were independent of gestational age. Both doses of INH-A21 were well tolerated, and the safety profile was similar to those of other IVIG preparations. These results suggest that a shorter dosing interval should be utilized between the first and second doses to achieve and maintain higher titers of anti-ClfA and anti-SdrG antibodies. Further studies examining INH-A21 for the prevention of late-onset sepsis in infants within the weight range studied are warranted.

Evidence-based referral results in significantly reduced mortality after congenital heart surgery.

OBJECTIVE: Significant interinstitutional variation in mortality after congenital heart surgery has been demonstrated. Noting an association between reduced mortality and higher volume, a center with a small annual case volume began in August 1998 to selectively refer to high-volume surgical centers based on published or "apparent" low mortality rates for specific cardiac lesions. This study was undertaken to evaluate the effect of evidence-based referral in this practice. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort comparison over a 10-year period for a small Midwestern pediatric cardiology practice. The institutional database was retrospectively reviewed for children (<18 years) undergoing surgery from August 1992 to July 2002. Data were divided into 3 time periods (August 1992 to July 1995, period 1; August 1995 to July 1998, period 2; and August 1998 to July 2002, period 3). Hospital discharge abstract data from 5 states (California, Illinois, Massachusetts, Pennsylvania, and Washington) in 1992, 1996, and 1998 provided contemporaneous benchmarks. Risk adjustment was performed using the Risk Adjustment in Congenital Heart Surgery-1 method. Risk category, age at surgery, prematurity, and major noncardiac structural anomaly were entered into a multivariate logistic regression model to compare in-hospital mortality adjusting for case-mix differences. RESULTS: A total of 514 congenital heart surgical cases were identified from August 1992 to July 2002; 507 cases (98.6%) were assigned to a risk category and analyzed further. Unadjusted in-hospital mortality rates were 9.3% in period 1, 5.9% in period 2, and 1.3% in period 3. Unadjusted mortality rates for cases from benchmark data were 6.4% in 1992, 4.8% in 1996, and 3.7% in 1998. Risk adjusted mortality was comparable to the benchmark data in periods 1 and 2, but superior outcomes (odds ratio = 0.24) were demonstrated in period 3. CONCLUSIONS: Evidence-based referrals from a small-volume pediatric cardiac center to large-volume institutions resulted in a reduction in mortality after congenital heart surgery.

Improving growth of very low birth weight infants in the first 28 days.

OBJECTIVE: To increase weight gain in the first 28 days after birth for very low birth weight (VLBW) infants by isolating and sharing meaningful process differences between high- and low-weight-gain centers within a neonatal network. DESIGN/METHODS: We identified weight gain as an important target for improvement in 1999 for our national group practice of neonatologists. Site-specific average weight gain during the first 28 days was the primary outcome measure. Our target population was defined as inborn infants who survived and remained in the hospital of birth, whose birth weights were between 401 and 1500 g (VLBW), and who were >22 weeks' estimated gestational age. A team of 6 neonatologists and 1 nurse met, reviewed processes that might influence growth, and developed a structured observation guide for site visits. Weight gain data were obtained from an existing administrative database for the period January 1, 1997, through June 30, 1999. Centers were ranked and divided into upper, middle, and lower thirds. Seven team members visited 1 high- and 1 low-weight-gain center without being informed of the center's performance. Following the site visits, the team isolated 16 meaningful differences between high- and low-weight-gain sites. Meaningful differences were defined as processes observed in all or virtually all (for this project, 6 or 7 of 7 centers) of the high and none or virtually none (for this project, 0 or 1 of 7) of the low centers. The meaningful differences were distributed to our medical directors in August 2000 along with their site-specific weight-gain performance. To document the impact of sharing this material, we compared weight gain in a baseline period of January 1 through December 31, 1999 and a posteducational intervention period of January 1 through September 30, 2001. RESULTS: Compared with neonates admitted to our national neonatal practice in 1999, neonates admitted in 2001 were similar in birth weight, gestational age at birth, exposure to antenatal steroids, and male gender. Average daily weight gain during the first 28 days increased from 10.4 +/- 6 g for neonates cared for in 1999 to 12.5 +/- 6 g for neonates cared for in 2001. Thirty-nine of 51 (76%) units noted improvements, 4 were unchanged and 8 noted a decrease in average weight gain. Despite similar average lengths of stay, the average discharge weight for neonates sent home increased from 2.15 +/- 0.5 kg for 1999 to 2.29 +/- 0.5 kg for 2001. There were no differences in frequencies of mortality or major morbidities, including severe intraventricular hemorrhage, retinopathy, or necrotizing enterocolitis, between the 2 time periods. An increase in the use of continuous positive airway pressure was noted in the post implementation period. CONCLUSIONS: Variation in common processes can alter clinical outcomes. Although temporal trends in weight gain may be, in part, responsible for this trend, it appears that isolation and implementation of meaningful differences in processes can augment our desire to rapidly improve clinical outcomes.