Alan R. Spitzer

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.

Increasing incidence of the neonatal abstinence syndrome in U.S. neonatal ICUs.

BACKGROUND The incidence of the neonatal abstinence syndrome, a drug-withdrawal syndrome that most commonly occurs after in utero exposure to opioids, is known to have increased during the past decade. However, recent trends in the incidence of the syndrome and changes in demographic characteristics and hospital treatment of these infants have not been well characterized. METHODS Using multiple cross-sectional analyses and a deidentified data set, we analyzed data from infants with the neonatal abstinence syndrome from 2004 through 2013 in 299 neonatal intensive care units (NICUs) across the United States. We evaluated trends in incidence and health care utilization and changes in infant and maternal clinical characteristics. RESULTS Among 674,845 infants admitted to NICUs, we identified 10,327 with the neonatal abstinence syndrome. From 2004 through 2013, the rate of NICU admissions for the neonatal abstinence syndrome increased from 7 cases per 1000 admissions to 27 cases per 1000 admissions; the median length of stay increased from 13 days to 19 days (P<0.001 for both trends). The total percentage of NICU days nationwide that were attributed to the neonatal abstinence syndrome increased from 0.6% to 4.0% (P<0.001 for trend), with eight centers reporting that more than 20% of all NICU days were attributed to the care of these infants in 2013. Infants increasingly received pharmacotherapy (74% in 2004-2005 vs. 87% in 2012-2013, P<0.001 for trend), with morphine the most commonly used drug (49% in 2004 vs. 72% in 2013, P<0.001 for trend). CONCLUSIONS From 2004 through 2013, the neonatal abstinence syndrome was responsible for a substantial and growing portion of resources dedicated to critically ill neonates in NICUs nationwide.

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 128914 neonates selected as the study cohort; 24111 were treated concurrently with ampicillin and cefotaxime and 104803 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.

Awake apnea associated with gastroesophageal reflux: A specific clinical syndrome

Fifteen infants with a specific clinical history including awake apnea were evaluated and compared with a control group of infants, using 24-hour studies of esophageal pH, nasal thermistor, impedance pneumography, and heart rate. Thirteen of the 15 children with awake apnea had clearly documented episodes of airway obstruction in associated with gastroesophageal reflux occurring at least twice during the study (mean 3.9 +/- 0.7, range 2 to 9). The control group did not show similar findings. All 15 children with awake apnea had frequent episodes of gastroesophageal reflux. Treatment with home monitoring and reflux precautions was successful in 10 of 15. Five children received therapy with urecholine hydrochloride because of continuing episodes of reflux-associated apnea. Two children subsequently required Nissen fundoplication, primarily for symptoms of severe esophagitis. Our data suggest that in children with awake apnea, the apnea is associated with gastroesophageal reflux. Medical management is usually successful, but fundoplication may be needed in refractory cases.

The Pediatrix BabySteps® Data Warehouse and the Pediatrix QualitySteps Improvement Project System—Tools for “Meaningful Use” in Continuous Quality Improvement

The Pediatrix BabySteps Clinical Data Warehouse (CDW) is a rich and novel tool allowing unbiased extraction of information from an entire neonatal population care by physicians and advanced practice nurses in Pediatrix Medical Group. Because it represents the practice of newborn medicine ranging from small community intensive care units to some of the largest neonatal intensive care units in the United States, it is highly representative of scope of practice in this country. Its value in defining outcome measures, quality improvement projects, and research continues to grow annually. Now coupled with the BabySteps QualitySteps program for defined clinical quality improvement projects, it represents a robust methodology for meaningful use of an electronic health care record, as designated during this era of health care reform. Continued growth of the CDW should result in continued important observations and improvements in neonatal care.

Changes in pulmonary function during the diuretic phase of respiratory distress syndrome

To evaluate the relationship between improvement in pulmonary function and spontaneous diuresis in respiratory distress syndrome, nine premature infants requiring mechanical ventilation for RDS were studied at a mean age of 11.9 hours prior to the onset of diuresis, at onset of diuresis, at maximum urine output (mean age 44.9 hours), and at 24 hours after maximum urine output. Prior to diuresis functional residual capacity decreased from mean +/- SEM of 16.2 +/- 2 to 13.3 +/- 1.2 ml/kg, and dynamic lung compliance decreased from 2.5 +/- 0.3 to 1.8 +/- 0.3 ml/cm H2O (P less than 0.05), indicating that the respiratory disease was worsening. There was no significant change in alveolar-arterial oxygen gradient, peak inflating pressure, or rate of intermittent mandatory ventilation over this period. At the time of maximum urine output, however, FRC had increased 36% (P less than 0.05). CL had increased by 60% to 2.8 +/- 0.4 ml/cm H2O (P less than 0.025), AaDO2 had decreased from 246 +/- 27 to 184 +/- 30 torr (P less than 0.005), and PIP had decreased from 14.9 +/- 2.2 to 11.3 +/- 2.1 cm/H2O (P less than 0.05). On follow-up study 24 hours after maximum urine output, there was no further significant improvement in FRC, CL or PIP, but IMV rate and AaDO2 continued to decrease. These data show that the pulmonary function in RDS deteriorates until the onset of diuresis, after which it rapidly improves. This diuresis may represent the removal of excess lung liquid and seems necessary for improvement in RDS.

Cardiac malposition, redistribution of fetal cardiac output, and left heart hypoplasia reduce survival in neonates with congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation☆☆☆★

OBJECTIVE To evaluate cardiac position, left ventricular (LV) mass, and distribution of fetal cardiac output in infants with congenital diaphragmatic hernia (CDH) who required extracorporeal membrane oxygenation (ECMO), and in control subjects. STUDY DESIGN Echocardiograms were performed on 23 neonates with CDH shortly after birth, and repeated within 5 days of repair on ECMO in 21 infants,aand on 12 infants receiving ECMO for other diagnoses, and on 10 healthy, term neonates. Cardiac angle between the midline saggital plane and the interventriculak septum was measured, and deviation from normal (45 degrees) was determined. The ratio of cross-sectional areas (proportional to flows) across the pulmonary (PV) and aortic (AV) valves was determined (PV2/AV2) in 19 infants with CDH and in the healthy control subjects. RESULTS Thirteen (57%) infants with CDH survived and 10 (43%) died, with no difference in cardiac deviation before surgical repair (35 +/- 13 degrees vs Cardiac deviation persisted after repair in nonsurvivors (27 +/- 14 degrees vs 800.01 and LV mass was significantly less (1.68 +/- 0.39 vs 3.05 +/- 1.20 gm/kg, p00.0005). Neonates requiring ECMO for other diagnoses and well term babies did not have cardiac angle deviations; both these groups had a greater LV mass than did the infants with CDH. The PV2/AV2 flow ratios were higher in infants with CDH (median, 1.73; range, 1.25 to 16.50) compared with those of the healthy infants (0.96, 0.79 to 1.69, p < 0.0002). CONCLUSIONS Cardiac malposition persisted despite CDH repair in nonsurvivors with low LV mass, and fetal cardiac output was redistributed away from the left ventricle. Lung hypoplasia with reduced pulmonary flow returning to the left atrium and altered left atrial hemodynamics may result in LV hypoplasia

Maximum diuresis—a factor in predicting recovery from respiratory distress syndrome and the development of bronchopulmonary dysplasia

compared with the amount of gas in the left upper quadrant; (2) evidence of free peritoneal fluid, especially in the right iliac fossaT; and (3) an abnormally thickened right abdominal wall, which is presumably the radiographic correlate of the edema mentioned above. Other signs that may be present on abdominal radiograph include lumbar scoliosis, blurring of the right psoas margin, or evidence of a calcified fecalith. The third clue to early diagnosis is an abnormal urinalysis. Our two patients are the only reported cases in whom urinary abnormalities were described. In both cases, clinicians were led to the prompt evaluation of renal function in suspecting that the primary process was in the retroperitoneal space. Although glomerulonephritis and nephrosis, as well as renal vein thrombosis, are known to occur in this age group, the correct diagnosis was further delayed by these studies. Since these patients had retrocecal appendicitis, the abnormal urinalysis may be a sign of an inflamed appendix in close proximity to the right urel.er.

Complex Multifactorial Nature of Significant Hyperbilirubinemia in Neonates

OBJECTIVE: To determine whether glucose-6-phosphate dehydrogenase (G6PD), uridine-diphosphoglucuronosyltransferase 1A1 (UGT1A1), and hepatic solute carrier organic anion transporter 1B1 (SLCO1B1) gene variants occur at greater frequency in neonates with significant hyperbilirubinemia. METHODS: Infants with gestational ages of ≥37 weeks and ages of <7 days were studied. Case subjects had ≥1 bilirubin level above the 95th percentile (high-risk zone), whereas control subjects had bilirubin levels of <40th percentile (low-risk zone) at study entry. RESULTS: A total of 153 case subjects (median bilirubin level: 15.7 mg/dL) and 299 control subjects (median bilirubin level: 4.6 mg/dL) were evaluated. There were no statistical differences in the frequencies of G6PD, UGT1A1, and SCLO1B1 gene variants between case and control subjects (G6PD: 5.2% vs 3.3%; UGT1A1: 14.4% vs 9.4%; SLCO1B1: 73.2% vs 73.6%). However, coexpression of the G6PD African A− mutation with UGT1A1 and/or SLCO1B1 variants was seen more frequently for case subjects. Case subjects more often demonstrated ≥2 factors contributing to hyperbilirubinemia, including ABO blood group heterospecificity in which the mother had blood group O (47.7% vs 11.4%), positive direct Coombs test results (33.3% vs 4%), sibling treated with phototherapy (16.3% vs 5.4%), maternal circulating blood group antibodies (10.5 vs 0.7%), maternal diabetes mellitus (13.1% vs 6.4%), and maternal East Asian ethnicity (6.5% vs 1.3%). CONCLUSIONS: Clinical contributors to hyperbilirubinemia were identified more frequently for case subjects but individually G6PD, UGT1A1, and SLCO1B1 variants were not. Coexpression of the G6PD African A− mutation with UGT1A1 and SLCO1B1 variants was seen more often for case subjects.

Elevation in plasma creatinine and renal failure in premature neonates without major anomalies: terminology, occurrence and factors associated with increased risk

Objective:The goal of this study was to describe the changes in plasma creatinine levels that occur in prematurely born neonates, to better understand the use of the terms ‘renal dysfunction’ and ‘renal failure’ among premature neonates, as well as to evaluate the demographic and outcome characteristics associated with renal problems in preterm neonates who have no major congenital anomalies.Study Design:Retrospective review of the Pediatrix neonatal intensive care patient clinical data warehouse.Result:The study cohort consisted of neonates born with an estimated gestational age of ⩽30 completed weeks in whom there was no report of any major anomalies (n=66 526). In this group of 66 526 neonates, there were 64 030 (96.2%) with no report of renal dysfunction or failure, 1239 (1.9%) in whom there was a diagnosis of renal dysfunction and 1257 infants (1.9%) with a diagnosis of renal failure. The clinical circumstances most strongly associated with a diagnosis of renal dysfunction and/or renal failures were low gestational age and birth weight. In addition, multivariate analysis showed that the factors associated with an increased risk of renal problems were vasopressor use during the first 7 days after birth, grade 3 or 4 intraventricular hemorrhage, a patent ductus arteriosus, necrotizing enterocolitis, male gender, the use of indomethacin, a positive blood culture during the first 7 days after birth, the use of high-frequency ventilation in the first 2 days after birth, non-White race and prolonged exposure to antibiotics. Mortality was higher in patients with renal problems than in neonates without renal problems (39.1 vs 10.2%, P<0.01) and higher in neonates with renal failure than in neonates with renal dysfunction (57.6 vs 20.1%, P<0.01).Conclusion:Renal dysfunction and/or failure are common diagnoses, especially in extremely premature neonates and there are potentially modifiable factors that increase the risk of renal problems.