Premedication for neonatal endotracheal intubation: results from the epidemiology of procedural pain in neonates study.

OBJECTIVES: To describe the frequency and nature of premedications used prior to neonatal endotracheal intubation; to confront observed practice with current recommendations; and to identify risk factors for the absence of premedication. DESIGN, SETTING, AND PATIENTS: Data concerning intubations were collected prospectively at the bedside as part of an observational study collecting around-the-clock data on all painful or stressful procedures performed in neonates during the first 14 days of their admission to 13 tertiary care units in the region of Paris, France, between 2005 and 2006. INTERVENTION: Observational study. MEASUREMENTS AND MAIN RESULTS: Specific premedication prior to endotracheal intubation was assessed. Ninety one intubations carried out on the same number of patients were analyzed. The specific premedication rate was 56% and included mostly opioids (67%) and midazolam (53%). Compared with recent guidance from the American Academy of Pediatrics, used premedications could be classified as "preferred" (12%), "acceptable" (18%), "not recommended" (27%), and "not described" (43%). In univariate analysis, infants without a specific premedication compared with others were younger at the time of intubation (median age: 0.7 vs. 2.0 days), displayed significantly more frequent spontaneous breathing at the time of intubation (31% vs. 12%) and a higher percentage of analgesia for all other painful procedures (median values: 16% vs. 6%). In multivariate analysis, no factor remained statistically significant. CONCLUSIONS: Premedication use prior to neonatal intubation was not systematically used and when used it was most frequently inconsistent with recent recommendations. No patient- or center-related independent risk factor for the absence of premedication was identified in this study.

Identification of SPOCK2 as a susceptibility gene for bronchopulmonary dysplasia.

RATIONALE: Bronchopulmonary dysplasia is the most common chronic respiratory disease in premature infants. Genetic factors might contribute to bronchopulmonary dysplasia susceptibility. OBJECTIVES: To identify genetic variants involved in bronchopulmonary dysplasia through a genome-wide association study. METHODS: We prospectively evaluated 418 premature neonates (gestational age <28 wk), of whom 22% developed bronchopulmonary dysplasia. Two discovery series were created, using a DNA pooling strategy in neonates from white and African ancestry. Polymorphisms associated with the disease were confirmed in an independent replication population. Genes were then explored by fine mapping and associations were replicated in an external Finnish population of 213 neonates. Validated genes expression patterns were studied in rat lung, after air or hyperoxia exposure. MEASUREMENTS AND MAIN RESULTS: SPOCK2 gene was identified by both discovery series. The most significant polymorphism (rs1245560; P = 1.66 × 10(-7)) was confirmed by individual genotyping, and in the replication population (P = 0.002). Fine mapping confirmed the association of rs1245560 with bronchopulmonary dysplasia in both white and African populations with adjusted odds ratios of 2.96 (95% confidence interval [CI], 1.37-6.40) and 4.87 (95% CI, 1.88-12.63), respectively. In white neonates, rs1049269 was also associated with the disease (odds ratio, 3.21; 95% CI, 1.51-6.82). These associations were replicated in the Finnish population. In newborn rat lungs, SPOCK2 mRNA levels markedly increased during the alveolar stage of lung development. After rat exposure to hyperoxia, SPOCK2 expression increased relative to air-exposed controls. CONCLUSIONS: We identified SPOCK2 as a new possible candidate susceptibility gene for bronchopulmonary dysplasia. Its lung expression pattern points toward a potential role in alveolarization.

Neurodevelopmental outcome at 2 years in children born preterm treated by amnioreduction or fetoscopic laser surgery for twin-to-twin transfusion syndrome: comparison with dichorionic twins.

OBJECTIVE: We sought to assess long-term neurodevelopment of children born prematurely treated for twin-to-twin transfusion syndrome and dichorionic (DC) twins. STUDY DESIGN: In all, 21 and 88 children treated with amnioreduction (AR) and fetoscopic laser surgery (FLS), respectively, and 222 DC twins matched for gestational age at delivery were assessed with Ages and Stages Questionnaire and standardized examination at 2 years of age. RESULTS: Normal development was noted in 81% in the AR group, 88.6% in the FLS group, and 93.1% in the DC twins. Minor and major neurologic impairment was found in 9.5% and 9.5% following AR, in 6.8% and 4.6% of FLS children, and in 3.4% and 3.4% in DC twins, respectively. Ages and Stages Questionnaire assessment was similar in FLS and DC children but scores were lower (P = .01) and domains were more often abnormal (60% vs 27%; P = .005) following AR. CONCLUSION: Neurodevelopmental outcome is similar in twin-to-twin transfusion syndrome survivors treated by FLS and in DC control subjects; but survivors treated with AR have an increased risk of neurodevelopmental delay at 2 years of age.

Epidemiology and treatment of painful procedures in neonates in intensive care units.

CONTEXT: Effective strategies to improve pain management in neonates require a clear understanding of the epidemiology and management of procedural pain. OBJECTIVE: To report epidemiological data on neonatal pain collected from a geographically defined region, based on direct bedside observation of neonates. DESIGN, SETTING, AND PATIENTS: Between September 2005 and January 2006, data on all painful and stressful procedures and corresponding analgesic therapy from the first 14 days of admission were prospectively collected within a 6-week period from 430 neonates admitted to tertiary care centers in the Paris region of France (11.3 millions inhabitants) for the Epidemiology of Procedural Pain in Neonates (EPIPPAIN) study. MAIN OUTCOME MEASURE: Number of procedures considered painful or stressful by health personnel and corresponding analgesic therapy. RESULTS: The mean (SD) gestational age and intensive care unit stay were 33.0 (4.6) weeks and 8.4 (4.6) calendar days, respectively. Neonates experienced 60,969 first-attempt procedures, with 42,413 (69.6%) painful and 18,556 (30.4%) stressful procedures; 11,546 supplemental attempts were performed during procedures including 10,366 (89.8%) for painful and 1180 (10.2%) for stressful procedures. Each neonate experienced a median of 115 (range, 4-613) procedures during the study period and 16 (range, 0-62) procedures per day of hospitalization. Of these, each neonate experienced a median of 75 (range, 3-364) painful procedures during the study period and 10 (range, 0-51) painful procedures per day of hospitalization. Of the 42,413 painful procedures, 2.1% were performed with pharmacological-only therapy; 18.2% with nonpharmacological-only interventions, 20.8% with pharmacological, nonpharmacological, or both types of therapy; and 79.2% without specific analgesia, and 34.2% were performed while the neonate was receiving concurrent analgesic or anesthetic infusions for other reasons. Prematurity, category of procedure, parental presence, surgery, daytime, and day of procedure after the first day of admission were associated with greater use of specific preprocedural analgesia, whereas mechanical ventilation, noninvasive ventilation and administration of nonspecific concurrent analgesia were associated with lower use of specific preprocedural analgesia. CONCLUSION: During neonatal intensive care in the Paris region, large numbers of painful and stressful procedures were performed, the majority of which were not accompanied by analgesia.

EMLA cream and nitrous oxide to alleviate pain induced by palivizumab (Synagis) intramuscular injections in infants and young children.

OBJECTIVE: Palivizumab (Synagis [Abbot Laboratories, Kent, United Kingdom]) is recommended for the prevention of severe lower respiratory tract infections caused by respiratory syncytial virus in infants at high risk. These injections are very painful, and currently the use of analgesics is not systematic. The objective of this study was to compare the efficacy of EMLA with premixed 50% nitrous oxide/oxygen, used alone or combined with EMLA, for pain alleviation during palivizumab injections. METHODS: This randomized, double-blind, multicenter study included children who were younger than 24 months. Each child randomly received during the first 3 monthly injections 3 different analgesic interventions: (1) EMLA: application of EMLA plus air inhalation; (2) nitrous oxide/oxygen: inhalation of 50/50 nitrous oxide/oxygen plus application of a placebo cream; and (3) nitrous oxide/oxygen plus EMLA: inhalation of 50/50 nitrous oxide/oxygen plus application of EMLA. Each child was his or her own control. Procedural pain was assessed through videotapes with the Modified Behavioral Pain Scale. The procedure itself was subdivided in 2 periods: (1) injection and (2) recovery (first 30 seconds after the removal of the needle). Modified Behavioral Pain Scale scores over time (injection and recovery periods) and among treatments were compared by repeated-measures analysis of variance. RESULTS: Fifty-five children were included. Mean +/- SD Modified Behavioral Pain Scale pain scores for EMLA, nitrous oxide/oxygen, and nitrous oxide/oxygen plus EMLA were, respectively, 9.3 +/- 1.0, 8.8 +/- 1.2, and 8.2 +/- 1.8 during the injection and 7.8 +/- 1.7, 7.4 +/- 1.9, and 6.9 +/- 2.4 during the recovery period. A significant time and treatment effect in favor of the combined nitrous oxide/oxygen plus EMLA was observed. CONCLUSIONS: The administration of 50/50 nitrous oxide/oxygen to infants and young children is effective in decreasing the pain associated with palivizumab intramuscular injections. The combined nitrous oxide/oxygen plus EMLA cream was more effective than either EMLA cream or nitrous oxide/oxygen alone.

Neonatal outcome in preterm monochorionic twins with twin-to-twin transfusion syndrome after intrauterine treatment with amnioreduction or fetoscopic laser surgery: comparison with dichorionic twins.

OBJECTIVE: The purpose of this study was to compare neonatal outcome in preterm neonates after twin-to-twin transfusion syndrome (TTTS) that was treated by amnioreduction or fetoscopic laser surgery (FLS) and in dichorionic neonates who were matched for gestational age at birth. STUDY DESIGN: Neonatal outcome was assessed in 137 TTTS preterm neonates who were treated primarily with either amnioreduction (n = 36) or FLS (n = 101) and compared with dichorionic twins (n = 242) who were delivered at our center at 24-34 weeks of gestation. RESULTS: Adverse neonatal outcome (death or severe cerebral lesions) was more frequent in the amnioreduction group than in the FLS and dichorionic groups. Overall neonatal outcome was comparable in FLS and dichorionic infants. However, neonatal morbidity was higher in FLS neonates at <30 weeks of gestation that was related mainly to failed laser therapy. CONCLUSION: In preterm TTTS cases, neonatal morbidity decreases independently with gestational age and after successful FLS. Neonatal morbidity that was specific of TTTS was higher in the amnioreduction group and in cases with failed laser therapy.

Assessment of implementation of a standardized parenteral formulation for early nutritional support of very preterm infants.

INTRODUCTION: Parenteral nutrition (PN) plays an important role in the nutritional support of very preterm newborns. It has been suggested that a high proportion of PN orders could be standardized. In 2002, we implemented in our unit the preparation of three standardized formulations for PN adapted to the nutritional requirements of premature infants<32 weeks. Following this change of practice, a retrospective observational study was conducted to evaluate the relevance of the implemented standardized PN regime. Twenty premature inborn infants<32 weeks gestation who had received standardized (STD) PN in 2003 were matched for 20 infants who had received individualized (IND) PN in 2001. Adequacy of nutrition was assessed by comparing daily intravenous nutrient intake and biochemical parameters during the first week. Amino-acid intakes on day 3 were higher in the STD group (1.5+/-0.2 g/kg/d vs. 0.9+/-0.5, p<0.001), and the calcium phosphate intakes were better balanced. The cumulated intake of amino acids for the first week was greater in the STD group (+20% ; p=0.0003). Biochemical parameters were similar in both groups. Insulin infusions were less frequent in the STD group (p<0.06). CONCLUSION: Standardized parenteral formulations provided higher early intakes of amino acid and glucose, a better calcium phosphate ratio, and a greater amount of amino-acid intakes during the first week while maintaining the same biochemical parameters. This strategy forms part of an approach concerning quality control and the respect of good professional practice for the preparation of parenteral nutrition solutions.

Foetal kidney maldevelopment in maternal use of angiotensin II type I receptor antagonists.

We report renal lesions observed in a foetus exposed throughout pregnancy to angiotensin II type I (AT 1) receptor antagonists. The mother suffered from essential hypertension and was treated with Cozaar (losartan 50 mg). Autopsy examination of the foetus revealed severe renal lesions, including tubular dysgenesis, hypertrophy of the endothelial and medial cells lining the arterial and arteriolar walls, hyperplasia of the juxtaglomerular apparatus and poorly developed vasa recta. Similar lesions have already been observed in foetuses of women treated with angiotensin-converting enzyme antagonists and also in foetuses and neonates of animals undergoing experimental blockade of the renin-angiotensin system. The purpose of this report is to describe structural lesions observed in the kidneys, and, particularly, vascular lesions. Our results suggest that the use of AT 1 receptor antagonists during pregnancy may have a severe deleterious effect on kidney development in the foetus.

Morphine does not provide adequate analgesia for acute procedural pain among preterm neonates.

BACKGROUND: Morphine alleviates prolonged pain, reduces behavioral and hormonal stress responses induced by surgery among term neonates, and improves ventilator synchrony and sedation among ventilated preterm neonates, but its analgesic effects on the acute pain caused by invasive procedures remain unclear. OBJECTIVE: To investigate the analgesic efficacy of intravenously administered morphine on heel stick-induced acute pain among preterm neonates. DESIGN: This study was nested within a prospective, randomized, double-blind, multicenter, placebo-controlled trial (the NEOPAIN Trial). SETTING: A tertiary-care NICU in a teaching hospital. PARTICIPANTS: Forty-two preterm neonates undergoing ventilation. INTERVENTIONS: Neonates were randomized to either the morphine (loading dose of 100 microg/kg, followed by infusions of 10-30 microg/kg per hour according to gestation, N = 21) or placebo (5% dextrose infusions, N = 21) group. Pain responses to 3 heel sticks were evaluated, ie, before the loading dose (T1), 2 to 3 hours after the loading dose (T2), and 20 to 28 hours after the loading dose (T3). MAIN OUTCOMES MEASURES: Pain was assessed with the Douleur Aiguë Nouveau-né (DAN) scale (behavioral pain scale) and the Premature Infant Pain Profile (PIPP) (multidimensional pain scale); plasma morphine levels were measured at T3. RESULTS: Infants in the placebo and morphine groups had similar gestational ages (mean +/- SD: 27.2 +/- 1.7 vs 27.3 +/- 1.8 weeks) and birth weights (972 +/- 270 vs 947 +/- 269 g). Mean +/- SD DAN pain scores at T1, T2, and T3 were 4.8 +/- 4.0, 4.6 +/- 2.9, and 4.7 +/- 3.6, respectively, for the placebo group and 4.5 +/- 3.8, 4.4 +/- 3.7, and 3.1 +/- 3.4 for the morphine group. The within-group factor (pain at T1, T2, and T3) was not statistically different over time. The between-group analysis (infants receiving placebo versus those receiving morphine) showed no significant differences. Mean +/- SD PIPP pain scores at T1, T2, and T3 were 11.5 +/- 4.8, 11.1 +/- 3.7, and 9.1 +/- 4.0, respectively, for the placebo group and 10.0 +/- 3.6, 8.8 +/- 4.9, and 7.8 +/- 3.6 for the morphine group. The within-group factor was statistically different over time. The between-group analysis showed no significant differences. Mean +/- SD plasma morphine levels at T3 were 0.44 +/- 1.79 ng/mL and 63.36 +/- 33.35 ng/mL for the placebo and morphine groups, respectively. There was no correlation between plasma morphine levels and pain scores at T3 (DAN, R = -0.05; PIPP, R = -0.02). CONCLUSIONS: Despite its routine use in the NICU, morphine given as a loading dose followed by continuous intravenous infusions does not appear to provide adequate analgesia for the acute pain caused by invasive procedures among ventilated preterm neonates.

Crossover trial of analgesic efficacy of glucose and pacifier in very preterm neonates during subcutaneous injections.

OBJECTIVE: Very preterm newborns undergo multiple invasive procedures. Nonpharmacological interventions are valuable alternatives for pain relief during minor procedures in neonates. Oral sucrose analgesia has been widely studied in term and preterm neonates during painful procedures. The analgesic effect of oral glucose in very preterm infants has not yet been reported. The objectives of this study were to assess the analgesic effect of orally administered glucose and to determine the synergetic analgesic effect of glucose and pacifiers during subcutaneous injections in very preterm neonates using a validated behavioral acute pain rating scale. DESIGN: Two crossover trials. SETTING: One neonatal intensive care unit in a community-based general hospital. METHODS: A prospective study was conducted in 40 very preterm neonates. Each infant received 2 treatments in a crossover manner during 2 consecutive subcutaneous injections of erythropoietin. The first trial (25 infants) was intended to compare oral 30% glucose (0.3 mL) versus placebo (0.3 mL of sterile water); the second trial (15 infants) compared oral 30% glucose (0.3 mL) versus oral 30% glucose (0.3 mL) followed by sucking a pacifier. The primary outcome measure was the evaluation of pain induced by a subcutaneous injection of erythropoietin, using Douleur Aiguë Nouveau-né scale (0 no pain, 10 maximum pain). RESULTS: Twenty-four infants completed the study in the first trial and 15 in the second one. Mean (95% confidence interval [CI]) gestational age, birth weight, postnatal age, and weight at inclusion for neonates in the first and second trial were, respectively, 28.1 (95% CI: 27.3-29.0) and 29.1 (95% CI: 27.8-30.4) weeks, 1036 (95% CI: 944-1128) and 995 (95% CI: 848-1141) g, 26.4 (95% CI: 22.4-30.3) and 26 (95% CI: 22.0-29.9) days, and 1234 (95% CI: 1120-1348) and 1209 (95% CI: 1059-1359) g. In the first trial, median (interquartile) pain scores for placebo and 30% glucose, respectively, were 7 (2.5-9.75) and 4.5 (1-6). In the second trial, median (interquartile) pain scores for 30% glucose and for 30% glucose plus pacifier, respectively, were 4 (2-7) and 4 (1-6). CONCLUSIONS: A small dose of 0.3 mL of 30% oral glucose has an analgesic effect in very preterm neonates during subcutaneous injections. This effect is clinically evident because it can be detected by a behavioral pain rating scale. The synergetic analgesic effect of glucose plus sucking a pacifier is less obvious in very preterm neonates as opposed to what other studies have showed in full-term infants.