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- Remifentanil-Induced Tolerance, Withdrawal or Hyperalgesia in Infants: A Randomized Controlled Trial. RAPIP Trial: Remifentanil-Based Analgesia and Sedation of Paediatric Intensive Care Patients. [JOURNAL ARTICLE]
- Neonatology 2013 Apr 26; 104(1):34-41.
Background:Short-acting opioids like remifentanil are suspected of an increased risk for tolerance, withdrawal and opioid-induced hyperalgesia (OIH). These potential adverse effects have never been investigated in neonates.
Objectives:To compare remifentanil and fentanyl concerning the incidence of tolerance, withdrawal and OIH.
Methods:23 mechanically ventilated infants received up to 96 h either a remifentanil- or fentanyl-based analgesia and sedation regimen with low-dose midazolam. We compared the required opioid doses and the number of opioid dose adjustments. Following extubation, withdrawal symptoms were assessed by a modification of the Finnegan score. OIH was evaluated by the CHIPPS scale and by testing the threshold of the flexion withdrawal reflex with calibrated von Frey filaments.
Results:Remifentanil had to be increased by 24% and fentanyl by 47% to keep the infants adequately sedated during mechanical ventilation. Following extubation, infants revealed no pronounced opioid withdrawal and low average Finnegan scores in both groups. Only 1 infant of the fentanyl group and 1 infant of the remifentanil group required methadone for treatment of withdrawal symptoms. Infants also revealed no signs of OIH and low CHIPPS scores in both groups. The median threshold of the flexion withdrawal reflex was 4.5 g (IQR = 2.3) in the fentanyl group and 2.7 g (IQR = 3.3) in the remifentanil group (p = 0.312), which is within the physiologic range of healthy infants.
Conclusions:Remifentanil does not seem to be associated with an increased risk for tolerance, withdrawal or OIH.
- Adrenal Function in Preterm Infants Undergoing Patent Ductus Arteriosus Ligation. [JOURNAL ARTICLE]
- Neonatology 2013 Apr 25; 104(1):28-33.
Background:Targeted milrinone treatment for low left ventricular output (LVO) reduces the incidence of acute cardiorespiratory instability following ligation of patent ductus arteriosus (PDA) in preterm infants. Despite this, some infants continue to experience postoperative deterioration. Adrenal insufficiency related to prematurity has been postulated as a possible mechanism.
Objectives:To describe adrenal function in premature infants undergoing PDA ligation and to investigate its association with pre- and postoperative clinical and echocardiography-derived indices of disease severity.
Methods:A retrospective cohort study was conducted over a 2-year period on infants who underwent PDA ligation and had preoperative adrenocorticotropic hormone (ACTH) stimulation. All infants were screened by echocardiography for low LVO at 1 h after surgery and treated with intravenous milrinone if LVO <200 ml/kg/min. The primary outcome evaluated was low LVO at 1 h after surgery. Secondary outcomes included hypotension and oxygenation and ventilation failure occurring within 24 h.
Results:A total of 35 infants at a median gestation of 25.4 (24.5-26.4) weeks and weight at birth of 700 (600-810) g were included. Baseline median cortisol measured preoperatively was 202 (137-403) nmol/l. Following the ACTH stimulation test, 3 infants had cortisol ≤500 nmol/l while 15 had ≤750 nmol/l. There was no association seen between any cortisol value and low LVO postoperatively. Post-ACTH cortisol ≤750 nmol/l was significantly associated with hypotension (p = 0.03) and oxygenation (p = 0.04) and ventilation (p = 0.008) failure. Receiver-operator characteristic curve showed a high predictive value of post-ACTH cortisol for all clinical outcomes.
Conclusions:Post-ACTH cortisol (≤750 nmol/l) may be associated with clinical indices of postoperative cardiorespiratory instability. Relative adrenal insufficiency may play a role in the etiology of post-PDA ligation hemodynamic and respiratory instability.
- All-Trans-Retinoic Acid Attenuates Intestinal Injury in a Neonatal Rat Model of Necrotizing Enterocolitis. [JOURNAL ARTICLE]
- Neonatology 2013 Apr 23; 104(1):22-27.
Background:Ischemia/reperfusion-induced intestinal injury is mediated by reactive oxygen species and inflammatory mediators.
Objectives:This study was designed to evaluate whether all-trans-retinoic acid (ATRA) administration can attenuate intestinal injury and to analyze the antioxidant and anti-inflammatory effects of ATRA in a neonatal rat model of necrotizing enterocolitis (NEC).
Methods:Twenty-nine Wistar albino rat pups were randomly divided into 3 groups: group 1 = control, group 2 = NEC and saline, and group 3 = NEC and ATRA treatment. NEC was induced by hyperosmolar enteral formula feeding and exposure to hypoxia after cold stress at +4°C and oxygen. Pups in group 3 were injected intraperitoneally with ATRA (0.5 mg/kg body weight) once a day prior to each NEC procedure, beginning on postnatal day 1 and daily through postnatal day 4. The pups were killed on the 4th day and their intestinal tissues were harvested for biochemical and histopathological analysis.
Results:Mucosal injury scores and intestinal malondialdehyde levels in group 2 were found to be significantly higher than other groups (p < 0.05). Intestinal superoxide dismutase and glutathione peroxidase activities in group 3 were significantly higher than group 2 (p = 0.04 and p = 0.04, respectively). Intestinal tissue tumor necrosis factor-α levels were significantly reduced with ATRA treatment in group 3 compared to group 2 (p < 0.001).
Conclusions:It is likely that oxidative stress and inflammatory mediators contributed to the pathogenesis of NEC and that ATRA had a protective effect on intestinal injury through its anti-inflammatory and antioxidant properties.
- Introduction of Hypothermia for Neonates with Perinatal Asphyxia in the Netherlands and Flanders. [JOURNAL ARTICLE]
- Neonatology 2013 Apr 23; 104(1):15-21.
Background:Therapeutic hypothermia was introduced in the Netherlands and Flanders, Belgium, in 2008. Since then, an increasing number of patients has been treated - up to 166 in 2010. Complications and outcome were registered in an online database.
Objectives:The aim of this study was to analyse complications and outcome after implementation.
Methods:Data were retrieved from an online database to which all centres had contributed.
Results:In 3 years, 332 patients were treated. Excluding 24 patients with congenital abnormalities or metabolic disorders, mortality was 31.8%. Of the 210 survivors without congenital malformations, 21 had cerebral palsy, another 19 a developmental delay of more than 3 months at the age of at least 24 months, and 2 had severe hearing loss. The total adverse outcome, combining death and adverse neurodevelopment, in 308 patients without congenital malformations is 45.5%, which is similar to that of the large trials.
Conclusions:The introduction of therapeutic hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders has been rapid and successful, with results similar to findings in the randomised controlled trials.
- Continuous Positive Airway Pressure Failure in Preterm Infants: Incidence, Predictors and Consequences. [JOURNAL ARTICLE]
- Neonatology 2013 Apr 4; 104(1):8-14.
Background:Preterm infants ≤32 weeks' gestation are increasingly being managed on continuous positive airway pressure (CPAP), without prior intubation and surfactant therapy. Some infants treated in this way ultimately fail on CPAP and require intubation and ventilation.
Objectives:To define the incidence, predictors and consequences of CPAP failure in preterm infants managed with CPAP from the outset.
Methods:Preterm infants 25-32 weeks' gestation were included in the study if inborn and managed with CPAP as the initial respiratory support, with division into two gestation ranges and grouping according to whether they were successfully managed on CPAP (CPAP-S) or failed on CPAP and required intubation <72 h (CPAP-F). Predictors of CPAP failure were sought, and outcomes compared between the groups.
Results:297 infants received CPAP, of which 65 (22%) failed, with CPAP failure being more likely at lower gestational age. Most infants failing CPAP had moderate or severe respiratory distress syndrome radiologically. In multivariate analysis, CPAP failure was found to be predicted by the highest FiO2 in the first hours of life. CPAP-F infants had a prolonged need for respiratory support and oxygen therapy, and a higher risk of death or bronchopulmonary dysplasia at 25-28 weeks' gestation (CPAP-F 53% vs. CPAP-S 14%, relative risk 3.8, 95% CI 1.6, 9.3) and a substantially higher risk of pneumothorax at 29-32 weeks.
Conclusion:CPAP failure in preterm infants usually occurs because of unremitting respiratory distress syndrome, is predicted by an FiO2 ≥0.3 in the first hours of life, and is associated with adverse outcomes.
- Intravenous Paracetamol for Patent Ductus Arteriosus in Premature Infants - A Lower Dose Is Also Effective. Concerning the Article by M.Y. Oncel et al: Intravenous Paracetamol Treatment in the Management of Patent Ductus Arteriosus in Extremely Low Birth Weight Infants [Neonatology 2013;103:166-169]. [LETTER]
- Neonatology 2013 Mar 26; 104(1):6-7.
- Volume Expansion Does Not Alter Cerebral Tissue Oxygen Extraction in Preterm Infants with Clinical Signs of Poor Perfusion. [JOURNAL ARTICLE]
- Neonatology 2013 Mar 26; 103(4):308-314.
Background:Preterm infants with signs of poor perfusion are often treated with volume expansion, although evidence regarding its effect on cerebral perfusion is lacking. Moreover, the effect is questionable in preterm infants with an adequate cerebrovascular autoregulation (CAR). A useful measure to assess perfusion is cerebral fractional tissue oxygen extraction (cFTOE).
Objectives:To assess the effect of volume expansion on cFTOE in preterm infants with signs of poor perfusion.
Methods:In this observational study, we assessed cFTOE using near-infrared spectroscopy in preterm infants with signs of poor perfusion before, during and 1 h after volume expansion treatment. Simultaneously, we measured mean arterial blood pressure (MABP). We tested the effect of volume expansion on both cFTOE and MABP, using multi-level analyses. We intended to define a subgroup that responded to volume expansion with an increase in blood pressure and a decrease in cFTOE, suggesting absent CAR.
Results:In 14 preterm infants, with a median gestational age of 26.7 weeks (25.0-28.7 weeks) and a median birth weight of 836 g (615-1,290 g), we found a small increase in MABP during (1.4 ± 1.4 mm Hg, p = 0.003) and after (1.8 ± 1.7 mm Hg, p = 0.001) volume expansion, but no change in cFTOE during (-0.19 ± 0.1% p = 0.44) or after (-0.53 ± 0.1% p = 0.34) volume expansion. We were unable to define a subgroup lacking CAR.
Conclusions:Cerebral perfusion, as assessed by cFTOE, does not improve in preterm infants with signs of poor perfusion following volume expansion. In these infants, either CAR is present or volume expansion is inadequate to affect cFTOE.
- Prenatal Hypoxia Downregulates the Expression of Pulmonary Vascular Endothelial Growth Factor and Its Receptors in Fetal Mice. [JOURNAL ARTICLE]
- Neonatology 2013 Mar 26; 103(4):300-307.
Background:Previous reports showed that prenatal hypoxia delays the process of lung maturation. Vascular endothelial growth factor (VEGF) and its receptors were important for lung development. However, the role of VEGF and VEGF receptors in altered fetal lung development and maturation induced by prenatal hypoxia remains unknown.
Objectives:To elucidate the role of VEGF and VEGF receptors in altered fetal lung development and maturation induced by prenatal hypoxia.
Methods:Lung sections of control and maternal hypoxic fetal mice were used for the determination of lung development and total RNA isolated from lung homogenates were used for determination of the expression patterns of VEGF, Flt-1, Flk-1, hypoxia-inducible factor (HIF)-1α, HIF-2α, surfactant protein (SP)-A, SP-B, SP-C, and SP-D by quantitative real-time RT-PCR.
Results:Prenatal hypoxia resulted in fetal mice body weight gain impairment, delayed fetal pulmonary aeration and maturation. Pulmonary SP-A, SP-B, SP-C, and SP-D mRNA were all decreased in the prenatal hypoxia group. In addition, we demonstrated that prenatal hypoxia inhibited the developmental increase of pulmonary HIF-1α and HIF-2α expression and resulted in decreasing VEGF and its receptors (Flt-1 and Flk-1) at the mRNA expression level and VEGF protein level in fetal lungs. These inhibitory effects persisted and progressed even when the dams were returned to air.
Conclusions:We suggest that prenatal hypoxia insults, at least in late gestation, influence pulmonary VEGF and VEGF receptor expression through the down-regulation of HIF pathways and impair fetal lung growth and maturation.
- Growth in Small-for-Gestational-Age Preterm-Born Children from 0 to 4 Years: The Role of both Prematurity and SGA Status. [JOURNAL ARTICLE]
- Neonatology 2013 Mar 26; 103(4):293-299.
Background:Fullterm small-for-gestational-age children (SGAs) are known for their ability to catch up on growth. Nevertheless, increased risk of growth restriction remains. Evidence on preterm SGA children's growth is lacking.
Objective:To determine absolute gains in height and weight, relative growth, and growth restriction in preterm SGAs from 0 to 4 years and how prematurity and SGA status affect these measures. Design/
Methods:Community-based cohort study, n = 1,648 preterm-born (gestational age <36 weeks, 57 SGA) and 605 term-born (12 SGA). We defined SGA as a birth weight less than -2 SD (P 2.3) compared to counterparts matched for gestational age. Height, weight, and head circumference were obtained from medical records and translated to z-scores. We defined growth restriction as height or weight less than -2 SD compared to fullterm appropriate-for-gestational-age children (AGAs).
Results:Absolute height and weight gains were similar, but the relative growth of preterms and fullterms differed. Preterm AGAs and fullterm SGAs, although not reaching it, caught up towards the fullterm AGA median (z-scores at 4 years: -0.3 to -1.0). By contrast, preterm SGA children's z-scores were still -1.4 to -1.7. Head circumference growth was less affected by prematurity and SGA birth (z-scores at 1 year: 0.1 to -0.7). Catch-up growth mainly took place during infancy. 30-39% of all preterm SGAs showed growth restriction at 4 years.
Conclusions:Growth in preterm SGAs is affected considerably by the joint effects of preterm birth and SGA status, resulting in a high proportion of growth restriction.
- From a Regional Cohort of Extremely Low Birth Weight Infants: Cardiac Function at the Age of 7 Years. [JOURNAL ARTICLE]
- Neonatology 2013 Mar 21; 103(4):287-292.