Individual variations in fentanyl pharmacokinetics and pharmacodynamics in preterm infants.

AIM: Fentanyl pharmacokinetics and pharmacodynamics are lacking in preterm infants. Our aim was to study these and their relation with a new formulation of fentanyl 5 µg/mL for procedural pain. METHODS: Preterm infants were given 0.5 (n = 20, median gestational age 26.5; range 23.3-34.1 weeks) and 2 µg/kg (n = 8, 27.4; 25.3-30.7 weeks) fentanyl, respectively, before skin-breaking procedures or tracheal intubation. Blood samples were collected after ten minutes, two, four, eight and 24 hours. Physiologic parameters were monitored and pain scores assessed. RESULTS: The median fentanyl concentrations were 0.18, 0.15, 0.15 and 0.57, 0.37, 0.35 ng/mL at 15-31 minutes, two and four hours and the half-lives were 1.6 to 20.5 or 4.1 to 32.6 hours for the low- and high-dose groups, respectively. A significant correlation was seen between weight at study inclusion and half-life (Spearman's r = -0.9, p < 0.001), volume of distribution (r = -0.8, p < 0.01) and clearance (r = -0.9, p < 0.01) in the low-dose group (n = 9). Pain assessment results were not correlated to pharmacokinetic variables. Fentanyl was well tolerated. CONCLUSION: The inter-individual variation of fentanyl pharmacokinetics is large in preterm infants, and the dose of 0.5 µg/kg seems not effective for skin-breaking procedures.

Fresh-frozen plasma as a source of exogenous insulin-like growth factor-I in the extremely preterm infant.

CONTEXT: Preterm birth is followed by a decrease in circulatory levels of IGF-I and IGF binding protein (IGFBP)-3, proteins with important neurogenic and angiogenic properties. OBJECTIVE: Our objective was to evaluate the effects of iv administration of fresh-frozen plasma (FFP) from adult donors on circulatory levels of IGF-I and IGFBP-3 in extremely preterm infants. DESIGN, SETTING, AND PATIENTS: A prospective cohort study was performed in 20 extremely preterm infants [mean (SD) gestational age 25.3 (1.3) wk] with clinical requirement of FFP during the first postnatal week. Sampling was performed before initiation of transfusion, directly after, and at 6, 12, 24, and 48 h after completed FFP transfusion. MAIN OUTCOME MEASURES: Concentrations of IGF-I and IGFBP-3 before and after transfusion of FFP were determined. RESULTS: FFP with a mean (SD) volume of 11 ml/kg (3.1) was administered at a median postnatal age of 2 d (range 1-7). Mean (SD) IGF-I and IGFBP-3 concentrations in administered FFP were 130 (39) and 2840 microg/liter (615), respectively. Immediately after FFP transfusion, mean (SD) concentrations of IGF-I increased by 133% from 11 (6.4) to 25 microg/liter (9.3) (P < 0.001) and IGFBP-3 by 61% from 815 (451) to 1311 microg/liter (508) (P < 0.001). Concentrations of IGF-I and IGFBP-3 remained higher at 6 (P < 0.001, P = 0.009) and 12 h (P = 0.017, P = 0.018), respectively, as compared with concentrations before FFP transfusion. Typical half-life of administrated IGF-I was 3.4 h for a 1-kg infant. CONCLUSION: Transfusion of FFP to extremely preterm infants during the first postnatal week elevates levels of IGF-I and IGFBP-3.

Inflammation at birth is associated with subnormal development in very preterm infants.

Preterm birth carries a risk for impaired developmental outcome. We have previously described an association between increased levels of proinflammatory cytokines during the first 72 postnatal hours and cerebral damage as detected by ultrasound in a cohort of 74 very preterm infants. Sixty-seven of 71 surviving children with a mean gestational age of 27.1 (2.0) wk were examined at 2 y corrected age with a standardized neurologic examination and with Bayley Scales of Infant Development. We hypothesized that proinflammatory cytokine concentrations at or shortly after birth would be associated with an adverse developmental outcome. Increased concentrations of TNF-alpha in cord blood odds ratio (95% confidence interval) 3.3 (1.1-10.2), p = 0.013 and at 6 h 7.8 (0.9-71.8), p = 0.015 and of IL-6 in cord blood 1.7 (1.0-2.9), p = 0.048 were associated with psychomotor developmental index <85. Increased concentrations of TNF-alpha in cord blood odds ratio (95% confidence interval) 3.6 (1.002-12.8), p = 0.044 and of IL-8 in cord blood 3.5 (1.2-10.6), p = 0.023 were associated with cerebral palsy. Associations of TNF-alpha and IL-8 in cord blood with the respective outcome measures remained significant after adjustment for other clinical variables. Proinflammation at birth is associated with impaired functional outcome at 2 y of corrected age in children with very preterm birth.

Lower stress responses after Newborn Individualized Developmental Care and Assessment Program care during eye screening examinations for retinopathy of prematurity: a randomized study.

OBJECTIVE: Screening examination for retinopathy of prematurity is distressing and painful. The aim of the present study was to investigate whether a Newborn Individualized Developmental Care and Assessment Program intervention during a retinopathy of prematurity examination results in less adverse behavioral, pain, and stress responses as compared with standard care. METHODS: The first 2 eye examinations in 36 preterm infants were evaluated. The infants were randomly assigned at the first eye examination to receive either Newborn Individualized Developmental Care and Assessment Program care or standard care. At the second examination, crossover of subject assignment was performed. The assessments included behavioral responses; recordings of heart rate, respiration, and oxygenation; pain scores (premature infant pain profile); and salivary cortisol at defined time points up to 4 hours after the eye examination. The nursing support given during the eye examinations (intervention score) were scored using predefined criteria. RESULTS: Altogether, 68 examinations were evaluated. Newborn Individualized Developmental Care and Assessment Program care was associated with better behavioral scores during the examination but there was no difference in heart rate, respiratory rate, oxygenation, or premature infant pain profile score between the 2 care strategies before or after the eye examination. Salivary cortisol increased from baseline to 30 minutes after the eye examination independent of care strategy and decreased significantly between 30 and 60 minutes when infants were subjected to Newborn Individualized Developmental Care and Assessment Program care but not after standard care. During the study period the intervention score for standard care increased and approached the score for Newborn Individualized Developmental Care and Assessment Program care at the later eye examinations. CONCLUSION: A Newborn Individualized Developmental Care and Assessment Program-based intervention during eye examination does not decrease pain responses but results in faster recovery, as measured by lower salivary cortisol 60 minutes after the examination. The differences were seen despite the influence from the Newborn Individualized Developmental Care and Assessment Program intervention on the standard care treatment that occurred during the study period.

Circulating interferon-gamma and white matter brain damage in preterm infants.

The fetal inflammatory response has been suggested as causal in neonatal morbidity. Serial levels of circulating cytokines were evaluated in 74 infants with a mean gestational age (GA) of 27.1 wk. Pro-inflammatory [tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-1 beta, IL-2, IL-6, IL-8, IL-12] [corrected] and modulatory (IL-4, IL-10) cytokines were analyzed from cord blood, and at 6, 24 [corrected] and 72 h postnatal age. Measure of cytokine burden over time was assessed by calculating the area under curve (AUC) for analyzed levels (0-72 h). Premature rupture of membranes (PROM) was associated with higher levels of IL-2 at birth and at 6 h, of IFN-gamma at 6 and 24 h postnatal age and of TNF-alpha at 6 and 24 h. Levels of IFN-gamma at 6, 24, and 72 h were increased in infants developing white matter brain damage (WMD) compared with those without WMD. Infants with arterial hypotension requiring dopamine treatment had an increase in IL-6 with a peak at 6 h of age. Severe intraventricular hemorrhage (IVH) was associated with increase in AUC [(IL-6) and (IL-8), odds ratio (OR) 2.8 and 13.2 respectively], whereas white matter brain damage (WMD) [corrected] was associated with increase in AUC (IFN-gamma; OR, 26.0) [corrected] A fetal immune response with increased postnatal levels of IFN-gamma was associated with development of WMD. PROM was associated with a T-helper 1 cytokine response with increased levels of IFN-gamma. Type of inflammatory response appears of importance for subsequent morbidity.

VWF-cleaving protease (ADAMTS13) in premature infants.

BACKGROUND: Patients with thrombotic thrombocytopenic purpura (TTP) are deficient in von Willebrand factor (VWF)-cleaving protease, called ADAMTS13, and are prone to develop abnormal intravascular platelet aggregation leading to focal cerebral ischaemia. We speculated that low levels of ADAMTS13 are present in premature infants. This might result in platelet aggregation with subsequent ischaemia, vessel rupture and haemorrhage, and thus contribute to intraventricular haemorrhage and periventricular leucomalacia (IVH and PVL). PATIENTS AND METHODS: Nine preterm infants with gestational ages 23.7 to 30.9 (median 25.7) wk, and 10 healthy term control infants with gestational ages 36.9 to 39 (median 37.9) wk were included. Blood was sampled from the umbilical cord at delivery, and levels of ADAMTS13, VWF antigen and VWF collagen binding activity were analysed. RESULTS: The mean ADAMTS13 level in preterm infants was lower than in the term infants, but the difference between the groups was not statistically significant. However, in the preterm group there was a positive correlation between ADAMTS13 and both gestational age (r = 0.70, p = 0.035) and birthweight (r = 0.83, p = 0.005). Three preterm infants had ADAMTS13 of 18-20%. One of these developed a germinal matrix haemorrhage and PVL, and this infant had the lowest measured ADAMTS13 of all. The levels of VWF antigenand VWF collagen bindingactivity were higher in the preterm infants. CONCLUSION: This pilot study showed that preterm infants have low levels of ADAMTS13. Enzyme substitution may be a therapeutic option if an association with IVH or PVL can be confirmed in larger patient groups.