The relative contributions of inflammation and ischemia to the pathogenesis of periventricular leukomalacia (PVL) have not been elucidated. We hypothesized that fetal cardiovascular function and ...cerebral blood flow velocity (BFV) would be decreased in a rat model of chorioamnionitis. We also tested whether placental inflammation was related to proximity to the cervix in our model of chorioamnionitis intracervical lipopolysaccharide (LPS) or vehicle (PBS) injection. On embryonic d 15, Sprague-Dawley rats underwent baseline maternal and fetal echocardiography, followed by LPS or PBS injection, then serial echocardiographic evaluations until embryonic day (ED) 21. One hour after birth, pups had middle cerebral artery (MCA) BFV measured. Placentas of LPS-exposed pups exhibited uniform, higher inflammation grades (p < 0.001). All fetal BFVs increased with advancing GA (p < 0.001) whereas resistance index (RI) decreased (p < 0.001). There was no difference in fetal BFV between the groups other than a reduced gestation-related increase in descending aorta BFV in LPS-exposed rats (p < 0.05). Newborn pups exposed to LPS had lower heart rate (p = 0.006) and MCA BFV (p = 0.024) and higher RI (p = 0.003) and pulsatility index (PI; p = 0.004). In conclusion, intracervical LPS injection produces an inflammation independent of placental position, a blunted increase in gestation-related aortic BFV, and a decrease in MCA BFV in newborn pups.
Premature infants exposed to chorioamnionitis are at increased risk for periventricular leukomalacia (PVL) and intraventricular hemorrhage (IVH), lesions that may result from inflammation and/or ...fluctuations in cerebral blood flow. The effect of chorioamnionitis on near-infrared spectroscopy (NIRS) measures of cerebral oxygen delivery has not been evaluated previously. Forty-nine infants born at 25-31 6/7 wk gestation underwent NIRS examination on d 1, 2, 3, and 7 of life. Variability in NIRS tracings was analyzed by partitioning each tracing into three components: long-term, intermediate, and short-term variability; the latter two components were analyzed. Chorioamnionitis-exposed infants manifest reduced intermediate variability in cerebral oxygenated and deoxygenated Hb but not total Hb. Infants with severe IVH/PVL had the lowest intermediate variability on d 1. Short-term variability was similar between chorioamnionitis-exposed and unexposed infants, and between infants with versus without severe IVH or PVL. We conclude that intermediate-term variability in NIRS cerebral oxygen delivery is reduced in chorioamnionitis-exposed infants. We speculate that intermediate variability represents the important time frame for evaluating the pathogenesis of perinatal brain injury. Further studies are needed to determine how these findings relate to cerebral blood flow autoregulation and oxygen utilization in premature infants.
In this case-control analysis, pulmonary hemorrhage cases (n = 22) were more likely than gestational age-matched controls (n = 44) to be small for gestational age, have moderate-to-large patent ...ductus arteriosus, extubate rapidly, and develop grade III-IV intraventricular hemorrhage ( P < .05). Cases were more likely to die ( P = .000), especially if not exposed to indomethacin ( P = .007).
We examined superior mesenteric artery blood flow velocity in response to feeding in infants randomized to trophic feeds (n = 16) or nil per os (n = 18) during previous treatment for patent ductus ...arteriosus. Blood flow velocity increased earlier in the fed infants, but was similar in the 2 groups at 30 minutes after feeding.
Pharmacologic agents are often used to treat newborns with prenatal opioid exposure (POE) despite known adverse effects on neurodevelopment. Alternative nonpharmacological interventions are needed.
...To examine efficacy of a vibrating crib mattress for treating newborns with POE.
In this dual-site randomized clinical trial, 208 term newborns with POE, enrolled from March 9, 2017, to March 10, 2020, were studied at their bedside throughout hospitalization.
Half the cohort received treatment as usual (TAU) and half received standard care plus low-level stochastic (random) vibrotactile stimulation (SVS) using a uniquely constructed crib mattress with a 3-hour on-off cycle. Study initiated in the newborn unit where newborns were randomized to TAU or SVS within 48 hours of birth. All infants whose symptoms met clinical criteria for pharmacologic treatment received morphine in the neonatal intensive care unit per standard care.
The a priori primary outcomes analyzed were pharmacotherapy (administration of morphine treatment AMT, first-line medication at both study sites number of infants treated, and cumulative morphine dose) and hospital length of stay. Intention-to-treat analysis was conducted.
Analyses were performed on 181 newborns who completed hospitalization at the study sites (mean SD gestational age, 39.0 1.2 weeks; mean SD birth weight, 3076 (489) g; 100 55.2% were female). Of the 181 analyzed infants, 121 (66.9%) were discharged without medication and 60 (33.1%) were transferred to the NICU for morphine treatment (31 51.7% TAU and 29 48.3% SVS). Treatment rate was not significantly different in the 2 groups: 35.6% (31 of 87 infants who received TAU) and 30.9% (29 of 94 infants who received SVS) (P = .60). Adjusting for site, sex, birth weight, opioid exposure, and feed type, infant duration on the vibrating mattress in the newborn unit was associated with reduction in AMT (adjusted odds ratio, 0.88 hours per day; 95% CI, 0.81-0.93 hours per day). This translated to a 50% relative reduction in AMT for infants who received SVS on average 6 hours per day. Among 32 infants transferred to the neonatal intensive care unit for morphine treatment who completed treatment within 3 weeks, those assigned to SVS finished treatment nearly twice as fast (hazard ratio, 1.96; 95% CI, 1.01-3.81), resulting in 3.18 fewer treatment days (95% CI, -0.47 to -0.04 days) and receiving a mean 1.76 mg/kg less morphine (95% CI, -3.02 to -0.50 mg/kg) than the TAU cohort. No effects of condition were observed among infants treated for more than 3 weeks (n = 28).
The findings of this clinical trial suggest that SVS may serve as a complementary nonpharmacologic intervention for newborns with POE. Reducing pharmacotherapy with SVS has implications for reduced hospitalization stays and costs, and possibly improved infant outcomes given the known adverse effects of morphine on neurodevelopment.
ClinicalTrials.gov Identifier: NCT02801331.
Chorioamnionitis and elevated cord blood inflammatory cytokine concentrations are associated with detectable disturbances of systemic and cerebral hemodynamics in premature newborns. Fifty-five ...infants (25-31 wk gestation) were enrolled. Chorioamnionitis was defined by placental histology. IL-6, IL-1beta, and tumor necrosis factor-alpha were quantified by ELISA. Blood pressure, heart rate, cardiac output, stroke volume, fractional shortening, and middle cerebral artery blood flow velocities were measured at 3 +/- 1 h after birth. Chorioamnionitis was evident in 22 placentas and was associated with increased IL-6 (p < 0.001), IL-1beta (p = 0.035), and heart rate (p = 0.027); and with decreased mean and diastolic blood pressure (p = 0.026 and p = 0.019, respectively). IL-6 concentration correlated inversely with systolic, mean, and diastolic blood pressures. Right ventricular cardiac output was elevated (p = 0.028) in infants with fetal vessel inflammation. Maternal temperature >or=38.0 degrees C and newborn immature-to-total white blood cell ratio >or=0.4 were associated with significant decreases in left ventricular fractional shortening (p = 0.001 and p = 0.005, respectively). Neither chorioamnionitis nor elevated cytokine concentrations were associated with changes in middle cerebral artery Doppler blood flow velocities. Chorioamnionitis and elevated cord blood IL-6 concentrations are associated with decreased blood pressure in premature newborns. Inflammation of the fetal vessels and nonspecific indicators of infection are associated with disturbances in cardiac function. Infants with chorioamnionitis and elevated cytokine concentrations do not manifest changes in cerebral Doppler indices within the first few postnatal hours. We speculate that cytokine-associated systemic hemodynamic disturbances in premature infants born after chorioamnionitis predispose such infants to perinatal brain injury.
IntroductionMRI and MR spectroscopy (MRS) provide early biomarkers of brain injury and treatment response in neonates with hypoxic-ischaemic encephalopathy). Still, there are challenges to ...incorporating neuroimaging biomarkers into multisite randomised controlled trials. In this paper, we provide the rationale for incorporating MRI and MRS biomarkers into the multisite, phase III high-dose erythropoietin for asphyxia and encephalopathy (HEAL) Trial, the MRI/S protocol and describe the strategies used for harmonisation across multiple MRI platforms.Methods and analysisNeonates with moderate or severe encephalopathy enrolled in the multisite HEAL trial undergo MRI and MRS between 96 and 144 hours of age using standardised neuroimaging protocols. MRI and MRS data are processed centrally and used to determine a brain injury score and quantitative measures of lactate and n-acetylaspartate. Harmonisation is achieved through standardisation—thereby reducing intrasite and intersite variance, real-time quality assurance monitoring and phantom scans.Ethics and disseminationIRB approval was obtained at each participating site and written consent obtained from parents prior to participation in HEAL. Additional oversight is provided by an National Institutes of Health-appointed data safety monitoring board and medical monitor.Trial registration numberNCT02811263; Pre-result.
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