Abstract Therapeutic drug monitoring is generally unnecessary in caffeine treatment for apnea of prematurity, as serum caffeine concentrations in preterm infants are normally markedly lower than those at which caffeine intoxication occurs. However, several studies have reported preterm infants having developed toxicity. This retrospective observational study, conducted at a tertiary center in Kagawa, Japan, aimed to evaluate the correlation between the maintenance dose and serum caffeine concentrations and determine the maintenance dose leading to suggested toxic caffeine levels. We included 24 preterm infants (gestational age, 27 ± 2.9 weeks; body weight, 991 ± 297 g) who were treated with caffeine citrate for apnea of prematurity between 2018 and 2021, and 272 samples were analyzed. Our primary outcome measure was the maintenance dose leading to suggested toxic caffeine levels. We found a positive correlation between caffeine dose and serum caffeine concentrations ( p < 0.05, r = 0.72). At doses of ≥ 8 mg/kg/day, 15% (16/109) of patients had serum caffeine concentrations above the suggested toxic levels. Patients who receive doses ≥ 8 mg/kg/day risk reaching the suggested toxic serum caffeine levels. It remains unclear whether suggested toxic caffeine concentrations are detrimental to neurological prognosis. Further investigation is required to understand the clinical effects/outcomes of high serum levels of caffeine and to obtain long-term neurodevelopmental follow-up data.
Neonatologists resuscitate asphyxiated neonates by every available means, including positive ventilation, oxygen therapy, and drugs. Asphyxiated neonates sometimes present symptoms that mimic those of inflammation, such as fever and edema. The main pathophysiology of the asphyxia is inflammation caused by hypoxic-ischemic reperfusion. At birth or in the perinatal period, neonates may suffer several, hypoxic insults, which can activate inflammatory cells and inflammatory mediator production leading to the release of larger quantities of reactive oxygen species (ROS). This in turn triggers the production of oxygen stress-induced high mobility group box-1 (HMGB-1), an endogenous damage-associated molecular patterns (DAMPs) protein bound to toll-like receptor (TLR) -4, which activates nuclear factor-kappa B (NF-κB), resulting in the production of excess inflammatory mediators. ROS and inflammatory mediators are produced not only in activated inflammatory cells but also in non-immune cells, such as endothelial cells. Hypothermia inhibits pro-inflammatory mediators. A combination therapy of hypothermia and medications, such as erythropoietin and melatonin, is attracting attention now. These medications have both anti-oxidant and anti-inflammatory effects. As the inflammatory response and oxidative stress play a critical role in the pathophysiology of neonatal asphyxia, these drugs may contribute to improving patient outcomes.
Background: Breastfeeding and holding are believed to foster the development of bonding between infant and mother in early infancy, and provide the opportunity for sensitive interactions. However, their mechanisms have yet to be elucidated fully. Objective: The purpose of this study was to identify the oxygenation state of the frontal cortex of infants and their mothers using near-infrared spectroscopy (NIRS), a noninvasive method. Methods: Twenty-one healthy infants (age: 4 weeks - 21 weeks old) and their mothers (age: 25–39 years old) participated in this study. Changes in the concentration of oxygenated hemoglobin and deoxygenated hemoglobin (deoxyHb) in the frontal cortex of 21 infant-mother pairs were measured simultaneously. The data were measured in three conditions: 1) Separation (the infant on a bed was separated from his/her mother by a screen); 2) Caring (the mother held her infant and spoke to him/her); and 3) Breastfeeding. Cross-lagged correlation analysis was performed between the infants’ and mothers’ oxygenated hemoglobin levels. Results: During separation, the oxygenated hemoglobin amplitude and frequency of infants and mothers was large. Changes in the oxygenated hemoglobin levels of infants while breastfeeding were small and fluctuated stably. In cross-lagged correlation analysis, the correlation between the oxygenated hemoglobin levels of infants and their mothers was significant. The average of phase different time (sec) maximized absolute value of correlation coefficient were 4.6 ± 7.4, 2.8 ± 8.28, 1.6 ± 6.69 on Separation, Caring, Breastfeeding, respectively. Conclusion: Breastfeeding gives the opportunity of skin-to-skin contact and sucking stimulation is transmitted to the mother's brain via the medulla oblongata. In the cross-lagged correlation analysis, it was found that during breastfeeding, the response time between infant and mother was short and infant and the oxygenated hemoglobin levels of infants and mother showed a strong correlation. The data suggest that breastfeeding affects mother-infant interaction through the brain hemodynamics of mothers and infants.
Perinatal hypoxic-ischemic brain injury of neonates remains a significant problem worldwide. During the resuscitation period, changes in cerebral hemoglobin oxygen saturation (ScO2) have been identified by near-infrared spectroscopy (NIRS). However, in asphyxiated neonates, the relationship between these changes and brain injury is not known. Three-wavelength near-infrared time-resolved spectroscopy, an advanced technology for NIRS, allows for the estimation of ScO2 and cerebral blood volume (CBV). Here, we studied changes in ScO2 and CBV during the resuscitation period after hypoxic-ischemic insult and the relationship between these changes after insult and histopathological brain injuries on day 5 after insult using an asphyxiated piglet model. Of 36 newborn piglets subjected to hypoxic-ischemic insult, 29 were analyzed. ScO2 and CBV were measured 0, 5, 10, 15, and 30 min after the insult. Brain tissue was histologically evaluated on day 5. ScO2 and CBV increased immediately after the insult, reached a peak, and then maintained a consistent value. The increase in CBV 5 to 30 min after the insult was significantly correlated with histopathological injury scores. However, there was no correlation with ScO2. In conclusion, an increase in CBV within 30 min after hypoxic-ischemic insult reflects the histopathological brain injury on day 5 after insult in a piglet model.
Abstract Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of morbidity and mortality in newborns in both high- and low-income countries. The important determinants of its pathophysiology are neural cells and vascular components. In neonatal HIE, increased vascular permeability due to damage to the blood–brain barrier is associated with seizures and poor outcomes in both translational and clinical studies. In our previous studies, hydrogen gas (H2) improved the neurological outcome of HIE and ameliorated the cell death. In this study, we used albumin immunohistochemistry to assess if H2 inhalation effectively reduced the cerebral vascular leakage. Of 33 piglets subjected to a hypoxic-ischemic insult, 26 piglets were ultimately analyzed. After the insult, the piglets were grouped into normothermia (NT), H2 inhalation (H2), hypothermia (TH), and H2 with TH (H2-TH) groups. The albumin immunohistochemistry score was lowest in the H2 group and significantly lower than in the NT group, suggesting the ability of H2 gas alone to ameliorate HIE-associated vascular leakage. To prove the effectiveness of H2 in vascular leakage, further experimental studies of a specific insult severity and target cells are required.
Plasma renin activity (PRA) was measured in 38 cases of aortitis syndrome. The values of resting peripheral vein blood PRA were 32.2±4.2 (SE) mμg/ml. These values were 3 times higher than those of normal subjects. Hypertension due to renal arterial stenosis was observed in 18 cases. Their resting PRA values were 41.2±6.0mμg/ml, while in the remaining 20 patients without renovascular hypertension those values were 24.2±5.4mμg/ml. The patients belonging to aortic arch type or extensive type had 2 times higher PRA values than those of abdominal type. The patients with stenosis or obstruction of common carotid arteries had significantly higher PRA values than the patients without these lesions. Hyperresponse of renin secretion to upright posture was also observed in the same patients with carotid artery stenosis. Abnormal renin release in Takayasu's arteritis disappeared after denervation of the carotid sinus nerve. The present study suggests that the unstable state of carotid sinus reflex is the main cause for the hypersecretion of renin.
