Postnatal adaptation of brain circulation in preterm infants

Global and regional postnatal cerebral circulatory changes in stable preterm infants were studied, and their relation to brain injury was assessed. Thirty-five preterm infants were studied on the first and second days of age. Cerebral blood flow (CBF) (mL/hg per min) and cerebral blood volume (CBV) (mL/hg) were measured using near-infrared spectroscopy. The cerebral blood flow velocity (cm/second) (peak systolic, diastolic flow, mean flow) and resistance index (RI) were determined in the internal carotid, anterior cerebral, and striate arteries by color Doppler flow imaging. Serial cerebral ultrasound studies were performed to detect changes in brain parenchymal echogenicity or intraventricular hemorrhage (IVH); the maximum severity of these findings was considered. CBF and cerebral blood flow velocity increased significantly with time, and such changes were independent of mean blood pressure, PO(2), PCO(2), hematocrit, or glycemia. In contrast, CBV and RI remained unchanged. According to the results of sonograms, no differences were found in postnatal CBF and cerebral blood flow velocity changes, regardless of whether patients had or did not have parenchymal lesions or IVH. However, higher CBV values were found on the second day in infants with IVH compared with infants without IVH. Early coupling of CBF and metabolic demands is independent of blood pressure. Improved venous return, instead of vasodilation, could be important in this adaptation.     

Delayed hemorrhagic infarction. A cause of late neonatal germinal matrix and intraventricular hemorrhage

Although a single perinatal or postnatal event may be directly correlated to intraventricular hemorrhage (IVH) in some infants, in other infants IVH may be related to a series of insults. Asphyxia, hypotension, and a pressure-passive low cerebral blood flow (CBF) may lead to an infarction. Subsequent events known to cause sudden rises in the CBF may then produce a hemorrhage into damaged tissues. We report two cases of this proposed model for delayed hemorrhage into infarcted tissues, or late IVH. Both neonates were severely asphyxiated, and both experienced profound hypotension and a low CBF on the first postnatal day. Late IVH was found in both neonates; at 2 to 3 months of age, one neonate was found to have computed tomographic evidence for diffuse encephalomalacia, and the other neonate was noted to have an occipital porencephalic cyst.     

CO2 has no therapeutic effect on early microvasospasm after experimental subarachnoid hemorrhage

In addition to delayed vasospasm also early brain injury, which occurs during the first few days after subarachnoid hemorrhage (SAH) when large cerebral arteries are still fully functional, plays an important role for the outcome after SAH. In the current study, we investigated the hypothesis that carbon dioxide (CO₂), a strong cerebral vasodilator, has a therapeutic potential against early posthemorrhagic microvasospasm. C57BL/6 mice (n=36) and Sprague-Dawley rats (n=23) were subjected to sham surgery or SAH by filament perforation. The pial microcirculation in the mice was visualized 3 and 24 hours after SAH using intravital fluorescence microscopy. Partial pressure of CO₂ (PaCO₂) was modulated by hyper- or hypoventilation or by inhalation of 10% CO₂. In rats, CO₂-mediated changes in cerebral blood flow (CBF) were measured at the same time points using laser Doppler fluxmetry. Increased PaCO₂ caused vasodilatation in sham-operated animals. Following SAH, however, cerebral arterioles were nonreactive to CO₂. This lack of microvascular CO₂ reactivity was accompanied by a complete loss of CO₂-induced hyperemia. Our data show that CO₂ is not able to dilate spastic microvessels and to increase CBF early after SAH. Future therapeutic approaches will therefore need to address mechanisms beyond CO₂.     

Effect of Intraventricular Hemorrhage on Cerebellar Growth in Preterm Neonates

The aim of this study is to evaluate cerebellar growth of preterm infants with intraventricular hemorrhage. Vermis height (VH) and transverse cerebellar diameter (TCD) were measured by cranial ultrasound in 18 preterm infants (26–30 weeks) with intraventricular hemorrhage (IVH) at first 3 days of life and at term equivalent age (TEA). IVH was diagnosed by ultrasonography and scaled in accordance with the definitions by Papile et al. Measurements were compared with 18 preterm (26–30 weeks) infants without IVH. Both VH and TCD of preterm infants with IVH were significantly lower than those of preterm ones without IVH at TEA (p?<?0.001). No significant difference was found for head circumference (p?=?0.158) and weight (p?=?0.092). In subgroup analysis, preterm infants with grades 3–4 IVH had significantly lower TCD (p?=?0.008) and head circumference (p?=?0.033) than the ones with grades 1–2 IVH. However, VH (p?=?0.102) and weight (p?=?0.480) did not show any difference between these subgroups. IVH may have a significant impact on cerebellar growth on preterm infants at TEA, specially those with a severe IVH. TCD is affected more than VH.     

Cerebral Blood Flow and CO2 Reactivity in Transient Ischemic Attacks: Comparison between TIAs due to the ICA Occlusion and ICA Mild Stenosis

Hemispheric mean cerebral blood flow (CBF), together with its CO₂ reactivity in response to hyperventilation, was investigated in 18 patients with transient ischemic attacks (TIAs) by intraarterial ₁₃₃Xe injection method in a subacute-chronic stage of the clinical course. In 8 patients, the lesion responsible for symptoms was regarded as unilateral internal carotid artery (ICA) occlusion, and in 10 patients, it was regarded as unilateral ICA mild stenosis <50% stenosis in diameter). Resting flow values were significantly (P < 0.05) decreased in the affected hemisphere of TIA due to the ICA occlusion as compared with the unaffected hemisphere of the same patient, regarded as the relative control. It was not decreased in the affected hemisphere of TIA due to the ICA mild stenosis as compared with the control. With respect to the responsiveness of CBF to changes in Pa_CO2, it was preserved in both TIAs, due to the ICA occlusion and ICA mild stenosis. Vasoparalysis was not observed in either types of TIAs in the subacute-chronic stage. However, in the relationship of blood pressure and CO₂ reactivity, expressed as ΔCBF(%)/ΔPa_CO2, pressure-dependent CO₂ reactivity as a group was observed with significance (P < 0.05) in 8 cases of TIA due to the ICA occlusion, while no such relationship was noted in 10 cases of TIA due to the ICA mild stenosis. Moreover, clinical features were different between TIAs due to the ICA occlusion and ICA mild stenosis, i.e., more typical, repeatable TIA (6.3 ± 3.7 times) with shorter duration (<30 minutes) was observed in TIAs due to the ICA mild stenosis, while more prolonged, less repeatable TIA (2.4 ± 1.4 times) was observed in TIAs due to fixed obstruction of the ICA. From these observations, two different possible mechanisms as to the pathogenesis of TIA might be expected, e.g., TIA of microembolic origin due to the ICA mild stenosis, and TIA of hemodynamic origin due to fixed obstruction of the ICA, for whom the bypass surgery might be beneficial, i.e., all TIAs are not based on the same mechanism.     

Bi-hemispheric CBF and Its CO2 Reactivity of TIAs and Completed Strokes in ICA Occlusions

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Bi-hemispheric cerebral blood flow (CBF) measurements during rest and hyperventilation, with intra-arteria1 ¹³³Xe injection method, were investigated in 19 cases, angiographically diagnosed as unilateral internal carotid artery (ICA) occlusion, including 8 cases with TIAs and 11 cases with completed strokes as the onset. Indices of cerebral vascular resistance and CO₂ reactivity with decreasing arterial\PCO₂ were also investigated.

A significant decrease (P < 0.05) of hemispheric mean CBF was noted in the ischemic hemisphere, but normal flow values in the unaffected hemisphere and preserved CO₂ responsiveness during hyperventilation were observed in both the affected and unaffected hemispheres in patients with TIAs. Moreover, a direct relationship between CBF and blood pressure, observed in 11 cases with completed strokes, was not recognized in 8 cases with TIAs.

A degree of the abnormalities of the affected hemisphere in cerebral circulation was suggested to be somewhat different between TIAs and completed strokes in ICA occlusions, and bi-hemispheric CBF measurements would be an useful method for evaluating the various indices of the CBF in ICA occlusions.     

Role of selected cytokines in the etiopathogenesis of intraventricular hemorrhage in preterm newborns

Proinflammatory cytokines are essential mediators and indicators of an inflammatory process occurring in the body. Their physiological role is to stimulate the immune response, yet their excessive propagation and interaction with cells outside the immune system may be linked to the risk of organ damage. This is specifically important in the case of immature tissues of fetuses and prematurely born infants. Analysis of the concentrations of specific cytokines in different compartments makes it possible to assess the risk of premature birth, preterm rupture of the membranes, and to determine an existing intrauterine infection. The purpose of this paper is to summarize the existing research concerning the relationships between the concentrations of specific proinflammatory cytokines in different compartments (maternal blood serum, amniotic fluid, umbilical cord blood, arterial and venous blood, and cerebrospinal fluid of the newborn) and the risk of intraventricular hemorrhage (IVH) and the degree of its severity. The paper takes also into account the assessment of the usefulness of cytokines as biomarkers for IVH and its complications (posthemorrhagic hydrocephalus, white matter injury).     

Impact of low-grade intraventricular hemorrhage on long-term neurodevelopmental outcome in preterm infants

Purpose

Despite a decreasing incidence, intraventricular hemorrhage (IVH) remains a point of major concern in neonatology due to its association to adverse neurodevelopmental outcome (NDO). Aim of this study was to compare outcome of preterm infants with different grades of IVH born below 32?weeks of gestational age (GA) with outcome of controls without IVH and to especially evaluate the influence of low grade IVH on NDO.

Methods

Four hundred seventy-one preterm infants with a GA below 32?weeks were admitted to our neonatal intensive care unit between 1994 and 2005 and included into analysis.

Results

IVH patients showed significantly lower mean psychomotor and mental developmental indices and a significantly higher percentage of cerebral palsy and visual impairment. Results of IVH patients born below 28?weeks of GA were significantly worse than results of IVH patients born at or above 28?weeks of GA. In all parameters, an increase of abnormal results with increasing grade of IVH could be observed; even patients with low-grade IVH (grades I and II) showed higher percentages of impairment compared to controls without any IVH.

Conclusion

Even low-grade IVH has an significant impact on neurodevelopmental outcome of preterm patients and gestational age influences the impact of intraventricular hemorrhage on neurodevelopmental outcome.     

Application of P(jv-a) CO2 in monitoring cerebral oxygen supply-demand balance in injured brain

Transcranial Doppler sonography (TCD) assayed cerebral blood flow (CBF) may vary between different intracranial pathologies. Blood gas analysis of the jugular bulb provides a novel way to estimate the global relationship between CBF and oxygen metabolism. In this study, 25 patients with brain trauma, spontaneous intracerebral hemorrhage, and acute cerebral infarction were recruited. Jugular venous oxygen saturation (SjvO₂) increased significantly at different time points after hyperventilation (p < 0.05). A negative correlation between the partial pressure of CO₂ between jugular venous bulb and radial artery blood (P(jv-a)CO₂) and CBF could be observed in acute brain injury and spontaneous intracerebral hemorrhage groups, while P(jv-a)CO₂ and CBF show positive correlation in acute cerebral infarction group. Our results suggest that serial P(jv-a)CO₂ analysis combing with SjvO₂ can be utilized to monitor the change of CBF for patients undergoing craniocerebral surgery.     

Is mechanical ventilation associated with intraventricular hemorrhage in preterm infants?

Background

The impact of mechanical ventilation on the incidence of intraventricular hemorrhage (IVH) in very low birth weight (VLBW) infants is unknown, simply because the vast majority of these infants have been routinely intubated and mechanically ventilated. There is a growing interest in the use of early nasal continuous positive airway pressure (ENCPAP) and avoiding mechanical ventilation.

Objectives

To examine the role of mechanical ventilation since delivery room in determining severe IVH in VLBW infants in two neonatal units that follow the same strategy of respiratory management using ENCPAP.

Methods

We collected data on delivery room intubation and mechanical ventilation during the first 3 days of life in VLBW infants. Logistic regression model was constructed to test the relationship between early mechanical ventilation and the diagnosis of severe IVH after controlling for significant confounding variables, such as BW, gender, duration of mechanical ventilation, and partial pressure of CO₂ (PCO₂).

Results

Of the studied 340 VLBW, 35 infants had severe IVH; most of them received mechanical ventilation that started either in the delivery room (n = 12) or during the first (n = 10) and second (n = 3) days of life. Severe IVH was independently associated with lower BW, mechanical ventilation in the delivery room, and the cumulative duration of mechanical ventilation during the first 3 days. The adjusted odds ratio for severe IVH in infants intubated in delivery room was (OR = 2.7, CI: 1.1–6.6, P = 0.03). Severe IVH was not associated with gender, prenatal steroids, early sepsis, or patent ductus arteriosus.

Conclusions

Mechanical ventilation plays a role in predicting severe IVH. Both the time at which ventilation was initiated and the duration of ventilation are important determinants of severe IVH. Risk for severe IVH in infants who were never intubated in delivery room or during the first 3 days of life is miniscule.     

Dysfunction of mouse cerebral arteries during early aging

Aging leads to a gradual decline in the fidelity of cerebral blood flow (CBF) responses to neuronal activation, resulting in an increased risk for stroke and dementia. However, it is currently unknown when age-related cerebrovascular dysfunction starts or which vascular components and functions are first affected. The aim of this study was to examine the function of microcirculation throughout aging in mice. Microcirculation was challenged by inhalation of 5% and 10% CO₂ or by forepaw stimulation in 6-week, 8-month, and 12-month-old FVB/N mice. The resulting dilation of pial vessels and increase in CBF was measured by intravital fluorescence microscopy and laser Doppler fluxmetry, respectively. Neurovascular coupling and astrocytic endfoot Ca²⁺ were measured in acute brain slices from 18-month-old mice. We did not reveal any changes in CBF after CO₂ reactivity up to an age of 12 months. However, direct visualization of pial vessels by in vivo microscopy showed a significant, age-dependent loss of CO₂ reactivity starting at 8 months of age. At the same age neurovascular coupling was also significantly affected. These results suggest that aging does not affect cerebral vessel function simultaneously, but starts in pial microvessels months before global changes in CBF are detectable.     

Progressive posthemorrhagic hydrocephalus leads to changes of amplitude-integrated EEG activity in preterm infants

Aim Intraventricular hemorrhage (IVH) is the most common cause of brain lesions in preterm infants. Among infants with IVH about 35% develop posthemorrhagic hydrocephalus (PPH) which may lead to secondary injury. Therapeutic interventions to reduce the increased intracranial pressure are invasive and carry a high risk of complications. Amplitude-integrated EEG (aEEG) allows continuous neurophysiological surveillance and may help in defining the optimal timing for intervention in infants with progressive PHH. In this report we show, for the first time, a change in aEEG activity in two preterm infants with PHH.Methods Cerebral activity was continuously monitored by aEEG provided by the Cerebral Function Monitor (Lectromed, UK) in two preterm infants with PPH.Results With increasing ventricular width, aEEG showed an increased discontinuity without distinguishable sleep-wake cycling in both infants. One infant showed an abrupt onset of a nearly isoelectric pattern without any change in clinical condition. Clinical signs of increased intracranial pressure developed 6–12 h later in both children. In one patient, aEEG activity returned to normal after successful shunting and reduction of intracranial pressure.Conclusion Continuous neurophysiological monitoring by aEEG may be of value in the diagnostic and therapeutic management of preterm infants with progressive PHH.     

Cerebral blood flow velocity in preterm neonates

The postnatal changes of cerebral blood flow velocity in 35 preterm neonates with or without complications were measured with a bidirectional Doppler flow meter. In the cases without complications, the pulsatility index for the anterior cerebral artery (ACA-PI) was high shortly after birth, and gradually decreased after 6 hrs as that in normal term neonates. However ACA-PI showed large variations in the cases with respiratory distress. On the other hand, ACA-PI in the cases with subependymal hemorrhage (SEH) was low during the first 6 hrs after birth, and thereafter showed no significant changes. ACA-PI in the cases with intraventricular hemorrhage (IVH) was high during the first 6 hrs after birth and then decreased when IVH was found on ultrasound scanning. ACA-PI increased gradually with progression of post-hemorrhagic ventricular dilatation. The difference of high PI in IVH and low PI in SEH during the first few hrs after birth suggests that the pathogenesis of SEH may be different from the mechanism of intraventricular rupture from SEH. Low PI values in the infants with SEH may be related to intrapartum events, while the changing patterns of high to low PI in the infants with IVH suggest postnatal hemodynamic changes.     

The contribution of arterial blood gases in cerebral blood flow regulation and fuel utilization in man at high altitude

The effects of partial acclimatization to high altitude (HA; 5,050 m) on cerebral metabolism and cerebrovascular function have not been characterized. We hypothesized (1) increased cerebrovascular reactivity (CVR) at HA; and (2) that CO₂ would affect cerebral metabolism more than hypoxia. PaO₂ and PaCO₂ were manipulated at sea level (SL) to simulate HA exposure, and at HA, SL blood gases were simulated; CVR was assessed at both altitudes. Arterial–jugular venous differences were measured to calculate cerebral metabolic rates and cerebral blood flow (CBF). We observed that (1) partial acclimatization yields a steeper CO₂-H⁺ relation in both arterial and jugular venous blood; yet (2) CVR did not change, despite (3) mean arterial pressure (MAP)-CO₂ reactivity being doubled at HA, thus indicating effective cerebral autoregulation. (4) At SL hypoxia increased CBF, and restoration of oxygen at HA reduced CBF, but neither had any effect on cerebral metabolism. Acclimatization resets the cerebrovasculature to chronic hypocapnia.     

L-arginine reactivity in cerebral vessels after severe traumatic brain injury

Abstract

Objectives: Traumatic brain injury (TBI) causes an early reduction of cerebral blood flow (CBF). The purpose was to study cerebrovascular endothelial function by examining the reactivity of cerebral vessels to L-arginine.

Methods: Fifty-one patients with severe TBI were prospectively studied by measuring cerebral hemodynamics before and after the administration of L-arginine, 300 mg/kg at 12 hours and at 48 hours after injury. These hemodynamic measurements, using transcranial Doppler techniques, included internal carotid flow volume as an estimate of hemispheric CBF, flow velocity in intracranial vessels, CO₂ reactivity, and dynamic pressure autoregulation using thigh cuff deflation and carotid compression methods. Changes in the hemodynamics with L-arginine administration were analyzed using a general linear mixed model.

Results: L-arginine produced no change in mean arterial pressure, intracranial pressure, or brain oxygenation. Overall, L-arginine induced an 11.3% increase in internal carotid artery flow volume (P=0.0190). This increase was larger at 48 hours than at 12 hours (P=0.0045), and tended to be larger in the less injured hemisphere at both time periods. The response of flow velocity in the intracranial vessels was similar, but smaller differences with administration of L-arginine were observed. There was a significant improvement in CO₂ reactivity with L-arginine, but no change in dynamic pressure autoregulation.

Discussion: The low response of the cerebral vessels to L-arginine at 12 hours post-injury with improvement at 48 hours suggests that dysfunction of cerebrovascular endothelium plays a role in the reduced CBF observed after TBI.     

Neuroendoscopic fenestration of the foramen of Monro without septostomy for unilateral hydrocephalus following neonatal intraventricular hemorrhage

Purpose  

Unilateral hydrocephalus is a rare type of hydrocephalus caused by germinal matrix hemorrhage–intraventricular hemorrhage (GMH–IVH) in preterm infants. We present a case of posthemorrhagic unilateral hydrocephalus in a preterm infant that was successfully treated with neuroendoscopic fenestration of the foramen of Monro without septostomy.     

The role of vascular resistance in BOLD responses to progressive hypercapnia

The ability of the cerebral vasculature to regulate vascular diameter, hence resistance and cerebral blood flow (CBF), in response to metabolic demands (neurovascular coupling), and perfusion pressure changes (autoregulation) may be assessed by measuring the CBF response to carbon dioxide (CO₂). In healthy individuals, the CBF response to a ramp CO₂ stimulus from hypocapnia to hypercapnia is assumed sigmoidal or linear. However, other response patterns commonly occur, especially in individuals with cerebrovascular disease, and these remain unexplained. CBF responses to CO₂ in a vascular region are determined by the combined effects of the innate vascular responses to CO₂ and the local perfusion pressure; the latter ensuing from pressure‐flow interactions within the cerebral vascular network. We modeled this situation as two vascular beds perfused in parallel from a fixed resistance source. Our premise is that all vascular beds have a sigmoidal reduction of resistance in response to a progressive rise in CO₂. Surrogate CBF data to test the model was provided by magnetic resonance imaging of blood oxygen level‐dependent (BOLD) signals. The model successfully generated all the various BOLD‐CO₂ response patterns, providing a physiological explanation of CBF distribution as relative differences in the network of vascular bed resistance responses to CO₂. Hum Brain Mapp 38:5590–5602, 2017. © 2017 Wiley Periodicals, Inc.     

Assessment of cerebrovascular reserve in unilateral middle cerebral artery stenosis using perfusion CT and CO2 inhalation tests

Purpose/Aim of the study: Cerebrovascular reactivity (CVR) is an important marker for assessing cerebrovascular disease. This study assessed the CVR by perfusion computed tomography (CT) and CO₂ inhalation tests in patients with unilateral middle cerebral artery (MCA) stenosis disease. Materials and Methods: Thirty-one patients with unilateral MCA stenosis disease diagnosed by digital subtraction angiography were studied. Patients were divided into two groups according to the degree of stenosis: severe and moderate. The regional cerebral blood flow (CBF) before and after CO₂ inhalation was determined by perfusion CT. Regional CVR values were obtained by the following formula: increase (%) = (post-CBF) ? (pre-CBF)/(pre-CBF) × 100%. Results: No significant differences in the mean CBF in the MCA stenosis region were found between the affected and contralateral sides before the CO₂ inhalation test; after the test, CBF was more significantly decreased on the affected side than on the contralateral side. The changes in CBF on the affected side were categorized into three types: increased CBF (17 cases), decreased CBF (12 cases) and no change in CBF (2 cases). The rate of CVR impairment among severe stenosis patients (13/19) was higher than that among moderate stenosis patients (3/12). CVR was significantly correlated with the degree of stenosis (r = 0.423, P = 0.018). Conclusion: CVR impairment was found in approximately half of patients with unilateral MCA stenosis. Along with an increase in the degree of stenosis, patients with unilateral MCA stenosis were more likely to exhibit CVR impairment. It is important to assess the CVR in patients with unilateral MCA stenosis, especially those with severe stenosis.     

The moment of intraventricular hemorrhage

A continuous monitoring of the germinal layer by linear scanning ultrasound has been proposed for the purpose of ascertaining the moment of intraventricular hemorrhage (IVH). Using a VHS videotape, we performed the 48 hours monitoring in 7 immature infants weighing less than 1,000 g who required respiratory support. Four cases of these developed IVH. In one case, which was 755 g in birth weight and 24 weeks in gestational age, the moment of IVH was successfully demonstrated on the ultrasonic monitor. At that moment, there were no significant changes in heart rate and systemic blood pressure. No direct manipulation or treatment, such as an endotracheal suctioning or a heel puncture which might induce a blood pressure fluctuation, was being given at the moment of IVH. About 15 minutes after the episode, abnormal seizure-like movement periodically developed.