Autoregulation of brain blood flow during hypotension and hypertension in infant lambs

To determine the limits of aortic blood pressure in infant lambs for autoregulation of global and regional brain blood flow, we studied 10 unsedated lambs during hypotension and 10 unsedated lambs during hypertension. In lambs 6 to 13 d old, we produced graded changes in aortic blood pressure by inflating a balloon occluder placed around either the inferior vena cava or the descending aorta. Using radiolabeled microspheres, we measured global and regional brain blood flow at the baseline, and then with each graded change in aortic blood pressure. In an additional step, we administered atropine to determine if its antimuscarinic properties alter the fall in brain blood flow with severe hypotension, or alter the rise in brain blood flow with severe hypertension. We concluded that in the unsedated infant lamb, global brain blood flow remains stable between mean aortic blood pressures of 6.0 to 10.0 kPa (45 to 82 torr), a range from approximately 38% below to 12% above normal mean aortic blood pressure. We noted that this autoregulatory range is essentially unchanged from that described for the fetal lamb at 80% of term gestation--even though the mean aortic blood pressure rises during this period of maturation by more than 2.7 kPa (20 torr). We found that the lower limit of autoregulation varies among the different brain regions and is lowest in the thalamus, pons, and medulla. We saw little variation of the upper limit among the brain regions. Finally, we determined that atropine does not alter brain blood flow during severe hypotension or severe hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of blood transfusion on brain blood flow autoregulation among stable preterm infants

Prior to and 24 h following blood transfusion serial determinations of both cerebral artery flow velocity waveforms and mean arterial blood pressure have been used to reconstruct the autoregulatory curve and its upper blood pressure limit among five stable preterm infants. Prior to transfusion the autoregulatory range of cerebral blood flow (CBF) was narrow due to a relatively low-set upper blood pressure limit. At 24 h after transfusion each individual has been re-examined. Following correction of anemia both a significant reduction of CBF velocities as well as a concomitant rise of the Pulsatility Index (PI) occurred over the entire range of blood pressures indicating a reduction of CBF after transfusion. In addition a right-sided shift of the upper limit towards higher mean blood pressures occurred after transfusion and resulted in an extension of the autoregulatory plateau of CBF. These favourable effects of blood transfusion ameliorating autoregulation of brain blood flow particularly at higher blood pressures might well bear important therapeutic perspectives in our effort to prevent intracranial haemorrhage among sick preterm infants.     

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目的了解窒息新生儿在听觉刺激诱发脑神经活动时的脑氧合代谢和脑血流量的改变。方法1998~2003年北京中日友好医院儿科选择窒息新生儿34例为窒息组,健康新生儿40名为对照组。使用近红外光谱仪,观察听觉刺激试验诱发的脑氧合血红蛋白[HbO2]、还原血红蛋白[HbH]和总血红蛋白[Hbtot]浓度的变化,并比较两组脑氧合代谢和脑血流量的改变。根据[HbO2]、[HbH]和[Hbtot]不同的变化,将氧合代谢曲线分为A([HbO2]、[HbH]和[Hbtot]均增加);B([HbO2]和[Hbtot]增加,[HbH]降低);C([HbO2]和[Hbtot]降低,[HbH]增加)3种曲线类型。结果窒息组中25例(25/34、73·5%)显示C型变化,对照组中28例(28/40、70·0%)显示A型变化,两组中A、C两型例数比较差异显著(P<0·05)。两组[HbO2]和[Hbtot]数值变化幅度比较差异显著(P<0·05)。结论窒息新生儿听觉刺激诱发相应皮层的神经活动时,显示局部脑血流量下降、氧合代谢降低,重度窒息儿更明显。     

Autoregulation of cerebral blood flow in newborn babies

Autoregulation is the result of a basic property of vascular smooth muscle cells where transmural pressure modifies muscle tone. As a result, flow is kept more or less constant over a range of blood pressures. In foetal lambs autoregulation develops from 0.6 gestation, whereas in extremely preterm babies the evidence is conflicting. Static autoregulation, measuring at steady state, is developed with a lower threshold at or below 30 mm Hg. The upper limit has not been determined. Dynamic autoregulation, measuring before steady state, appears not to be operating in preterm babies. The reason for this discrepancy is unknown and the clinical relevance is uncertain. In term and preterm babies with hypoxic-ischaemic brain injury, or with arterial hypotension treated with dopamine static autoregulation has been found absent. For clinical practice the relation between pressure and blood flow is less important than the relation between arterial pCO(2) and blood flow.     

Autoregulation of cerebral blood flow in the newborn beagle puppy

Regional cerebral blood flow (RCBF) was measured in 17 newborn beagle puppies under conditions of moderate hypotension, normotension, and moderate hypertension. RCBF demonstrated autoregulation over the blood pressure range 35-70 mm Hg. When arterial pressure exceeded 75 mm Hg, RCBF increased significantly for all grey matter structures, 2 of 4 white matter structures, and 2 of 3 germinal matrix structures. The magnitude of the hypertension-induced increase in RCBF was highest for thalamic and mesencephalic nuclei, intermediate in cerebral cortex and other subcortical nuclei, and lowest in white matter. The hypertension-induced increase in CBF was low (similar to white matter) in some areas of germinal matrix but higher (similar to midline cerebral cortex) to rostral germinal matrix. The differences in RCBF during hypertension between rostral germinal matrix and cerebral white matter may partially explain the vulnerability of the germinal matrix to hemorrhage.     

Regional cerebral blood flow velocity patterns in newborn infants

Using range-gated pulsed Doppler sonography, cerebral blood flow velocity (CBFV) waveforms from the anterior cerebral artery (ACA), middle cerebral artery (MCA) and circle of Willis artery (CW) were examined in a total of 34 newborn infants. We compared the pulsatility index (PI) from the three cerebral arteries sampled in 10 term and 10 preterm (29 +/- 2 weeks) newborn infants without a history of perinatal asphyxia or intracranial pathology. The Pl in the ACA ranged from 0.60 to 1.03. There were no significant differences in Pl between the three vessels by paired comparisons. The Pl of the MCA differed from that of the ACA by 0.00 +/- 0.05. The variation coefficient (CV) was 7%. For CW with ACA, the difference was 0.00 +/- 0.04 and CV was 6%. Both intra- and interexaminer variation in Pl measurements were studied in another 14 infants. The variation coefficients were 5-8% for all three cerebral arteries. We showed that CBFV waveform patterns were similar in regional cerebral arteries, with Pl being a consistent CBFV index. In normal cerebral circulation, the intervessel Pl differences were within observer variations. Deviation from this may suggest abnormal regional cerebral haemodynamics.     

Cerebral blood flow and sleep state in the normal newborn infant.

The cerebral blood flow (CBF) index measured by venous occlusion plethysmography in 12 normal newborn infants was found to vary significantly with sleep state. Criteria for definition of sleep state are described. The cerebral blood flow index in active sleep was 23% higher than in quiet sleep, and there were smaller, but consistent and significant, differences between intermediate and active or quiet sleep.     

Blood flow distribution and brain metabolism during tolazoline-induced hypotension in newborn dogs

Tolazoline is used in neonatal intensive care to treat hypoxia secondary to persistent pulmonary hypertension of the newborn. Its use is often complicated by systemic hypotension. We compared the effect of tolazoline-induced hypotension on organ blood flow, regional brain blood flow, and cerebral metabolism in hypoxic newborn dogs whose mean arterial pressure fell by more than 20% with a second group whose blood pressure fell by less than 20%. Blood flows were measured by the radioactive microsphere technique. We found no changes in organ blood flow, regional brain blood flow, and cerebral metabolism in hypoxic animals whose mean arterial blood pressure decreased less than 20% during tolazoline administration. However, in those animals whose mean arterial blood pressure decreased more than 20%, we found a decrease in cerebral blood flow. As a consequence of decreased cerebral blood flow, cerebral oxygen delivery decreased. However, oxygen extraction increased so that cerebral metabolic rate was preserved.     

The association between preterm newborn hypotension and hypoxemia and outcome during the first year

Ninety-eight newborn infants, less than 34 weeks at birth, were studied to examine the relationship between newborn hypotension and hypoxemia and brain damage. Heart rate, blood pressure and oxygen tension were recorded continuously during the 96 h following delivery. Outcome measures included neuropathology in children who died, and motor and cognitive development at one year corrected age in children who survived. There were 22 children with a minor and 27 with a major abnormal outcome. There was a relationship between newborn hypotension, newborn hypoxemia and low birth weight, and a major abnormal outcome. The probability of a major abnormal outcome increased from 8% in newborns with no hypotension or hypoxemia, to 53% in children with both hypotension and hypoxemia. These findings support the contention that combinations of sustained newborn hypotension and hypoxemia are important factors in the development of brain damage, accounting for a major abnormal outcome.     

Intrauterine growth restriction ameliorates the effects of gradual hemorrhagic hypotension on regional cerebral blood flow and brain oxygen uptake in newborn piglets

Data are scant regarding the development of cerebrovascular autoregulation in intrauterine growth-restricted (IUGR) newborns. We tested the hypothesis that IUGR improves the ability of neonates to withstand critical periods of gradual hemorrhagic hypotension by optimizing cerebrovascular autoregulation. Studies were conducted on 1-d-old anesthetized piglets divided into groups of normal weight (NW, n = 14, body weight = 1518 +/- 122 g) and IUGR (n = 14, body weight = 829 +/- 50 g) animals. Physiologic parameters, including regional cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO(2)), were similar in NW and IUGR piglets under baseline conditions. Controlled arterial blood loss [hemorrhagic hypotension (HH)] induced a stepwise reduction of the mean arterial blood pressure of 49 +/- 3 mm Hg (mild HH), 39 +/- 3 mm Hg (moderate HH), and 30 +/- 3 mm Hg (severe HH) in seven NW and seven IUGR piglets (p < 0.05). In NW piglets, cortical CBF and CMRO(2) was reduced already at moderate HH (p < 0.05). A similar CMRO(2) reduction occurred during severe HH in NW and IUGR piglets (p < 0.05). In addition, during mild and moderate HH, primarily in IUGR piglets, an increase in regional CBF of brainstem, cerebellum, and thalamus was shown compared with baseline values (p < 0.05). Furthermore, under these conditions, cerebral cortex blood flow was maintained in newborn IUGR animals. In contrast, NW piglets exhibited a significant reduction in CBF (p < 0.05) during moderate HH. Thus, IUGR resulted in an improved ability to withstand critical periods of gradual oxygen deficit as shown by improved cerebrovascular autoregulation during hemorrhagic hypotension.     

Postnatal development of the cerebral blood flow velocity response to changes in CO2 and mean arterial blood pressure in the piglet

Cerebral blood flow velocity was studied during changes (haemorrhage) in mean arterial blood pressure or P _aCO₂ in 56 (aged 0–26 days) anaesthetized and ventilated piglets. The CO₂ reactivity increased with age from 6.5% kPa⁻'(< 1 day) to adult levels of 25% kPa⁻¹ for piglets over 4 days old. The mean arterial blood pressure reactivity was reduced from 1.3% mmHg⁻¹ (< 1 day old) to 0.0%/ mmHg (> 4 days old). The reactivities were similar with two different anesthetics: chloralose/urethane or pentobarbital. To validate the cerebral blood flow velocity data, both electromagnetic flow and precerebral Doppler ultrasound velocity were recorded from the same common carotid artery with extracranial branches tied off. There were no differences between the results with these two methods nor between these results and those obtained when the cerebral blood flow velocities were recorded from an intracerebral artery and the electromagnetic flowmeter recorded from the carotid artery. The vessel diameter appears stable during these interventions. In conclusion, the autoregulatory response and the reaction to P _aCO₂ appear poorly developed in the newborn piglet, but rapidly mature during the first 4 days of life.     

Cerebral vascular effects of hypovolemia and dopamine infusions: a study in newborn piglets

Aim: Despite widespread use, effects of volume boluses and dopamine in hypotensive newborn infants remain controversial. We aimed to elucidate if hypovolemia alone impairs cerebral autoregulation (CA) and if dopamine affects cerebral vasculature. Methods: In 12 piglets, cerebral perfusion (laser‐Doppler flux) and oxygenation [near‐infrared spectroscopy (NIRS)] were examined during dopamine (20–50 μg/kg per minute) and nonpharmacologically induced blood pressure (ABP) changes. Effect on cerebral perfusion and oxygenation was quantified as frequency gain between ABP and laser‐Doppler flux (gain‐LDF) and NIRS [gain‐oxygenation index (OI)], respectively. Gain quantifies change in perfusion or oxygenation per ABP‐change. CA was estimated as gain‐LDF during nonpharmacologically induced ABP changes, that is, as degree of impairment. Dopamine’s cerebrovascular effect was estimated by contrasting gain during dopamine‐ and nonpharmacologically induced ABP changes. Measurements were conducted during both normovolemia‐ and haemorrhage‐induced hypovolemia. Results: Hypovolemia elicited hypotension (p = 0.02) as well as increasing impairment of CA (p = 0.01). However, hypovolemia without hypotension did not affect CA significantly. Dopamine increased perfusion significantly compared to nonpharmacological challenges (mean difference: 1.5%/mmHg, 95% CI: 0.5–2.6, p = 0.007). Oxygenation was, however, similar (mean difference: 0.01 μmol/L per mmHg, 95% CI: ?0.03 to 0.05, p = 0.7). Conclusion: Our findings do not support that hypovolemia alone impairs CA. Furthermore, dopamine seems to increase cerebral perfusion but not oxygenation.     

Effect of the cyclo-oxygenase blocker ibuprofen on cerebral blood volume and cerebral blood flow during normocarbia and hypercarbia in newborn piglets

Indomethacin modifies baseline cerebral haemodynamics and metabolism, as well as vasomotor adaptive responses. However, the significance of arachidonic acid metabolites in the regulation of cerebral circulation remains unclear. A study was made of the effect of inhibition of the cyclo-oxygenase pathway on baseline cerebral haemodynamics and CO2-induced vasodilation using the more specific cyclo-oxygenase blocker ibuprofen in a neonatal pig model. Two methods were used: radiolabelled microspheres to measure cerebral blood flow and near infrared spectroscopy to calculate absolute changes in cerebral blood volume. The relationship between CO2-induced changes in these two haemodynamic parameters was evaluated. Fifteen newborn piglets <7 d old received an i.v. infusion of either ibuprofen (30 mg/kg) (IB group, n = 8) or saline (control group, n = 7). Cerebral blood flow and absolute changes in cerebral blood volume were measured while the piglets were breathing room air at baseline and 30 min after infusion of ibuprofen or saline, and 15 min and 30 min after inducing hypercarbia. Global and regional cerebral blood flow (ml/hg/min) and absolute changes in cerebral blood volume (ml/hg) did not vary between baseline and 30 min after infusion of ibuprofen or saline. During hypercarbia, global and regional cerebral blood flow and absolute changes in cerebral blood volume increased significantly in both the ibuprofen and control groups (p < 0.01). The mean percentage increases in blood flow and blood volume at each measurement were almost identical, with approximately 90% of the increase in both parameters occurring after 15 min of hypercarbia, then reaching a plateau. However, we found no agreement between cerebral blood flow changes and absolute changes in cerebral blood volume. We conclude that ibuprofen did not alter either baseline cerebral circulation or physiological CO2-induced vasodilation in newborn pigs. We speculate that hypercarbic cerebral vasodilation could be caused either by mediators other than the cyclo-oxygenase metabolites of arachidonic acid or by a direct effect on vessel walls.     

The effects of variations in PaCO2 on brain blood flow and cardiac output in the newborn piglet

The acute effects of normoxemic hypocarbia and hypercarbia were examined in six newborn piglets. Brain blood flow was maintained during hypocarbia until extremely low PaCO2 (less than 15 mm Hg) levels were achieved at which time total brain and cerebral blood flow decreased significantly from baseline values. Blood flow to the thalamus, cerebellum and brain stem was unchanged from baseline conditions during hypocarbia. This suggests that the newborn brain is relatively insensitive to moderate degrees of hypocarbia. Extreme hypocarbia (PaCO2 less than 15 mm Hg) was associated with a significant increase in heart rate, accompanied by a significant decrease in mean arterial blood pressure; however, cardiac output was not significantly different from baseline determinations. Hypercarbia with normoxemia was associated with significant increases in total brain blood flow, with greater blood flow to the brain stem, cerebellum, and thalamus than to the cerebrum. The percentage of cardiac output received by the brain was also significantly increased, although total cardiac output was unchanged. This demonstrates that the newborn cerebral vasculature is sensitive to hypercarbia and that regional differences in sensitivity may account for the greater increments in blood flow to the caudal portions of the brain than that to the cerebrum.     

Autoradiographic determination of regional cerebral blood flow during hypoglycemia in newborn dogs

To ascertain the regional cerebral blood flow (CBF) responses to hypoglycemia, nine newborn dogs were treated with insulin to blood glucose concentrations ranging from 1 to 35 mg/dl (mean 22 mg/dl). Systemic physiologic monitoring revealed no differences in mean arterial blood pressure, heart rate, paO2, paCO2, pHa, or blood lactate in the hypoglycemis animals and five normoglycemic controls. Significant increases in CBF occurred in 17 of 20 analyzed structures of brain in the hypoglycemic puppies, ranging from 158 to 446% of the normoglyycemic values. The percent increases in CBF were greatest in brainstem structures compared to other major regions of brain. A positive correlation existed between mean arterial blood pressure and cerebral cortical blood flow, suggesting a loss of CBF autoregulation during hypoglycemia. The pathophysiologic mechanism for the elevations in regional CBF might relate to stimulation of beta-adrenergic receptors in brain, as has been shown in adults.     

Nitric oxide donor increases cerebral blood flow and oxygenation during kainic acid-induced seizures in newborn rabbits

BACKGROUND: We investigated the hypothesis that sodium nitroprusside (SNP), a nitric oxide (NO) donor, increased the cerebral blood flow and oxygenation during kainic acid (KA)-induced seizures in newborn rabbits. METHODS: After KA administration (i.v. 12 mg/kg)to induce seizures, either 1.2 mg/kg SNP (SNP group, i.v., n = 6) or 1 mL normal saline (vehicle group, i.v., n = 6)was given. Regional cerebral blood flow (rCBF), cerebral oxyhemoglobin(oxy-Hb), deoxyhemoglobin (deoxy-Hb), total hemoglobin (t-Hb), mean arterial blood pressure (MABP), heart rate (HR) and electroencephalography(EEG) were continuously monitored throughout the experiment, lasting at least 60 min after the KA administration. RESULTS: The value for rCBF was greatly increased during seizures in the SNP group than in the vehicle group. The values for oxy-Hb and t-Hb were significantly increased, and deoxy-Hb was significantly decreased. There were ameliorations of cerebral oxygenation in the SNP group during the acute phase of seizures in the neonatal animals, compared with the vehicle group. There were no significant differences in the MABP, HR, arterial blood gases, rectal and brain temperatures, blood hemoglobin concentrations,blood glucose levels, the latencies to first abnormal discharges in EEG, the total sum of the duration of abnormal discharges in EEG and the incidences of subclinical electric status epileptics between the two groups. CONCLUSIONS: These results suggest that the treatment with SNP contributed to the increases in cerebral blood flow and oxygenation, and that EEG abnormalities were unchanged by the treatment with SNP during neonatal seizures.     

近红外光谱仪早期监测脑血流自主调节功能预测早产儿脑损伤

目的探讨早产儿脑血流自主调节功能影响因素及近红外光谱仪(NIRS)在早产儿脑损伤早期诊断中的价值。方法对2003年5月至2005年2月间在NICU住院的61例早产儿,在生后12~36h内应用NIRS监测早产儿脑血流自主调节功能(HbD-MABP相关系数r≥0.5为脑血流自主调节功能受损),分析其影响因素及与早产儿脑损伤的相关性。结果61例早产儿中29例(47.5%)脑血流自主调节功能受损,胎龄越小、出生体重越低,脑血流自主调节功能越易损伤;有重度窒息、低氧血症及使用nCPAP或呼吸机辅助通气者,脑血流自主调节功能容易损伤;脑血流自主调节功能受损的29例早产儿全部(100%)发生脑损伤,而32例脑血流自主调节功能正常者仅9例(18.1%)发生脑损伤。结论对早产儿在生后早期应用NIRS监测有助于了解脑血流自主调节功能状态;胎龄、体重、重度窒息、低氧血症及使用nCPAP或呼吸机辅助通气等均是影响脑血流自主调节功能的重要因素;脑血流自主调节功能受损者脑损伤发生率高。     

Effect of light and hyperoxia on ocular blood flow in the newborn piglet

Ocular blood flow was studied in newborn piglets during light exposure and light combined with hyperoxia. Light caused a significant increase in ocular blood flow which returned to values not significantly different from baseline levels during superimposed hyperoxia. None of these experimental conditions changed total cerebral blood flow or cardiac output. The findings indicate that light might be a regulator of ocular blood flow. This influence of light on ocular blood flow may be of importance in the pathophysiology of retinopathy of prematurity.     

Effect of phenobarbital on cerebral blood flow in the newborn piglet under stress

Heart rate, cardiac output, mean arterial blood pressure (MABP), and cerebral blood flow (CBF) were measured in 12 newborn piglets (6 controls and 6 pretreated with 20 mg/kg phenobarbital), under two different stresses: pain stimulation and intravenous injection of 2.5 mg/kg phenylephrine. Phenobarbital prevented pain-induced tachycardia (p less than 0.05 versus controls) but failed to prevent hemodynamic changes induced by phenylephrine. CBF remained relatively constant throughout the study. A better correlation between cerebral vascular resistance and MABP was noted in the phenobarbital group (r = 0.58, p less than 0.01) than in the controls (r = 0.15, p = NS), suggesting that phenobarbital potentiates the vasoconstrictor effect of catecholamines.