CBF reactivity in hypotensive and normotensive preterm infants

Perinatal distress in the preterm neonate, and the consequent loss of cerebrovascular autoregulation, has been implicated in the pathogenesis of neonatal cerebral lesions. A component of this distress is thought to be hypotension. We examined the autoregulatory capacity of hypotensive and normotensive infants using the 133Xe technique to measure cerebral blood flow. Global CBF was measured during only normotension in 5 infants, and during both hypotension and normotension in 11 infants. All the infants were ventilated and blood pressure was measured using an intra-arterial catheter. Fourteen CBF measurements were made on the normotensive infants. Forty-seven CBF measurements were made on the hypotensive infants, 34 measurements during hypotension and 13 during normotension. The global CBF of the normotensive and hypotensive infants were 13.3 and 13.6 mL/100 g/min, respectively. The mean arterial blood pressure (MABP)-CBF reactivity (95% CI) of the normotensive and hypotensive infants were 1.9% (-0.8% to 4.7%)/mm Hg and 1.9% (0.8% to 3.0%)/mm Hg, respectively. The CO2-CBF reactivity (95%CI) of the normotensive and hypotensive infants was 11.1% (6.8% to 15.5%)/KPa deltaPaCO2 and 4.1% (-5.0% to 14.1%)/KPa deltaPaCO2. The implications of these calculated CBF reactivities is that normotensive infants may have intact autoregulation but with a diminished response to fluctuations in PaCO2. The hypotensive infants appear to have attenuated or absent autoregulation with little or no response in CBF to changes in PaCO2.     

The effects of hypercapnia on cerebral autoregulation in ventilated very low birth weight infants

Permissive hypercapnia, a strategy allowing high Pa(CO2), is widely used by neonatologists to minimize lung damage in ventilated very low birth weight (VLBW) infants. While hypercapnia increases cerebral blood flow (CBF), its effects on cerebral autoregulation of VLBW infants are unknown. Monitoring of mean CBF velocity (mCBFv), Pa(CO2), and mean arterial blood pressure (MABP) from 43 ventilated VLBW infants during the first week of life was performed during and after 117 tracheal suctioning procedures. Autoregulation status was determined during tracheal suctioning because it perturbs cerebral and systemic hemodynamics. The slope of the relationship between mCBFv and MABP was estimated when Pa(CO2) was fixed at 30, 35, 40, 45, 50, 55, and 60 mm Hg. A slope near or equal to 0 suggests intact autoregulation, i.e. CBF is not influenced by MABP. Increasing values >0 indicate progressively impaired autoregulation. Infants weighed 905 +/- 259 g and were 26.9 +/- 2.3 wk gestation. The autoregulatory slope increased as Pa(CO2)) increased from 30 to 60 mm Hg. While the slopes for Pa(CO2) values of 30 to 40 mm Hg were not statistically different from 0, slopes for Pa(CO2) > or = 45 mm Hg indicated a progressive loss of cerebral autoregulation. The autoregulatory slope increases with increasing Pa(CO2), suggesting the cerebral circulation becomes progressively pressure passive with hypercapnia. These data raise concerns regarding the use of permissive hypercapnia in ventilated VLBW infants during the first week of life, as impaired autoregulation during this period may be associated with increased vulnerability to brain injury.     

Noninvasive detection of changes in cerebral blood flow by near-infrared spectroscopy in a piglet model of hydrocephalus

Formulation of rational interventions in infantile hydrocephalus is limited by the inability to monitor cerebral hemodynamics quantitatively, continuously, and noninvasively. Near-infrared spectroscopy (NIRS) measures changes in cerebral concentration of oxygenated and deoxygenated hemoglobin (HbO(2) and Hb); HbD is the derived difference between HbO(2) and Hb. Our previous work showed that HbD reflected cerebral blood flow (CBF) measured by radioactive microspheres in a piglet model of systemic hypotension. This study was designed to determine whether NIRS detected important changes in cerebral perfusion and oxygenation in a piglet model of hydrocephalus and whether changes in HbD accurately reflected changes in CBF. Acute hydrocephalus was produced in neonatal piglets by intraventricular infusion of "mock cerebrospinal fluid." Intracranial pressure (ICP) was maintained for several minutes at approximately 10, 20, and 30 mm Hg above the baseline ICP. CBF was measured in cerebral cortex, white matter, and basal ganglia at each ICP by radioactive microspheres. Changes in HbO(2) and Hb were measured continuously by NIRS. Cerebral perfusion pressure declined with increasing ICP, and this decline was accompanied by significant decreases in HbD measured by NIRS and CBF measured by radioactive microspheres. There was a strong correlation between changes in HbD and individual changes in CBF in cerebral cortex, white matter, and basal ganglia (all p < 0.0001). This study demonstrates that changes in HbD reflect changes in CBF over a wide range of ICP in a model of acute hydrocephalus. This reproducible and easily obtained measurement by NIRS could facilitate considerably decisions concerning therapeutic interventions.     

Autoregulation of cerebral blood flow in the preterm fetal lamb

The purpose of the present study was to determine if autoregulation of cerebral blood flow (CBF) is present in the preterm fetal lamb and, if present, to measure the range of mean arterial blood pressure over which autoregulation exists. Thirty-seven measurements of CBF were made in seven preterm fetal lambs (118-122 days gestation) over a mean carotid arterial blood pressure (CBP) range of 18-90 mm Hg. CBF was measured by the radionuclide-labeled microsphere technique. CBP was altered by graduated inflation of balloons placed around the brachiocephalic trunk and the aortic isthmus. To eliminate the effects of reflex changes in heart rate, the carotid sinus and aortic nerve were ablated bilaterally. CBF was linearly related to mean CBP from 18-45 mm Hg, constant over a mean CBP of 45-80 mm Hg, and again linear from 80-90 mm Hg. Resting mean CBP (normotension) was 53.8 +/- 1.9 mm Hg during the control period and 51.7 +/- 0.8 mm Hg during the equilibration periods. This study demonstrates that although autoregulation of CBF is intact in the preterm fetal lamb, the range is narrowed compared to the term lamb and resting mean CBP lies close to the lower limit of autoregulation.     

Identification of pressure passive cerebral perfusion and its mediators after infant cardiac surgery

Cerebrovascular pressure autoregulation (CPA) regulates cerebral blood flow (CBF) in relation to changes in mean arterial blood pressure (MAP). Identification of a pressure-passive cerebral perfusion and the potentially modifiable physiologic factors underlying it has been difficult to achieve in sick infants. We previously validated the near-infrared spectroscopy-derived hemoglobin difference (HbD) signal (cerebral oxyhemoglobin - deoxyhemoglobin) as a reliable measure of changes in CBF in animal models. We now sought to determine whether continuous measurements of DeltaHbD would correlate to middle cerebral artery flow velocity (CBFV), allow identification and quantification of pressure-passive state, and help to delineate potentially modifiable factors. We enrolled 43 infants (2 d to 7 mo old) who were undergoing open cardiac surgery and cardiopulmonary bypass. At 6 and 20 h after surgery, we measured changes in HbD, CBFV (by transcranial Doppler), and MAP at different end-tidal CO(2) levels. We assigned a pressure-passive index (PPI) to each study on the basis of the relative duration of significant coherence between DeltaMAP and DeltaHbD. We found a significant relationship between DeltaHbD and DeltaCBFV at both time points. At 6 h after surgery, we showed high concordance (coherence > 0.5; PPI > or = 41%) between DeltaMAP and DeltaHbD, consistent with disturbed CPA in 13% of infants. End-tidal CO(2) values > or = 40 mm Hg and higher MAP variability both were associated with increased odds (p < 0.001) of autoregulatory failure. This approach provides a means to identify and quantify disturbances of CPA. High CO(2) levels and fluctuating MAP are two important preventable factors associated with disturbed CPA.     

近红外光谱仪监测脑血流及血管自主调节功能的实验研究

目的评价近红外光谱仪（NIRS）脑氧合指标与新生猪脑血流的相关性,以寻找能最好反映脑血流变化及脑血管自主调节功能的NIRS指标。方法10头出生前1～3d新生猪随机分为两组：正常对照组（6头）、低血压组（4头）。人为动脉放血造成血压及脑血流的改变。应用NIRS连续监测脑组织氧合血红蛋白（△HbO2）与还原血红蛋白（△HHb）的动态变化,计算二者之和tHb（△tHb=△HbO2＋△HHb）．及二者之差△HbD（△HbD=△HbO2-△HHb）。同时应用彩色微球技术定量测定脑血流的变化,并对测定结果进行线性回归分析。结果对NIRS测定的△tHb、△HbD和彩色微球定量测得的全脑（GCBF）以及大脑皮层脑血流（CBFc）之间的关系进行线性回归分析。正常生理条件下,△HbD和△tHb与GCBF存在显著相关,相关系数分别为r1a=0．409和r1b=0．440,P均〈0．05;△HbD和△tHb与CBFc也存在显著相关,相关系数分别为r2a=0．394和r2b=0．400,P均〈0．05。低血压条件下,新生猪仅在M△BP降至35mmHg（1mmHg=0．133kPa）时脑血流才显著降低（P〈0．05）,而随着血压的逐渐降低,△HHb逐渐增高（P〈0．01）,△HbO,和△tHb先有升高趋势（P〈0．05）,然后在M△BP降至35mmHg时才显著降低（P〈0．01）,△HbD与GCBF、CBFc采用线性回归分析所得的相关系数r3a=0．890、r3b=0．887差异有统计学意义,P均〈0．01;而△tHb与GCBF、CBFc采用线性回归分析所得的相关系数r4a=0．395、r4b=0．375差异均无统计学意义,P均〉0．05,△HbD与脑血流的变化趋势相同,二者密切相关;而△tHb与脑血流的变化未存在相关。新生猪M△BP〉35mmHg时脑血流与血压不相关,提示自主调节功能完整,将调节功能完整的新生猪脑血流、△HbD与相应的M△BP值行线性回归分析显示相关系数〈0．5;M△BP〈35mmHg时脑血流与血压相关,提示自主调节功能受损,将调节功能受损的新生猪脑血流、△HbD与相应的M△BP值行线性回归分析显示相关系数〉0．5。结论正常生理及低血压条件下,△HbD均能很好反映出脑血流的动态变化;△tHb仅在正常生理条件下能用来反映脑血流的动态变化。1～3d新生猪脑血管自主调节的下限为35mmHg,NIRS氧合指标△HbD与M△BP的相关性可以反映新生猪的脑血管自主调节状态。     

Fluctuating pressure-passivity is common in the cerebral circulation of sick premature infants

Cerebral blood flow pressure-passivity results when pressure autoregulation is impaired, or overwhelmed, and is thought to underlie cerebrovascular injury in the premature infant. Earlier bedside observations suggested that transient periods of cerebral pressure-passivity occurred in premature infants. However, these transient events cannot be detected reliably by intermittent static measurements of pressure autoregulation. We therefore used continuous bedside recordings of mean arterial pressure (MAP; from an indwelling arterial catheter) and cerebral perfusion [using the near-infrared spectroscopy (NIRS) Hb difference (HbD) signal) to detect cerebral pressure-passivity in the first 5 d after birth in infants with birth weight <1500 g. Because the Hb difference (HbD) signal [HbD = oxyhemoglobin (HbO2) - Hb] correlates with cerebral blood flow (CBF), we used coherence between MAP and HbD to define pressure-passivity. We measured the prevalence of pressure-passivity using a pressure-passive index (PPI), defined as the percentage of 10-min epochs with significant low-frequency coherence between the MAP and HbD signals. Pressure-passivity occurred in 87 of 90 premature infants, with a mean PPI of 20.3%. Cerebral pressure-passivity was significantly associated with low gestational age and birth weight, systemic hypotension, and maternal hemodynamic factors, but not with markers of maternal infection. Future studies using consistent serial brain imaging are needed to define the relationship between PPI and cerebrovascular injury in the sick premature infant.     

Effect of sympathetic nervous system on cerebral blood flow in the newborn piglet

The role of the sympathetic nervous system on cerebral blood flow (CBF) autoregulation was evaluated in newborn piglets. Six animals were studied after ablation of the right superior sympathetic ganglion and compared to 6 control animals. Mean arterial blood pressure (MABP) was decreased by successive blood withdrawal and CBF was measured by radioactive microspheres. In denervated animals, MABP and CBF correlated positively according to a parabolic curve showing an absence of autoregulation when MABP is above 50 mm Hg (y = 0.079x2 - 5.9x + 154, p less than 0.01). In control animals, CBF remains stable throughout the experiment (y = 0.28x + 5). These data suggest a shift to the left of the upper limit of the autoregulation range in denervated animals and consequently a poor adaptation to increased MABP.     

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.     

Effect of indomethacin on the regulation of cerebral blood flow during respiratory alkalosis in newborn piglets

The effect of cyclooxygenase inhibition by indomethacin on regional cerebral blood flow (CBF) during hypocapnia induced by hyperventilation and during hypercapnia induced by CO2 inhalation was examined. CBF was measured in 27 anesthetized, ventilated piglets (2-8 d) using microspheres in control and indomethacin treated animals (5 mg/kg) after hyperventilation or inhalation of 6% CO2. In the control group (n = 6), CBF decreased significantly (p less than 0.05) to all regions of the brain after hyperventilation with a 32% decrease in the cerebral cortex. In the indomethacin-treated group (n = 6), blood flow significantly decreased by 35 to 49% in all regions of the brain, except the cerebral white matter, during normocapnia with no further decrease in flow during subsequent hypocapnia. Although CBF increased significantly after indomethacin treatment during hypercapnia the response was markedly attenuated with blood flow to the cerebral gray matter, hippocampus and pons rising only 42, 25, and 42% in contrast to 108, 75, and 225% in the control group. Since indomethacin decreased resting CBF, unilateral sympathetic nerve stimulation at 15 Hz was used to test the specificity of indomethacin on hypocapnic vasoconstriction (n = 5). Unilateral sympathetic nerve stimulation caused a further statistically significant decrease in CBF on the stimulated side after hyperventilation with indomethacin (12%), which was comparable to that which occurred during normocapnia (16%). The data demonstrate that indomethacin attenuates the cerebrovascular sensitivity to both increases and decreases in CO2/H+ and implicate a possible role for vasoactive prostanoids in mediating the response of CBF to fluctuations in CO2 in newborn piglets.     

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.     

Developmentally increased cerebrovascular NO in newborn pigs curtails cerebral blood flow autoregulation.

We tested the hypothesis that a reduced ability of the newborn (1-2 d old) to autoregulate cerebral blood flow (CBF) during acute hypertension is contributed by an increased synthesis of nitric oxide (NO) from endothelial (e) and neuronal NO synthase (nNOS). As previously reported, CBF (measured by radiolabeled microsphere technique) in newborn pigs remained constant only between 50 and 90 mm Hg of mean arterial blood pressure. Treatment of newborn pigs with Nomega-monomethyl-L-arginine or specific nNOS inhibitors 7-nitroindazole monosodium, 3-bromo-7-nitroindazole, and 1-(2-trifluoromethylphenyl) imidazole extended the upper limit of CBF autoregulation as seen in saline-treated (control) juvenile (4-6-wk-old) animals. Cerebrovascular production of nitrite (stable NO oxidation product) in vivo was markedly increased during hypertension (mean arterial blood pressure > 90 mm Hg) in newborn but not in the juvenile pigs. Inhibition of NOS with Nomega-monomethyl-L-arginine, 7-nitroindazole monosodium, 3-bromo-7-nitroindazole, or 1-(2-trifluoromethylphenyl) imidazole prevented the hypertension-induced increase in nitrite levels. In addition, eNOS and nNOS protein expression and activity were 2- to 3-fold higher (p < 0.05) in the cerebral microvasculature of newborn than in the tissues of juvenile pigs. It is concluded that during acute hypertension, excess production of NO associated with increased activity of NOS curtails the upper limit of CBF autoregulation in the newborn subject; in addition, nNOS seems to serve a significant role in this important physiologic function.     

Pressure ventilation increases brain vascular prostacyclin production in newborn pigs

Using awake, chronically catheterized newborn pigs, we measured cerebral blood flow (CBF), net cerebral vascular 6-keto-prostaglandin F1 alpha production, and cerebral metabolic rate of oxygen (CMRO2) during hypercapnia and during hypercapnia at increased mean airway pressure (Paw), both before and after treatment with indomethacin. CBF nearly doubled during hypercapnia. The hypercapnia-induced cerebral hyperemia was maintained when Paw was increased from 3 +/- 2 to 16 +/- 4 cm H2O during hypercapnia. Sagittal sinus pressure increased in proportion to the increase in Paw, and cardiac output was unchanged. Net cerebral production of 6-keto-prostaglandin F1 alpha increased from 9 +/- 1 to 15 +/- 1 ng/min/100 g tissue during hypercapnia and increased dramatically to 57 +/- 1 ng/min/100 g when hypercapnia was coupled with an increase in Paw. CMRO2 was not changed by either hypercapnia or increased Paw. After indomethacin, CBF decreased and cerebral vasodilation to hypercapnia did not occur. After indomethacin, adding increased Paw during hypercapnia dropped CBF below baseline, adversely affecting CMRO2. These results suggest that cerebral hypercapnia hyperemia requires brain prostanoid production and that when Paw is increased during hypercapnia, the contribution of prostanoids to maintaining CBF is increased. Increasing ventilation pressure during hypercapnia in piglets pretreated with indomethacin compromises CBF sufficiently to reduce CMRO2.     

Quantitative near infrared spectroscopy measurement of cerebral hemodynamics in newborn piglets

Severely premature infants are often at increased risk of cerebral hemorrhage and/or ischemic injury caused by immature autoregulatory control of blood flow to the brain. If blood flow is too high, the infant is at risk of hemorrhage, whereas too little blood flow can result in ischemic injury. The development of a noninvasive, bedside means of measuring cerebral hemodynamics would greatly facilitate both diagnosis and monitoring of afflicted individuals. It is to this end that we have developed a near infrared spectroscopy (NIRS) system that allows for quantitative, bedside measurement of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). The technique requires an i.v. injection of the near infrared chromophore indocyanine green. Six newborn piglets, median age of 18 h (range 6-54 h), median weight of 1.75 kg (range 1.5-2.1 kg), were studied. Measurements of CBF, CBV, and MTT were made at normocapnia, hypocapnia, and hypercapnia to test the technique over a range of hemodynamic conditions. The accuracy of our new approach has been determined by direct comparison with measurements made using a previously validated computed tomography technique. Paired t tests showed no significant difference between computed tomography and NIRS measurements of CBF, CBV, and MTT, and mean biases between the two methods were -2.05 mL x min(-1) x 100 g(-1), -0.18 mL x 100 g(-1), and 0.43 s, respectively. The precision of NIRS CBF, CBV, and MTT measurements, as determined by repeated-measures ANOVA, was 9.71%, 13.05%, and 7.57%, respectively.     

Arterial oxygenation determines autoregulation of cerebral blood flow in the fetal lamb

We examined autoregulation of cerebral blood flow (CBF) over the range of oxygen tension commonly observed in the chronic fetal lamb preparation. Seventeen animals were surgically prepared under general anesthesia for chronic in utero studies. Based on measured resting arterial PO2 and calculated % saturation 24-48 h after surgery, two groups were defined: a normoxic group of eight with saturation of 57% or higher (our laboratory normal for physiologically stable preparations) and an hypoxic group of nine with saturation less than 57%. Regional CBF was measured with radiolabeled 15-microns microspheres. Autoregulation of CBF was assessed by measuring the change in CBF when fetal mean arterial blood pressure (MABP) was acutely decreased and increased by withdrawal and reinfusion of fetal blood. In normoxic animals CBF was constant over an MABP range of 42-61 torr in all four areas of the brain examined: cerebral hemispheres, basal ganglia, cerebellum, and brain stem. In hypoxic animals CBF was pressure dependent in all areas over an MABP range of 46-73 torr, i.e., autoregulation was abolished. These studies demonstrate that the mechanism of autoregulation is functionally developed in the mature fetal lamb, but operationally dependent upon arterial oxygen concentration. Below a saturation of approximately 50-60% CBF varies directly with perfusion pressure.     

Cerebral blood flow and carbon dioxide reactivity in children with bacterial meningitis

We examined total and regional cerebral blood flow (CBF) by stable xenon computed tomography in 20 seriously ill children with acute bacterial meningitis to determine whether CBF was reduced and to examine the changes in CBF during hyperventilation. In 13 children, total CBF was normal (62 +/- 20 ml/min/100 gm) but marked local variability of flow was seen. In five other children, total CBF was significantly reduced (26 +/- 10 ml/min/100 gm; p less than 0.05), with flow reduced more in white matter (8 +/- 5 ml/min/100 gm) than in gray matter (30 +/- 15 ml/min/100 gm). Autoregulation of CBF appeared to be present in these 18 children within a range of mean arterial blood pressure from 56 to 102 mm Hg. In the remaining two infants, brain dead within the first 24 hours, total flow was uniformly absent, averaging 3 +/- 3 ml/min/100 gm. In seven children, CBF was determined at two carbon dioxide tension (PCO2) levels: 40 (+/- 3) mm Hg and 29 (+/- 3) mm Hg. In six children, total CBF decreased 33%, from 52 (+/- 25) to 35 (+/- 15) ml/min/100 gm; the mean percentage of change in CBF per millimeter of mercury of PCO2 was 3.0%. Regional variability of perfusion to changes in PCO2 was marked in all six children. The percentage of change in CBF per millimeter of mercury of PCO2 was similar in frontal gray matter (3.1%) but higher in white matter (4.5%). In the seventh patient a paradoxical response was observed; total and regional CBF increased 25% after hyperventilation. Our findings demonstrate that (1) CBF in children with bacterial meningitis may be substantially decreased globally, with even more variability noted regionally, (2) autoregulation of CBF is preserved, (3) CBF/CO2 responsitivity varies among patients and in different regions of the brain in the same patient, and (4) hyperventilation can reduce CBF below ischemic thresholds.     

Regional cerebral blood flow after hemorrhagic hypotension in the preterm, near-term, and newborn lamb

Developmental changes in regional cerebral blood flow (CBF) responses to hemorrhagic hypotension during normoxia and normocapnia were determined using radioactively labeled microspheres to measure flow to the cortex, brainstem, cerebellum, white matter, caudate nucleus, and choroid plexus in three groups of chronically catheterized lambs: 90- to 100-d preterm fetal lambs (n = 9); 125- to 136-d near-term fetal lambs (n = 9); and newborn lambs 5- to 35-d-old (n = 8). Heart rate, central venous pressure, and arterial blood pressure were monitored continuously and arterial blood gas tensions, pH, Hb, and oxygen saturation together with regional CBF were measured periodically. Hemorrhagic hypotension produced a mean decrease in arterial blood pressure of 27 +/- 4, 23 +/- 2, and 41 +/- 4% in the three groups, respectively, whereas reinfusion of the lamb's blood resulted in a return to control blood pressure within 3% in all three groups. In the pre-term fetal lamb, CBF decreased significantly in all regions during hypotension. In the near-term fetal lamb, only blood flow to the cortex decreased significantly during hypotension. In the newborn lamb, only the choroid plexus demonstrated a significant decrease in blood flow during hypotension. The lower limit of regional CBF autoregulation was identical to the resting mean arterial pressure in fetal life but significantly lower in newborn lambs. These experiments demonstrate for the first time that vulnerability to hypotension decreases with increasing maturity and that the brainstem, the phylogenetically oldest region of the brain, is the least vulnerable to the effects of hypotension at any age in the lamb model.     

Regional cerebral blood flow: studies in the fetal lamb during hypoxia, hypercapnia, acidosis, and hypotension

In order to determine the relative roles of O2 tension and content, CO2 tension, hydrogen ion concentration, arterial blood pressure, and cardiac output in the regulation of fetal cerebral blood flow (CBF), we used radioactively labeled microspheres to measure flow to 20 major brain regions in 24 chronically catheterized fetal lambs. We continually monitored fetal heart rate and blood pressure, and periodically measured arterial PO2, PCO2, pH, and hematocrit. In addition to CBF measurements during control periods, we measured CBF during: 1) hypoxia (O2 content less than 6 ml X dl-1; O2 tension less than 15 torr) induced by having the ewe breathe a gas mixture with low O2 concentration, 2) hypercapnia (PCO2 greater than 50 torr) induced by increasing the maternal inspired CO2, 3) acidosis and alkalosis (7.60 greater than pH greater than 6.60) induced by infusing lactic acid or bicarbonate into the fetus, and 4) hypotension (blood pressure less than 35 mm Hg) and hypertension (blood pressure greater than 55 mm Hg) induced by rapidly phlebotomizing or transfusing the fetus. We used multiple regression analysis and analysis of covariance to examine the dependence of total cerebral blood flow on arterial O2 tension and content, CO2 tension, pH, blood pressure, and cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impairment of cerebral blood flow autoregulation in the newborn lamb by hypoxia

Autoregulation of cerebral blood flow has been demonstrated in both fetal and newborn animal models under normoxic conditions. In the present experiments we have attempted to define the minimal hypoxic insult which impairs autoregulation in the newborn lamb and to assess the time to recovery. We measured cerebral blood flow by the intracarotid 133Xe method in fifteen 4- to 9-day-old lambs and tested autoregulation of cerebral blood flow by increasing blood pressure 20-30% with phenylephrine. Autoregulation was tested in the control state and at successive time intervals after an hypoxic stress (PaO2 of 30 mm Hg) of 10 or 20 min. We found that cerebral autoregulation was abolished after 20 min of hypoxia and recovered within 7 h. Since this model identifies the minimal hypoxic insult to abolish autoregulation it might be used to study means to protect autoregulation or to hasten its recovery after hypoxia.     

Cerebral blood flow velocity in term newborn infants: changes associated with ductal flow

The effects of ductal closure on range-gated pulsed Doppler cerebral blood flow velocity (CBFV) patterns in the internal carotid, anterior cerebral, and middle cerebral arteries were studied in 10 normal term infants (mean birth weight 3302 +/- 294 g (SD) and mean gestational age 39.6 +/- 1.3 weeks). Pulsatility was calculated from flow velocities and used as an estimate of cerebral blood flow (CBF). Ductal closure was associated with a rise in mean blood pressure from 45.0 +/- 4.2 to 51.3 +/- 6.5 mm Hg (P less than 0.05) and a significant decrease in pulsatility in all three vessels (mean = 0.77 +/- 0.07 vs 0.70 +/- 0.05 (P less than 0.02]. Changes in pulsatility were correlated with changes in mean blood pressure (P less than 0.02), providing evidence that systemic blood pressure may influence postnatal cerebral arterial pulsatility indices. We also noted significant differences in the velocity and pulsatility of individual vessels that were independent of blood pressure, suggesting that Doppler flow studies may be useful in describing regional CBF patterns. The temporal association between ductal closure and decreased pulsatility suggests that CBFV patterns reflect ductal shunting in normal term newborn infants. Diastolic runoff and reduced systemic blood pressure in the presence of ductal shunting appear to reduce diastolic flow velocity and increase CBFV pulsatility in normal term infants during the first days of life. Normal mechanisms of cerebral autoregulation compensate for decreased flow with vasodilation; therefore the increased pulsatility associated with ductal shunting may be due to diastolic runoff rather than increased cerebrovascular resistance.