Cerebral blood flow, PaCO2 changes, and visual evoked potentials in mechanically ventilated, preterm infants

Two estimations of global cerebral blood flow (CBF) using 133-Xenon clearance were done with an interval of about one hour in 16 mechanically ventilated, newborn infants, of less than 33 weeks gestational age. In eight infants CBF was estimated just before a change in ventilator settings, and again when the PaCO2 was stable. In the remaining eight infants small spontaneous changes in PaCO2 occurred. The CBF-CO2 reactivity was similar in the two groups (+67%/kPa (95% confidence interval 13-146) and 52%/kPa (24-86)) and considerably higher than the CBF-CO2 reactivity estimated from the interindividual variation of flow and PaCO2 (+19%/kPa (4-36)). There were no significant relations between CBF and arterial blood pressure. Flash evoked potentials (VEP) were recorded during the 133-Xenon clearances in 8 of the infants. VEP showed no relation to changes in CBF, even when the blood flow rose from the lowest levels. CBF and VEP were obtained once in 9 other infants. Among the 17 infants, the latency of the first negative wave of the VEP was not related to the CBF level. Mean CBF in the 25 infants was 12.3 ml/100 g/min (range 4.3 to 18.9), mean PaCO2 was 4.2 kPa (range 2.3 to 6.4). Thus, CBF-CO2 reactivity appeared to be normal in these clinically stable, mechanically ventilated, preterm infants, suggesting that their low cerebral blood flow was well regulated. The absence of a relation of CBF with VEP suggested that cerebral blood flow was not critically decreased.     

Limited role for nitric oxide in mediating cerebrovascular control of newborn piglets.

AIMS: To investigate the effects of the nitric oxide (NO) synthase inhibitor L-nitro-arginine methyl ester (L-NAME) on cerebral blood flow, and its response to alterations in arterial carbon dioxide tension (CBF-CO2 reactivity). METHODS: Cerebral blood flow was measured six times at varying arterial carbon dioxide tension (PaCO2) using the intravenous 133Xenon clearance technique in eight mechanically ventilated piglets of less than 24 hours postnatal age. After the third measurement L-NAME was administered as a bolus (20 mg/kg) and subsequently infused (10 mg/kg/hour). RESULTS: PaCO2 ranged between 2.7-8.9 kPa. Cerebral blood flow decreased by 14.0% (95% confidence interval 1.9-27.4) after L-NAME. CBF-CO2 reactivity was 18.4% per kPa (95% CI 14.1-22.2) before L-NAME and 15.2%/kPa (95% CI 11.1-19.3) afterwards; the difference between the CBF-CO2 reactivities was 3.2%/kPa (95% CI -0.4-6.8): these were not significantly different. CONCLUSIONS: Inhibition of nitric oxide synthesis reduces cerebral blood flow no more than a 0.5-1.0 kPa fall in PaCO2. Nitric oxide is not an important mediator of CBF-CO2 reactivity.     

Near infrared spectroscopy-measured changes in cerebral blood volume and cytochrome aa3 in newborn lambs exposed to hypoxia and hypercapnia, and ischemia: a comparison with changes in brain perfusion and O2 metabolism.

OBJECTIVES: Validation of near infrared spectroscopy (NIRS)-measured changes in cerebral blood volume (deltaCBV) and cytochrome aa3 (deltaCytaa3) as estimators of changes in brain perfusion and oxygenation in the newborn lamb during hypoxia and hypercarbia, and additional hypotension. METHODS AND MATERIALS: In 33 newborn lambs brain perfusion assessed by carotid artery blood flow (deltaQcar: ml/min)and cerebral metabolic rate of oxygen (deltaCMRO2: ml O2/min) were related to NIRS-derived deltaCBV (ml/100 g) and deltaCytaa3 (microM) during combined hypoxia and hypercarbia and additional hypotension. Combined hypoxia and hypercapnia was induced by ventilation with 6-8% of O2 and 10% of CO2 during 30 min, and additional hypotension ( < 35 mmHg for 5 min) was induced by careful withdrawal of blood. RESULTS: CBV increased during hypoxia and hypercarbia, decreased during additional hypotension and was related to deltaQcar: (0.009 ml/100 g change per ml/min Qcar: P < 0.0001). Cytaa3 increased during hypoxia and hypercarbia, decreased during subsequent additional hypotension andshowed a reverse relationship with deltaCMRO2 (-1.65 microM change per ml O2/min CMRO2: P <0.0001). Cytaa3 remained above baseline during reperfusion. CONCLUSIONS: deltaCBV estimates changes in brain perfusion, but overestimates brain perfusion during hypotension. The pattern of deltaCytaa3 suggests less oxygen utilisation by brain tissue during hypoxia and subsequent reperfusion.     

High brain tissue oxygen tension during ventilation with 100% oxygen after fetal asphyxia in newborn sheep

The optimal inhaled oxygen fraction for newborn resuscitation is still not settled. We hypothesized that short-lasting oxygen ventilation after intrauterine asphyxia would not cause arterial or cerebral hyperoxia, and therefore be innocuous. The umbilical cord of fetal sheep was clamped and 10 min later, after delivery, ventilation with air (n = 7) or with 100% oxygen for 3 (n = 6) or 30 min (n = 5), followed by air, was started. Among the 11 lambs given 100% oxygen, oxygen tension (PO2) was 10.7 (1.8-56) kPa [median (range)] in arterial samples taken after 2.5 min of ventilation. In those ventilated with 100% oxygen for 30 min, brain tissue PO2 (PbtO2) increased from less than 0.1 kPa in each lamb to individual maxima of 56 (30-61) kPa, whereas in those given oxygen for just 3 min, PbtO2 peaked at 4.2 (2.9-46) kPa. The maximal PbtO2 in air-ventilated lambs was 2.9 (0.8-5.4) kPa. Heart rate and blood pressure increased equally fast in the three groups. Thus, prolonged ventilation with 100% oxygen caused an increase in PbtO2 of a magnitude previously only reported under hyperbaric conditions. Reducing the time of 100% oxygen ventilation to 3 min did not consistently avert systemic hyperoxia.     

Cerebral pressure autoregulation and vasoreactivity in the newborn rat

Perinatal brain injury has been associated with impaired cerebral blood flow (CBF) pressure autoregulation. The brain of 3- to 5-d-old rat pups is immature and similar to that of a preterm infant, and therefore we tested cerebral vasoreactivity in that animal. CBF pressure autoregulation was tested in 20 Wistar pups during normocapnia and hypercapnia, respectively. Hypotension was induced by hemorrhage and cerebral perfusion was monitored with laser Doppler flowmetry and near-infrared spectroscopy. Systolic blood pressure was measured noninvasively from the tail. During normocapnia, the autoregulatory plateau was narrow. Resting systolic blood pressure (SBP) was 39.2 mm Hg and CBF remained constant until SBP decreased below 36.0 mm Hg (SE 0.8). Below the lower limit, CBF declined by a mean of 2.7% per mm Hg [95% confidence interval (CI), 2.4-3.0%], and hemoglobin difference (HbD) and total hemoglobin (HbT) changed proportionally to CBF. After inhalation of carbon dioxide, CBF increased significantly by a mean of 17.7% (95% CI, 13.7-22.8%). The CBF-CO2 reactivity was estimated to 13.4% per kPa (95% CI, 2-24.8%), p=0.026. Over the range of SBP (6-54 mm Hg), a linear relationship between CBF and SBP was found during hypercapnia, indicating abolished pressure autoregulation. A linear correlation between CBF and HbD was found (r=0.80). CBF pressure autoregulation and reactivity to CO2 operate in the newborn rat. This model may be useful for future investigations concerning perinatal pathophysiology in the immature brain.     

Indomethacin does not diminish the pulmonary vascular response of the fetus to increased oxygen tension

This study was performed to determine whether prostaglandins play a role in the increase in pulmonary blood flow in the fetal lamb caused by an increase in oxygen tension similar to that occurring at birth. To increase fetal oxygen tension without ventilating the lungs, nine pregnant ewes with chronically instrumented fetuses were exposed to 100% oxygen at 3 atmospheres absolute pressure for 20 min in a hyperbaric chamber. This exposure increased pulmonary arterial oxygen tension in the nine fetuses from 20 +/- 1 to 54 +/- 9 torr. It increased pulmonary blood flow from fetal to newborn values, 31 +/- 3 to 295 +/- 20 ml/kg/min. It did not change pulmonary arterial pressure, 52 +/- 2 torr during normoxia and 50 +/- 2 torr during hyperoxia. Treating five of these fetuses with 3.2 +/- 0.4 mg/kg of indomethacin during hyperbaric oxygenation did not alter these effects (PO2 = 51 +/- 8 torr, pulmonary blood flow = 283 +/- 13 ml/kg/min, and pulmonary arterial pressure = 48 +/- 2 torr). We conclude that the increase in pulmonary blood flow caused by an increase in oxygen tension in the fetus is not maintained by prostaglandins.     

Nitration of Bax and Bcl-2 proteins during hypoxia in cerebral cortex of newborn piglets and the effect of nitric oxide synthase inhibition.

Previous studies have shown that cerebral tissue hypoxia results in increased expression of Bax protein, thereby altering the ratio of Bax to Bcl-2 or formation of Bax/Bcl-2 heterodimer. Hypoxia also induces the generation of nitric oxide free radicals in the cerebral cortex of newborn animals. The present study tests the hypothesis that tissue hypoxia will result in nitration of Bax and Bcl-2 proteins in the neuronal nuclei of newborn piglets. Studies were performed in 22 piglets, 3-5 days old, divided into normoxic (n = 7), hypoxic (n = 9) and hypoxic + NNLA (n = 6) groups. Hypoxia was induced by decreasing the FiO(2) (5-7%) for 60 min and cerebral hypoxia documented by determining tissue ATP and phosphocreatine (PCr) levels. The density of protein bands was expressed as absorbance (OD x mm(2)). PCr levels were 3.03 +/- 0.85 micromol/g brain in the normoxic group and 0.88 +/- 0.32 micromol/g brain in the hypoxic group (p < 0.001 vs. normoxia) and 0.55 +/- 0.13 (p < 0.001 vs. normoxia) in the NNLA-treated hypoxic group. There was increased nitration of Bax protein in hypoxic neuronal nuclei as compared to normoxic and NNLA-treated-hypoxic group nuclei: 211.61 +/- 25.93 versus 124.8 +/- 14.88 and 133.86 +/- 7.42 OD x mm(2), respectively (p < 0.001 vs. normoxia). Nitration of Bcl-2 was not altered significantly in either group. We conclude that there is increased nitric oxide-mediated nitration of Bax in cortical neuronal nuclei during hypoxia and that this increase correlates inversely with the decrease in tissue energy levels. We speculate that, during hypoxia, nitration of Bax and Bcl-2 proteins may regulate heterodimer formation and activation of programmed cell death mechanisms.     

A newborn rat model for the study of cerebral hemodynamics by near-infrared spectroscopy and laser-Doppler flowmetry in the immature brain

An animal model for the study of cerebrovascular physiology in the immature brain was developed. Twelve 3- to 5-day-old rat pups were maintained on spontaneous breathing under light anesthesia for either 1 or 2 h. Transcutaneous carbon dioxide tension and arterial oxygen saturation were monitored. Continuous infusion of doxapram limited respiratory acidosis. Cerebral blood flow (CBF) and volume (CBV) could be monitored by near-infrared spectroscopy (NIRS) and laser-Doppler flowmetry (LDF) in spite of some movement artifacts. CBV and CBF were 6.0 +/- 0.3 SE ml/100 g and 36.3 +/- 3.1 SE ml/100 g/min, respectively, and remained stable during the study. Cerebrovascular responses, as monitored by LDF and NIRS, to hypoxic and hypercapnic gas mixtures were consistent.     

Hypoxemia and reoxygenation with 21% or 100% oxygen in newborn pigs: changes in blood pressure, base deficit, and hypoxanthine and brain morphology.

To study whether room air is as effective as 100% O2 in resuscitation after hypoxia, hypoxemia (PaO2 2.3-4.3 kPa) was induced in newborn pigs (2-5 d old) by ventilation with 8% O2 in nitrogen. When systolic blood pressure had fallen to 20 mm Hg, animals were randomly reoxygenated with either 21% O2 (group 1, n = 9) or 100% O2 (group 2, n = 11) for 20 min followed by 21% O2 in both groups. Controls (group 3, n = 5) were ventilated with 21% O2 throughout the experiment. Base deficit peaked at 31 +/- 5 mmol/L (mean +/- SD) for both hypoxic groups at 5 min of reoxygenation and then normalized over the following 3 h. There were no statistically significant differences between the two groups during reoxygenation concerning blood pressure, heart rate, base deficit, or plasma hypoxanthine. Hypoxanthine peaked at 165 +/- 40 and 143 +/- 42 mumol/L in group 1 and 2 (NS), respectively, and was eliminated monoexponentially in both groups with an initial half-life for excess hypoxanthine of 48 +/- 21 and 51 +/- 27 min (NS), respectively. Blinded pathologic examination of cerebral cortex, cerebellum, and hippocampus after 4 d showed no statistically significant differences with regard to brain damage. We conclude that 21% O2 is as effective as 100% O2 for normalizing blood pressure, heart rate, base deficit, and plasma hypoxanthine after severe neonatal hypoxemia in piglets and that the extent of the hypoxic brain damage is similar in the two groups.     

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.     

Loss of CO2 reactivity of cerebral blood flow is associated with severe brain damage in mechanically ventilated very low birth weight infants.

BACKGROUND: Early detection of pathophysiological factors associated with permanent and severe brain damage in preterm infants requiring intensive care is a major issue in neonatal neurology. The aim of this study was to investigate if an abnormal CO2 reactivity of cerebral blood flow in high risk very low birth weight infants is associated with severe brain injury demonstrated at autopsy or by neurodevelopment examination at 18 months. METHODS: The CO2 reactivity of cerebral blood flow (xenon-133) was measured in 18 mechanically ventilated, severely ill, very low birthweight infants (gestational age 26-32 weeks, birthweight: 630-1360 g) during the first 36 hours of life. Cerebral outcome was assessed on autopsy findings (n = 8) or at the age of 18 months using Bayley developmental scales (n = 10). RESULTS: Eight infants with normal development at 18 months (within mean +/- 2.5 SD of reference group) and two infants with normal cerebral autopsy findings had a median CO2 reactivity of 24.4%/kPa CO2 (interquartile range 14.7-41.2). Two infants with abnormal development (> 2.5 SD below mean) and six infants with hypoxic-ischaemic encephalopathy at autopsy has a median CO2 reactivity of 3.4%/kPa CO2 (interquartile range 8.0-11.7). CONCLUSION: In mechanically ventilated very low birthweight infants low CO2 reactivity of cerebral blood flow (below 10%/kPa CO2) during the first 36 hours of life was associated with poor neurodevelopmental outcome or hypoxic-ischaemic encephalopathy at autopsy. Loss of CO2 reactivity may play a role in the pathogenesis of hypoxic ischaemic encephalopathy. It is a candidate for predicting early severe brain damage in preterm infants requiring intensive care and for controlling the effect of early interventions.     

Nitric oxide synthesis inhibition during cerebral hypoxemia and reoxygenation with 100% oxygen in newborn pigs

The objective of our study was to evaluate the effects of N(sigma)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of the nitric oxide (NO) pathway, on cerebral microcirculation during hypoxemia and reoxygenation with 100% oxygen in newborn pigs. Twenty-two pigs were randomized to hypoxemia [inspired fraction of oxygen (FIO(2)) 0.08; 20 min] and reoxygenation (FIO(2) 1.0; 60 min) or normoxia. The hypoxemic animals were further randomized to receive either an intravenous bolus injection of 5 mg/kg L-NAME (n = 8) or a corresponding volume of isotonic saline (n = 8) 30 min before the onset of hypoxemia. The normoxemic group (n = 6) received the same pretreatment with L-NAME. Cerebral hemodynamics were assessed by laser Doppler flowmetry and intracranial pressure monitoring. The cerebral NO concentration was continuously measured using an electrochemical sensor. Pretreatment with L-NAME resulted in a more severe systemic hypotension and reduced cerebral microcirculation during the period of hypoxemia compared with the saline/hypoxemia group. NO synthesis inhibition during reoxygenation with 100% oxygen, however, blunted the increase in NO concentration (p < 0.05) without reduction of cerebral blood flow and cerebral perfusion pressure. In conclusion, in this newborn pig model, pretreatment with a bolus infusion of L-NAME induced severe hypotension and reduced cerebral microcirculation during hypoxemia. However, it appears to have no significant adverse effect on cerebral hemodynamics during the period of reoxygenation with 100% oxygen. This deleterious effect during hypoxemia limits the use of L-NAME as a preventive drug but suggests beneficial effects during reoxygenation with 100% oxygen.     

Retinal, choroidal and total ocular blood flow response to hypercarbia during spontaneous breathing and mechanical ventilation

The effect of hypercarbia on ocular blood flow was studied in the newborn piglet with the isotope-labeled microsphere method. Blood flow measurements were made during spontaneous breathing and during paralyzation (pancuronium) and mechanical ventilation. Retinal blood flow increased from 0.40 +/- 0.07 (mean +/- SEM) ml/min/g at baseline levels to 0.91 +/- 0.17 ml/min/g at a PaCO2 level of 11.0 kPa during spontaneous ventilation. A similar response was observed during paralyzation and mechanical ventilation (0.89 +/- 0.15 ml/min/g at a PaCO2 of 11.1 kPa). For choroidal blood flow, however, the increase caused by hypercarbia during spontaneous ventilation (16.14 +/- 3.69 to 29.15 +/- 3.22 ml/min/g) was significantly reduced when the animals were paralyzed and mechanically ventilated (15.99 +/- 2.99 to 23.51 +/- 3.41 ml/min/g). Since choroidal blood flow accounts for 60-80% of oxygen delivery to the retina, paralyzation and mechanical ventilation may significantly reduce oxygen delivery to the retina during hypercarbia.     

Cerebral blood flow and metabolism following pancuronium bromide in newborn lambs

The purpose of this study was to evaluate cerebral blood flow and metabolism following pancuronium bromide paralysis in healthy newborn lambs. Cerebral blood flow and cerebral metabolic rate for O2 and glucose were measured along with blood pressure and blood gases before and again at 15 and 60 min following pancuronium paralysis in seven newborn lambs. Pancuronium bromide paralysis had no effect on any of these parameters either at 15 or 60 min of paralysis. Total cerebral blood flow, cerebral metabolic rate for O2, and cerebral metabolic rate for glucose were 87 +/- 6 ml/min/100 g, 258 +/- 10 mumol O2/min/100 g, and 53 +/- 10 mmol glucose/min/100 g, respectively. Neither was any change in regional cerebral blood flow noted. In spite of being connected immediately to the ventilator, however, some animals experienced a transient increase (average = 32%) in blood pressure, that was not associated with an increase in end tidal CO2. The data suggest that pancuronium paralysis in healthy awake newborn lambs does not lead to any alteration in cerebral blood flow or metabolism.     

Effects of indomethacin upon cerebral hemodynamics of newborn pigs

Treatment of unanesthetized newborn pigs with indomethacin trihydrate (5 +/- 1 mg/kg, intravenous) decreased cerebral blood flow uniformly throughout the brain by 18-28% without changing cardiac output, arterial pressure, or arterial blood gases and pH. Breathing 10% O2, 9% CO2 with the balance N2 (hypoxia/hypercapnia) caused cerebral blood flow to increase from 102 +/- 12 to 218 +/- 19 ml/100 g . min. Intravenous administration of indomethacin during hypoxia/hypercapnia caused a uniform decrease in cerebral flow throughout the brain to levels (94 +/- 5 ml/100 g . min) indistinguishable from those when the piglet was breathing ambient air. Further, 2.5 h later, the cerebral hyperemia caused by hypoxia/hypercapnia was attenuated markedly (129 +/- 19 ml/100 g . min). Vehicle treatment did not alter resting cerebral blood flow or cerebral hyperemia in response to hypoxia/hypercapnia. Measurements of 6-keto-prostaglandin F1 alpha, thromboxane B2, and prostaglandin E2 demonstrated that intravenously administered indomethacin crossed the blood-brain barrier of newborn pigs in sufficient quantity to inhibit prostanoid release into the cerebrospinal fluid passing over the surface of the brain. The mechanism by which indomethacin reduces cerebral blood flow and attenuates cerebral hyperemia cannot be determined from the present experiments. We conclude that intravenous administration of indomethacin decreases cerebral blood flow and attenuates cerebral hyperemia induced by severe, combined hypoxia/hypercapnia in newborn pigs.     

The effect of hyperoxia on reactive oxygen species (ROS) in rat petrosal ganglion neurons during development using organotypic slices

Hyperoxia, during development in rats, results in hypoxic chemosensitivity ablation, carotid body hypoplasia, and reduced chemoafferents. We hypothesized that hyperoxia increases reactive oxygen species (ROS) in cell bodies of chemoafferents. Organotypic slices of petrosal-nodose ganglia from rats at day of life (DOL) 5-6 and 17-18 were exposed to 8%, 21%, or 95% O(2) for 4 h in the presence or absence of the ROS-sensitive fluorescent indicator, CM-H(2)DCFDA, and propidium iodide was used to determine the relationship between cell death and oxygen tension. In tissue slices from DOL 5-6 rats, fluorescence intensity was 182.5 +/- 2.9 for hypoxia, 217.5 +/- 3.3 for normoxia, and 336.6 +/- 3.8 for hyperoxia, (mean +/- SEM, p < 0.001, ANOVA). Normoxia increased ROS levels by 19.2% from hypoxia (p < 0.01) with a further increase of 54.8% from normoxia to hyperoxia (p < 0.001). In tissue slices from DOL 17-18 rats, ROS levels increased with increasing oxygen tension but were less than in younger animals (p < 0.01, ANOVA). The antioxidants, NAC and TEMPO-9-AC, attenuated ROS levels and cell death. Electron microscopy demonstrated that hyperoxia damages the ultrastructure within petrosal ganglion neurons. Hyperoxic-induced increased levels of ROS in petrosal ganglion neurons may contribute to loss of hypoxic chemosensitivity during early postnatal development.     

Theophylline stimulates fetal breathing movements during hypoxia

The respiratory responses to theophylline during normoxia and hypoxia were determined in 13 unanesthetized fetal sheep. Theophylline (plasma levels approximately 111 mumol/L) increased the incidence of fetal breathing movements measured over 120 min from 37.7 +/- 4.8% to 61.1 +/- 5.7% (SEM) in normoxic fetuses. In isocapnic hypoxia (arterial O2 tension approximately 1.86 kPa), theophylline increased the incidence from 20.0 +/- 6.3 to 52.0 +/- 6.1%. Theophylline also resulted in an increase in the slope of inspiration during both normoxia and hypoxia. We conclude that adenosine modulates fetal respiratory drive during normoxia and hypoxia.     

The effect of theophylline on regional cerebral blood flow responses to hypoxia in newborn piglets

Theophylline attenuates cerebral hypoxic hyperemia in several adult models and this is thought to be due to receptor-mediated antagonism of adenosine, a proposed mediator of hypoxic hyperemia. This attenuation of hypoxic hyperemia reduces cerebral oxygen delivery and may thus jeopardize cerebral oxidative metabolism. With these considerations in mind, and because theophylline is widely used in neonatal medicine, the present study was designed to investigate the effect of theophylline on regional cerebral blood flow, cerebral oxygen delivery, and cerebral metabolic rate for oxygen during normoxia and hypoxia in the newborn piglet model. In 16 newborn piglets, regional cerebral blood flow (microspheres) increased 250-350% during hypoxia (PaO2 20-30 torr), while cerebral oxygen delivery and cerebral metabolic rate for oxygen were maintained at normoxic levels. Eight of these piglets were then given 10 mg/kg theophylline ethylenediamine intravenously and studies during normoxia and hypoxia were repeated; the remaining eight piglets served as time controls. Regional cerebral blood flow, cerebral oxygen delivery, and cerebral metabolic rate for oxygen during normoxia and hypoxia were not influenced by theophylline, despite plasma theophylline levels of 55-65 mumol/liter, and cerebrospinal fluid theophylline levels of 30-40 mumol/liter. These negative results are reassuring with respect to hypoxic cerebral blood flow control in theophylline-medicated infants. However, they do not support a role for adenosine as a mediator of cerebral hypoxic hyperemia in this model.     

Effect of extracorporeal membrane oxygenation on cerebral blood flow and cerebral oxygen metabolism in newborn sheep

Extracorporeal membrane oxygenation (ECMO) supplies respiratory support to term or near-term infants with respiratory failure. Although infants requiring this therapy may have already sustained significant hypoxia and/or ischemia predisposing them to neurologic injury, the high incidence of neuroimaging abnormalities in the ECMO population raises concerns about the additional neurologic risk associated with the ECMO procedure itself. Our study was undertaken to evaluate the effects of ECMO on the normal neonatal cerebral circulation. Thirteen newborn lambs (1-7 d of age) were placed on normothermic venoarterial ECMO using a silicone membrane oxygenator and roller occlusion pump. Regional brain blood flows, cerebral oxygen consumption, fractional oxygen extraction, and oxygen transport were determined 30 and 120 min after initiation of ECMO. Neither cerebral blood flow (baseline, 60.2 +/- 23.6; 30 min, 56.1 +/- 18.1; 120 min 56.1 +/- 12.9 mL/100 g/min) nor oxygen metabolism (cerebral oxygen consumption: baseline, 4.48 +/- 1.48; 30 min, 3.86 +/- 1.53; 120 min, 4.10 +/- 1.32 mL/100 g/min and oxygen extraction: baseline, 0.52 +/- 0.09; 30 min, 0.47 +/- 0.14; 120 min, 0.46 +/- 0.14 mL/100 g/min) changed after the initiation of ECMO. Regional and left/right blood flow differences were not noted. These findings suggest that in healthy newborn lambs, initiation of ECMO does not alter cerebral blood flow or oxygen metabolism.     

Cerebral blood volume measured using near-infrared spectroscopy and radiolabels in the immature lamb brain.

Near-infrared spectroscopy (NIRS) is a technique that is increasingly being used for the noninvasive measurement of cerebral blood volume (CBV) in newborn infants, but it has not been fully validated against established methods. These experiments in immature lambs (gestation 92+/-1 d, mean+/-SEM) compared CBV measured using NIRS-derived estimates of oxygenated Hb (n = 5) with CBV estimated with radiolabeled indicators (125I-labeled serum albumin and 51Cr-labeled red blood cells, n = 10). Total brain CBV (mL/100 g tissue) measured using NIRS was 2.5+/-0.2 compared with 2.5+/-0.2 using radiolabels (NS). Regional tissue plasma, red blood cells, and whole blood volumes from radiolabels varied significantly (p < or = 0.05) throughout the brain. Whole blood volume (mL/100 g tissue) was largest in choroid plexus (16.2+/-2.1) and least in white matter (0.7+/-0.1) with a significant hierarchy evident among regions: choroid plexus > cerebellum > cortex > brain stem = midbrain > white matter. Regional plasma and red blood cell distributions were similar to whole blood, being highest in choroid plexus (13.0+/-1.6 and 3.2+/-0.9, respectively), and least in white matter (0.8+/-0.1 and 0, respectively). These data from the immature lamb brain indicate that total CBV measured with NIRS is essentially identical with the volumes obtained using intravascular radiolabels. Among cerebral regions, white matter contributes little to the global blood volume measured with NIRS because its red blood cell content is very low.