Miles Tsuji

Cerebral intravascular oxygenation correlates with mean arterial pressure in critically ill premature infants.

Objectives. Premature infants experience brain injury, ie, germinal matrix–intraventricular hemorrhage (GMH-IVH) and periventricular leukomalacia (PVL), in considerable part because of disturbances in cerebral blood flow (CBF). Because such infants are susceptible to major fluctuations in mean arterial blood pressure (MAP), impaired cerebrovascular autoregulation would increase the likelihood for the changes in CBF that could result in GMH-IVH and PVL. The objectives of this study were to determine whether a state of impaired cerebrovascular autoregulation could be identified reliably and conveniently at the bedside, the frequency of any such impairment, and the relation of the impairment to the subsequent occurrence of severe GMH-IVH and PVL. Patients and Methods. To monitor the cerebral circulation continuously and noninvasively, we used near-infrared spectroscopy (NIRS) to determine quantitative changes in cerebral concentrations of oxygenated hemoglobin (HbO2) and deoxygenated hemoglobin (Hb) from the first hours of life. Our previous experimental study showed a strong correlation between a measure of cerebral intravascular oxygenation (HbD), ie, HbD = HbO2 − Hb, determined by NIRS, and volemic CBF, determined by radioactive microspheres. We studied 32 very low birth weight premature infants (gestational age: 23–31 weeks; birth weight: 605-1870 g) requiring mechanical ventilation, supplemental oxygen, and invasive blood pressure monitoring by NIRS from 1 to 3 days of age. MAP measured by arterial catheter pressure transducer and arterial oxygen saturation measured by pulse oximetry were recorded simultaneously. The relationship of MAP to HbD was quantitated by coherence analysis. Results. Concordant changes (coherence scores >.5) in HbD and MAP, consistent with impaired cerebrovascular autoregulation, were observed in 17 of the 32 infants (53%). Eight of the 17 infants (47%) developed severe GMH-IVH or PVL or both. Of the 15 infants with apparently intact autoregulation, ie, coherence scores <.5, only 2 (13%) developed severe ultrasonographic lesions. Thus, for the entire study population of 32 infants, 8 of the 10 with severe lesions exhibited coherence scores >.5. Conclusions. We conclude that NIRS can be used in a noninvasive manner at the bedside to identify premature infants with impaired cerebrovascular autoregulation, that this impairment is relatively common in such infants, and that the presence of this impairment is associated with a high likelihood of occurrence of severe GMH-IVH/PVL.

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.

Near Infrared Spectroscopy Detects Cerebral Ischemia during Hypotension in Piglets

We have previously reported concordant changes in cerebral intravascular oxygenation measured by near infrared spectroscopy (NIRS) and mean arterial blood pressure (MAP) in premature infants. We hypothesized that the cerebral oxygenation changes are caused by MAP-induced alterations in cerebral blood flow (CBF) and studied these parameters in neonatal piglets (n = 6). Changes in cerebral intravascular oxygenation were measured by NIRS from the hemoglobin difference (HbD) signal (oxyhemoglobin-deoxyhemoglobin). CBF was measured by the radioactive microsphere technique. The cerebral circulation was also monitored by Doppler determinations of CBF velocity (time average mean velocity) in the anterior cerebral artery. Hypotension to <50% of baseline MAP was achieved by a ligature around the ascending aorta. Arterial oxygenation was maintained constant by mechanical ventilation. As observed in our studies of premature infants, cerebral HbD and MAP showed concordant changes. Hypotension was accompanied by significant decreases both in CBF (42.8 ± 12.5% of baseline p < 0.01) and HbD (-65.0 ± 22.0 µmol/L·dpf, p < 0.01). HbD was significantly correlated with MAP (p < 0.05) and time average mean velocity (p = 0.01). Importantly, decreases in cerebral total hemoglobin (HbT), a measure of cerebral blood volume, did not correlate significantly with decreases in MAP. We conclude that 1) decreases in cerebral intravascular oxygenation, as assessed by NIRS, observed with decreases in MAP reflect a decline in CBF, and hence oxygen delivery, 2) the HbD signal is more sensitive to changes in CBF than the HbT signal, and 3) NIRS recordings may have clinical utility in detecting cerebral ischemia.

Effects of pH on brain energetics after hypothermic circulatory arrest

The pH management that provides optimal organ protection during hypothermic circulatory arrest is uncertain. Recent retrospective clinical data suggest that the pH-stat strategy (maintenance of pH at 7.40 corrected to core temperature) may improve brain protection during hypothermic cardiopulmonary bypass with a period of circulatory arrest in infants. The impact of alpha-stat (group A) and pH-stat (group P) strategies on recovery of cerebral high-energy phosphates and intracellular pH measured by magnetic resonance spectroscopy (A, n = 7; P, n = 5), organ blood flow measured by microspheres, cerebral metabolic rate measured by oxygen and glucose extraction (A, n = 7; P, n = 6), and cerebral edema was studied in 25 4-week-old piglets undergoing core cooling and 1 hour of circulatory arrest at 15 degrees C. Group P had greater cerebral blood flow during core cooling (54.3% +/- 4.7% versus 34.2% +/- 1.5% of normothermic baseline, respectively; p = 0.001). The intracellular pH during core cooling showed an alkaline shift in both groups but became more alkaline in group A than in group P at the end of cooling (7.08 to 7.63 versus 7.09 to 7.41, respectively; p = 0.013). Recovery of cerebral adenosine triphosphate (p = 0.046) and intracellular pH (p = 0.014) in the initial 30 minutes of reperfusion was faster in group P. The cerebral intracellular pH became more acidotic during early reperfusion in group A, whereas it showed continuous recovery in group P. Brain water content postoperatively was less in group P (0.8075) than in group A (0.8124) (p = 0.05). These results suggest that compared with alpha-stat, the pH-stat strategy provides better early brain recovery after deep hypothermic cardiopulmonary bypass with circulatory arrest in the immature animal. Possible mechanisms include improved brain cooling by increased blood flow to subcortical areas, improved oxygen delivery, and reduction of reperfusion injury, as well as an alkaline shift in intracellular pH with hypothermia in spite of a stable blood pH.

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 ΔHbD 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 CO2 levels. We assigned a pressure-passive index (PPI) to each study on the basis of the relative duration of significant coherence between ΔMAP and ΔHbD. We found a significant relationship between ΔHbD and ΔCBFV at both time points. At 6 h after surgery, we showed high concordance (coherence >0.5; PPI ≥41%) between ΔMAP and ΔHbD, consistent with disturbed CPA in 13% of infants. End-tidal CO2 values ≥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 CO2 levels and fluctuating MAP are two important preventable factors associated with disturbed CPA.

Reduction of cytochrome aa3 measured by near-infrared spectroscopy predicts cerebral energy loss in hypoxic piglets

ABSTRACT: Near-infrared spectroscopy is a noninvasive monitoring technique that allows quantitative measurement of changes in cerebral oxygenated Hb (HbO2), deoxygenated Hb (Hb), total Hb, and oxidized cytochrome aa3 (CytO2). Changes in cerebral Hb oxygenation and CytO2 have been measured in human neonates and infants under a variety of conditions. However, the association of these measurements with cerebral high-energy phosphate loss is not known. We studied simultaneous changes in cerebral HbO2, Hb, total Hb, and CytO2 by near-infrared spectroscopy and changes in nucleoside triphosphate (NTP, mostly ATP) and phosphocreatine (PC) concentrations and intracellular pH by in vivo 31P-labeled magnetic resonance spectroscopy. Four-wk-old piglets (n = 8) underwent sequential hypoxic episodes of increasing severity (inspired O2 concentration, 12, 8, 6, 4, and 0%). Animals were anesthetized and mechanically ventilated. At all levels of hypoxia, cerebral HbO2 decreased, and Hb increased. Loss of PC or NTP was not observed until inspired O2 concentration was decreased to less than 12%. With such severe hypoxia, hypotension, intracellular acidosis, and increasingly severe PC and NTP depletions occurred. Decreases in PC and NTP correlated closely with decreased CytO2 and arterial blood pressure (p < 0.0001) but not with changes in HbO2 and Hb. In conclusion, cerebral hypoxemia is readily detected by near-infrared spectroscopy as a decrease in HbO2 and an increase in Hb. However, relative changes in cerebral HbO2 and Hb have low predictive value for cerebral energy failure. Reduction of CytO2 is highly correlated with decreased brain energy state and may indicate impending cellular injury.

Effects of aprotinin on acute recovery of cerebral metabolism in piglets after hypothermic circulatory arrest

Brain protection during cardiopulmonary bypass and hypothermic circulatory arrest is incomplete. Activation of blood protease cascades may contribute to cellular injury under these conditions. To test this hypothesis, effects of the protease inhibitor aprotinin on recovery of brain energy metabolism after hypothermic circulatory arrest were studied in the piglet. Twenty-four 4-week-old piglets (10 aprotinin-treated and 14 control) underwent core cooling, 1 hour of circulatory arrest at 15 degrees C, reperfusion and rewarming (45 minutes), and normothermic perfusion (3 hours) on cardiopulmonary bypass. Cerebral high-energy phosphate concentration and intracellular pH were studied by phosphorus-31 magnetic resonance spectroscopy in 12 animals. In the remaining animals cerebral and regional blood flow were measured with radioactive microspheres and carotid artery blood flow was measured with an electromagnetic flowmeter. Cerebral oxygen and glucose extraction were measured, and vascular resistance responses to endothelium-dependent (acetylcholine) and -independent (nitroglycerin) vasodilators were calculated. Recovery of cerebral adenosine triphosphate (p = 0.02) and intracellular pH (p = 0.04) in the initial 30 minutes of reperfusion was accelerated in the aprotinin-treated piglets. These piglets showed a greater in vivo cerebral and systemic endothelium-mediated vasodilation (acetylcholine response: cerebral p < 0.01, systemic p = 0.04) after reperfusion. The response to endothelium-independent vasodilation (nitroglycerin) was the same in both groups. Carotid blood flow tended to be greater at 20 minutes of reperfusion and less during 45 to 80 minutes after reperfusion in the aprotinin-treated animals. Brain water content postoperatively was 0.8077 in the aprotinin group and 0.8122 in control animals (p = 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)

Functional Maturation of Creatine Kinase in Rat Brain

The physiological role of the phosphocreatine (PCr)/creatine kinase (CK) system has been studied in rat brain by comparing maturational changes in in vivo CK-catalyzed reaction rate and activities of CK isoenzymes. The CK-catalyzed reaction rates, measured by 31P-nuclear magnetic resonance spectroscopy, increased 4-fold between 12 and 17 days of age. The mitochondrial CK (Mi-CK) isoenzyme, as a percentage of total CK, increased to the same extent over this relatively narrow age period. Cytosolic CK (B-CK) was active earlier and, with the total CK activity, increased steadily over a longer time course. An immunohistochemical study of cerebellum showed Mi-CK predominantly in gray matter, while the cytosolic CK was present in rather large concentrations in both gray and white matter. In the molecular layer, B-CK was most prominent in the Bergmann glial cells, while Mi-CK was more prominent in Purkinje neurons. During development a redistribution of Mi-CK from the Purkinje cell bodies to their processes was observed. These results point to regional differences in CK content and in isoenzyme-specific localizations. The increase in CK activity is temporally coincident with the maturational appearance of closely coupled decreases in brain PCr and ATP during hypoxia. These maturational changes suggest that the activity of the PCr/CK system, particularly the Mi-CK isoenzyme, is central in regulation of brain ATP.

Cerebral Oxygenation Measured by Near Infrared Spectroscopy during Cardiopulmonary Bypass and Deep Hypothermic Circulatory Arrest in Piglets

Near infrared spectroscopy (NIRS) shows large changes in cerebral oxyhemoglobin (Hbo2), deoxyhemoglobin (Hb), and oxidation state of cytochrome aa3 (Cyto2) in infants undergoing cardiopulmonary bypass and deep hypothermic circulatory arrest (CPB-DHCA). To evaluate the physiologic significance of these clinical NIRS measurements, we applied the technique in a piglet model of CPB-DHCA. After an initial stabilization period on CPB, animals (n = 8) were cooled to 15°C, subjected to DHCA for 1 h, then reperfused with rewarming and monitored for 180 min. NIRS measurements were compared with determinations of cerebral blood flow (CBF). During cooling, Cyto2 decreased markedly, whereas Hbo2 increased. DHCA was associated with a sharp decrease in Hbo2, a corresponding increase in Hb, and a smaller, less consistent further decrease in Cyto2. NIRS measurements recovered toward baseline with reperfusion. CBF decreased during cooling and recovered to baseline levels with reperfusion. These findings are consistent with existing human data and show that 1) cooling is associated with increased oxygenation of cerebral hemoglobin despite a reduction in CBF; 2) Cyto2 becomes more reduced during cooling, consistent with a net cellular oxygen deficit; and 3) DHCA is associated with rapid cerebral hemoglobin deoxygenation and a small further reduction of Cyto2.

Phosphocreatine and ATP regulation in the hypoxic developing rat brain

Decreased brain ATP and phosphocreatine (PCr) concentrations and intracellular pH were compared in hypoxic 4-, 10-11, and 24-25-day-old rats. Surface coil 31P-nuclear magnetic resonance (NMR) spectra were acquired in vivo every minute before, during, and after 7 min of breathing 4% O2. At all ages PCr decreased rapidly. At the two younger ages, the nucleoside triphosphate signal was still 80-85% of pre-hypoxic values, indicating 20-30% decrease in ATP, when PCr was almost fully depleted. At 24-25 days, PCr initially decreased 40-50% with an ATP loss of about 30%. Then, PCr and ATP decreased simultaneously. The decrease in brain pH was greatest at 24-25 days. More electrocortical seizure activity during hypoxia was seen at 10-11 days than at other ages. Seizure activity was seen only when ATP was less than 20% depleted and was not associated with more rapid decreases in ATP or PCr. At all ages, loss of electrocortical activity occurred when ATP was about 30% depleted. Brain creatine kinase catalyzed flux, measured by the NMR saturation transfer experiment before the hypoxic period, was 4-fold higher at 24-25 days than at 4- or 10-11 days. In conclusion, the temporally coupled depletion of PCr and ATP during hypoxia, which is characteristic of the mature brain, is seen only after the maturational increase in brain CK activity.