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Auditory-evoked cerebral oxygenation changes in hypoxic-ischemic encephalopathy of newborn infants monitored by near infrared spectroscopy
Early Human Development 67 (2002) 113 – 121 www.elsevier.com/locate/earlhumdev
Auditory-evoked cerebral oxygenation changes in hypoxic-ischemic encephalopathy of newborn infants monitored by near infrared spectroscopy Saying Chen a, Kaoru Sakatani b,*, Wemara Lichty c,d, Pan Ning a, Shimin Zhao e, Huancong Zuo b a Department of Pediatrics, China – Japan Friendship Hospital, China Department of Neurosurgery, China – Japan Friendship Hospital, Yinghua East Road, Hepingli, Beijing 100029, China c Tsinghua University/China – Japan Friendship Hospital Medical Sciences Institute, China d Psychology Department, Stanford University, Stanford, CA, USA e Department of Pediatrics, Beijing Union Hospital, China
b
Received 22 June 2001; received in revised form 12 December 2001; accepted 11 January 2002
Abstract Recent neuronal activation studies have demonstrated the presence of regional cerebral blood flow (rCBF) increases in response to neuronal activation in normal newborns. In the present study, using near infrared spectroscopy (NIRS), we evaluated the evoked cerebral blood oxygenation (CBO) changes in hypoxic-ischemic encephalopathy (HIE) of newborns. We studied 20 normal newborns and 22 HIE newborns; mild HIE (n = 9), moderate HIE (n = 7), and severe HIE (n = 6). The babies were from 1 to 3 days postdelivery. We measured the concentration changes of deoxyhemoglobin (DeoxyHb), oxyhemoglobin (Oxy-Hb), and total hemoglobin (Total-Hb) induced by auditory stimulation in the frontal lobes. The normal and HIE groups showed different Oxy-Hb and Total-Hb responses. In normal newborns, 19 out of 20 normal subjects showed increases of Oxy-Hb and Total-Hb, whereas 14 out of 22 subjects showed decreases of Oxy-Hb and Total-Hb during the stimulation (v2 = 19.95, p < 0.001). In addition, there was a strong negative correlation between HIE severity and changes of Total-Hb (r = 0.73, p < 0.001). These results suggest that infants with HIE have decreased rCBF in the frontal lobes during auditory stimulation. D 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Asphyxia; Cerebral blood flow; Development; Neuronal activity; Oxygen metabolism
*
Corresponding author. Present address: Department of Neurosurgery, Nihon University School of Medicine, 30-1 Ohyaguchi Kahi-Machi, Itabashi-Ku, Tokyo 173-8610, Japan. Tel.: +81-3-3972-811 ext. 2481; fax: +81-33554-0425. E-mail address: [email protected] (K. Sakatani). 0378-3782/02/$ - see front matter D 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 3 7 8 2 ( 0 2 ) 0 0 0 0 4 - X
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1. Introduction Perinatal hypoxic-ischemic injury causes hypoxic-ischemic encephalopathy (HIE), which is one of the important causes of perinatal infantile death and neuronal deficits. The changes in cerebral oxygen metabolism and hemodynamics to which occur hypoxicischemic insults, trigger the process of cell death [1 –3]. However, the precise pathophysiology of the development of HIE is still largely unknown. Doppler ultrasound has been utilized to evaluate the cerebral hemodynamic changes in HIE [4,5]. However, it can measure only cerebral blood flow velocity within large vessels. In contrast, near infrared spectroscopy (NIRS), an optical diagnostic technique, allows us to measure changes in both cerebral blood oxygenation (CBO) and hemodynamics [6]; its safety and portability make it an ideal tool for evaluating the development of cerebral hypoxic-ischemic injury in newborn infants [7– 10]. NIRS has revealed the abnormal CBO and hemodynamics in HIE newborns. However, the previous studies on the CBO and hemodynamics in the HIE newborns were limited to the resting state [4,5,7 – 10]. Recently, NIRS has been applied to evaluate activity-dependent CBO changes in the visual cortex [11] and the frontal lobe of normal newborns [12]. These studies have demonstrated increases of oxygenated hemoglobin (Oxy-Hb) and total hemoglobin (TotalHb) at the activated cortical areas, indicating that the regional cerebral blood flow (rCBF) increases in the activating areas [13 –15]. Thus, the vasodilatory response to neuronal activity in normal newborns is similar to the response observed in normal adults [16 – 22]. In contrast, newborns and adults have different deoxyhemoglobin (Deoxy-Hb) responses during neuronal activity. Normal adults tend to show a decrease [16 – 22]; whereas, newborns tend to show increases [11,12]. The objective of the present study was to evaluate the CBO response to neuronal activation in the newborns with HIE. To do this, we compared the CBO response to auditory stimulation in the frontal lobe of normal newborns and HIE newborns. We found that Oxy-Hb and Total-Hb decreased during neuronal activation in the HIE newborns, indicating that the rCBF decreased at the activating area.
2. Subjects and methods We studied 20 normal newborns and 22 HIE newborns, who were admitted to the neonatal intensive care unit at the China – Japan Friendship Hospital from September 1996 to August 1998. According to the clinical grading system of HIE [23], these subjects were classified into four groups, including normal (n = 20), mild HIE (n = 9), moderate HIE (n = 7), and severe HIE (n = 6). Table 1 shows the clinical profiles of each group. Newborn infants with congenital abnormalities were excluded. There were no significant differences in sex, gestational age, birth weights, arterial blood gas (PO2, PCO2, and pH), and systemic O2 saturation among the groups ( p > 0.05). We measured auditory-evoked CBO changes as in our previous NIRS study on normal newborn infants [12]. Briefly, we used the NIRO-500 (Hamamatsu Photonics K.K.); nearinfrared light from laser diodes was directed at the head through a fiberoptic bundle
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Table 1 Clinical profile of the subjects
Sex (M/F) Gestational age (weeks) Apgar score 1 min 5 min Body weight (g) Blood gas (pH) PaCO2 SaCO2 Postnatal age (days) at CBO measurements
Normal
Mild HIE
Moderate HIE
Severe HIE
9:11 39.3 F 1.0
5:4 39.4 F 2.1
5:2 39.6 F 1.3
3:3 37.8 F 2.8
10 F 1 10 F 0 3625 F 535 7.40 F 0.08 34 F 2 96 F 1 3F0
6F3 8F3 3193 F 605 7.33 F 0.06 39 F 2 97 F 1 2F1
6F1 8F2 3475 F 179 7.29 F 0.12 41 F 3 94 F 2 2F1
3F1 5F2 3013 F 662 7.30 F 0.04 42 F 2 93 F 2 3F1
Data is mean F S.E.M.
(‘‘optode’’) and reflected light was collected in the receiving fiberoptic bundle and transmitted to a photomultiplier tube. Using an algorithm developed by Cope et al. [24], absolute concentration changes of Oxy-Hb, Deoxy-Hb, and Total-Hb were continuously analyzed by means of a computer interfaced with the apparatus. NIRS data are expressed in arbitrary
Fig. 1. (A, B, C) Typical examples of the three common NIRS parameter changes (Patterns A, B, C) in the frontal lobes induced by auditory stimulation. Pattern A was an increase in Oxy-Hb and Total-Hb with an increase of Deoxy-Hb. Pattern B was an increase in Oxy-Hb and Total-Hb accompanied by a decrease or no change in Deoxy-Hb. Pattern C was a decrease in Oxy-Hb and Total-Hb with an increase or decrease of Deoxy-Hb. The ordinates indicate concentration changes of Oxy-Hb, Deoxy-Hb, and Total-Hb in arbitrary units (a.u.). Horizontal thick bars indicate the period of the stimulation.
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units. The optode distance was 4 cm and the midpoint was placed at the center of the forehead. The postnatal age at CBO measurements in each group was 1– 3 days (see Table 1). Auditory stimulation (popular piano music; 60 db) was presented through a pair of earphones. Subjects were lying in their beds during the experiment. Subjects who started straining or crying were eliminated from the analysis because straining or crying could impede cerebral venous return [25]. We analyzed the changes of NIRS parameters (Oxy-Hb, Deoxy-Hb, and Total-Hb) by subtracting mean baseline values (10 min) from mean stimulation values (10 min). For qualitative pattern analysis of Oxy-Hb, Deoxy-Hb, and Total-Hb responses to the stimulation, we classified several common patterns according to the NIRS parameter changes [12,16,17,26]. For quantitative analysis, chi-square, correlations, t-test, and oneway ANOVAs were performed. Data for the normal newborn group were discussed in a previous article about the auditory-evoked CBO change in normal newborns [12].
3. Results The normal and HIE groups showed different Oxy-Hb and Total-Hb responses; 19 of the 20 normal subjects showed increases of Oxy-Hb and Total-Hb; whereas, 14 of the 22 HIE subjects showed decreases of Oxy-Hb and Total-Hb during stimulation (v2 = 19.95, p < 0.001).
Fig. 2. Patterns of NIRS parameter changes induced by auditory stimulation in the normal newborn group and the HIE newborn group. (A – C) on the abscissa represent the patterns of NIRS parameter changes during the stimulation. ‘‘ + ’’ and ‘‘ ’’ below (A – C) indicate an increase and a decrease of the NIRS parameters designated in the left during the stimulation, respectively; no change for 0. The ordinate indicates percentage of the patterns in normal newborns (white bar) and HIE newborns (black bar).
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The auditory stimulation caused several patterns of the CBO changes in the frontal lobes of normal and HIE newborns. Most of the CBO changes measured by NIRS could be classified into the three response patterns, examples of which are shown in Fig. 1. These response patterns were observed in our previous NIRS activation studies [12,16,17,26].
Fig. 3. (A) The mean changes of Oxy-Hb, Deoxy-Hb, and Total-Hb in the normal newborn group and the HIE newborn group. The * means t-test showed normals and HIE differed on that NIRS parameter, p < 0.001. (B) The relationship between the clinical grading of HIE and the mean changes of Oxy-Hb, Deoxy-Hb, and Total-Hb. The ordinates indicate concentration changes of Oxy-Hb (black bar), Deoxy-Hb (gray bar), and Total-Hb (white bar) in arbitrary units (a.u.). A one-way ANOVA was done for each NIRS parameter: * means significantly different form normal group ( p < 0.05). Additional analyses showed that mild and severe groups differed, p < 0.05 and the remaining comparisons showed a trend, p < 0.10.
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Pattern A was an increase in Oxy-Hb and Total-Hb with an increase of Deoxy-Hb (Fig. 1). Pattern B was an increase in Oxy-Hb and Total-Hb accompanied by a decrease or no change in Deoxy-Hb. Pattern C was a decrease in Oxy-Hb and Total-Hb with an increase or decrease of Deoxy-Hb. Besides the three common patterns, we observed two other response patterns which will not be discussed here because they occurred infrequently. Comparison of the normal newborn group and the HIE newborn group revealed striking differences in the occurrence of the NIRS response patterns (v2 = 18.02). Fig. 2 summarizes the occurrence of the NIRS response patterns (Patterns A, B, and C) induced by the auditory stimulation for the normal group and the HIE group. In the normal group, 13 out of 20 subjects (65.0%) showed Pattern A; while 6 (30.0%) out of 20 subjects showed Pattern B. One (5.0%) subject showed other CBO changes. None of the normal newborns showed Pattern C. In contrast, in the HIE newborn groups, 14 out of 22 subjects (63.6%) showed Pattern C during the auditory stimulation. In the subjects with Pattern C, nine (40.1%) subjects showed an increase of Deoxy-Hb while five (22.7%) subjects showed a decrease of Deoxy-Hb. Patterns A and B were observed in four (18.2%) and two (9.1%) subjects, respectively. Two (9.1%) subjects showed other changes. In addition to qualitative analyses, quantitative analyses were performed to compare the normal and HIE groups. Fig. 3A summarizes the mean changes of Oxy-Hb, Deoxy-Hb, and Total-Hb in the normal newborn group and the HIE newborn group. The t-tests revealed that the groups were significantly different for Oxy-Hb ( p < 0.001) and Total-Hb ( p < 0.001) with normal subjects showing a mean increase and the HIE showing a mean decrease. In contrast, Deoxy-Hb was similar for the groups ( p > 0.05). Finally, we evaluated the relationship between the clinical grading of HIE and changes in NIRS parameters. Correlations of the NIRS parameters and severity were obtained by assigning values to the groups (i.e., normal = 0, mild = 1, moderate = 2, severe = 3). Striking evidence for a relationship between HIE severity and activity-dependent rCBF response was provided by a strong negative correlation between HIE severity and changes of Total-Hb (r = 0.73, p < 0.001). To determine if the four groups differed, a one-way ANOVA was performed for each of the NIRS parameters. There was a significant effect for Oxy-Hb ( F = 17.56, p < 0.001) and Total-Hb ( F = 13.43, p < 0.001). Post hoc Student Newman Keuls analyses revealed that all of the HIE groups were significantly different from the normal group ( p < 0.05). In addition, the HIE groups differed with the mild HIE and severe HIE groups, being significantly different ( p < 0.05), and the mild HIE vs. moderate HIE comparisons and the moderate vs. severe HIE comparisons revealing a trend p < 0.10.
4. Discussion The present study is the first evaluation of the activity-dependent CBO changes in the HIE newborns. The results demonstrated that auditory stimulation caused CBO changes in the frontal lobes of both normal and HIE newborns. However, there were striking differences in the characteristics of CBO changes between the normal newborns and the HIE newborns. That is, most normal newborns showed increases of Oxy-Hb and Total-Hb during the stimulation, while many HIE newborns showed decreases of Oxy-Hb and Total-
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Hb. In addition, there was a strong negative correlation between HIE severity and changes of Total-Hb. In the normal newborns, Pattern A was most commonly observed in the frontal lobes during auditory stimulation. This is consistent with the CBO changes in the visual cortex of infants during photo-stimulation evaluated by NIRS [11]. In Pattern A, the Total-Hb increase indicates an increase of rCBF because Total-Hb correlates with CBF changes under conditions with constant hematocrit and perfusion pressure [13 – 15]. Therefore, normal newborns have a similar activity-dependent rCBF response to that of normal adults. However, in contrast to the normal adults, Deoxy-Hb increased in association with increases of Oxy-Hb and Total-Hb in most normal newborn. It was suggested that increments in O2 consumption exceed increments in O2 delivery during neuronal activity in newborns [12]. In the HIE newborns, Pattern C was most commonly observed in the frontal lobes during auditory stimulation. In Pattern C, both Oxy-Hb and Total-Hb decreased during the stimulation suggesting that rCBF decreases in the frontal lobes. This is supported by the finding that simultaneous measurements of NIRS and PET demonstrated that a decrease in Oxy-Hb and Total-Hb was associated with rCBF decrease at the NIRS recording region [18,19]. The pathophysiological mechanism of the rCBF decrease during neuronal activities is not yet clear. However, the following mechanisms should be considered. First, a stealing of blood flow. If the NIRS measurement area of the frontal lobes is not activated by the stimulation due to brain damage, the surviving cortex near the measurement area is activated and may steal the blood flow at the measurement area, resulting in decreased rCBF. Such a stealing of blood flow was observed in the brain tumor adjacent to the activating cortical area [27]. In this mechanism, Deoxy-Hb may increase, decrease, or not change, depending on the balance of O2 consumption and O2 delivery, which is altered by the stealing of blood flow. Secondly, an inhibitory synaptic activity. PET studies have demonstrated that regional depressions of synaptic activity decreased the rCBF and cerebral metabolic rate for O2 (CMRO2) [28]. However, in 9 out of 14 subjects with Pattern C, Deoxy-Hb increased during the activation, which is not consistent with the decreased CMRO2 observed by PET. Finally, the control level of rCBF at rest may affect the activity-dependent CBO response. However, the present NIRS study did not evaluate the pre-stimulation level of rCBF. In addition, such effects have not been evaluated. Although neuronal activation methods were different in newborns and adults, Pattern C has been observed in some normal adults [16,17,20– 22]. Approximately 20% of normal adults showed Pattern C in the left prefrontal cortex during language tasks [16,17]. Interestingly, compared to younger subjects, older subjects showed a greater frequency of Pattern C [17,22]. In addition, in the patients with Alzheimer’s disease, Pattern C was most commonly observed in the left superior parietal cortex during mental tasks [18]. These results suggest that the HIE brain, the aged brain, and the degenerated brain may have similar responses to neuronal stimulation. Finally, it should be emphasized that although the physiological mechanism of the activity-dependent rCBF decrease in HIE is not yet clear, the present method of combining NIRS and auditory stimulation may be a useful and easy diagnostic technique to evaluate the development of HIE.
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References [1] Greisen G, Med S. Cerebral blood flow and energy metabolism in the newborn. Clin Perinatol 1997;24: 531 – 46. [2] Fellman V, Raivio AK. Reperfusion injury as the mechanism of brain damage after perinatal asphyxia. Pediatr Res 1997;41:599 – 606. [3] Vannucci RC, Perlman JM. Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics 1997;100:1004 – 14. [4] Lin FK, Hung KL, Wang NK. Cerebral blood flow velocity in newborn infants with asphyxia. J Formosan Med Assoc 1990;89:190 – 3. [5] Gray PH, Tudehope DI, Masel JP, Burns YR, Mohay HA, Ocallaghan MJ, et al. Perinatal hypoxic-ischaemic brain injury: prediction of outcome. Dev Med Child Neurol 1993;35:965 – 73. [6] Barfield CP, Yu VY, Noma O, Kukita J, Cussen LJ, Oates A, et al. Cerebral blood volume measured using near infrared spectroscopy and radiolabels in the immature lamb brain. Pediatr Res 1999;46:50 – 6. [7] Reynolds EOR, McCormick DC, Roth SC, Edwards AD, Wyatt JS. New noninvasive methods for the investigation of cerebral oxidative metabolism and hemodynamics in newborn infants. Ann Med 1991;23: 681 – 6. [8] Wyatt JS. Near infrared spectroscopy in asphyxial brain injury. Clin Perinatol 1993;20:369 – 78. [9] von Bel F, Dorrepaal CA, Benders JNL, Zeeuwe PEM, Bor MVD, Berger HM. Changes in cerebral hemodynamics and oxygenation in the first 24 h after birth asphyxia. Pediatrics 1993;92:365 – 71. [10] Meek JH, Elwell CE, McCormick DC, Edwards AD, Townsend JP, Stewart AL, et al. Abnormal cerebral hemodynamics in perinatally asphyxiated neonates related to outcome. Arch Dis Child Fetal Neonat Ed 1999;81:F110 – 5. [11] Meek JH, Firbank M, Elwell CE, Atkinson J, Braddick O, Wyatt JS. Regional hemodynamic responses to visual stimulation in awake infants. Pediatr Res 1998;43:840 – 3. [12] Sakatani K, Chen S, Lichty W, Zuo H, Wang Y. Cerebral blood oxygenation changes induced by auditory stimulation in newborn infants measured by near infrared spectroscopy. Early Hum Dev 1999;55:229 – 36. [13] Pryds O, Greisen G, Skov LL, Friis-Hansen B. Carbon dioxide-related changes in cerebral blood volume and cerebral blood flow in mechanically ventilated preterm neonates: comparison of near infrared spectrophotometry and 133 Xenon clearance. Pediatr Res 1990;27:445 – 9. [14] Ferrari M, Wilson DA, Hanley DF, Traystman RJ. Effects of graded hypotension on cerebral blood flow, blood volume, and mean transit time in dogs. Am J Physiol 1992;262(6):H1908 – 14. [15] Sakatani K, Ohtaki M, Jibu M, Hashi K. Effects of hyperventilation and CO2 inhalation on cerebral oxygen metabolism of Moyamoya disease measured by near infrared spectroscopy. In: Tubokawa T, Marumarou A, Robertson C, Teasdale G, editors. Neurochemical monitoring in the intensive care unit. Hong Kong: Springer; 1995. p. 226 – 34. [16] Sakatani K, Xie Y, Lichty W, Li S, Zuo H. Language-activated cerebral blood oxygenation and hemodynamic changes of the left prefrontal cortex in post stroke aphasic patients: a near infrared spectroscopy (NIRS). Stroke 1998;29:1299 – 304. [17] Sakatani K, Lichty W, Y Xie Y, Li S, Zuo H. Effects of aging on language-activated cerebral blood oxygenation changes of the left prefrontal cortex. J Stroke Cerebrovasc Dis 1999;8:398 – 403. [18] Hock C, Villringer K, Mu¨ller-Spahn F, Wenzel R, Heekeren H, Schuh-Hofer S, et al. Decrease in parietal cerebral hemoglobin oxygenation during performance of a verbal fluency task in patients with Alzheimer’s disease monitored by means of near infrared spectroscopy (NIRS)-correlation with simultaneous rCBF-PET measurements. Brain Res 1997;755:293 – 303. [19] Hoshi Y, Onoe H, Watanabe Y, Anderson J, Bergstro¨m M, Lilja A, et al. Nonsynchronous behavior of neuronal activity, oxidative metabolism, and blood supply during mental tasks in man. Neurosci Lett 1994;172:129 – 33. [20] Hoshi Y, Tamura M. Detection of dynamic changes in cerebral oxygenation coupled to neuronal function during mental work in man. Neurosci Lett 1993;150:5 – 8. [21] Hoshi Y, Tamura M. Dynamic multichannel near infrared optical imaging of human brain activity. J Appl Physiol 1993;75:1842 – 6. [22] Hock C, Mu¨ller-Spahn F, Schuh-Hofer S, Hofmann M, Dirnagl U, Villringer A. Age dependency of changes
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Auditory-evoked cerebral oxygenation changes in hypoxic-ischemic encephalopathy of newborn infants monitored by near infrared spectroscopy Saying Chen a, Kaoru Sakatani b,*, Wemara Lichty c,d, Pan Ning a, Shimin Zhao e, Huancong Zuo b a Department of Pediatrics, China – Japan Friendship Hospital, China Department of Neurosurgery, China – Japan Friendship Hospital, Yinghua East Road, Hepingli, Beijing 100029, China c Tsinghua University/China – Japan Friendship Hospital Medical Sciences Institute, China d Psychology Department, Stanford University, Stanford, CA, USA e Department of Pediatrics, Beijing Union Hospital, China
b
Received 22 June 2001; received in revised form 12 December 2001; accepted 11 January 2002
Abstract Recent neuronal activation studies have demonstrated the presence of regional cerebral blood flow (rCBF) increases in response to neuronal activation in normal newborns. In the present study, using near infrared spectroscopy (NIRS), we evaluated the evoked cerebral blood oxygenation (CBO) changes in hypoxic-ischemic encephalopathy (HIE) of newborns. We studied 20 normal newborns and 22 HIE newborns; mild HIE (n = 9), moderate HIE (n = 7), and severe HIE (n = 6). The babies were from 1 to 3 days postdelivery. We measured the concentration changes of deoxyhemoglobin (DeoxyHb), oxyhemoglobin (Oxy-Hb), and total hemoglobin (Total-Hb) induced by auditory stimulation in the frontal lobes. The normal and HIE groups showed different Oxy-Hb and Total-Hb responses. In normal newborns, 19 out of 20 normal subjects showed increases of Oxy-Hb and Total-Hb, whereas 14 out of 22 subjects showed decreases of Oxy-Hb and Total-Hb during the stimulation (v2 = 19.95, p < 0.001). In addition, there was a strong negative correlation between HIE severity and changes of Total-Hb (r = 0.73, p < 0.001). These results suggest that infants with HIE have decreased rCBF in the frontal lobes during auditory stimulation. D 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Asphyxia; Cerebral blood flow; Development; Neuronal activity; Oxygen metabolism
*
Corresponding author. Present address: Department of Neurosurgery, Nihon University School of Medicine, 30-1 Ohyaguchi Kahi-Machi, Itabashi-Ku, Tokyo 173-8610, Japan. Tel.: +81-3-3972-811 ext. 2481; fax: +81-33554-0425. E-mail address: [email protected] (K. Sakatani). 0378-3782/02/$ - see front matter D 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 3 7 8 2 ( 0 2 ) 0 0 0 0 4 - X
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1. Introduction Perinatal hypoxic-ischemic injury causes hypoxic-ischemic encephalopathy (HIE), which is one of the important causes of perinatal infantile death and neuronal deficits. The changes in cerebral oxygen metabolism and hemodynamics to which occur hypoxicischemic insults, trigger the process of cell death [1 –3]. However, the precise pathophysiology of the development of HIE is still largely unknown. Doppler ultrasound has been utilized to evaluate the cerebral hemodynamic changes in HIE [4,5]. However, it can measure only cerebral blood flow velocity within large vessels. In contrast, near infrared spectroscopy (NIRS), an optical diagnostic technique, allows us to measure changes in both cerebral blood oxygenation (CBO) and hemodynamics [6]; its safety and portability make it an ideal tool for evaluating the development of cerebral hypoxic-ischemic injury in newborn infants [7– 10]. NIRS has revealed the abnormal CBO and hemodynamics in HIE newborns. However, the previous studies on the CBO and hemodynamics in the HIE newborns were limited to the resting state [4,5,7 – 10]. Recently, NIRS has been applied to evaluate activity-dependent CBO changes in the visual cortex [11] and the frontal lobe of normal newborns [12]. These studies have demonstrated increases of oxygenated hemoglobin (Oxy-Hb) and total hemoglobin (TotalHb) at the activated cortical areas, indicating that the regional cerebral blood flow (rCBF) increases in the activating areas [13 –15]. Thus, the vasodilatory response to neuronal activity in normal newborns is similar to the response observed in normal adults [16 – 22]. In contrast, newborns and adults have different deoxyhemoglobin (Deoxy-Hb) responses during neuronal activity. Normal adults tend to show a decrease [16 – 22]; whereas, newborns tend to show increases [11,12]. The objective of the present study was to evaluate the CBO response to neuronal activation in the newborns with HIE. To do this, we compared the CBO response to auditory stimulation in the frontal lobe of normal newborns and HIE newborns. We found that Oxy-Hb and Total-Hb decreased during neuronal activation in the HIE newborns, indicating that the rCBF decreased at the activating area.
2. Subjects and methods We studied 20 normal newborns and 22 HIE newborns, who were admitted to the neonatal intensive care unit at the China – Japan Friendship Hospital from September 1996 to August 1998. According to the clinical grading system of HIE [23], these subjects were classified into four groups, including normal (n = 20), mild HIE (n = 9), moderate HIE (n = 7), and severe HIE (n = 6). Table 1 shows the clinical profiles of each group. Newborn infants with congenital abnormalities were excluded. There were no significant differences in sex, gestational age, birth weights, arterial blood gas (PO2, PCO2, and pH), and systemic O2 saturation among the groups ( p > 0.05). We measured auditory-evoked CBO changes as in our previous NIRS study on normal newborn infants [12]. Briefly, we used the NIRO-500 (Hamamatsu Photonics K.K.); nearinfrared light from laser diodes was directed at the head through a fiberoptic bundle
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Table 1 Clinical profile of the subjects
Sex (M/F) Gestational age (weeks) Apgar score 1 min 5 min Body weight (g) Blood gas (pH) PaCO2 SaCO2 Postnatal age (days) at CBO measurements
Normal
Mild HIE
Moderate HIE
Severe HIE
9:11 39.3 F 1.0
5:4 39.4 F 2.1
5:2 39.6 F 1.3
3:3 37.8 F 2.8
10 F 1 10 F 0 3625 F 535 7.40 F 0.08 34 F 2 96 F 1 3F0
6F3 8F3 3193 F 605 7.33 F 0.06 39 F 2 97 F 1 2F1
6F1 8F2 3475 F 179 7.29 F 0.12 41 F 3 94 F 2 2F1
3F1 5F2 3013 F 662 7.30 F 0.04 42 F 2 93 F 2 3F1
Data is mean F S.E.M.
(‘‘optode’’) and reflected light was collected in the receiving fiberoptic bundle and transmitted to a photomultiplier tube. Using an algorithm developed by Cope et al. [24], absolute concentration changes of Oxy-Hb, Deoxy-Hb, and Total-Hb were continuously analyzed by means of a computer interfaced with the apparatus. NIRS data are expressed in arbitrary
Fig. 1. (A, B, C) Typical examples of the three common NIRS parameter changes (Patterns A, B, C) in the frontal lobes induced by auditory stimulation. Pattern A was an increase in Oxy-Hb and Total-Hb with an increase of Deoxy-Hb. Pattern B was an increase in Oxy-Hb and Total-Hb accompanied by a decrease or no change in Deoxy-Hb. Pattern C was a decrease in Oxy-Hb and Total-Hb with an increase or decrease of Deoxy-Hb. The ordinates indicate concentration changes of Oxy-Hb, Deoxy-Hb, and Total-Hb in arbitrary units (a.u.). Horizontal thick bars indicate the period of the stimulation.
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units. The optode distance was 4 cm and the midpoint was placed at the center of the forehead. The postnatal age at CBO measurements in each group was 1– 3 days (see Table 1). Auditory stimulation (popular piano music; 60 db) was presented through a pair of earphones. Subjects were lying in their beds during the experiment. Subjects who started straining or crying were eliminated from the analysis because straining or crying could impede cerebral venous return [25]. We analyzed the changes of NIRS parameters (Oxy-Hb, Deoxy-Hb, and Total-Hb) by subtracting mean baseline values (10 min) from mean stimulation values (10 min). For qualitative pattern analysis of Oxy-Hb, Deoxy-Hb, and Total-Hb responses to the stimulation, we classified several common patterns according to the NIRS parameter changes [12,16,17,26]. For quantitative analysis, chi-square, correlations, t-test, and oneway ANOVAs were performed. Data for the normal newborn group were discussed in a previous article about the auditory-evoked CBO change in normal newborns [12].
3. Results The normal and HIE groups showed different Oxy-Hb and Total-Hb responses; 19 of the 20 normal subjects showed increases of Oxy-Hb and Total-Hb; whereas, 14 of the 22 HIE subjects showed decreases of Oxy-Hb and Total-Hb during stimulation (v2 = 19.95, p < 0.001).
Fig. 2. Patterns of NIRS parameter changes induced by auditory stimulation in the normal newborn group and the HIE newborn group. (A – C) on the abscissa represent the patterns of NIRS parameter changes during the stimulation. ‘‘ + ’’ and ‘‘ ’’ below (A – C) indicate an increase and a decrease of the NIRS parameters designated in the left during the stimulation, respectively; no change for 0. The ordinate indicates percentage of the patterns in normal newborns (white bar) and HIE newborns (black bar).
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The auditory stimulation caused several patterns of the CBO changes in the frontal lobes of normal and HIE newborns. Most of the CBO changes measured by NIRS could be classified into the three response patterns, examples of which are shown in Fig. 1. These response patterns were observed in our previous NIRS activation studies [12,16,17,26].
Fig. 3. (A) The mean changes of Oxy-Hb, Deoxy-Hb, and Total-Hb in the normal newborn group and the HIE newborn group. The * means t-test showed normals and HIE differed on that NIRS parameter, p < 0.001. (B) The relationship between the clinical grading of HIE and the mean changes of Oxy-Hb, Deoxy-Hb, and Total-Hb. The ordinates indicate concentration changes of Oxy-Hb (black bar), Deoxy-Hb (gray bar), and Total-Hb (white bar) in arbitrary units (a.u.). A one-way ANOVA was done for each NIRS parameter: * means significantly different form normal group ( p < 0.05). Additional analyses showed that mild and severe groups differed, p < 0.05 and the remaining comparisons showed a trend, p < 0.10.
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Pattern A was an increase in Oxy-Hb and Total-Hb with an increase of Deoxy-Hb (Fig. 1). Pattern B was an increase in Oxy-Hb and Total-Hb accompanied by a decrease or no change in Deoxy-Hb. Pattern C was a decrease in Oxy-Hb and Total-Hb with an increase or decrease of Deoxy-Hb. Besides the three common patterns, we observed two other response patterns which will not be discussed here because they occurred infrequently. Comparison of the normal newborn group and the HIE newborn group revealed striking differences in the occurrence of the NIRS response patterns (v2 = 18.02). Fig. 2 summarizes the occurrence of the NIRS response patterns (Patterns A, B, and C) induced by the auditory stimulation for the normal group and the HIE group. In the normal group, 13 out of 20 subjects (65.0%) showed Pattern A; while 6 (30.0%) out of 20 subjects showed Pattern B. One (5.0%) subject showed other CBO changes. None of the normal newborns showed Pattern C. In contrast, in the HIE newborn groups, 14 out of 22 subjects (63.6%) showed Pattern C during the auditory stimulation. In the subjects with Pattern C, nine (40.1%) subjects showed an increase of Deoxy-Hb while five (22.7%) subjects showed a decrease of Deoxy-Hb. Patterns A and B were observed in four (18.2%) and two (9.1%) subjects, respectively. Two (9.1%) subjects showed other changes. In addition to qualitative analyses, quantitative analyses were performed to compare the normal and HIE groups. Fig. 3A summarizes the mean changes of Oxy-Hb, Deoxy-Hb, and Total-Hb in the normal newborn group and the HIE newborn group. The t-tests revealed that the groups were significantly different for Oxy-Hb ( p < 0.001) and Total-Hb ( p < 0.001) with normal subjects showing a mean increase and the HIE showing a mean decrease. In contrast, Deoxy-Hb was similar for the groups ( p > 0.05). Finally, we evaluated the relationship between the clinical grading of HIE and changes in NIRS parameters. Correlations of the NIRS parameters and severity were obtained by assigning values to the groups (i.e., normal = 0, mild = 1, moderate = 2, severe = 3). Striking evidence for a relationship between HIE severity and activity-dependent rCBF response was provided by a strong negative correlation between HIE severity and changes of Total-Hb (r = 0.73, p < 0.001). To determine if the four groups differed, a one-way ANOVA was performed for each of the NIRS parameters. There was a significant effect for Oxy-Hb ( F = 17.56, p < 0.001) and Total-Hb ( F = 13.43, p < 0.001). Post hoc Student Newman Keuls analyses revealed that all of the HIE groups were significantly different from the normal group ( p < 0.05). In addition, the HIE groups differed with the mild HIE and severe HIE groups, being significantly different ( p < 0.05), and the mild HIE vs. moderate HIE comparisons and the moderate vs. severe HIE comparisons revealing a trend p < 0.10.
4. Discussion The present study is the first evaluation of the activity-dependent CBO changes in the HIE newborns. The results demonstrated that auditory stimulation caused CBO changes in the frontal lobes of both normal and HIE newborns. However, there were striking differences in the characteristics of CBO changes between the normal newborns and the HIE newborns. That is, most normal newborns showed increases of Oxy-Hb and Total-Hb during the stimulation, while many HIE newborns showed decreases of Oxy-Hb and Total-
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Hb. In addition, there was a strong negative correlation between HIE severity and changes of Total-Hb. In the normal newborns, Pattern A was most commonly observed in the frontal lobes during auditory stimulation. This is consistent with the CBO changes in the visual cortex of infants during photo-stimulation evaluated by NIRS [11]. In Pattern A, the Total-Hb increase indicates an increase of rCBF because Total-Hb correlates with CBF changes under conditions with constant hematocrit and perfusion pressure [13 – 15]. Therefore, normal newborns have a similar activity-dependent rCBF response to that of normal adults. However, in contrast to the normal adults, Deoxy-Hb increased in association with increases of Oxy-Hb and Total-Hb in most normal newborn. It was suggested that increments in O2 consumption exceed increments in O2 delivery during neuronal activity in newborns [12]. In the HIE newborns, Pattern C was most commonly observed in the frontal lobes during auditory stimulation. In Pattern C, both Oxy-Hb and Total-Hb decreased during the stimulation suggesting that rCBF decreases in the frontal lobes. This is supported by the finding that simultaneous measurements of NIRS and PET demonstrated that a decrease in Oxy-Hb and Total-Hb was associated with rCBF decrease at the NIRS recording region [18,19]. The pathophysiological mechanism of the rCBF decrease during neuronal activities is not yet clear. However, the following mechanisms should be considered. First, a stealing of blood flow. If the NIRS measurement area of the frontal lobes is not activated by the stimulation due to brain damage, the surviving cortex near the measurement area is activated and may steal the blood flow at the measurement area, resulting in decreased rCBF. Such a stealing of blood flow was observed in the brain tumor adjacent to the activating cortical area [27]. In this mechanism, Deoxy-Hb may increase, decrease, or not change, depending on the balance of O2 consumption and O2 delivery, which is altered by the stealing of blood flow. Secondly, an inhibitory synaptic activity. PET studies have demonstrated that regional depressions of synaptic activity decreased the rCBF and cerebral metabolic rate for O2 (CMRO2) [28]. However, in 9 out of 14 subjects with Pattern C, Deoxy-Hb increased during the activation, which is not consistent with the decreased CMRO2 observed by PET. Finally, the control level of rCBF at rest may affect the activity-dependent CBO response. However, the present NIRS study did not evaluate the pre-stimulation level of rCBF. In addition, such effects have not been evaluated. Although neuronal activation methods were different in newborns and adults, Pattern C has been observed in some normal adults [16,17,20– 22]. Approximately 20% of normal adults showed Pattern C in the left prefrontal cortex during language tasks [16,17]. Interestingly, compared to younger subjects, older subjects showed a greater frequency of Pattern C [17,22]. In addition, in the patients with Alzheimer’s disease, Pattern C was most commonly observed in the left superior parietal cortex during mental tasks [18]. These results suggest that the HIE brain, the aged brain, and the degenerated brain may have similar responses to neuronal stimulation. Finally, it should be emphasized that although the physiological mechanism of the activity-dependent rCBF decrease in HIE is not yet clear, the present method of combining NIRS and auditory stimulation may be a useful and easy diagnostic technique to evaluate the development of HIE.
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