Brain-stem auditory impairment during the neonatal period in term infants after asphyxia: dynamic changes in brain-stem auditory evoked response to clicks of different rates

Clinical Neurophysiology 115 (2004) 1605–1615 www.elsevier.com/locate/clinph

Brain-stem auditory impairment during the neonatal period in term infants after asphyxia: dynamic changes in brain-stem auditory evoked response to clicks of different rates Ze D. Jianga,b,*, Rong Yina, Xiao M. Shaoa, Andrew R. Wilkinsonb b

a Children’s Hospital, Shanghai Medical University, Shanghai, China Neonatal Unit, Department of Paediatrics, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK

Accepted 21 February 2004 Available online 27 March 2004

Abstract Objective: To explore dynamic changes in brain-stem auditory electrophysiology during the neonatal period in term infants after perinatal asphyxia. Methods: Sixty-eight term newborn infants who suffered asphyxia were studied on days 1, 3, 5, 7, 14 and 30 after birth. Brain-stem auditory evoked response (BAER) was recorded with clicks, delivered at 21, 51 and 91 s21 and $ 40 dB above BAER threshold of each subject. Results: During the neonatal period wave I latency in the infants after asphyxia increased slightly while later BAER components changed more significantly. On the first day after birth wave III and V latencies and I– V and III – V intervals increased significantly at all rates of clicks (ANOVA P , 0:01 – 0:001). On day 3, the latencies and intervals increased further. III – V/I – III interval ratio increased at 51 and 91 s21, suggesting a relatively more significant increase in III –V interval than in I – III interval at higher rates. Thereafter, wave III and V latencies and all intervals decreased progressively, although these BAER variables were still significantly longer than in normal controls on days 5 and 7 ðP , 0:05 – 0:001Þ: On day 30, all latencies and intervals approached near normal values, with a slight increase in wave V latency and I – V and III – V intervals at 51 and 91 s21. Conclusions: Perinatal asphyxia has a major effect on central auditory function, resulting in acute impairment. The impairment progresses during the first 3 days and then tends towards recovery. By 1 month the impaired auditory function has largely returned to normal. Significant increase in click rates can moderately improve the detection of auditory impairment. Significance: After perinatal asphyxia early detection of hypoxic-ischaemic damage to the central auditory system and initialisation of neuroprotective and therapeutic measures during the first hours after birth are critical to prevent or reduce deterioration of central impairment. q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Hearing; Auditory function; Brain-stem auditory evoked response; Evoked potentials; Neonate; Asphyxia; Hypoxia-ischaemia

1. Introduction Histopathological studies revealed that after perinatal asphyxia hypoxic-ischaemic discrete lesions are very common in the brain-stem (Dambska et al., 1987; Leech and Alvord, 1977; Myers, 1977; Natsume et al., 1995; Pasternak, 1993). The lesions frequently involve the auditory pathway, including loss of neurones with gliosis or ischaemic cell changes in the cochlear nuclei, superior * Corresponding author. Address: Neonatal Unit, Department of Paediatrics, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. Tel.: þ44-1865-221364; fax: þ 44-1865-221366. E-mail address: [email protected] (Z.D. Jiang).

olive and inferior colliculus. These findings suggest that auditory neurons in the neonatal brain-stem are vulnerable to hypoxic-ischaemic insult and that study of functional integrity of the auditory brain-stem can shed light on the effect of perinatal asphyxia on the central auditory system. A non-invasive and objective test that reflects functional status of the auditory brain-stem is the brain-stem auditory evoked response (BAER, Chiappa, 1990; Henderson-Smart et al., 1991). This response has been shown to be very sensitive to arterial blood oxygen levels and hypoxia (Freeman et al., 1991; Friss et al., 1994; Inagaki et al., 1997; Sohmer et al., 1986a,b; Urbani and Lucertini, 1994; Volpe, 2001), and has been used to assess both peripheral

1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2004.02.017

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and central auditory function in infants after perinatal asphyxia (e.g. Barden and Peltzman, 1980; Hecox et al., 1981; Kileny et al., 1980; Majnemer and Rosenblatt, 1995; Majnemer et al., 1988; Yasuhara et al., 1986). We have also previously studied the BAER in infants after perinatal asphyxia and found that this test is valuable in detection of hypoxic-ischaemic auditory impairment (Jiang, 1995; Jiang, 1998; Jiang and Tierney, 1996a; Jiang et al., 2001, 2004b). Recently, the BAER has been used to evaluate neuroprotective effect of hypothermia on neonatal hypoxic-ischaemic brain damage in experimental rats (Tomimatsu et al., 2002, 2003). It appears that the BAER, other than the diagnostic value for hypoxic-ischaemic auditory impairment, may help judge the value of neuroprotective and/or therapeutic interventions. The repetition rate of acoustic stimuli to elicit BAER is known to have a significant effect on the response (Chiappa, 1990). Changes in the BAER with the increase in the rate of stimuli primarily reflect neural processes concerning the efficacy of synaptic transmission and metabolic status of auditory neurones following a temporal challenge (Ken-Dror et al., 1987). The rate effect has been extensively studied in animal models with various experimental conditions, e.g. hypothermia which affects both axons and synapses (Sohmer et al., 1989), barbiturate level which affects mainly on synaptic efficacy (Sohmer and Goitein, 1988), hypoxia, hypoglycaemia, hypercapnia and acidemia (Freeman et al., 1991). In human infants, the rate effect has been used to study dynamic properties of the developing auditory system (Jiang and Tieney, 1996b; Jiang et al., 1998, 2001, 2002, 2004a,b; Ken-Dror et al., 1987; Lasky, 1997). In clinical settings, routinely used relatively low rates of stimuli (usually 10 – 21 s21) can elicit a clear, easily identifiable BAER waveform. Nevertheless, a stimulus condition that is optimal for eliciting the most easily identifiable BAER waveform may not be optimal for demonstrating neuropathology. The increase in repetition rate of the stimuli in BAER testing has been shown to be useful in detecting the presence of brain-stem abnormalities such as hypoxic-ischaemic encephalopathy, demyelinating disease and brain tumour (Chiappa, 1990). Abnormalities in stimulus rate-dependent change in the BAER may be associated with pathology in the central nervous system. Some neuropathology such as spastic quadriplegia or severe head trauma may manifest an abnormality in the BAER only at a high stimulus rate (e.g. Gerling and Finitzo-Hieber, 1983). Therefore, this method has been suggested to be a ‘stress test’ for the dynamic properties of the auditory brainstem in some neurological disorders, although not all agree (Chiappa, 1990; Freeman et al., 1991; Gerling and Finitzo-Hieber, 1983; Hecox et al., 1981; Jiang, 1999; Jiang et al., 2001, 2002, 2004a,b; Paludetti et al., 1983; Pratt et al., 1981). Currently, a number of neuroprotective and therapeutic measures for hypoxic-ischaemic brain damage are under

investigation, particularly controlled hypothermia which has attracted considerable interest (e.g. Azzopardi et al., 2000; Groenendaal and de Vries, 2000; Taylor et al., 2002; Whitelaw, 2000; Wyatt and Thoresen, 1997). Better understanding of the detailed process of hypoxic-ischaemic brain damage and auditory impairment after asphyxia is of great importance for studying any early intervention aimed at improving the outcome. Previous studies of the BAER in infants after perinatal asphyxia were mainly carried out either shortly after birth or some weeks, months or years after birth. There is a lack of systematic studies on dynamic changes in the BAER during the neonatal period, particularly the first few days after birth. In the reported study, we serially recorded and analysed the BAER on various days during the neonatal period in term infants who suffered perinatal asphyxia. The BAER was elicited by clicks at both conventionally used relatively low rate (21 s21) and higher rates (51 and 91 s21). Wave latencies and interpeak intervals in the BAER were analysed in detail with a major purpose to investigate the process of functional changes of the central auditory system during the neonatal period following asphyxia.

2. Materials and methods 2.1. Subjects The diagnosis of perinatal asphyxia was based on: (a) clinical signs of hypoxic-ischaemic encephalopathy (hypotonia with reduced or no spontaneous movements, increased threshold for primitive reflexes, lethargy or coma, absence or very weak suck and requirement of tube feeds, or seizures), and other signs of hypoxia, including frequent depression and failure of breathing spontaneously at birth (Evans and Levene, 1999; Levene, 2001); (b) depression of the Apgar score (# 6 at 5 min); (c) others: meconium staining of the amniotic fluid, umbilical cord blood pH , 7.10. Excluded were those who had congenital malformation, congenital or perinatal infection of the central nervous system, prolonged hyperbilirubinaemia, neonatal meningitis. Eighty-six newborn infants who suffered perinatal asphyxia, 49 boys and 37 girls, were recruited from the Neonatal Unit, Department of Paediatrics, John Radcliffe Hospital, University of Oxford, UK ðn ¼ 28Þ; and from the Neonatal Unit, Children’s Hospital of Fudan University, Shanghai, China ðn ¼ 58Þ: Gestational age ranged from 37 to 42 week (39.2 ^ 1.3 week), and birthweight between 2525 and 4550 g week (3395 ^ 468 g). Forty-one healthy newborn infants, 18 boys and 23 girls, were recruited as normal controls from the maternity words, Department of Obstetrics and Gynaecology, John Radcliffe Hospital, University of Oxford, UK. Gestational age ranged between 37 and 41 week (39.0 ^ 1.3 week). Birthweight was all above the 10th centile of the Oxford population (Yudkin et al., 1987). All infants had an Apgar score $ 8 at

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both 1 and 5 min. Monaural BAER thresholds, defined as the minimum intensity of clicks that evoked reproducible wave V at 21 s21, were all less than 20 dB normal hearing level (nHL). None had any major perinatal problems or complications. 2.2. Recording of the BAER Serial recording of the BAER in the infants after perinatal asphyxia was carried out on days 1, 3, 5, 7, 14 and 30 after birth. For each subject, the recording was made, as many times as appropriate, between 2 and 5 times during the first month. The number of infants on each study day ranged between 26 and 45. In the controls, BAER was recorded twice during the first month, i.e. on days 1 –3 (first recording) and day 30 (second recording), respectively. No recordings were made in between the 2 days due to the ethical difficulty to record the BAER on any other days during the neonatal period after discharge. A Nicolet Bravo Evoked Potential System (Nicolet Biomedical Inc., Madison, WI) was used to record and analyse the BAER. The recording was started shortly after the subjects fell asleep naturally or following a feed. No drug sedation was used. During the recording the subjects lay supine in the cot. Brain electrical activity was measured between goldplated disk electrodes placed at the middle forehead (þ ), the ipsilateral earlobe (2 ) and the contralateral earlobe (ground). Interelectrode impedances were maintained below 10 kV. Acoustic stimuli were rarefaction clicks, generated by rectangular pulses 100 ms in duration and delivered monaurally to the TDH 39 earphones. Brain responses evoked by the clicks were amplified and bandpassed with filtering between 100 and 3000 Hz prior to inputting to the averager. Both the ongoing filtered EEG and the running averaged BAER were monitored while averaging. Sampling was discontinued whenever there were excessive muscle artefacts on the monitoring oscilloscope. Each run, or recording, included the averaged responses to 2048 clicks. Sweep duration was 12 ms. A click intensity of 60 dB nHL was used in all subjects. In order to compare the data of BAER central components in the infants after perinatal asphyxia with those in the normal controls at the same hearing level ($40 dB above the threshold of each subject), higher intensities (70–90 dB nHL) were also used in those who had a BAER threshold . 20 dB nHL. Three repetition rates of clicks were presented in the order of 21, 51 and 91 s21 in the first run and in reverse order in the second run. The left ear was tested in all subjects. Duplicate recordings were made for each stimulus condition to check the reproducibility. 2.3. Analysis of BAER data Mean measurements of two replicable recordings to each stimulus condition were used for data analyses.

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Wave latencies, interpeak intervals in the BAER were measured. All data in the infants after asphyxia were compared with those in the normal controls at the same intensity level ($ 40 dB) above the threshold of each subject, i.e. at 60 dB nHL for thresholds # 20, 70 dB nHL for thresholds . 20– 30, $ 80 dB nHL for thresholds . 30 or 40 dB nHL. Nevertheless, in order to minimise the potential effect of peripheral hearing impairment on BAER central components and assess central function more accurately, data from the infants who had a BAER threshold . 25 dB nHL ðn ¼ 18Þ were excluded from the analysis. Thus, data presented here were those from the infants who had a threshold # 25 dB nHL ðn ¼ 68Þ: Mean and SD of each BAER variable at each stimulus condition in the infants after asphyxia were compared with the normal controls at comparable ages using one-way ANOVA. We have recently serially recorded the BAER on days 1, 3, 5 and 7 in 36 newborn infants who had temporary (1 min) low Apgar scores but no clinical signs of hypoxicischaemic encephalopathy and other abnormalities. No significant change in the BAER were found at 21, 51 and 91 s21 from day 1 to 7, although wave latencies and intervals tended to decrease thereafter (unpublished data). This finding suggests that there is no significant maturational effect on the BAER during the first week of life, and the minimal maturational effect during this relatively short period can be ignored. Thus, the data in the infants after asphyxia on days 1, 3, 5 and 7 was compared with the controls on days 1– 3. No statistical comparison was made for the data of the infants after asphyxia on day 14 because there were no control data on day 14. The data in the infants after asphyxia on day 30 were compared with the controls on the same day. In order to determine whether higher repetition rates of clicks was more effective in detecting auditory impairment after perinatal asphyxia net effect of increasing click rate on wave latencies and interpeak intervals from 21 to 51 and 91 s21 in the infants after asphyxia was calculated and compared with that in the control group. If higher rates can improve the detection the net effect after asphyxia would be significantly different from zero. As described by Pratt et al. (1981), the net effect was calculated by subtracting the values of BAER variables at 21 s21 from their counterparts obtained using 51 and 91 s21, respectively.

3. Results Fig. 1 shows BAER sample recordings on day 3 in a normal infant (A) and an infant who suffered from perinatal asphyxia (B). Although there were no apparent differences in the BAER between the two infants at 21 and 51 s21 clicks, all wave latencies and I– V and, in particular, III –V intervals increased at 91 s21 in the infant after asphyxia, compared with those in the normal infant.

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Fig. 2. Change in the mean and SE of wave I latency at different repetition rates of click stimuli ($40 dB above BAER threshold) during the neonatal period. The symbols stand for the data of normal control infants on days 1–3, infants on days 1, 3, 5, 7, 14 and 30, and the controls on day 30 in sequence.

Fig. 1. Sample recordings of the BAER on day 3 at various rates of clicks. (A) Normal infant; (B) infant after perinatal asphyxia.

3.1. Wave latencies 3.1.1. On day 1 In general, the later components of the BAER, i.e. those with longer latency, increased more significantly than the earlier components, i.e. those with shorter latency. In comparison with those in the controls on days 1 –3, wave I latency in the infants after asphyxia increased slightly at all 21, 51 and 91 s21 clicks, without any statistical significance (Fig. 2). Wave III latency increased significantly at all these rates (ANOVA P , 0:01 – 0:001; Fig. 3). Wave V latency also increased, but more significantly, at all rates (all P , 0:001; Fig. 4).

(P , 0:05 – 0:01 for wave III latency and all P , 0:01 for wave V latency). On day 14, the two latencies continued to decrease (Figs. 2 –4). 3.1.4. On day 30 All wave latencies in the infants after asphyxia approached near the values in the normal controls on the same day. Wave I latency did not differ significantly from that in the controls at any rates of clicks (Fig. 2). Both wave III and V latencies still tended to increase slightly (Figs. 3 and 4). Wave III latency did not have any significant difference from the controls at any rates, while wave

3.1.2. On day 3 Wave I latency in the infants after asphyxia did not show any further significant changes (Fig. 2). In comparison with those on day 1, however, both wave III latency and, in particular, wave V latency increased further. The two latencies differed more significantly from the controls at all 21, 51 and 91 s21 clicks (all P , 0:001; Figs. 3 and 4). 3.1.3. After day 3 Wave I latency did not show any significant change (Fig. 2). Both wave III and V latencies decreased progressively at all 21, 51 and 91 s21 (Figs. 3 and 4). In comparison with those in the controls on days 1 –3, the two latencies in the infants after asphyxia still increased significantly at all the rates used on both day 5 (P , 0:01 – 0:001 for wave III latency and all P , 0:001 for wave V latency) and day 7

Fig. 3. Change in the mean and SE of wave III latency at different repetition rates of click stimuli ($40 dB above BAER threshold) during the neonatal period. The symbols stand for the data of normal control infants on days 1–3, infants on days 1, 3, 5, 7, 14 and 30, and the controls on day 30 in sequence.

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Fig. 4. Change in the mean and SE of wave V latency at different repetition rates of click stimuli ($40 dB above BAER threshold) during the neonatal period. The symbols stand for the data of normal control infants on days 1–3, infants on days 1, 3, 5, 7, 14 and 30, and the controls on day 30 in sequence.

Fig. 6. Change in the mean and SE of I –III interval at different repetition rates of click stimuli ($40 dB above BAER threshold) during the neonatal period. The symbols stand for the data of normal control infants on days 1 –3, infants on days 1, 3, 5, 7, 14 and 30, and the controls on day 30 in sequence.

V latency differed significantly from the controls at higher rates (P , 0:05 at both 51 and 91 s21).

particularly at higher rates. III– V/I – III interval ratio did not differ significantly from the controls at 21 and 51 s21 clicks, but increased significantly at 91 s21 (P , 0:05; Fig. 8).

3.2. Interpeak intervals 3.2.1. On day 1 I– V interpeak interval in the infants after asphyxia increased significantly at all 21, 51, and 91 s21 clicks, compared with the normal controls (ANOVA all P , 0:01; Fig. 5). Of the two subcomponents, III –V interpeak interval increased more significantly (P , 0:01 – 0:001; Fig. 7) than I– III interpeak interval (all P , 0:05; Fig. 6) at all rates,

3.2.2. On day 3 Compared to those on day 1, both the I– V and III –V intervals in the infants after asphyxia increased further at all 21, 51, and 91 s21 clicks, which was slightly more significant at higher rates than at lower rates (P , 0:05 – 0:01; Figs. 5 and 7). The two intervals differed more significantly from the controls (all P , 0:001). The I – III interval also increased slightly further, with no

Fig. 5. Change in the mean and SE of I –V interval at different repetition rates of click stimuli ($40 dB above BAER threshold) during the neonatal period. The symbols stand for the data of normal control infants on days 1–3, infants on days 1, 3, 5, 7, 14 and 30, and the controls on day 30 in sequence.

Fig. 7. Change in the mean and SE of III–V interval at different repetition rates of click stimuli ($40 dB above BAER threshold) during the neonatal period. The symbols stand for the data of normal control infants on days 1 –3, infants on days 1, 3, 5, 7, 14 and 30, and the controls on day 30 in sequence.

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3.3. Net effect of increasing click rate on BAER latencies and intervals Tables 1 and 2 present means and SDs of the differences in BAER variables between 51 and 21 s21 clicks and between 91 and 21 s21 on different days in the controls and the infants after asphyxia, respectively. During the first week, the net effect at 51– 21 s21 clicks in the infants after asphyxia differed significantly from the controls on days 5 and 7 in the I– V interval, and on day 7 in the III– V interval. The net effect at 91 – 21 s21 differed significantly between the two groups on all days tested during the first weeks in III – V interval, on most days in I– V interval and on days 3 and 7 in III– V/I – III interval ratio (Table 2). On day 30, no significant differences were found between the two groups in the net effect in any BAER variables. Fig. 8. Change in the mean and SE of III– V/I–III interval ratio at different repetition rates of click stimuli ($40 dB above BAER threshold) during the neonatal period. The symbols stand for the data of normal control infants on days 1–3, infants on days 1, 3, 5, 7, 14 and 30, and the controls on day 30 in sequence.

significant differences from that on day 1, and differed more significantly from the controls at all rates used (P , 0:05 – 0:01; Fig. 6). The further increase was relatively more significant for III – V interval than for I– III interval, which was also reflected by the change in the III – V/I – III interval ratio that increased significantly at 51 s21 ðP , 0:05Þ and 91 s21 (P , 0:001; Fig. 8). 3.2.3. After day 3 All the I – V, I – III and III – V intervals decreased progressively (Figs. 5– 7). On day 5, both the I –V and III –V intervals in the infants after asphyxia still increased significantly at all rates, compared with those in the controls on days 1 –3 (all P , 0:001). The I– III interval also still increased, but less significantly ðP , 0:05 – 0:01Þ: On day 7, all intervals decreased further. Compared to those in the controls, the intervals in the infants after asphyxia still increased significantly at 51 and 91 s21 (all P , 0:01 for the I– V and III –V intervals, P , 0:05 for the I– III interval, Figs. 5 –7). On day 14, the intervals decreased further (Figs. 5 –7). From day 5 the III– V/I – III interval ratio gradually decreased at all rates used (Fig. 8). 3.2.4. On day 30 All the I– V, I– III and III –V intervals in the infants after asphyxia decreased further and approached near the values in the controls on the same day (Figs. 5– 7). However, both the I –V and III– V intervals still differed those in the controls at 51 and 91 s21 clicks (all P , 0:05). The I– III interval did not differ significantly from the controls at 21 and 51 s21, but still increased at the highest 91 s21 ðP , 0:05Þ: The III– V/I – III interval ratio decreased to the values in the controls at all rates (Fig. 8).

4. Discussion The present study revealed a detailed process of general changes in brain-stem auditory electrophysiology during the neonatal period in infants after perinatal asphyxia. The hypoxic-ischaemic auditory impairment progresses during the first 3 days after birth, reaching a peak on day 3, and then tends to recover progressively. The first week, particularly the first 3 days, is a critical period for hypoxic-ischaemic damage to the central auditory system. By the end of the neonatal period, the impaired neural conduction along the brain-stem auditory pathway has largely returned to normal. Abnormalities in the I– V and III– V intervals tended to be more significant at higher rates, mainly at the highest 91 s21 clicks. Table 1 Means and SDs of the differences in BAER variables (ms) between 51 and 21 s21 clicks and between 91 and 21 s21 on days 1–3 and day 30 after birth in normal controls Day tested

BAER variable

51–21 s21

91– 21 s21

Mean

SD

Mean

SD

1 –3

Wave I latency Wave III latency Wave V latency I– V interval I– III interval III–V interval III–V/I–III ratio

0.18 0.25 0.42 0.22 0.07 0.16 0.03

0.09 0.13 0.13 0.14 0.12 0.14 0.06

0.35 0.55 0.90 0.51 0.19 0.32 0.06

0.16 0.19 0.29 0.21 0.17 0.15 0.07

30

Wave I latency Wave III latency Wave V latency I– V interval I– III interval III–V interval III–V/I–III ratio

0.15 0.23 0.37 0.22 0.07 0.17 0.02

0.07 0.08 0.09 0.09 0.07 0.08 0.04

0.27 0.43 0.75 0.46 0.16 0.30 0.05

0.07 0.11 0.12 0.12 0.10 0.10 0.06

Z.D. Jiang et al. / Clinical Neurophysiology 115 (2004) 1605–1615 Table 2 Means and SDs of the differences in BAER variables (ms) between 51 and 21 s21 clicks and between 91 and 21 s21 on different days after birth in infants after perinatal asphyxia and the comparison with those in normal controls in Table 1 (ANOVA) Day tested BAER variable

51 –21 s21

91–21 s21

Mean

SD

Mean

SD

1

Wave I latency Wave III latency Wave V latency I– V interval I– III interval III–V interval III–V/I–III ratio

0.15 0.22 0.39 0.25 0.09 0.18 0.03

0.06 0.06 0.09 0.11 0.09 0.11 0.05

0.31 0.49 0.86 0.54 0.16 0.38 0.08

0.10 0.09 0.15 0.13 0.13 0.13* 0.06

3

Wave I latency Wave III latency Wave V latency I– V interval I– III interval III–V interval III–V/I–III ratio

0.15 0.24 0.43 0.26 0.09 0.18 0.04

0.09 0.12 0.15 0.12 0.08 0.10 0.04

0.32 0.49 0.89 0.58 0.16 0.42 0.10

0.11 0.15 0.20 0.17* 0.10 0.15** 0.06**

5

Wave I latency Wave III latency Wave V latency I– V interval I– III interval III–V interval III–V/I–III ratio

0.14 0.25 0.46 0.31 0.11 0.20 0.04

0.09 0.13 0.13 0.14* 0.12 0.12 0.07

0.29 0.46 0.90 0.58 0.18 0.40 0.08

0.12 0.15 0.20 0.17* 0.13 0.16* 0.08

7

Wave I latency Wave III latency Wave V latency I– V interval I– III interval III–V interval III–V/I–III ratio

0.11 0.24 0.47 0.32 0.11 0.20 0.04

0.08 0.10 0.13 0.11** 0.09 0.09* 0.05

0.29 0.48 0.90 0.63 0.08 0.43 0.09

0.20 0.13 0.21 0.17** 0.11 0.15** 0.06

14

Wave I latency Wave III latency Wave V latency I– V interval I– III interval III–V interval III–V/I–III ratio

0.11 0.28 0.35 0.23 0.06 0.17 0.05

0.08 0.10 0.13 0.11 0.09 0.07 0.04

0.27 0.41 0.75 0.49 0.15 0.35 0.08

0.10 0.14 0.17 0.14 0.11 0.12 0.07

30

Wave I latency Wave III latency Wave V latency I– V interval I– III interval III–V interval III–V/I–III ratio

0.17 0.25 0.42 0.25 0.08 0.14 0.04

0.07 0.11 0.13 0.12 0.10 0.08 0.05

0.33 0.50 0.82 0.49 0.19 0.30 0.06

0.13 0.18 0.20 0.14 0.13 0.13 0.08

*P , 0:05; **P , 0:01; ***P , 0:001: Statistical comparison was made between the infants after asphyxia on days 1, 3, 5 and 7 and the controls on days 1– 3,and between the two groups on day 30. No comparison was made for the infants after asphyxia on day 14 because no control data were available on around day 14.

4.1. BAER changes after perinatal asphyxia Perinatal asphyxia is one of the major risks for auditory impairment in newborn infants (Borg, 1997; Flint, 1983; Jiang, 1995; Jiang and Tierney, 1996a; Jiang et al., 2001,

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2004b; Mencher and Mencher, 1999). In the previous studies of the BAER in newborn infants after asphyxia, some authors reported that wave V latency was slightly shortened although it was not statistically different from the controls (e.g. Barden and Peltzman, 1980). However, more authors reported that BAER wave latencies and interpeak intervals increased after perinatal asphyxia (Hecox et al., 1981; Kileny et al., 1980; Majnemer et al., 1988; Yasuhara et al., 1986). In the present study, we found that after excluding the infants who had threshold elevation (. 25 dB nHL) the later components of the BAER in the infants after asphyxia changed more significantly than the earlier components. During the neonatal period, wave I latency tended to increase slightly. In contrast, wave V latency and the I –V, I –III and III –V intervals increased significantly during the first a few days after birth, and then tended towards recovery. Apparently, the central auditory pathway is more susceptible to hypoxic-ischaemic damage than the peripheral pathway. This is in agreement with previous reports that the neonatal brain is more susceptible to hypoxic-ischaemic damage than the ear (Borg, 1997). The significant increase in wave latencies and intervals indicates that following perinatal asphyxia the pathology due to hypoxic-ischaemic insult to the central auditory system interferes with nerve conduction which is related to myelination and synaptic transmission of the neonatal auditory system. Due to the ethical difficulty, the normal controls in the present study were only recorded on days 1 –3 after birth and on day 30, with no follow-up in between. Therefore, there would be some errors, mainly in the maturational effect on the BAER, for the comparison between the study and the control groups. Nevertheless, our recent study of the BAER on days 1, 3, 5, and 7 in newborn infants with temporary (1 min) low Apgar scores but no clinical signs of hypoxic-ischaemic encephalopathy and other abnormalities suggests that the maturational effect during this relatively short period is minimal, and can be ignored (unpublished data). In the present study, the general trends of the differences in BAER variables between the two groups are very obvious. Suppose we draw straight lines to connect the data on days 1 – 3 and day 30 in the controls in Figs. 2 – 7. We will see very clearly that the data of wave III and V latencies and all intervals in the study group are all above the lines, particularly during the first week after birth. Apparently, the increase in the wave latencies and intervals in the study group is predominantly due to the effect of neural impairment after perinatal asphyxia. In particular, the further increase in BAER latencies and intervals on days 3 –5 in the study group cannot be explained by maturational effect or change. After the first week, the latencies and intervals decreased with the increase in post-natal days until the end of the first month, but still above the lines. This finding implies that in addition to the maturational change as in the controls, there is some effect of neural impairment due to asphyxia, leading to slow neural

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conduction. Because of the lack of control data on day 14, no statistical comparison was made for the data in the infants after asphyxia on this day. However, the data on day 14 demonstrated a general trend of change in the BAER in between day 7 and the end of the first month after perinatal asphyxia. In addition to the maturational effect, there are other perinatal problems or conditions such as hyperbilirubinaemia, neonatal meningitis, and treatments with ototoxic drugs that may alter the neonatal BAER (e.g. Chiappa, 1990). These factors generally affect the peripheral hearing more than the central auditory system, resulting in an elevation in hearing threshold and increase in wave I latency. For instance, Nakamura et al. (1985) reported that in infants with hyperbilirubinemia wave I latency increased significantly whereas I– V interval did not show any significant change. In this study, the effects of these confounding factors on the BAER were not systematically studied on each study day. However, those who had prolonged hyperbilirubinaemia, meningitis and persistent pulmonary hypertension were excluded. Effort to minimise any possible peripheral effects on the BAER were made by excluding the data from the infants who had a BAER threshold . 25 dB nHL. None of the subjects had a significant increase in wave I latency. Thus, although the possible effects of some confounding perinatal problems or conditions on the BAER cannot be completely excluded, the differences between the study and control groups predominantly reflect the effect of asphyxia on the neonatal auditory brain-stem. 4.2. Peripheral auditory impairment and the measurement of central BAER components The measurement of central BAER components is affected by peripheral auditory impairment. In patients with high-frequency sensorineural hearing loss, the I –V interval tended to be shortened (e.g. Coats and Martin, 1977). Gerling and Finitzo-Hieber (1983) studied the BAER at different rates of clicks in patients with pathology in the central nervous system. The authors found that the patients with impaired auditory sensitivity demonstrated significantly less wave latency shift than either their patients with normal auditory sensitivity or normal subjects. Abnormal wave V latency change occurred in 12% of the patients with normal auditory sensitivity and 8% of patients with impaired auditory sensitivity. Using norms based on normal-hearing subjects for patients with hearing impairment would allow a much higher false-negative error. The authors proposed that it should be cautious to judge the BAER results when the patient with suspected pathology in the central nervous system also has impaired hearing. Cochlear dysfunction in the high frequency region can cause a shift in the relative contributions of different regions of the cochlea to the click response, from the normally dominant high frequency region (2 – 4 kHz) to lower frequency regions of the cochlea associated with longer

latencies, mainly wave I latency (Coats and Martin, 1977; Don and Eggermont, 1978; van der Drift et al., 1987; Gorga et al., 1985; Stapells et al., 1990). Thus, patients with high frequency hearing loss due to cochlear dysfunction can be associated with shortening of I–V interval. Peripheral auditory disorders are not uncommon in the neonate. After perinatal asphyxia, the increase in BAER wave latencies in some cases can be partly related to peripheral auditory disorders. In the present study, in order to minimise any significant effect of peripheral disorders on central BAER components, the data of the subjects who had a BAER threshold . 25 dB nHL were excluded. All data were analysed at $ 40 dB above BAER threshold of each subject who had a threshold # 20 dB nHL. There was no difference in the hearing level at which BAER was recorded between the infants after asphyxia (49.8 ^ 6.4 dB) and the controls (49.2 ^ 5.7 dB) ðP . 0:05Þ: Therefore, the changes in BAER intervals during the neonatal period after perinatal asphyxia essentially represent the dynamic changes in functional integrity of the neonatal auditory brain-stem following hypoxia-ischaemia, although we cannot completely exclude any subtle degree of peripheral auditory disorders in some of the subjects, which may lead to a slight increase in wave I latency. 4.3. Auditory impairment after perinatal asphyxia In infants who suffer perinatal asphyxia, the lack of sufficient oxygen supply to the stria vascularis in the inner ear suppresses the sodium –potassium pump and in turn depresses the endocochlear potential of scala media (Sohmer et al., 1986a). This reduces auditory sensitivity, and leads to sensory auditory impairment. After asphyxia, hypoxaemia can directly damage the auditory system, and indirectly affect the system by way of cardiovascular collapse and cerebral ischaemia, resulting in an acute impairment in both the cochlea and auditory neural pathway, i.e. sensorineural impairment. In the BAER, the impairment manifests an increase in wave latencies and interpeak intervals. In this study, the increase in wave III and V latencies cannot be mainly explained by the effect of peripheral impairment. At all repetition rates of click stimuli, the two latencies increased much more significantly than wave I latency. After correcting or cancelling the effect of the increase in wave I latency on later BAER components, wave III and, in particular, wave V latencies still increased significantly, as confirmed by the increase in I– V, I– III and III – V intervals which suggests an impairment in central conduction of the auditory system. Thus, the significant increase in the two latencies is mainly due to central auditory impairment following hypoxia-ischaemia. These electrophysiological findings are consistent with previous histopathological observations that perinatal asphyxia often causes discrete lesions in brain-stem auditory nuclei

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(Dambska et al., 1987; Leech and Alvord, 1977; Myers, 1977; Natsume et al., 1995; Pasternak, 1993). The neonatal brain is subject not only to hypoxia but also to ischaemia and hypercarbia, leading to cerebral edema and various circulatory disturbances (Volpe, 2001). Hypoxiaischaemia disturbs the metabolism of neurons and depresses the electrophysiological function of synapses in the brain. The efficacy of synaptic transmission is related to the mechanisms for synthesis, release and uptake of neurotransmitters. Severe hypoxia-ischaemia causes excessive release of glutamate from the pre-synaptic transmitter site and compromises the uptake pumps of glutamate within the synaptic cleft. This causes a significant increase in the concentration of glutamate increases and irreversible neuronal injury (Benveniste et al., 1984; Johnston et al., 2001; Represa et al., 1989). 4.4. The process of auditory impairment during the neonatal period following perinatal asphyxia and the implications Our data in infants after perinatal asphyxia during the first a few days of life suggest that hypoxia-ischaemia has a major effect on central auditory function. The significant increase in wave V latency and all interpeak intervals on day 1 reflects acute hypoxic-ischaemic damage to the central auditory system, resulting in a significant impairment in neural conduction. The further increase in wave III and V latencies and all intervals on day 3 implies that during the first 3 days of life the hypoxic-ischaemic damage to the central auditory system progresses and the impairment in central auditory function deteriorates. Neural damage during the post-ischaemic period results mainly from disorders of cerebral metabolism and blood flow occurring after injury, leading to further tissue injury and cerebral edema, rather than a result of the initial insults. The ultimate degree of auditory impairment may depend substantially on the injury during post-ischaemic period. The present study revealed that changes in the BAER following hypoxia-ischaemia may progress for some period after birth. The deterioration of auditory impairment on day 3 is in agreement with the notion of secondary energy failure and secondary cerebral hypoperfusion after perinatal asphyxia. These findings imply a delayed neuronal impairment following hypoxia-ischaemia. Increasing evidence suggests that following hypoxia-ischaemia some cells die during the immediate insult, but many more may die hours or days later (Gunn et al., 1997; Kirino, 1997; Taylor et al., 2002). The delayed cell death or deteriorating neural function shortly after birth provides an opportunity for therapy aimed at preventing further brain damage or deterioration. Our data suggest that the first 3 days is the most crucial time of hypoxic-ischaemic brain damage. It may be possible to intervene with neuroprotective and therapeutic measures before the occurring of delayed neuron death, preventing or reducing further damage.

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The present study found that after the first 3 days hypoxic-ischaemic damage to the central auditory system tends towards recovery. However, the central components in the BAER were still significantly abnormal on day 5 at all click rates used and on day 7 at higher rates, suggesting that the central auditory function is still abnormal up to the end of the first week. Thus, the first week, particularly the first 3 days, is a critical period of hypoxic-ischaemic damage to the neonatal auditory brain-stem. After the first week the impaired central auditory system due to hypoxia-ischaemia recover significantly and progressively. This process continues up to the end of the neonatal period. By then, all wave latencies and interpeak intervals approached near normal values. At higher rates, however, wave V latencies and all intervals are still slightly abnormal. It appears that by the end of the neonatal period the impaired neural conduction in the auditory brain-stem has largely recovered, although it has not completely returned to normal. The III –V interval in the infants after perinatal asphyxia changed slightly more than the I–III interval at all rates of clicks, although the dynamic changes in the two intervals during the neonatal period were generally similar. This is consistent with the finding that the III– V/I – III interval ratio tended to increase slightly during the first week, particularly around days 3– 5. These findings indicate that following hypoxia-ischaemia the more central part of the auditory brain-stem is impaired slightly more than the more peripheral part. There were individual variations in the dynamic changes in the BAER. Some subjects, mainly those after mild asphyxia, recovered sooner than the others, mainly those after severe, prolonged asphyxia. In fewer cases, BAER wave latencies and intervals increased further some days or 1 week after birth. This is comparable with some previous reports that following asphyxia brain damage may progress for variable periods of time after the occurrence of hypoxiaischaemia (e.g. Volpe, 2001). In conclusion, the dynamic changes in the BAER demonstrate a general trend of electrophysiological changes in the auditory brain-stem in infants who suffered perinatal asphyxia. Our findings are of important clinical implication that intervention with neuroprotective and therapeutic measures after perinatal asphyxia should be initialised during the first hours after birth in order to prevent or reduce the deterioration of central impairment. 4.5. Increasing click rates can moderately improve the detection of auditory impairment The method of increasing the rate while recording the BAER has been suggested by some authors to improve the detection of neuropathology (Chiappa, 1990; Gerling and Finitzo-Hieber, 1983; Hecox et al., 1981; Jiang, 1999; Jiang et al., 2001, 2002, 2004a; Paludetti et al., 1983; Pratt et al., 1981). We have also previously studied the BAER at

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different rates in both normal population and children who had various clinical problems such as asphyxia, intrauterine growth retardation, very pre-term birth or bacterial meningitis (Henderson-Smart et al., 1991; Jiang, 1996, 1999; Jiang and Tierney, 1996b; Jiang et al., 1998, 2001, 2002, 2004a). We have found that in some cases the auditory neuropathology that cannot be detected by the BAER recorded with low-rate stimulation can be detected with high-rate stimulation, suggesting the increase in click rate can improve the detection of some neuropathology. In this study, the dynamic changes in the BAER of infants after perinatal asphyxia were essentially similar among different rates of clicks, although abnormalities in the I– V and III– V intervals tended to be slightly more significant at higher rates, mainly at 91 s21. In cats with experimental hypoxia, Freeman et al. (1991) found no significant effect of increasing stimulus rate on the detection of pathological BAER. This is somewhat similar to our present finding that in infants after asphyxia there were no appreciable more BAER abnormalities at 51 s21 than at 21 s21. It seems that the rate 51 or 55 s21 is not stressful enough to improve the detection of neuropathology. In the present study, a significant increase in the rate, i.e. 91 s21, appears to be more effective than a moderate increase, i.e. 51 s21, in detection of abnormalities. This observation is consistent with our previous findings (Jiang, 1999; Jiang et al., 2001, 2002, 2004a). Thus, in order to improve the detection of neuropathology by increasing stimulus rate the rate used should be high enough to effectively stress the large number of neurons along the brain-stem auditory pathway. In infants who have a normal BAER recorded with conventional low-rate stimulation, we cannot rule out a possible abnormality that can be detected with very highrate stimulation.

Acknowledgements Grants from the Defeating Deafness, WellChild Trust and Wellcome Trust, UK, and Chun-Hui Scheme of Education Ministry, China, made this research possible. The doctors and nurses at the Neonatal Unit of the Department of Paediatrics, John Radcliffe Hospital, University of Oxford and in the Children’s Hospital, Fudan University, Shanghai are gratefully appreciated for their enthusiastic support and assistance in the recruitment of subjects and collection of data.

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