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ARTICLE |
a Neonatal Unit, Department of Paediatrics, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
b Department of Neonatology, Children's Hospital, Fudan University, Shanghai, China
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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METHODS. Forty-one very preterm infants with bronchopulmonary dysplasia were studied at postconceptional ages of 37 to 42 weeks. Brainstem auditory evoked responses were recorded and analyzed by using the maximal length sequence technique.
RESULTS. Compared with term control subjects, wave V latency in the maximal length sequence brainstem auditory evoked response of the infants with bronchopulmonary dysplasia increased significantly at all 91 to 910 clicks per second rates. Similarly, I–V and particularly III–V interpeak intervals increased significantly. The III–V/I–III interval ratio also increased significantly at all click rates. All of these abnormalities became more significant as the click rate was increased. Compared with healthy, very preterm control subjects, all of these maximal length sequence brainstem auditory evoked response variables increased significantly at all click rates, although the differences between the 2 groups were slightly smaller than those between the infants with bronchopulmonary dysplasia and the term control subjects. The wave I and III latencies and I–III interval in the infants with bronchopulmonary dysplasia did not show any abnormalities. The slopes of the wave V latency-rate function and I–V and particularly III–V interval-rate functions for the infants with bronchopulmonary dysplasia were significantly steeper than those for both term and healthy, very preterm control subjects. The slope of the III–V/I–III interval ratio-rate function for the infants with bronchopulmonary dysplasia was also significantly steeper than those for the 2 control groups.
CONCLUSIONS. The results suggest poor myelination and synaptic function of the brainstem in infants with bronchopulmonary dysplasia, resulting in impaired functional integrity. In comparison, peripheral neural function was relatively intact.
Key Words: bronchopulmonary dysplasia • brainstem auditory evoked potentials • central nervous system • neonatology • neurodevelopmental deficits
Abbreviations: BAER—brainstem auditory evoked response • BPD—bronchopulmonary dysplasia • CNS—central nervous system • nHL—normal hearing level • MLS—maximal length sequence
Bronchopulmonary dysplasia (BPD) is a major lung disease in infants born very preterm.1–3 Increasing evidence suggests that the survivors of BPD have high incidence rates of neurologic impairment and developmental deficits, such that BPD has become one of the greatest risk factors of neurodevelopmental problems in infants.2–9 Early detection of neurologic impairment, preferably with noninvasive objective methods that can be used conveniently at the bedside, can provide important information for clinical management of infants with BPD.
The pathophysiological processes underlying neurologic impairment and developmental deficits after BPD remain poorly understood.1,5,9 Animal experiments with BPD revealed that prolonged or chronic sublethal hypoxia, which occurs during the course of BPD, may result in severe impairments in corticogenesis in the developing brain and a significant decrease in subcortical white matter.10 Hypoxemia affects the functional integrity and development of the immature brain, and brainstem auditory neurons are particularly sensitive to severe hypoxemia.11–13 Infants who suffer BPD often experience frequent episodes of hypoxemia or prolonged hypoxemia. It is possible that frequent episodes of hypoxemia or prolonged hypoxemia impair the functional integrity of the neonatal auditory brainstem.
Earlier reports on brain myelination in infants with BPD are somewhat controversial. Myelination was found to be accelerated in some infants with BPD but delayed in others.14 Additional study is needed to clarify whether brain myelination is accelerated or delayed. Synapses in the developing brain transmit developmental and regulatory signals between neurons. The efficacy of synaptic transmission is an important index of the functional integrity of synapses in the central nervous system (CNS). It is unclear whether synaptic efficacy is affected by BPD. Hypoxia disturbs the metabolism of neurons and depresses the electrophysiological function of synapses in the brain. We hypothesize that prolonged or chronic hypoxemia associated with BPD affects the efficacy of synaptic transmission in the brain, in addition to impairing myelination of the brain.
The neonatal brainstem auditory evoked response (BAER) (also known as the auditory brainstem response) reflects the functional integrity and development of the auditory brainstem. This response is very sensitive to arterial blood oxygen levels and hypoxia or hypoxia-ischemia.11,13,15–17 It has been widely used to examine brainstem auditory function in infants after perinatal hypoxia or hypoxia-ischemia.18–21 Increases in the repetition rate of click stimuli to elicit the BAER potentially can increase the detection of neuropathological conditions that affect the brainstem auditory pathway.18,21,22 However, the averaging techniques used in conventional BAER testing impose a rate limit of 
100 clicks per second, which restricts the ability to increase click rates to improve the detection of neuropathological conditions.
We have used a relatively new technique, the maximal length sequence (MLS), to study the BAER in infants with perinatal problems, to improve detection of brainstem abnormalities.23–26 This technique can present acoustic stimuli at much higher repetition rates (up to 1000 clicks per second or even higher) than possible with conventional averaging techniques, providing a much stronger physiological/temporal challenge to brainstem auditory neurons.11,23–28 This stimulus "stress" offers the potential to improve the detection of some neuropathological conditions that may not be detected by presenting less-stressful stimuli (ie, low-rate stimulation) with conventional averaging techniques. This is particularly important for early and subtle neuropathological conditions that may not be detected through conventional investigations.26
Our studies showed that MLS BAER data, which can be recorded conveniently and analyzed at the bedside in a busy NICU, can improve the detection of neuropathological conditions that affect the auditory brainstem in some perinatal problems, typically hypoxia-ischemia.23–26 To gain new insights into the pathophysiological processes underlying neurologic impairment after BPD, we studied the MLS BAER in very preterm infants with BPD. Particular attention was paid to examining myelination, as reflected by MLS BAER latencies and interpeak intervals, and the efficacy of synaptic function, as reflected by stimulus rate-dependent changes in MLS BAER variables.21–26,29 To examine whether any abnormal findings in infants with BPD might be related to very preterm birth, the MLS BAER data were compared with those of age-matched, very preterm infants without BPD, in addition to term infants. If the possible abnormalities are attributable to the effects of very preterm birth, then there should be no significant differences in the MLS BAER data between the very preterm infants with BPD and those without BPD.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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1 more time, >2 weeks after birth. Any infants who had severe (grade III or IV) intraventricular hemorrhage or periventricular leukomalacia were excluded, to minimize any possible confounding effect of major brain lesions on the MLS BAER. All subjects passed our neonatal hearing screening program with distortion product otoacoustic emission, to avoid the influence of significant peripheral auditory problems on MLS BAER central components. Any infants who had documented peripheral auditory impairment were excluded from the study. The study group was composed of 41 very preterm infants with BPD who were recruited from the neonatal unit of John Radcliffe Hospital, University of Oxford (Oxford, United Kingdom). The criteria for BPD included requirements for supplementary oxygen or ventilatory support beyond postconceptional age of 36 weeks to maintain PaO2 at >50 mm Hg, clinical signs of chronic lung disease, and radiographic evidence of BPD (persistent strands of density in both lungs). The gestational ages of the subjects ranged from 23 to 31 weeks (mean ± SD: 27.6 ± 2.2 weeks), with birth weights of 559 to 1650 g (mean ± SD: 1196 ± 269 g). MLS BAER recordings were conducted at postconceptional ages of 37 to 42 weeks (mean ± SD: 39.3 ± 1.8 weeks).
The normal, term control subjects were 41 healthy infants with gestational ages of 37 to 41 weeks (mean ± SD: 39.0 ± 1.2 weeks) who were recruited from the maternity wards of John Radcliffe Hospital; none had any perinatal problems. The subjects had a monaural BAER threshold, defined as the minimal intensity of clicks that evoked a reproducible wave V at 21 clicks per second, of <20 dB normal hearing level (nHL) at the time of testing. The MLS BAER was recorded at postconceptional ages of 37 to 42 weeks (mean ± SD: 39.2 ± 1.3 weeks).
The healthy, very preterm control subjects were 40 infants who had no BPD or any other major perinatal complications or problems, as specified above. They were recruited from the neonatal unit of John Radcliffe Hospital. Their gestational ages ranged from 24 to 31 weeks (mean ± SD: 28.3 ± 2.6 weeks), with birth weights of 595 to 1890 g (mean ± SD: 1215 ± 337 g), which did not differ significantly from the study group. MLS BAER recordings were conducted at postconceptional ages of 37 to 42 weeks (mean ± SD: 39.7 ± 1.7 weeks).
The MLS BAER Technique
Our previous studies of conventional BAER testing suggested that stimulus repetition rates of >91 clicks per second could be more effective in detecting neurologic impairment of the brain.21,22 However, increases in the stimulus rates are limited by the need to prevent responses from overlapping one another. Conventional evoked potential instruments, or averagers, use stimuli separated by fixed interstimulus intervals (time intervals between the stimuli). The lower limit of these fixed intervals is determined by the duration of the electrophysiological response. Conventional stimulation and recording techniques require that the brainwave response to one stimulus be completed before delivery of the next stimulus. Stimulation before response completion results in overlapping waveforms, which are difficult to interpret. In the case of the BAER, response components last for 10 to 12 milliseconds after stimulus onset, which imposes a limit of 10 to 12 milliseconds on the interpulse interval (corresponding to a rate of 100–80 clicks per second). Refractory periods for auditory neurons are <10 milliseconds. Therefore, the use of stimulus rates of 
100 clicks per second limits the study of adaptive or recovery processes and the diagnosis of neuropathological conditions.
To circumvent the rate limitations imposed by conventional averaging, one method is to use pseudorandom pulse trains that are binary sequences, called MLS, as acoustic stimuli. Unlike the uniformly spaced stimuli used in conventional BAER testing, the MLS technique uses patterned stimulus presentation. Different patterned sequences of stimuli are created by omitting a portion (eg, 50%) of the stimuli in a pseudorandom manner. Mathematically, a MLS is a quasi-random binary sequence represented by a train of +1 second and –1 second. In its audiological application, it may be presented as +1 second and 0 seconds or as clicks and silences. This stimulus consists of distinct pulses of uniform polarity and amplitude, occurring at pseudorandom time intervals. Each pulse sequence is actually a series of pulses. Therefore, the accepted value and the number entered in the sweep count represent the number of sequences, not the number of discrete pulses as in conventional BAER testing. When there are 50% gaps in the MLS stimulus patterns, the actual repetition rate fluctuates over time and the average rates are actually one half of the rates presented.
The nature of the stimuli and the newly developed processing technique make it unnecessary to wait for the response of each pulse to be completed before application of a new pulse. Therefore, pulses can be delivered at maximal rates of up to 1000 clicks per second or even higher. The patterned sequences of stimuli are generated by the averaging computer, and this information is then used to perform on-line deconvolution (separation, alignment, and averaging) of overlapping individual responses. As in conventional BAER recording, each waveform of the response is filtered and the waveforms are averaged. By mathematically cross-correlating the collected data with a recovery sequence, the final MLS BAER is obtained for analysis.
The MLS technique permits the overlapping of responses to successive stimuli. This allows presentation of stimuli at much higher rates than is possible with conventional methods. Because the higher rates provide a much stronger physiological/temporal challenge to auditory neurons and permit a more-exhaustive sampling of physiological recovery or "fatigue" than is possible with conventional stimulation, this technique potentially can improve the sensitivity of BAER testing for the diagnosis of neuropathological conditions, as shown in our studies of infants with some perinatal problems and newborn piglets treated with hypoxia-ischemia.11,23–26
MLS BAER Recording
There were no significant differences between the 3 groups of infants in the postconceptional ages at which the recordings were conducted. The study was approved by the Central Oxford Research Ethics Committee. Informed consent was obtained from the parents and the pediatrician in charge of each subject. The MLS BAER was recorded by using a Spirit 2000 evoked potential system (Nicolet Biomedical, Madison, WI).
The infants lay supine in a bassinet. No sedatives were used. Before the recording, the auditory meatus was inspected and cleaned of any vernix or wax. After skin preparation, gold-plated disk electrodes were placed on the middle forehead (positive), the left (ipsilateral) earlobe (negative), and the right (contralateral) earlobe (ground). Interelectrode impedances were maintained at <5 k
. Rarefaction clicks of 100 microseconds were delivered to the left ear through a TDH 39 earphone (Nicolet Biomedical Inc, Madison, WI), which were comfortably placed over the ear with great care to avoid collapsing the ear canals. After the infant fell asleep naturally, often after a feeding, MLS BAER recording was started.
First, the conventional BAER was recorded with 21 clicks per second to determine the BAER threshold (the lowest intensity at which wave V can be recognized reliably). Then, MLS BAER recording was started with 60-dB nHL clicks. Higher intensities were also used for subjects who had increased BAER thresholds (>20 dB nHL). The clicks were presented at 91, 227, 455, and 910 clicks per second in the first run and in a reverse sequence in the second run. The brain responses evoked by the clicks were amplified and filtered at 100 to 3000 Hz. An automatic rejection system was used to exclude sweeps that exceeded 91% of the sensitivity parameter setting of 51 µV (artifact). Whenever there were excessive muscle artifacts on the monitoring oscilloscope, sampling was discontinued manually until the artifacts reduced significantly. Each run included brain responses to 1500 trains of clicks. Duplicate recordings were made in response to each stimulus condition, to examine reproducibility. Sweep duration was 24 milliseconds.
MLS BAER Analysis
Analyses were conducted blinded to the medical history and clinical data of each subject. The measurements of MLS BAER components in 2 replicated recordings were averaged. The data obtained in response to 60-dB nHL clicks were analyzed in detail. For infants with thresholds of >20 dB nHL, however, the analysis was based on data collected at higher click intensities (ie, 70 dB nHL for thresholds of >20–30 dB nHL; n = 6 in the BPD group and n = 4 in the healthy, very preterm group; 80 dB nHL for thresholds of >30–40 dB nHL; n = 4 in the BPD group and n = 1 in the healthy, very preterm control group). Therefore, all data for the study group and the group of very preterm infants without BPD were analyzed at a hearing level 40 dB above the BAER threshold of each subject, which was the same as for the normal term control subjects. This allowed us to cancel the influence of slight threshold elevations on MLS BAER measurements and to compare MLS BAER data between groups at the same hearing level (ie, 40 dB above their thresholds). Any infants who had significant threshold elevations (>40 dB nHL) were excluded from the study, to avoid any significant effect of peripheral auditory impairment on MLS BAER measurements.
The BAER thresholds for the BPD, normal term, and healthy very preterm infants were 17 ± 8 dB nHL (range: 5–35 dB nHL), 15 ± 7 dB nHL (range: 5–40 dB nHL), and 11 ± 5 dB nHL (range: 5–20 dB nHL), respectively. The hearing levels (ie, the decibels above their thresholds) at which MLS BAER recordings were analyzed were 48 ± 9 dB nHL (range: 40–55 dB nHL), 47 ± 6 dB nHL (range: 40–55 dB nHL), and 49 ± 5 dB nHL (range: 40–55 dB nHL), respectively, which did not differ significantly.
Comparisons of the mean and SD of each MLS BAER variable at each stimulus condition between the groups was conducted by using analysis of variance with a SPSS package (SPSS, Chicago, IL). Differences between groups were assessed with the posthoc Tukey test. The level of significance in probability was .05. The relationship between MLS BAER variables and the repetition rate of clicks was examined with correlation and regression analyses. The slope (or regression coefficient) of the latency- or interval-rate function was calculated for each MLS BAER variable. A one-sample t test of the slopes of latency-rate functions was conducted for each MLS BAER variable, to determine whether the slopes of the linear latency- and interval-rate functions were consistently different from 0. Any functions that were significantly greater than 0 at the .05 level or better were then compared between different groups of subjects, to detect any differences in the changes in MLS BAER data with varying repetition rates of click stimuli, or rate-dependent changes.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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I–V and III–V intervals in the infants with BPD were longer at all click rates, compared with the 2 control groups (Fig 3, A and C). Both the I–V and III–V intervals differed significantly among the 3 groups, and the differences were increased with the increase in click rates (P < .01 to P < .0001 for the I–V interval and P < .001 to P < .0001 for the III–V interval). In contrast, the I–III interval in the infants with BPD was similar to that in the normal term control subjects and was slightly longer than that in the very preterm infants without BPD (Fig 3B). There were no statistical differences among the 3 groups of infants at any click rates. The III–V/I–III interval ratio in the infants with BPD was greater than that in the very preterm and particularly term control subjects (Fig 4). Analysis of variance showed that the interval ratio differed among the 3 groups, which was more significant at higher rates than at low rates (P < .001 to P < .0001).
Comparison Between Infants With BPD and Normal, Term Control Subjects
Compared with the term infants, the latencies of waves I and III in the infants with BPD, although they tended to be longer, did not show any significant differences (Fig 2, A and B). However, wave V latency was significant longer than that in the term control subjects at all 91 to 910 clicks per second rates (P < .001 to P < .0001) (Fig 2C). I–V and, in particular, III–V intervals in the infants with BPD were significant longer than those in the term control subjects at all click rates (P < .001 to P < .0001) (Fig 3, A and C). The increases in all of these MLS BAER variables became more significant as the click rate was increased. However, the I–III interval in the infants with BPD was similar to that in the term control subjects at all click rates (Fig 3B). The III–V/I–III interval ratio in the infants with BPD was significantly greater than that in the term control subjects, and the difference increased with the increase in click rates (P < .001 to P < .0001) (Fig 4). No statistically significant differences were found between the 2 groups of infants in the amplitudes of waves I, III, and V, although wave V amplitude tended to be smaller in the infants with BPD than in the control subjects at 910 clicks per second.
Similar to those in the term infants, all wave latencies, all interpeak intervals, and the III–V/I–III interval ratio in the infants with BPD correlated positively and significantly with click rates (r = 0.44–0.83; all P < .01). Compared with other MLS BAER variables, wave V latency and I–V and III–V intervals had better correlations (r = 0.79–0.83). Regression analyses showed that all latency- and interval-rate functions were greater than 0 at the .05 level or better. No significant differences were found between the infants with BPD and the term control subjects in the slopes of latency-rate functions for waves I and III and the I–III interval-rate function. However, the slopes of the wave V latency-rate function and the I–V and particularly III–V interval-rate functions were significantly steeper for the infants with BPD than for the term control subjects (all P < .01). The slope of the III–V/I–III interval ratio-rate function for the infants with BPD was also steeper (P < .01).
Comparison Between Infants With BPD and Healthy, Very Preterm Control Subjects
The latencies of waves I, III, and V in the infants with BPD all tended to be longer than those in the healthy, very preterm infants without BPD (Fig 2). Wave I and III latencies did not differ significantly between the 2 groups. Wave V latency in the infants with BPD was significantly longer than that in the infants without BPD, and the difference increased with the increases in click rates (P < .05 to P < .001) (Fig 2C). All interpeak intervals in the infants with BPD tended to be longer at all click rates (Fig 3). The I–V interval in the infants with BPD was significantly longer than that in the infants without BPD at all click rates, particularly 455 and 910 clicks per second (P < .05 to P < .0001) (Fig 3A). This was also the case for the III–V interval, but the differences between the 2 groups at various click rates tended to be more significant (P < .01 to P < .0001) (Fig 3, A and C). The III–V/I–III interval ratio in the infants with BPD was also greater than that in the infants without BPD, mainly at very high rates (P < .05 at 91 clicks per second, P < .01 at 455 clicks per second, and P < .001 at 910 clicks per second) (Fig 4). In general, the differences between the 2 groups at various rates were slightly smaller than those noted when the infants with BPD were compared with the term control subjects. The I–III interval in the infants with BPD tended to be longer than that in the infants without BPD at higher rates, but there was no significant difference. The amplitudes of waves I, III, and V were similar in the 2 groups, without any significant differences.
All wave latencies, all interpeak intervals, and the III–V/I–III interval ratio in the very preterm infants without BPD correlated positively and significantly with click rates (r = 0.52–0.773; all P < .01). Regression analyses showed that, similar to the infants with BPD, the latency- and interval-rate functions in the infants without BPD were all greater than 0 at the .05 level or better. The slope of the latency-rate function for wave V in the infants with BPD was significantly steeper than that in the infants without BPD (P < .05), although the slopes of latency-rate functions for waves I and III were similar in the 2 groups. The slopes of the I–V and III–V interval-rate functions for the infants with BPD were significantly steeper than those for the infants without BPD (P < .01 and P < .01, respectively). The slopes of the I–III interval-rate function and III–V/I–III interval ratio-rate function for the infants with BPD were also steeper than those for the infants without BPD (P < .05 and P < .05, respectively).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The infants with BPD showed major abnormalities in MLS BAER central components, that is, components that are related mainly to central neural function, including wave V latency and I–V and III–V intervals, which were particularly significant at very high rates (455 and 910 clicks per second). In contrast, no apparent abnormalities were found in the components that are related mainly to peripheral auditory function, including wave I and III latencies. There were also no abnormalities in the I–III interval, which reflects the functional integrity of the more-peripheral or caudal part of the auditory brainstem. Therefore, the increase in wave V latency and I–V interval in the infants with BPD must be fundamentally produced by the significant increase in the III–V interval, which reflects the functional integrity of the more-central or rostral part of the auditory brainstem. This is supported by the significant increase in the III–V/I–III interval ratio. These results suggest that neural conduction, mainly related to myelination, in the more-central or rostral part of the auditory brainstem is delayed or impaired after BPD.
In the BAER, the stimulus rate-dependent change (ie, the change in the BAER with the increase in stimulus presentation rate) reflects primarily neural processes concerning the efficacy of central synaptic transmission, as well as neural synchronization and the metabolic status of auditory neurons in the brainstem after the presentation of a physiological challenge.21,22,27,31 The abnormalities in MLS BAER central components in the infants with BPD generally increased with increases in the rate of clicks. The increased slopes of the wave V latency-rate function and I–V and particularly III–V interval-rate functions suggest that the stimulus rate-dependent changes in MLS BAER central components are increased. This is supported by the increased slope of the III–V/I–III interval ratio-rate function. These increases indicate that auditory neurons in the more-central part of the brainstem in infants with BPD are vulnerable to physiological/temporal challenges of acoustic stimulation, resulting in decreased efficacy of central synaptic transmission or decreased ability of central neurons to recover in time to transmit the next stimulus-evoked response. Therefore, in addition to the impairment in myelination, central synaptic efficacy in the brainstem is impaired after BPD. The increased abnormalities in the MLS BAER with the increase in click rate may be also related to impairments in synaptic processing, refractory period, and synchronization.
Our previous studies showed that preterm birth itself does not have any major effect on the BAER.22,32 In comparison with the age-matched, healthy, very preterm infants without BPD, MLS BAER central components in the infants with BPD also increased, although the differences between the 2 groups were slightly smaller than those between the infants with BPD and the term control subjects. The differences were more significant with the increases in click rates. The slopes of the I–V and III–V interval-rate functions and III–V/I–III interval ratio-rate function for the infants with BPD were all steeper than those for the very preterm infants without BPD, which suggests that stimulus rate-dependent changes in MLS BAER central components increased in infants with BPD, compared with those without BPD. All of these results indicate that the MLS BAER abnormalities are not attributable to the effects of very preterm birth but are attributable mainly to the effects of BPD and associated perinatal conditions.
Severe hypoxemia disturbs the metabolism of neurons, depresses the electrophysiological function of synapses, and interferes with nerve conduction.33 This can lead to neuronal impairment or dysfunction of the immature brain. Auditory neurons in the neonatal brainstem are vulnerable to hypoxic-ischemic insult. Severe perinatal hypoxia-ischemia can produce discrete lesions in the brainstem that often involve the auditory pathway, including loss of neurons with gliosis or ischemic cell changes in the cochlear nuclei, superior olive, and inferior colliculus.12,34–36 Our MLS BAER studies in humans and animal models have revealed that perinatal hypoxia-ischemia has a major effect on the neonatal auditory brainstem.11,23–26
Major clinical events for infants with BPD include frequent episodes of hypoxemia or prolonged hypoxemia. Our infants with BPD showed major abnormalities in MLS BAER central components, reflecting impaired functional integrity and development of the auditory brainstem. The abnormalities are most likely to be attributable mainly to frequent episodes of hypoxemia or prolonged sublethal hypoxemia associated with BPD. During childhood, however, the pathophysiological development of neurodevelopmental deficits in BPD survivors is more likely to be multifactorial, including hypoxemia during the course of BPD, postnatal growth deficiencies, and altered environmental stimulation.37–39
In BPD, the prolonged hypoxemia is often associated with periods of oxygen desaturation, as well as suboptimal respiratory mechanics.1 BPD is associated invariably with therapy with high oxygen concentrations for prolonged periods. The prolonged exposure to high oxygen concentrations has complex biochemical, microscopic, and gross anatomic effects on lung tissues, which can injure the immature lungs and cause more hypoxemia. Furthermore, infants with BPD often have associated adverse clinical conditions or complications, such as great immaturity, respiratory distress syndrome, patent ductus arteriosus, disrupted alveolar and capillary development, pulmonary interstitial emphysema, oxygen toxicity, or perinatal infection or inflammation.1 These may directly or indirectly produce some damage in the immature brain, contributing to the MLS BAER abnormalities.
Major brain injuries, such as severe intraventricular hemorrhage, periventricular leukomalacia, or hypoxic-ischemic encephalopathy, can result in BAER abnormalities. In the present study, none of our subjects had severe intraventricular hemorrhage, periventricular leukomalacia, or hypoxic-ischemic encephalopathy. Therefore, the confounding effects of major brain injuries can be excluded from the MLS BAER abnormalities found in our infants with BPD. In addition, none of our subjects had other major perinatal complications (severe intrauterine growth restriction, congenital malformation or congenital or perinatal infection of the CNS, hyperbilirubinemia, neonatal meningitis, or persistent pulmonary hypertension), which may affect the functional integrity of the auditory brainstem and result in BAER abnormalities. Therefore, there were no confounding effects on our MLS BAER results attributable to other major perinatal complications or problems.
Some of our subjects were monitored for several months to 2 years. The MLS BAER abnormalities in the infants with BPD generally resolved with improvements in clinical condition, although there were still certain degrees of abnormalities in some of the infants. Those who had persistent BAER abnormalities often had unfavorable neurodevelopment during postnatal life.
In the past several years, we have used the MLS BAER to study the functional integrity of the auditory brainstem in infants after severe perinatal hypoxia or hypoxia-ischemia, and we have found that this relatively new technique is a valuable method to improve the detection of hypoxic-ischemic brain damage.11,23–26 In the present study, the abnormalities in MLS BAER components in the infants with BPD generally increased with the increases in click rate and often occurred at the very high rates of 455 and 910 clicks per second, which cannot be achieved in conventional BAER testing. The increases in wave V latency, I–V and III–V intervals, and III–V/I–III interval ratio were most significant at 455 and 910 clicks per second. These findings indicate that the MLS BAER can also detect less-severe brainstem auditory impairment related to prolonged or chronic sublethal hypoxia, providing important information for clinical management of infants with BPD.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Early detection of brain damage or neurologic impairment in infants with BPD is essential for clinical management of these infants and improvements in outcomes. To date, there are few reports regarding early detection using noninvasive objective tests that can be used conveniently at the bedside. This study shows that MLS BAER testing holds promise to be such a test. Abnormalities in MLS BAER central components offer an early indicator of neurologic impairment in infants with BPD.
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ACKNOWLEDGMENTS |
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We thank the nurses and doctors in the neonatal unit and maternity wards of John Radcliffe Hospital for their enthusiastic support and assistance in recruiting subjects and collecting data.
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FOOTNOTES |
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Address correspondence to Ze D. Jiang, MD, PhD, Neonatal Unit, Department of Paediatrics, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom. E-mail: zedong.jiang{at}paediatrics.ox.ac.uk
The authors have indicated they have no financial relationships relevant to this article to disclose.
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