Predictive value of early amplitude integrated electroencephalogram (aEEG) in sleep related problems in children with perinatal hypoxic-ischemia (HIE)

Our research protocol was approved by IRB of Children’s Hospital of Soochow University (IRB approval number: 2017038). All participants received consent form their parents. We initially included 101 neonates who were born in local hospital, diagnosed for HIE (1 min Apgar score < 7), and transferred to Children’s Hospital of Soochow University within 1wk after birth between Jan. 2016 and Jan. 2018. Within the 73 cases that were diagnosed as severe HIE, 16 of them were transferred to our hospital late than 6 h after birth and thus were ineligible for hypothermia treatment [26‐29]. The left were eligible for hypothermia treatment. However, due to lack of devices and personnel, we did not implement hypothermia treatment for neonates prior to Jan. 2019. Follow-up interviews of neonates with severe HIE revealed that 2 died < 2 yr, 5 with cerebral palsy, 2 with secondary epilepsy, 8 with language developmental disorders and 28 with various degrees of developmental retardation. Exclusion criteria include: gestational age < 37 or > 42 weeks, major ischemic stroke, congenital malformations, chromosomal abnormalities and central nervous infections. General information of participants was listed in Table 1.

We placed a pair of biparietal electrodes at P3/P4 for aEEG recording (Natus 580-NLICU1, USA). The aEEG recording was continuously performed for 24 h, immediately after transferring to our hospital, with a paper speed of 6 cm/h. The initial time for aEEG recording was within 72 h after birth (35.128 ± 19.953 h).

The aEEG patterns were analyzed by 2 independent technicians. The following parameters, according to [14] and others [11, 30],were used for pattern analysis:

We investigated sleep and circadian rhythm problems by telephone interview in the cohort of HIE patients who received aEEG recordings during their hospitalization (see above section) using a self-designed questionnaire that was used in a previous study [12]. Telephone interview was completed when children were between 26 to 42 months. In brief, we include 7 variables: 1) Unfixed nocturnal sleep-onset time; 2) Extensive settling time (> 20 min); 3) Insufficient sleep (< 11 h); 4) Change in daily sleep schedule; 5) Snore loudly; 6) Sleep breathing problems; 7) Frequent wakes at night (> 2 times/night). Note: detailed description for each variable please refer to [12]. For individual variables, we applied a 0–2 scale: 0 for never happened in the past 6 months, 1 for 3 times/week in the past 6 months, and 2 for > 3 times/week in the past 6 months. The sum of all variables is attributed as sleep score. For each variable, we averaged results from two interviews with a 3-week interval. Exclusion criteria: 1) Refuse of parents or guardian to provide detailed information during telephone interview; 2) Taking sleep affective medications (e.g. anticonvulsant, sedatives, and neurostimulant drugs) within the past months before telephone interview; 3) A follow-up physical examination that discovered traumatic injuries and/or developmental abnormalities leading to severe up-airway obstruction, if sleep breathing problem was identified during telephone interview.

Quantitative variables were compared by t-test, and qualitative variables were compared by the χ² test or Fisher’s exact test. Skew distribution data was presented as median (interquartile) and the differences between groups were examined by nonparametric test. The correlation between aEEG/SWC and daily sleep parameters, and aEEG parameters and daily sleep parameters were described using spearman correlation coefficient, with P values present. The Statistical analyses were conducted using IBM SPSS Statistics version 25.0 software. A P value less than 0.05 (two-sided) indicated statistical significance.

We included 101 neonates with HIE that were transferred to our hospital within hours after birth. The mean gestational age was 281.57 ± 37.84 d, and the mean birth weight was 3337.77 ± 516.08 g, with 68 males and 33 females. aEEG recording was started at a median age of 36 h (35.13 ± 19.96) for 24 h. Within them, 53.5% (54/101) showed normal background pattern (BP) with continuous normal voltage (CNV) recordings (Fig. 1A). The BP of the left (47/101) showed abnormalities including discontinuous normal voltage (DNV), burst suppression (BS), low voltage (LV) and flat trace (FT) (Fig. 1B-E). To investigate the predictive roles of aEEG patterns in neonates with HIE, we then divided the cohort in two groups: normal or abnormal aEEG BP and discovered no significant differences in gestational age, weight, sex, and the degree of HIE (Table 1). In addition, the degrees of HIE were independent of these characteristics (additional file 1). To perform detailed analysis of aEEG recordings, we scored aEEG recordings based on the frequency of normal vs abnormal BPs, the establishment of SWC, and the occurrence of seizures and quantified parameters that reflect brain activity and the variability of recorded signal (see method section for aEEG recording). Among these parameters, aEEG BP, SWC, seizures scores and their sum, along with low and high base voltages, indicators for cerebral activity, are statistically different between normal and abnormal BP groups (Fig. 1F). In contrast, the upper high voltage and bandwidth are independent from aEEG normality and thus could serve as reference parameters (Fig. 1F).

In a serial of follow-ups, we investigated the sleep quality and maintenance of normal behavioral rhythm activities in HIE neonates who received aEEG recordings. Based on the results of questionnaire, while the total sleep scores showed no statistical differences, neonates with abnormal aEEG BP tend to have more problems in maintaining daily sleep schedule, frequent night wake up and breathing during sleep (Table 2). In contrast, such differences were not observed in neonates with various degrees of HIE (additional file 2). These results indicated that aEEG BP normality might correlate with sleep-related circadian rhythm and breathing problems. To further test this, we calculated the correlations between seven sleep-related parameters with aEEG BP normality. In light with the comparison between neonates with either normal or abnormal aEEG BP groups, we found that aEEG BP is correlated with sleep schedule change and breathing problems (Table 3). Consistent with previous findings, the establishment of SWC was severely compromised in neonates with severe HIE (SWC score: 0.10 ± 0.36 (mild and moderate HIE) vs 0.66 ± 0.80 (severe HIE), t test, P < 0.001). However, the early establishment of SWC is not correlated with any developmental sleep-related issues (Table 3).

To investigate whether and how aEEG recording might play predictive roles in sleep related problems, we then performed correlation studies between individual aEEG parameters and sleep-related variables. Within these parameters, we identified that aEEG sum score and low base voltage are correlated with changes of daily sleep schedules, a circadian rhythm related issue. In contrast, BP score is correlated with sleep breathing problems (Table 4). These results indicated that individual aEEG parameters show distinct predictive roles in sleep related problems during child development.