Reference Values for Amplitude-Integrated Electroencephalographic Activity in Preterm Infants Younger Than 30 Weeks’ Gestational Age

PATIENTS AND METHODS

Newborn infants with a gestational age (GA) of <30 weeks admitted to the neonatal intensive care unit at the Vienna University Children’s Hospital (Vienna, Austria) were eligible for inclusion in the study. All infants were studied prospectively by using aEEG and cranial ultrasound.

Evaluation of aEEG Tracings

In the reference group, the first aEEG recording obtained during the first 2 weeks of life was evaluated. Tracings were evaluated visually and classified according to a modified version of the method adapted from Hellström-Westas et al¹⁹ and Thornberg and Thiringer.¹⁸ Descriptive analysis of aEEG tracings was done by dividing each trace in 10-minute epochs. These 10-minute epochs were classified into 3 pattern categories as follows (Fig 1):

• Discontinuous low-voltage pattern: tracing with irregular bandwidth and marked variations of amplitude and voltage, minimal amplitude <3 μV, and maximal amplitude between 15 and 30 μV.

• Discontinuous high-voltage pattern: tracing with irregular bandwidth and marked variations of amplitude and voltage, minimal amplitude between 3 and 5 μV, and maximal amplitude between 20 and 40 μV.

• Continuous pattern: tracing with regular bandwidth, without marked variations of amplitude and voltage, minimal amplitude >5 μV, and maximal amplitude between 20 and 40 μV.

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Fig 1.

The 3 observed types of aEEG patterns in a patient of 28 + 2 weeks’ GA (the period between 2 vertical bars corresponds to 10 minutes).

This classification is based on visual perception, which can be confirmed by quantitative analysis of minimal and maximal amplitudes. Although there is an overlap concerning maximal amplitudes between the discontinuous low-voltage (15–30 μV) and the discontinuous high-voltage (20–40 μV) patterns, there is a clear distinction concerning minimal amplitudes (<3 μV for the discontinuous low-voltage pattern versus 3 to 5 μV for the discontinuous high-voltage pattern).

Sleep-wake cycles were defined as cyclical sinusoidal variations of both amplitude and continuity of aEEG activity with a minimum epoch duration of 20 minutes.^19,20 Bursts were defined as amplitudes >100 μV.

RESULTS

During the study period from January 1, 2000 to March 31, 2002, a total of 230 preterm infants <30 weeks of gestation were admitted to the neonatal intensive care unit of Vienna University Children’s Hospital. Of the 230 infants, 86 fulfilled the inclusion criteria. In 11 of 86 infants no aEEG tracings during the first week of life were available. The remaining 75 (33%) infants were in the following groups: 24 to 25 weeks’ GA (including [weeks + days] 24 + 0 to 25 + 6; n = 11); 26 to 27 weeks’ GA (including 26 + 0 to 27 + 6; n = 38); and 28 to 29 weeks’ GA (including 28 + 0 to 29 + 6; n = 26). One patient born in the 23rd week of gestation was included in the 24- to 25-week group.

Median GA was 27 weeks (range: 23–29 weeks), and median birth weight was 940 g (range: 491-1646 g). aEEG recordings were performed at a median postnatal age of 5 days (range: 1–14 days). Median duration of the recordings was 3.8 hours (range: 1.5–19.7 hours), and median impedance of the tracing was 3 kO (range: 2–20 kO).

The median duration of the discontinuous low-voltage pattern showed an inverse correlation to GA (r = −.408; P < .001), decreasing from 55.6% at 24 to 25 weeks to 34.0% at 26 to 27 weeks and 7.1% at 28 to 29 weeks.

The median duration of the continuous pattern increased with increasing GA (r = .373; P < .001), ranging from 0% at 24 to 25 weeks to 5.9% at 26 to 27 weeks and 16.9% at 28 to 29 weeks.

The duration of the discontinuous high-voltage pattern showed a nonsignificant trend to increase with higher GA.

The median number of bursts per hour showed an inverse correlation to GA (r = −.364; P = .001) decreasing from 20.4 per hour at 24 to 25 weeks to 14.9 per hour at 26 to 27 weeks and 4.4 per hour at 28 to 29 weeks.

The results are summarized in Table 1.

Cyclical variations of aEEG patterns were observed in all infants of the reference group. At lower GA, the patterns mostly varied between the discontinuous low-voltage and discontinuous high-voltage patterns (Fig 2), whereas at higher GA patterns mostly varied between the discontinuous high-voltage and continuous patterns (Fig 3).

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Fig 2.

Cyclical rhythmical variations as a change between the discontinuous low-voltage and discontinuous high-voltage patterns in a patient of 26 + 0 weeks’ GA (the period between 2 vertical bars corresponds to 10 minutes).

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Fig 3.

Cyclical rhythmic variations as a change between the discontinuous high-voltage and continuous patterns in a patient of 29 + 5 weeks’ GA (the period between 2 vertical bars corresponds to 10 minutes).

DISCUSSION

The present study describes for the first time the characteristics and developmental changes in aEEG background activity during the first 2 weeks of life in neurologically normal and clinically stable preterm infants <30 weeks’ GA. Analysis of aEEG background activity showed that with higher GA the relative amount of continuous activity increased while discontinuous activity decreased. The number of aEEG amplitudes >100 μV decreased with increasing GA. Cyclical changes in aEEG background activity resembling early sleep-wake cycles could be observed in all preterm infants during the first 2 weeks of life.

To date, only 3 studies have investigated aEEG activity in preterm infants. Thornberg and Thiringer¹⁸ studied healthy preterm infants between 30 and 36 weeks’ GA. They described a broader, discontinuous pattern and a more narrow, continuous pattern of aEGG activity in 30- to 31-week-old infants. These patterns correspond well to the continuous and discontinuous high-voltage patterns found in the more mature infants in the present study (Fig 3). Hellstrom-Westas et al¹⁹ studied aEEG activity in extremely low birth weight infants between 26 and 33 weeks’ GA during the first week of life. A more recent study by the same group described the use of aEEG for prediction of outcome in preterm infants with large IVHs.¹⁶ In contrast to findings in the current study, “burst suppression” was the prevailing pattern in the vast majority of infants. Only a small number of infants had brief episodes of intermixed continuous activity. However, most infants in these studies were severely ill, required ventilation at the time of the recording, and had received phenobarbitone, which may have caused increased aEEG discontinuity.²³ By contrast, the infants in the current study were neurologically normal and clinically stable at the time of the recording and had not received any sedative medication. Therefore, the results of the current study are most reliable.

aEEG background activity in preterm infants commonly is classified into continuous and discontinuous patterns.^16,19 However, based on our experience with aEEG in very preterm infants,²⁰ we determined that there are 2 discernible discontinuous aEEG patterns in most preterm infants: one pattern that resembles a more immature form of discontinuity (frequently labeled burst suppression) with lower minimum amplitudes (<3 μV) and higher maximum amplitudes; and one pattern that resembles a more mature form of discontinuity with higher minimum amplitudes (between 3 and 5 μV) and higher maximum amplitudes. In the current study, we therefore decided to divide the discontinuous pattern further into 2 called the “discontinuous low-voltage” (which shows a peak at 24–25 weeks’ GA) and “discontinuous high-voltage” (which shows a peak at 26–27 weeks’ GA) patterns (Figs 1 and 2).

In keeping with the results from the present study, other investigators using conventional EEG in preterm infants found that with increasing GA continuous background activity increased while discontinuous activity decreased.^6,24,25 Similarly, the interburst interval, a surrogate measure of EEG discontinuity, was reported to decrease as GA increases.^5,6,24,25 Interestingly, in the present study, periods of continuous aEEG activity were found in preterm infants as early as 23 weeks of gestation. Hayakawa et al,⁶ using 8-channel conventional EEG, also found brief episodes of continuous activity as early as 23 weeks’ GA. Connell et al²⁵ found brief periods of continuous activity at 26 weeks’ GA. Other authors did not find continuous activity at these early GAs.^5,26 However, this discrepancy may be explained by differences in the study population. Further, most of the infants in our study received caffeine citrate for treatment of apnea. Possibly, the central arousing effects of caffeine led to an increase of continuous activity in the infants.

Cyclical variations of aEEG background activity could be detected in even the most premature infants in our study. These variations may be interpreted as early sleep states.^19,20 Similar variations of aEEG activity were found in 2 other studies using aEEG and clinical observation. The authors referred to these patterns as “sleep-wake cycles.”^19,27 The concept of sleep states in the very premature infant is controversial. Earlier studies suggested that organized sleep states do not appear before 32 weeks of gestation.^28,29 However, possibly because of improvements in neonatal intensive care in the last decades, more recent studies have described rudimentary sleep states in extremely premature infants.^5,30 Intact sleep organization is a prognostic factor in preterm infants.^31,32 Thus, the presence of cyclical variations of aEEG activity may be useful for prediction of outcome in preterm infants.¹⁹ In that context, it is of interest that only a few of the infants with large IVH in the study by Hellstrom-Westas et al had sleep-wake cycles.¹⁶

The possibility exists that the cyclical variations of aEEG activity found in the present study were caused by changes in environmental factors during the recording and do not represent changes in state. However, because impedance remained unchanged during the recording, technical artifacts can largely be excluded. The fact that the aEEG changes were also observed between routine nursing care rounds when the infants were not disturbed makes reactivity to handling also unlikely.¹⁹ We therefore hypothesize that the cyclical variations of aEEG activity found in our cohort of preterm infants are early, rudimentary sleep states that may represent switches between different, possibly thalamocortical and neocortical pattern generators.³³

The number of burst (amplitudes >100 μV) per hour on aEEG background activity found in the preterm infants in the present study was relatively high compared with term infants. Although in term infants the presence of repeated bursts may indicate seizure activity,⁸ our results show that in neurologically normal and clinically stable preterm infants <30 weeks’ GA, the presence of bursts seems to be a physiologic phenomenon. This finding is in agreement with conventional EEG studies, in which amplitudes up to 500 μV may still be physiologic.²⁶

The present study aimed to establish normal values and patterns for aEEG activity in healthy preterm infants <30 weeks of gestation. However, the criteria of what constitutes a healthy, normal preterm infant are not easy to define, because prematurity itself is a pathology. We defined “healthy” in our study population as the absence of neurologic abnormalities (including sedation and analgesia) at the time of the aEEG recording and a normal cranial ultrasound scan throughout the study period. Therefore, the data of the preterm infants in this study may be considered normal values.

CONCLUSIONS

The characteristics and development of aEEG activity during the first 2 weeks of life were described in this cohort of 75 neurologically normal and clinically stable preterm infants <30 weeks’ GA. Percentiles for frequencies of discontinuous and continuous patterns have been established and may be used as reference values for patients at these very early GAs. Cyclical variations of aEEG background activity corresponding to early sleep-wake cycles can be found in preterm infants as early as 23 weeks’ GA.