Stabilizing immature breathing patterns of preterm infants using stochastic mechanosensory stimulation

Abstract

Breathing patterns in preterm infants consist of highly variable interbreath intervals (IBIs) that might originate from nonlinear properties of the respiratory oscillator and its input-output responses to peripheral and central signals. Here, we explore a property of nonlinear control, the potential for large improvement in the stability of breathing using low-level exogenous stochastic stimulation. Stimulation was administered to 10 preterm infants (postconceptional age: mean 33.3 wk, SD 1.7) using a mattress with embedded actuators that delivered small stochastic displacements (0.021 mm root mean square, 0.090 mm maximum, 30-60 Hz); this stimulus was subthreshold for causing arousal from sleep to wakefulness or other detectable changes in the behavioral state evaluated with polysomnography. We used a test-retest protocol with multiple 10-min intervals of stimulation, each paired with 10-min intervals of no stimulation. Stimulation induced an approximately 50% reduction (P = 0.003) in the variance of IBIs and an approximately 50% reduction (P = 0.002) in the incidence of IBIs > 5 s. The improved stability of eupneic breathing was associated with an approximately 65% reduction (P = 0.04) in the duration of O(2) desaturation. Our findings suggest that nonlinear properties of the immature respiratory control system can be harnessed using afferent stimuli to stabilize eupneic breathing, thereby potentially reducing the incidence of apnea and hypoxia.

Fig. 1.

Example of protocol in one infant (infant 4) showing alternating stimulus condition (top), behavioral state [awake (AW), active sleep (AS), intermediate sleep (IS), and quiet sleep (QS)], and analysis of interbreath intervals [IBI variance, IBI > 5 s, and IBI (bottom)]. The dotted bar represents a period of feeding during which signals were not recorded.

Fig. 2.

Plot of IBI variance in the off condition and on condition for each infant. ■, Infant 1; ▲, infant 2; ▼, infant 3; ◆, infant 4; ●, infant 5; □, infant 6; △, infant 7; ▽, infant 8; ◇, infant 9; ○, infant 10. The mean IBI variance in the on condition (0.46 s²) was reduced by 50% (P = 0.003) compared with the off condition (0.91 s²).

Fig. 3.

A: plot of the incidence of IBI > 5 s in the off condition and on condition for each infant. ■, Infant 1; ▲, infant 2; ▼, infant 3; ◆, infant 4; ●, infant 5; □, infant 6; △, infant 7; ▽, infant 8; ◇, infant 9; ○, infant 10. The mean incidence of IBI > 5 s in the on condition (18.62 h⁻¹) was reduced by 50% (P = 0.002) compared with the off condition (37.07 h⁻¹). B: plot of the ratio of values in the on condition and off condition, showing a strong correlation between the stimulation-associated reductions in IBI variance and the incidence >5 s (r = 0.733, P = 0.008). The solid line is the linear regression.

Fig. 4.

Plot of incidences of IBIs within specified ranges, normalized as a ratio between the on condition and off condition (I_on/I_off). A ratio of 1 (dotted line) reflects identical incidences in the two conditions. Error bars are SDs of the ratio across subjects. The reduction was significant (*P < 0.05) for IBI of 5–10 s and IBI >10 s. Mean (SD) values for incidences are as follows: IBI < 2 s, on condition 2,927 h⁻¹ (SD 681) and off condition 2,616 h⁻¹ (SD 625); IBI of 2–5 s, on condition 129 h⁻¹ (SD 102) and off condition 176 h⁻¹ (SD 98); IBI of 5–10 s, on condition 17.4 h⁻¹ (SD 15.9) and off condition 33.8 h⁻¹ (SD 25.0); and IBI > 10 s, on condition 1.18 h⁻¹ (SD 2.00) and off condition 3.31 h⁻¹ (SD 3.50). Apnea > 20 s was subjected to resuscitative measures by the medical staff and was recorded only twice in the entire study. Both instances occurred in infant 2 during the off condition.

Fig. 5.

Example (infant 3) of temporal changes in breathing patterns after the onset of stimulation and offset of stimulation. A: onset of stimulation (at the end of the 10-min off interval) was associated with a rapid switch from periodic to regular breathing (top), with was associated with reduced variability in IBI and in wavelet-derived power ≤2 s and reduced power of periodicities >5 s. B: offset of stimulation (at the end of the 10-min on interval) was associated with a gradual (over ∼1 min) evolution in the breathing pattern from eupnea to a progressively less stable pattern with increasing variability in IBI and wavelet power <2 s and a rise in wavelet power >5 s, which corresponded to the emergence of periodic breathing and apnea pattern. The bottom images show the contour plot of wavelet power. The color scale was mapped to log of normalized power using the normalized energy function (65). Note the complex temporal evolution of a range of periodicities, induced by the onset and offset of stimulation.

Fig. 6.

Summary of findings with the stimulation on condition compared with the off condition. See Table 2 for values in each condition. Error bars represent intervals of 95% confidence around the mean values.