Premature infants have immature respiratory control and cerebral autoregulation. We aimed to investigate changes in cerebral oxygenation during apnea with and without peripheral oxygen desaturation in premature infants.
This prospective observational study was conducted at Inha University Hospital. Near-infrared spectroscopy (NIRS)-monitored regional cerebral oxygen saturation (rScO2) and pulse oximeter-monitored peripheral oxygen saturation (SpO2) were assessed during the first week of life in 16 stable, spontaneously breathing preterm infants. Apneic episodes that lasted for ≥20 seconds or were accompanied by desaturation or bradycardia were included for analysis. The average rScO2 value during the 5-minute prior to apnea (baseline), the lowest rScO2 value following apnea (nadir), the time to recover to baseline (recovery time), the area under the curve (AUC), and the overshoot above the baseline after recovery were analyzed.
The median gestational age and birth weight of the infants were 29.2 weeks (interquartile range [IQR], 28.5 to 30.5) and 1,130 g (IQR, 985 to 1,245), respectively. A total of 73 apneic episodes were recorded at a median postnatal age of 2 days (IQR, 1 to 4). The rScO2 decreased significantly following apneic episodes regardless accompanied desaturation. There were no differences in baseline, nadir, or overshoot rScO2 between the two groups. However, the rScO2 AUC for apnea with desaturation was significantly higher than that for apnea without desaturation.
Cerebral oxygenation can significantly decrease during apnea, especially when accompanied by reduced SpO2. These results add the evidence for the clinical utility of NIRS in monitoring premature infants.
Most preterm infants born before 32 weeks of gestation experience apnea. Despite the frequency of apnea of prematurity, it is not well understood whether apnea in preterm infants is related to cerebral ischemia [
Since its introduction in 1977 [
A peripheral oxygen saturation (SpO2) of <85%, measured using pulse oximetry, has been identified as significantly impacting cerebral oxygenation in neonates with apnea of prematurity [
This was a prospective observational study conducted in the neonatal intensive care unit of Inha University Hospital, Incheon, Korea. Sixteen stable, spontaneously breathing preterm infants with gestational ages (GA) of <32 weeks were included. Caffeine was administered (loading dose 10 to 20 mg/kg, maintenance dose 5 mg/kg daily) to all infants. Mild respiratory support with nasal continuous positive airway pressure or high-flow nasal cannula therapy was permitted. Infants requiring invasive mechanical ventilation, those with grade 2 or higher intraventricular hemorrhage (IVH), or those with major congenital anomalies were excluded. The Inha University Hospital Institutional Review Board approved the study protocol (2017-03-014), and written informed consent was obtained from the infants’ parents.
Heart rate (HR), SpO2, and rScO2 measurements were started within 24 hours after birth and continued for the first week of life. Apnea was defined as a period with no breathing, (1) lasting for ≥20 seconds, or (2) accompanied by desaturation (SpO2 <85%) or bradycardia (HR <100/min), even if at of shorter duration. Of a total of 135 apneic episodes of 16 patients, we selected 73 episodes that did not overlap within 30 minutes. Because we aimed to investigate the effect on cerebral oxygenation of an individual apneic episode and its difference based on the presence of peripheral desaturation, we excluded repeated or overlapped apneas within 30 minutes. We divided the apneic episodes into two groups: with or without peripheral oxygen desaturation (SpO2 <85%).
Obstetric and neonatal data were collected from medical records. We measured rScO2 using the INVOS 5100 cerebral oximeter (Somanetics Corp., Troy, MI, USA). An INVOS 5100 neonatal sensor was attached to the skin of each infant’s forehead. Continuous measurements with a sampling interval of 5 seconds were recorded and transferred to a personal computer. SpO2 and HR were measured using a Radical-7 Pulse CO-Oximeter (Masimo Corp., Irvine, CA, USA). An LNCS Neo-L adhesive sensor (Masimo Corp.) was attached to the right hand of each infant. Measurements were recorded every 10 seconds and transferred to a personal computer through an RS-232 serial communication port. Data were collected simultaneously using dedicated software. In addition, available data regarding the patients’ clinical characteristics, hemoglobin, hematocrit, and capillary blood gas analysis results were collected.
For each apneic episode, the baseline rScO2 value was calculated as the average during the 5 minutes before the apneic episode. The nadir was recorded as the lowest rScO2 value during the 5 minutes after the onset of apnea. The time to recover to baseline (recovery time), area under the curve (AUC) from baseline, and overshoot following the recovery of rScO2 were also analyzed (
Baseline demographic characteristics of the included patients are presented in
A total of 73 episodes of apnea were analyzed. The median postmenstrual and postnatal ages at episodes were 29.6 weeks (IQR, 27.3 to 30.6) and 2 days (IQR, 1 to 4), respectively.
According to the repeated-measures ANOVA, although rScO2 decreased significantly following apnea in both groups (
This study shows that, regardless of whether SpO2 is reduced, apneic episodes are associated with a decrease in cerebral oxygenation in very preterm infants. This observation provides important insight into the potentially deleterious effects of repeated episodes of apnea, especially with regard to the possibility of causing or exacerbating hypoxic-ischemic brain injury. When apneic episodes are accompanied by peripheral desaturation, cerebral ischemia could be prolonged, and it could take more time to recover. Additionally, these results contribute to the body of knowledge about the clinical utility of NIRS in monitoring cerebral circulation.
The strong dependence of rScO2 on SpO2 seen in our study is not surprising. NIRS measures the ratio of oxygenated hemoglobin to total hemoglobin in the area covered by a dedicated sensor, which includes a mixture of oxygen saturation values from arterial, capillary, and venous blood [
Regarding the association between rScO2 and SpO2, Schmid et al. [
Interestingly, in most of the apneic episodes (62/73, 84.9%) in our study, cerebral saturation briefly increased from baseline for 5 to 20 seconds after recovery from a reduction following apnea, even though none was supported by an increased fraction of inhaled oxygen (FiO2) to assist recovery from apnea. In our study, 17 apneic episodes (23.3%) recovered spontaneously, and tactile stimulation was applied in the remaining cases (76.7%) to facilitate recovery from apnea. However, there were no differences in the levels and durations of rScO2 overshoot between apneic episodes in patients with and without desaturation. Baerts et al. [
There are several potential limitations to this study. First, there was an intentional selection bias, in that we excluded repeated episodes of apnea within a 30-minute interval, because we aimed to demonstrate the effects on cerebral oxygenation of individual apneic episodes with and without peripheral desaturation. This selection bias could result in no differences in HR or the frequency of bradycardia between the two groups. Repeated apnea within a short interval likely to be associated with profound desaturation and bradycardia, and would therefore have a more dramatic effect on cerebral oxygenation. Further studies are required to investigate the increased harm to the brain caused by frequently repeated apneic episodes. Second, we did not analyze cerebral fractional tissue oxygen extraction (cFTOE), which reflects regional oxygen delivery or consumption; rather, we analyzed only changes in rScO2 during apneic episodes, whether accompanied by a reduction in SpO2 or not. The cFTOE is calculated as the ratio between peripheral saturation minus cerebral saturation and peripheral saturation [(SpO2–rScO2)/SpO2] [
In this study, we observed that cerebral oxygenation in preterm infants can significantly decrease during apnea, especially when accompanied by reduced SpO2 (<85%). Because the NIRS technique does not allow separate measurement of changes in oxygenation and perfusion, it is difficult to comment on whether the brain parenchyma was exposed to hypoxia or not. Since we observed posthypoxic overshoots in cerebral oxygenation, reflecting posthypoxic vasodilation and reperfusion, we can speculate that the brain parenchyma may have been subjected to hypoxia during apnea. This indicates that cerebral desaturation may be an effective indicator of cerebral circulation during apnea in preterm infants. In this context, neuroprotective management could be guided by continuous rScO2 monitoring with regard to systemic-cerebral hemodynamic interactions.
Less is known about the long-term effects of short but frequent episodes of hypoxemia and post-hyperoxemia on the brains of preterm infants. Regardless of the exact mechanism, we can infer that this is likely a contributing factor to neuronal injury and the start of the cascade leading to neuronal death or gliosis. Further studies are warranted to determine the detailed mechanisms and factors influencing rScO2 variation, the rScO2 threshold that indicates brain injuries, and the long-term outcome.
The Inha University Hospital Institutional Review Board approved the protocol (2017-03-014), and written informed consent was obtained from the parents.
No potential conflict of interest relevant to this article was reported.
Conceptualization or design: S.H.C., J.L.
Acquisition, analysis, or interpretation of data: S.H.C., J.L., S.K.N., Y.H.J.
Drafting the work or revising: S.H.C., J.L., S.K.N, Y.H.J.
Final approval of the manuscript: S.H.C., J.L., S.K.N, Y.H.J.
This work was supported by a 2017 Inha University Hospital Research Grant.
Representative tracing of regional cerebral oxygen saturation (rScO2) during an apneic episode, demonstrating the values, time frames, and points of interest used for the analysis during apneic episodes. Baseline: average rScO2 during the 5 minutes before the apneic episode; nadir: the lowest value of rScO2 during the 5 minutes after the onset of apnea; recovery time: time to recover to baseline rScO2; area under the curve (AUC): area of the difference from baseline during recovery; overshoot: the highest value of rScO2 after recovery of rScO2.
Box plots of cerebral oxygen saturation (rScO2) during apnea with and without peripheral desaturation. According to the repeated-measures analysis of variance, although rScO2 decreased significantly following apnea in both groups (
Baseline Demographics of Patients (n=16)
Variable | Value |
---|---|
Gestational age (wk) | 29.2 (28.5–30.5) |
Birth weight (g) | 1,130 (985–1,245) |
Apgar score 1 min | 2 (1–5) |
Apgar score 5 min | 3.5 (3–6.25) |
Vaginal delivery:Cesarean section | 7:9 (43.8:56.2) |
Antenatal steroids | 11 (68.8) |
Maternal oligohydramnios | 1 (6.3) |
Maternal preeclampsia | 5 (31.3) |
Small for gestational age | 1 (6.3) |
Respiratory distress syndrome | 9 (56.3) |
Germinal matrix hemorrhage | 1 (6.3) |
Caffeine use | 16 (100) |
Values are expressed as median (interquartile ranges) or number (%).
Clinical Characteristics at the Time of Apneic Episodes
Characteristic | With desaturation (n=29) | Without desaturation (n=44) | |
---|---|---|---|
Postnatal age (d) | 2 (1–3) | 2 (1–4.5) | 0.234 |
Postmenstrual age (wk) | 29.6 (27.3–30.4) | 29.9 (27.4–30.7) | 0.435 |
Heart rate, baseline (/min) | 136 (80–152) | 137 (116–154) | 0.364 |
Heart rate <100/min | 11 (37.9) | 8 (18.2) | 0.108 |
Heart rate <80/min | 5 (17.2) | 4 (9.1) | 0.469 |
Blood pressure (mm Hg) | |||
Mean | 38.0 (34.0–41.7) | 38.3 (35.7–41.0) | 0.580 |
Systolic | 57.0 (50.0–59.0) | 53.0 (50.0–58.5) | 0.469 |
Diastolic | 29.0 (26.0–31.0) | 30.0 (28.0–35.0) | 0.152 |
Respiratory support | 0.739 | ||
None | 9 (31.0) | 13 (29.5) | |
Oxygen | 2 (6.9) | 1 (2.3) | |
Nasal continuous positive airway pressure | 6 (20.7) | 8 (18.2) | |
Highflow nasal cannula | 12 (41.4) | 22 (50.0) | |
Fraction of inhaled oxygen | 0.21 (0.21–0.21) | 0.21 (0.21–0.21) | 0.462 |
Capillary blood gas analysis | |||
pH | 7.34 (7.31–7.36) | 7.37 (7.29–7.41) | 0.198 |
pCO2 (mm Hg) | 34.1 (30.3–44.4) | 35.2 (30.5–40.0) | 0.787 |
BE (mmol/L) | –5.1 (–8.8 to –3.3) | –4.7 (–9.2 to –2.2) | 0.628 |
Hemoglobin concentration (g/dL) | 16.9 (14.5–17.9) | 16.4 (12.0–18.7) | 0.906 |
Blood glucose (mg/dL) | 109 (93–118) | 109 (8–140) | 0.573 |
Feeding | 0.002 | ||
None | 10 (34.5) | 2 (4.5) | |
Breast milk | 13 (44.8) | 24 (54.5) | |
Formula milk | 6 (20.7) | 18 (40.9) | |
Recovery type | 0.403 | ||
Spontaneously | 5 (17.2) | 12 (27.3) | |
By tactile stimulation | 24 (82.8) | 32 (72.7) | |
Comorbidities | |||
Patent ductus arteriosus | 17 (58.6) | 32 (72.7) | 0.309 |
Necrotizing enterocolitis | 2 (6.9) | 0 | 0.154 |
Values are expressed as median (interquartile range) or number (%).
Abbreviations: pCO2, partial pressure of carbon dioxide; BE, base excess.
Baseline (5-Minute Average), Nadir (during Following 5 Minutes), Recovery Time, and AUC of rScO2
Variable | Total apnea (n=73) | With desaturation (n=29) | Without desaturation (n=44) | Adjusted |
|
---|---|---|---|---|---|
rScO2, baseline | 75.7 (70.8–81.1) | 76.3 (70.6–81.1) | 75.5 (71.2–82.0) | 0.550 |
|
rScO2, nadir | 65.0 (59.0–72.0) | 62.0 (56.0–69.5) | 68.0 (63.0–74.0) | 0.053 |
|
∆rScO2, decrease at nadir |
10.1 (6.3–15.5) | 12.1 (8.6–20.7) | 8.4 (5.4–11.1) | 0.104 |
|
rScO2 recovery time (min) | 2.0 (1.2–4.0) | 3.1 (1.5–4.2) | 1.8 (1.1–3.4) | 0.036 |
0.155 |
rScO2, AUC (% min) | 9.2 (3.9–18.4) | 15.7 (6.6–30.2) | 6.2 (3.1–14.1) | 0.005 |
0.023 |
rScO2, overshoot | 76.0 (73.0–83.8) | 76.5 (73.0–84.0) | 76.0 (73.0–83.0) | 0.931 |
|
∆rScO2, increase at overshoot |
1.4 (0.6–2.5) | 1.4 (0.6–2.3) | 1.4 (0.6–2.8) | 0.941 |
|
Duration of overshoot (sec) | 9.5 (5.0–20.0) | 12.0 (5.0–21.0) | 9.0 (5.0–20.0) | 0.994 |
|
Values are expressed as median (interquartile range).
Adjusted for feeding type;
Repeated-measures analysis of variance was applied to compare two groups,
rScO2, baseline: rScO2, nadir;
Mann-Whitney
rScO2, overshoot: rScO2, baseline.
Abbreviations: AUC, area under the curve; rScO2, regional cerebral oxygen saturation.