Measuring cerebrovascular autoregulation in preterm infants using near-infrared spectroscopy: an overview of the literature

Figures & data

Table 1. Overview of the results from the literature search, presented in chronological order.

Author/year of publication	Characteristics of patient cohorts (number of infants, GA, age at recording, and specific characteristics)	Input parameters (all using spontaneous fluctuations)	Output parameters (NIRS device and accompanying signal, sampling time/rate, and setup)	Definition for (impaired) autoregulation	Methods of measurement: -Duration of measurement -Duration of single epoch -Mathematical approach -Frequency band -% overlap	Clinical implication/main results; data interpretation by the authors
Stammwitz 2016	N = 31 26–32 weeks <6 h, 12–16 h, 24–28 h, 68–76 h Stable hemodynamics, most ventilated Clinical setting	MABP HR	Critikon Cerebral Oxygenation Monitor 2001: O2Hb, HHb, tHb, OI 2 Hz Sensor was placed frontoparietally.	Not explicitly defined	≥12-min epochs without artifacts 0–0.01 Hz, and 0–0.1 Hz frequency. Coherence spectra between tHb or OI and MABP or HR (both appeared interchangeable).	Low coherences during the first 24 h were associated with unfavorable outcome: IVH grade ≥3, abnormal MDI, and mortality.
Kleiser 2016	N = 4 26–33 weeks 1–4 weeks Clinical setting	HR, SpO2	Self-developed multi-distance NIRS (OxyPrem): StO2 and FTOE Optode was positioned over the left prefrontal cortex	Not explicitly defined	Nonlinear regression based on alternating conditional expectation and maximal information-based nonparametric exploration.	High nonlinear correlation between HR and FTOE in one neonate with reduced health status.
da Costa 2015	N = 60 23–32 weeks 5–228 h Clinical setting	MABP HR	NIRO200NX: TOI 10-s averages of HR and TOI Sensor placed on one side of the temporoparietal area of the infant’s head.	Lowest TOHRx represents maximal autoregulation within infants.	2 h (with 1-min update) TOHRx: linear correlation coefficient over 5-min epochs with 1 min moving window after removal of artifacts and low-pass filtering and downsampling of the data resulting in one sample every 10 s.	Deviation from MABP at strongest vascular reactivity is related to poor outcome and intraventricular hemorrhage (retrospectively).
Eriksen 2015	N = 60^a 27 ± 1 weeks Day 1 38% ventilated Clinical setting	MABP	NIRO 300: TOI Sampling rate 0.1 Hz Probe secured to the frontotemporal or frontoparietal region of the head with a flexible bandage.	COx ≥0.4 and coherence ≥0.5	Linear correlation (COx) 5-min epochs with 1 min (80% overlap) moving window. Moving coherence: 0.003–0.04 Hz frequency band. 10-min epochs with 50% overlap. TFA coherence and gain. Aim: to describe the relation between time- and frequency-domain analyses, Pearson’s correlation coefficient was used.	Poor concordance between COx and TFA methods to assess autoregulation (r =  0.21, p = 0.097). COx appears more robust than coherence and gain.
Caicedo 2014	N = 9 <32 weeks, first 3 days of life. 5 with IVH grade III-IV matched to 4 without (GA, BW, and gender). Clinical setting	MABP HR	INVOS 4100–5100: rSO2, Sampling rate 1 Hz.	Relation between HR, MABP, and rSO2	Median filter of seven samples. Artifacts removed. Using PRSA or BPRSA.	Nonlinear relationship between ABP and rSO2 for both increasing (input signal increase) and decreasing (input signal decrease) anchor points. Especially in the patients with IVH, the time profiles of the PRSA curves showed impaired autoregulation.
Eriksen 2014	N = 60^a 26 ± 1 weeks Day 1 Clinical setting	MABP	NIRO-300: TOI, sampling rate 2 Hz Probe secured to the frontotemporal or frontoparietal region of the head with a flexible bandage.	A negative COx indicates an intact autoregulation, as a result of constriction of the cerebral arteries in response to increases in MABP.	2.3 h sampling. Moving linear correlation coefficient between 10-s samples of TOI and MABP, calculated with 10-min epoch with 1 min moving window. The mean of six COx values gave one COx for each 10-min epoch. One grand mean for each infant was calculated as a weighted mean, using the variability in MABP in 10-min epoch as weighting factor.	COx was not associated with GA, BW, CRIB score, and gender and not affected by treatment with antibiotics, development of IVH, or mortality. Higher COx in infants receiving saline bolus or surfactant. Only dopamine had significant negative influence COx in multivariate model: COx was 0.41 in the dopamine group and 0.08 in the group of infants not treated with dopamine (p < 0.001)
Mitra 2014	N = 31 23–32 weeks 1–6 days All ventilated Clinical setting	MABP HR	NIRO200NX: TOI	Zero or negative TOx suggests intact autoregulation.	At least 2 h TOx (moving correlation coefficient between MABP and TOI) and TOHRx (see da Costa above)	Higher TOHRx related to higher CRIB score. TOHRx and CRIB: r = 0.55; p = 0.0013, FvHRx and CRIB: r = 0.51; p = 0.0035. Positive TOHRx related to more inotropic support, more PDA and more IVH.
Riera 2014	N = 54 27 ± 2 weeks Day 1–2 Clinical setting	MABP, SVC flow	NIRO200NX: TOI Sampling rate 2 Hz Sensor placed at the frontoparietal level.	Threshold BiAR-COH of 0.58 and COH 0.52 identified low SVC flow.	9.5 h (mean) 30-min epochs (for COH 10 min segments with 50% overlap) at frequency 0.003–0.04 Hz (VLF). BiAR-COH. Coherence.	BiAR-COH associated with IVH grade 3–4 (OR 2.5, p < 0.001), mortality (OR 3.4, p < 0.001), and the need for hemodynamic support (OR 1.3, p < 0.001).
Verhagen 2014	N = 25 25–31 weeks 2–64 h Clinical setting	MABP SpO2	INVOS 4100–5100: rSO2, FTOE One sample every 5 min Probe was placed on the left frontoparietal side of the infant’s head and kept in place by an elastic bandage.	Negative Spearman correlation between FTOE and MABP suggests intact autoregulation.	24 h	No relation with clinical characteristics, including CRIB score, PVE, IVH, PDA, and mortality.
Alderliesten 2013	N = 30 infants with IVH vs. 60 without IVH 24–31 weeks 0–72 h Clinical setting	MABP	INVOS 4100–5100: rSO2. Sampling rate 1 Hz. Probe was placed on the frontoparietal side of the infant’s head and attached firmly with an elastic bandage.	Correlation between MABP and rSO2, r value > 0.5 considered as impaired autoregulation.	Average of 10 × 1 min correlation within 24–36 h before IVH and within 24 h after IVH	More time with impaired autoregulation before (14% vs. 9%; p < 0.01) and after (15% vs. 9%; p < 0.01) IVH compared to controls.
Hahn 2012	N = 60^a 27 ± 1 weeks Day 1 38% ventilated Clinical setting	ABP	NIRO-300: TOI 2 Hz Probes secured to the frontotemporal or frontoparietal region of the head with a flexible bandage.	TFA (coherence and gain) Coherence value >0.47 in the VLF range and >0.45 in the LF range.	2.3 ± 0.5 h 10-min epochs (3.5-min segments with 50% overlap) of VLF (0.003–0.04 Hz) and LF (0.04–0.1 Hz) bands.	No association between MABP, coherence, or gain with IVH or mortality. No association with inflammation (IL-6).
Caicedo 2012	N = 18 25–29 weeks	MABP	NIRO 300: TOI 6 Hz	n.a.	2–4 h A comparison of various mathematical approaches: -Correlation coefficient -TFA coherence -Modified coherence -Transfer function gain -Variance-based analysis -Sensitivity analysis -Elementary effects approach	n.a.
Wong 2012	N = 32 <29 weeks 1–3 days All mechanically ventilated Clinical setting	MABP	NIRO 200: TOI 6 Hz The probes were placed over the temporoparietal region.	TFA (coherence and gain) High coherence values, possibly with a simultaneous high gain, suggests impaired autoregulation.	4–6 h/day 20-min epochs 0.003–0.02 Hz frequency band TFA	A high coherence and gain was associated with increased cerebral injury or death. Coherence also related to MABP variation (R^2 = 0.12–0.19, p = 0.03 and 0.01, on day 1 and 3, respectively)
Caicedo 2011 Adv Exp Med	N = 53 29 ± 2 weeks Clinical setting	MABP	INVOS 4100 and NIRO 300: rSO2 and TOI 0.33 Hz (filtered)	Correlation or (partial) coherence coefficient: >0.5 considered as impaired autoregulation.	6–70 h 20-min epochs Correlation coefficient TFA (coherence) Partial coherence (Welch method): 10-min epochs with 75% overlap at the 0.003–0.1 Hz frequency band	Using correlation, the time with supposed impaired autoregulation related to CRIB score. No relation with outcome parameters (not specified by authors).
Caicedo 2011 Ped Res	N = 54 24–40 weeks Clinical setting	MABP	INVOS 4100 and NIRO 300: HbT and HbD vs. rSO2 and TOI 0.33 Hz	n.a.	10–20-min epochs 75% overlap, at 0.0042–0.00837 Hz for 60s data and 0.0033–0.04 Hz for 3s data. Correlation and TFA coherence.	Correlation and coherence show little agreement within patients, especially during periods with limited MABP variability HbD and HbT seem less robust than rSO2 or TOI, with similar scores.
Gilmore 2011	N = 23 26 ± 1 weeks 1–3 days All ventilated for at least some part of the recording Clinical setting	MABP	Foresight: rSO2 0.5 Hz	Intact autoregulation defined as COx <0.5	0.6–4 days 5-min epochs Low-pass filtered. Moving correlation coefficient (COx), with 97% overlap.	Significant relationship between lower MABP and impaired autoregulation (r = 0.51, p = 0.013).
Zhang 2011	N = 17 24–29 weeks 1–3 h Clinical setting	MABP	NIRO 300: HbO2, HHb, HbD, and TOI Synchronized converted data at 8 Hz	Relation with CRIB-II score and various cross-spectral TFA functions.	10 min artifact-free epoch, TFA (gain, phase, and coherence) according to Welch using 4-min epochs and 75% overlap. 0.02–0.04 Hz (VLF), 0.04–0.15 Hz (LF), and 0.15–0.25 Hz (MF) frequency bands.	Moderate correlation between CRIB score and MABP-HHb phase in the LF range and higher correlations between CRIB score and MABP-HHb coherence in LF range
De Smet 2010	N = 30 Three sets of preterm infants from three different hospitals in clinical setting Approximately 28 ± 3	MABP	Critikon Cerebral Oximeter: HbD, INVOS4100: rSO2, NIRO 300: TOI SpO2	Correlation coefficient or TFA coherence >0.5 suggests impaired autoregulation.	10, 12.5, and 15-min epochs, 50% overlap. 0.0033–0.04 Hz frequency band. Correlation coefficient TFA (coherence) Partial coherence, for eliminating effect of fluctuating SpO2	Partial coherence method appeared more accurate in predicting brain damage and more sensitive for detecting impaired autoregulation
Hahn 2010	N = 22 24–29 weeks 1 to 2 days 9% artificially ventilated Clinical setting	MABP	NIRO 300: TOI 2 Hz Probes secured to the frontotemporal or frontoparietal region of the head with a flexible bandage.	High coherence suggests impaired autoregulation.	1.2–3.7 h At 0.003–0.04 Hz and 0.04–0.1 Hz frequency bands. 10-min epochs, 50% overlap TFA (coherence)	Precision of autoregulation measurement can be improved by taking MABP variation into account.
De Smet 2009	N = 20 24–39 weeks 570–1470 g	MABP	NIRO-300: HbD and TOI 0.2 Hz	Higher concordance between HbD and MABP (new scoring system introduces for critical percentage of recording time) suggests impaired autoregulation.	1.5–23.5 h Correlation coefficient TFA (partial coherence)	TOI shows similar results compared to HbD as output parameter.
O’Leary 2009	N = 88 23–30 weeks First 5 days Clinical setting	MABP	NIRO-500: HbO2, Hb, HbD 2 Hz	Higher gain and higher coherence indicate impaired autoregulation.	<12 h 10-min epochs at low- (0.05–0.25 Hz), medium- (0.25–0.5 Hz), and high- (0.5–1.0 Hz) frequency range. TFA (coherence and gain).	Higher gain was associated with increased risk of developing GMH/IVH or PVL, only in the low-frequency range (p = 0.03–0.05).
Wong 2008	N = 24 26 ± 2 weeks 28 ± 22 h Clinical setting	MABP	NIRO-300: TOI 1 Hz Probes are placed over the temporoparietal region of the infants head	Coherence value >0.5 and higher gain in the 0.003–0.1 Hz range suggest impaired autoregulation.	2–4 h 20-min epochs (five segments of 10 min with 75% successive segment overlap) at ULF (0.003–0 .02 Hz), VLF (0.02–0.05 Hz), and LF (0.05–0.1 Hz). TFA (coherence and gain)	Higher coherence and higher gain in the ULF range (0.003–0.03 Hz), were found in the sickest preterm infants, with strong correlation with CRIB score (r = 0.57, p < 0.01). No association between the averaged coherence and ultrasound cerebral abnormalities.
Soul 2007	N = 90 23–30 weeks First 5 days Clinical setting No preexisting major brain injury/malformations or genetic syndromes	MABP	NIRO 500: HbO2, Hb, HbD 2 Hz	Coherence values >0.77 suggest impaired autoregulation.	10-min epochs at LF range (0–0.04 Hz). TFA (coherence)	Impaired autoregulation is associated with low GA (p = 0.018), low BW (p = 0.038), and hypotension (r = 0.46, p < 0.0001), maternal hemodynamic factors (pregnancy-induced hypertension, hemorrhage during labor, and placental infarction).
Morren 2003	Several preterm infants, no further clinical information	ABP	NIRO 300: HbD 0.2 Hz	n.a.	30-min epochs 0–0.1-Hz frequency range Correlation coefficient TFA (coherence) A (near) linear model for assessment of common part for two signals (CPC).	Correlation and common part analyses seem more sensitive for parallel changes in ABP and HbD than coherence analysis.
Tsuji 2000	N = 32 23–31 weeks First 3 days High risk for brain injury Clinical setting	MABP	NIRO 500: HbO2, HHb, HbD 2 Hz Probe 1 cm above the supraorbital ridge with the transmitting optode 1 cm lateral to the midsagittal plane on either the right or the left forehead and the receiving optode 3 cm lateral to the transmitting optode.	Coherence value >0.5 suggests impaired autoregulation.	30-min epochs at ULF (0–0.01 Hz), VLF (0.01–0.05 Hz), and LF (0.05–0.1 Hz) frequency bands. TFA (coherence)	Higher coherence in the VLF range with grade 3–4 GMH-IVH or PVL. More severe ultrasound abnormalities when coherence was >0.5 somewhere in the first 3 days of life (47% versus 13%).

The six columns correspond to the six paragraphs 6.1 through 6.6.

ABP: arterial blood pressure; BPRSA: bivariate phase-rectified signal averaging; BiAR-COH: bivariate autoregressive spectral coherence; BW: birth weight; COH: coherence; CRIB score: clinical risk index for babies-score; COx: cerebral oximetry index; FTOE: fractional tissue oxygen extraction (SpO₂ − rSO₂)/SpO₂); GA: gestational age; Hb: hemoglobin; HbD = HbO₂ − HHb; HHb: deoxy-hemoblobin; HbO₂: oxygenated hemoglobin; HbT: total hemoglobin; HR: heart rate; IL: interleukin; IVH: intraventricular hemorrhage; LF: low frequency; MABP: mean arterial blood pressure; MDI: mental developmental index; MF: mid frequency; n.a.: not applicable; NIRS: near-infrared spectroscopy; O₂Hb: oxygenated hemoglobin; OI: oxygen index (O₂Hb − HHb/2); PDA: patent ductus arteriosus; PRSA: phase-rectified signal averaging; PVE: periventricular echodensities; PVL: periventricular leukomalacia; rSO₂: regional cerebral oxygen saturation; SpO₂: arterial oxygen saturation; StO₂: tissue oxygen saturation; SVC flow: superior vena cava flow; TFA: transfer function analysis; tHb: total hemoglobin; TOHRx: tissue oxygenation heart rate reactivity index; TOx: tissue oxygenation; TOI: tissue oxygenation index; VLF: very low frequency; ULF: ultralow frequency; OR: odds ratio; GMH/IVH: germinal matrix or intraventricular hemorrhage.

^aSame population.

Figure 1. Relationship between TCD blood flow velocity and mean ABP in neonates. Upper panel: completely impaired autoregulation. Lower panel: intact autoregulation is suggested above the (lower) ABP threshold of 36 mmHg. From the material previously presented by Rhee et al J Perinat 2014; 34; 926–931. Abbreviations: ABP; arterial blood pressure, FV; flow velocity.

Figure 2. Recording of two preterm babies which one had permanently good autoregulation (negative TOHRx-mean −0.35; upper panel) and disturbed autoregulation(mostly positive TOHRX, mean 0.35- lower panel).Red line depicts elusive demarcation between working and disturbed autoregulation (0.25). TOI- tissue oxygenation index, HR- heart rate, SapO2- arterial saturation, MAP- mean arterial pressure, TOHRx- autoregulation index. X -axis: time scale. Based on clinical material described by Da Costa et al. [60]. Full color available online.

Figure 3. Example of high TFA for TOI and MAP values in the ultralow frequency from the Wong et al. study in 2 preterm born infants born at 23 and 25 weeks gestation, shown respectively in (a) and (b) [34]. The infant in (a) showed fluctuations of TOI of higher magnitude in response to changes in MAP, compared with the infant in (b). Accordingly, the value of gain in the ULF range for the recording in (a) was higher than the value for the recording in (b) (0.8 vs 0.4%/mm Hg, respectively). Note that both recordings showed concordant changes between MAP and TOI waveforms, with the ULF coherence values both at 0.6. Reproduced with permission from Pediatrics, Vol. 121, Page(s) e604-11, Copyright © 2008 by the AAP. Abbreviations: TOI; tissue oxygenation index, MAP; mean arterial pressure, ULG; ultra-low frequency.

Figure 4. Example of determination of ABP_opt (in this cases minimum of the U-shape curve suggest ‘optimum’ at ABP = 29 mm Hg) using clinical data previously published by Da Costa et al. [60] (with permission from the authors). Abbreviations: ABP; arterial blood pressure, TOHRx; tissue oxygenation heart rate reactivity index.

Bauer A, Barthel P, Muller A, et al. Bivariate phase-rectified signal averaging – a novel technique for cross-correlation analysis in noisy nonstationary signals. J Electrocardiol. 2009;42(6):602–606.

 PubMed Web of Science ®Google Scholar

Wong FY, Leung TS, Austin T, et al. Impaired autoregulation in preterm infants identified by using spatially resolved spectroscopy. Pediatrics. 2008;121(3):e604–11.

 PubMed Web of Science ®Google Scholar