Near-infrared spectroscopy (NIRS) can monitor regional cerebral oxygen saturation (rScO 2 ), mostly representing oxygen supply to the brain. The ratio between rScO 2 and systemic oxygen saturation (SaO 2 ) estimates cerebral fractional tissue oxygen extraction (cFTOE), reflecting oxygen utilization. The balance between oxygen supply and utilization provides insight into neonatal cerebral physiology as well as pathology.
Recent data suggest that NIRS-monitored cerebral oxygen saturation and extraction, as indicated by rScO 2 and cFTOE, respectively, can be of great value with real clinical relevance; they have been increasingly incorporated into standard clinical monitoring regimens in neonatal intensive care. The noninvasive and bedside nature of NIRS monitoring and its ability to monitor cerebral oxygen saturation continuously and directly are attractive features. However, the inter- and intrapatient variability of the measurements and the fact that NIRS is a trend monitor rather than a technique capable of directly monitoring cerebral perfusion in absolute values remain obstacles to overcome. Yet substantial changes in rScO 2 can alert the caregiver regarding ongoing and potentially harmful changes in brain oxygenation. Thus NIRS has the potential to provide opportunities for timely interventions.
In addition, NIRS-monitored changes in brain oxygenation when used in conjunction with other monitoring devices—such as pulse oximetry-monitored SaO 2 , blood pressure monitoring, heart rate, and electrical brain activity—have the potential to reveal conditions that might be associated with poor long-term outcomes. The combination of the different monitoring approaches can also be used in pharmacodynamic research. Finally, NIRS monitoring has shown its usefulness in several clinical conditions, as described in this chapter, and reliable reference values are now available, increasing its clinical applicability.
Keywordscerebral oxygenation, near-infrared spectroscopy, neonate, preterm infant
The status of cerebral oxygenation is not always represented appropriately by systemic arterial oxygenation. Oxygenation monitoring of the brain by near-infrared spectroscopy (NIRS) is therefore an important additive measure in neonatal intensive care.
Monitoring cerebral oxygenation by NIRS—in addition to arterial saturation monitoring by pulse oximetry, blood pressure, and brain function by amplitude-integrated electroencephalography—can help to prevent brain damage as well as unnecessary treatment of the neonate.
Cerebral oxygenation can be stabilized in the neonate by using a dedicated treatment guideline in combination with cerebral oxygenation monitoring by NIRS.
Survival of the extremely preterm infant has greatly improved over the past decades. However, perinatal brain damage with adverse neurodevelopmental outcome continues to affect a considerable number of these infants. Although the etiology of brain damage is multifactorial and partly unknown (see Chapter 7 , Chapter 8 ), hypoxia, hyperoxia, specific and nonspecific inflammation, and hemodynamic instability during the first days of postnatal life play an important role. It is clear that further advances in survival and improvements in neurodevelopmental outcome can be achieved only if we learn more about the underlying pathophysiology so that more effective treatment modalities can be established. The first step in this direction is to develop the ability to continuously monitor clinically relevant hemodynamic variables and, if possible, treat the underlying condition at an early stage. Continuous monitoring of physiologic parameters such as heart rate, blood pressure, arterial oxygen saturation (SaO 2 ), temperature, and, with increasing frequency, electrical activity of the brain using amplitude-integrated electroencephalography (aEEG) have been integrated into the monitoring practices of neonatal intensive care units (NICUs). aEEG has recently been introduced into neonatal intensive care as a novel monitoring technique to continuously assess cerebral function. Both the aEEG background patterns and analysis of the raw EEG signal have been used for the evaluation of neurologic function. The fewer number of channels compared with the classic full EEG improves its applicability, and the use of aEEG seems to have increased in neonatal intensive care. Other novel techniques used to continuously monitor additional hemodynamic parameters, such as cardiac output, are discussed in detail in Chapter 10 , Chapter 21 .
Discontinuous techniques to assess cerebral condition—such as cranial ultrasound, Doppler flow-velocity measurements, and (advanced) magnetic resonance imaging (MRI)—have also been increasingly integrated into the care of the sick neonate (see Chapter 10 , Chapter 15 , Chapter 16 ). However, these techniques do not provide continuous information on the perfusion and oxygenation of the neonatal brain, and MRI is not a bedside technique, at least at present.
Thus we need a reliable and practical clinical tool that monitors oxygenation of the neonatal brain noninvasively and continuously so that conditions potentially leading to brain injury can be recognized in a timely manner. A promising method is monitoring cerebral oxygenation by NIRS.
As discussed in Chapter 17 in detail, the use of NIRS to monitor cerebral perfusion and oxygenation was first described by Jobsis in 1977. Since then, a great number of studies have been performed measuring cerebral oxygenation and assessing cerebral blood flow, cerebral blood volume, and fractional oxygen extraction (CFOE) in neonates using instruments based mainly on the Beer-Lambert law, which relates the attenuation of light to the properties of a material through which light is traveling. The early instruments were designed for research work; accordingly they remained difficult to use in the clinical setting due to movement artifacts and because absolute values were not provided. The introduction of spatially resolved spectroscopy made it possible to use a new approach to monitor cerebral oxygenation in the clinical setting. Spatially resolved spectroscopy measures the absorption of the emitted light by two or more detectors. By using the diffusion equation, absolute values can be calculated assuming that the scattering for the different distances is constant. Another method is to subtract the measurement of the closest detector from the measurement of the farthest detector so as to minimize the influence of the superficial tissue layers. For instruments using this algorithm, further calibration in vitro and in vivo is still in progress. As also discussed in Chapter 17 , the different NIRS instruments used at present have different principles of measurement and different wavelengths, optode distances, and types (laser or LED) and numbers of light emitters. However, they all measure the status of cerebral oxygenation by using either the tissue oxygenation index (TOI) or regional cerebral oxygen saturation (rScO 2 ). Despite the different approaches, the measures of cerebral oxygenation reflect mixed tissue oxygen saturation by assuming that the contribution to the perfusion of the tissue interrogated is 25%, 5%, and 70% by the arteries, capillaries, and veins, respectively. The value is provided as an absolute number that can be measured continuously and over prolonged periods of time.
For most of the instruments, a good correlation with jugular venous oxygen saturation has been documented. The values are not identical, however, primarily because TOI and rScO 2 reflect the changes in oxygenation in the arterial, capillary, and venous compartments. A comparison in adults between the different monitoring techniques during changes in oxygenation and changes in the partial pressure of arterial carbon dioxide (PaCO 2 ) has also yielded a good correlation between the TOI and rScO 2 . In addition, in comparing the left and right sides of the brain, the Bland-Altman limits of agreement for rScO 2 were −8.5 to +9.5%, with even smaller limits during stable SaO 2 values between 85% and 97%. However, due to the limitations of the technology (see Chapter 17 , Chapter 21 ), it is obvious that these measurements are better used for trend measurements rather than precise tissue oxygenation values.
Clinical monitoring of cerebral oxygenation by NIRS has already become routine in pediatric and adult intensive care and during cardiac surgical procedures in all age groups. However, although information concerning brain tissue oxygenation may be important in considering the type and timing of an intervention and in assessing its impact on outcome, the use of NIRS has not yet been universally implemented in the daily care of neonates in the NICU. Although the accumulating evidence supporting the use of NIRS in clinical practice is encouraging, the information available is still not overwhelmingly convincing.
In addition to TOI or CrSO 2 , cerebral fractional tissue oxygen extraction (cFTOE) is another important NIRS parameter. Cerebral fractional tissue oxygen extraction is derived from rScO 2 and SaO 2 based on the formula: SaO 2 − rScO 2 / SaO 2 . Thus cFTOE is a surrogate indicator of the actual CFOE, which can be measured with the validated jugular venous occlusion technique (see Chapter 17 ). Naulaers et al. reported a positive correlation between NIRS-calculated cFTOE and actual fractional oxygen extraction of the brain in a newborn piglet model. Because cFTOE is a ratio of two variables, an increase might indicate either reduced oxygen delivery to the brain with constant oxygen consumption or increased cerebral oxygen consumption not satisfied by oxygen delivery. The opposite is true in the case of a decrease in the cFTOE, reflecting either a decrease in oxygen extraction because of decreased oxygen utilization or an increase in oxygen delivery to the brain while cerebral oxygen consumption has remained unchanged. Obviously both parameters might change at the same time, although relatively rapid changes in cerebral oxygen utilization are less common. Although NIRS-derived cFTOE is a less accurate parameter compared with fractional oxygen extraction determined by the jugular occlusion technique, the clear advantage of cFTOE is that we can now continuously assess cerebral oxygen extraction.
Feasibility of Near-Infrared Spectroscopy–Monitored Regional Cerebral Oxygen Saturation and Cerebral Fractional Tissue Oxygen Extraction in Clinical Practice in the Neonatal Intensive Care Unit
In order to assess the utility of NIRS-monitored rScO 2 in clinical practice, it is essential to also obtain data on the signal-to-noise ratio and the inter- and intrapatient variability. As compared with pulse oximetry-measured SaO 2 , a reliable and accepted trend monitor for systemic arterial oxygenation, the signal-to-noise ratio is larger for NIRS-measured rScO 2 . However, when the signal is averaged over a longer period (e.g., over 30 to 60 seconds), a reliable NIRS signal can be obtained with an acceptable signal-to-noise ratio. With respect to intrapatient variability, differences of up to 7% or more have been reported when subsequent measurements are performed with repeated placement of the NIRS sensor. The limits of agreement after sensor replacement are in the range of −17% to +17%. These values are more than double the limits of agreement for SaO 2 . On the other hand, Menke et al. described a good reproducibility of NIRS-measured rScO 2 with an intermeasurement variance only slightly higher than the physiologic baseline variation. In comparing values during simultaneous monitoring of the left and right frontoparietal regions of the brain, limits of agreement of 7% to 9% have been reported. Moreover, it appears that the experience of the investigator also plays an important role in the quality of the information obtained.
Reference values of rScO 2 or TOI during normal arterial oxygen saturations have been reported in several studies including preterm neonates. Of note is that not all studies incorporated postnatal age or the clinical status of the infant in reporting their findings. Mean values (±SD) of rScO 2 or TOI ranged between 61% and 75% (from ±7% to ±12%), or values comparable with those obtained in adults ( Table 18.1 ).
|n = 94 (40)
n = 19 (rScO 2 /TOI) (29)
n = 9 (rScO 2 ) (47)
n = 14 (rScO 2 ) (45)
|Day 12 [0–365]
Day 4.5 [0–190]
8 min after birth
68% (IQR 55–80)
|n = 155 (TOI) (41)
n = 20 (TOI) (38)
n = 20 (46)
(GA <32 weeks)
|n = 15 (TOI) (21)
n = 253 (TOI) (42)
n = 40 (rScO 2 ) (43)
n = 38 (rScO 2 ) (44)
n = 999 (rScO 2 ) (48)
Over the past decade or so, more and more NIRS devices with special neonatal or pediatric sensors and algorithms have become available. Before interpreting the absolute values, however, attention must be paid to the differences between the old and new sensors. Indeed, studies have shown that in neonates, the newer, smaller sensors may measure up to 15% higher values compared with the previously used adult sensors. Therefore reference values for the neonatal or pediatric sensors in preterm and term neonates are needed before their implementation in clinical practice. Indeed, a large study by Alderliesten et al. of 999 preterm infants has recently provided reference values for rScO 2 and cFTOE for different types of sensors. Graphs of reference value curves allow for bedside interpretation of NIRS-monitored cerebral oxygenation ( Fig. 18.1 ). These reference values can then be used for comparison with values obtained during conditions that may affect cerebral oxygenation (discussed later).
Importantly, an association between rScO 2 values in neonates and functional or histologic compromise of the brain has been documented. Several animal studies in newborn piglets and one human study in neonates with hypoplastic left heart syndrome who underwent open heart surgery have reported that rScO 2 or TOI values lower than 35% to 45% for more than 30 to 90 minutes are associated with functional (mitochondrial dysfunction or energy failure) and/or histologic damage, especially in the hippocampus (a brain region very vulnerable to hypoxia in the perinatal period). Moreover, a number of studies, mostly performed in adult cardiac intensive care units, have reported that a 20% decrease from the baseline or an absolute rScO 2 value of less than 50% before intervention is associated with hypoxic-ischemic brain lesions. Thus these findings suggest that rScO 2 values below 45% to 50% for a prolonged period of time should be avoided if possible. A large international randomized controlled clinical trial has investigated whether it is possible to detect and prevent cerebral oxygenation outside the assumed normal limits of 55% to 85% with NIRS monitoring to prevent neurologic injury and improve neurodevelopmental outcome. The SafeBoosc II trial (Safeguarding the Brains of Our Smallest Children) randomized infants to either visible or shielded NIRS registration of cerebral oxygenation and compared the burden of hypoxia and hyperoxia between the two groups. Infants with visible NIRS tracings spent a significantly shorter time outside the normal range mainly due to a reduction in the hypoxic burden because of clinical interventions. These findings indicate that unfavorable cerebral oxygen saturations can be detected by NIRS and prevented by timely interventions.
Similar to the bedside detection and prevention of prolonged cerebral hypoxia , continuous monitoring of rScO 2 can also contribute to the prevention of prolonged cerebral hyperoxia , especially in the extremely preterm infant who is particularly prone to oxygen toxicity. The importance of avoiding hyperoxia has been increasingly recognized, as an association between normal oxygen saturations and improved long-term neurodevelopmental outcome in extremely preterm infants has been documented. With these considerations and the presented data in mind, NIRS-monitored rScO 2 or TOI and NIRS-derived cFTOE are likely to play an important role in monitoring and improving cerebral oxygenation in sick neonates into the future.
Application of the Sensor and Its Pitfalls
The most important issue regarding the clinical application of noninvasive monitoring of cerebral oxygenation by NIRS is the ability to perform reliable, long-term monitoring in the most immature and unstable neonate without disturbing the infant. A critical part of initiating the process is the application of the sensor to the head. With appropriate placement, the sensor will allow reliable monitoring of the rScO 2 or TOI for a number of days without damaging the vulnerable skin, particularly of the very preterm infant. In addition, the sensor in place should not limit access to performing ultrasound studies of the brain, placement of electrodes for aEEG monitoring, and attachment of CPAP devices. In our experience, application of the NIRS sensor with a soft dark elastic bandage to the frontoparietal region of the head provides protection from ambient light and does not irritate or damage the skin of even the smallest infants while allowing reliable monitoring of rScO 2 for extended periods of time. Fig. 18.2 shows an example of the application of the NIRS sensor used in all of our clinical studies. Alternatively, application of sensors using the original adhesive tape on the skin is possible, and this method is advocated by the manufacturers for most commercially available sensors (see Fig. 18.2 ).
Introduction of the system with structured theoretical courses and practical training for nurses and medical staff is a very important prerequisite for the successful use of this monitoring method in clinical practice. In addition, staff education about the potential benefits and risks of using NIRS is of great importance. In gaining experience, nursing staff in the authors’ institutions have been able to recognize inappropriate transducer placement, improper transducer fixation, or insufficient transducer shielding. In our experience, this resulted in extended periods of uninterrupted and reliable rScO 2 monitoring even in the smallest infants (<600 g) comparable with pulse oximetry-monitored SaO 2 . In monitoring and interpreting the values in daily clinical practice, one must be aware of several pitfalls. We have already discussed the importance of proper sensor application to prevent movement artifacts and the effect of ambient light. Yet despite these precautionary measures, phototherapy light will sometimes cause disturbances in rScO 2 monitoring. Accordingly, covering the sensor with an additional dark sheet during periods of phototherapy is recommended to ensure more reliable signal acquisition. Other factors such as dislocation of the NIRS sensor or the presence of hair, hematoma, edema, and/or other materials such as the plasters of the aEEG electrodes on the head can also cause disturbances of the NIRS signal. Interestingly, the influence of the curvature of the skull and head circumference seems negligible.
Relation to Other Monitoring Devices
NIRS-monitored changes in brain oxygenation, represented by rScO 2 (or TOI) and cFTOE, generate important information in addition to that obtained from other monitoring devices such as pulse oximetry-monitored SaO 2 , indwelling blood pressure monitoring, and heart rate/ electrical brain activity monitors. Monitoring SaO 2 is necessary to calculate cFTOE, as described earlier. The relationship between blood pressure and rScO 2 may provide information about the presence or lack of cerebral blood flow autoregulation (see Chapter 2 , Chapter 21 ). As for the use of aEEG in combination with NIRS, our group has reported that persistent and unusually high rScO 2 values in term infants with severe perinatal asphyxia—probably due to profound vasodilation with or without vasoparalysis of the cerebral vascular bed and a decreased utilization of oxygen—were strongly associated with an abnormal aEEG pattern after the first postnatal day and adverse neurodevelopmental outcome at 2 years of age. These findings indicate that the monitoring of cerebral oxygenation and oxygen extraction with NIRS along with other parameters reveals conditions at an early stage that might be associated with poor long-term outcomes. The combination of the different parameters monitored can also be used in pharmacodynamic research. Medications given to neonates often have effects on both cerebral metabolism and hemodynamics; thus using the combination of NIRS, aEEG, and hemodynamic parameters such as blood pressure and heart rate will provide additional valuable information. An example is the use of propofol, which has direct effects on both blood pressure and cerebral metabolism. Further research in neurovascular coupling in preterm infants is ongoing. Finally, efforts to develop a comprehensive, real-time cardiorespiratory and neurocritical care monitoring system are described in Chapter 21 .
Clinical Conditions Associated With Low Regional Cerebral Oxygen Saturation
Perlman et al. reported first that ductal steal has an impact on cerebral perfusion and is a risk factor for cerebral damage in the preterm infant. Thus a hemodynamically significant patent ductus arteriosus (PDA) is a condition potentially associated with decreased oxygen delivery to the brain due to the impact of the diastolic runoff in the cerebral vessels and the associated changes in perfusion pressure on cerebral oxygen delivery throughout the entire cardiac cycle. Several recent reports using NIRS-monitored rScO 2 found a substantial decrease in cerebral oxygenation to sometimes critically low values in the presence of a hemodynamically significant PDA but with recovery to normal values after successful ductal closure. The ductal diameter is the echocardiographic ductal characteristic that is best related to rScO 2 , with the largest diameter resulting in the lowest rScO 2 values. It appears that infants with a hemodynamically significant PDA unresponsive to pharmacologic closure with cyclooxygenase (COX) inhibitors are especially at risk before and during surgical ligation. Indeed, in a study of 20 infants, we found extremely low rScO 2 and high cFTOE values before and during ligation. Infants undergoing surgical ligation of the ductus are often exposed to low rScO 2 values for a prolonged period of time, which may adversely affect brain development. It was shown that the rScO 2 values before ductal closure are significantly associated with cerebellar growth as measured by MRI, with potential negative implications for neurodevelopment. Moreover, early ductal screening and treatment seems to reduce in-hospital mortality.
The monitoring of cerebral oxygenation has provided us with early information on the impact of left-to-right shunting across the duct on cerebral oxygenation as well as on the effectiveness of the treatment initiated to close the PDA. Fig. 18.3A provides a representative example of the impact of a hemodynamically significant PDA on cerebral oxygenation and the effect of successful pharmacologic closure of the duct with indomethacin. It should be noted that, unlike ibuprofen, indomethacin decreases and stabilizes cerebral blood flow via mechanisms independent of the drug’s effect on the COX enzyme.