Cerebral Circulation and Hypotension in the Premature Infant: Diagnosis and Treatment

Abstract

Despite advances in our understanding of developmental hemodynamics and our ability to better monitor the cardiovascular status in neonates, the definition of the “normal” gestational age– and postnatal age–dependent blood pressure range has remained an elusive target. In fact, as a blood pressure value may be associated with normal blood flow—and thus oxygen delivery in a given patient at a certain point in time—while the same value might represent an abnormal blood pressure associated with decreased blood flow and abnormal oxygen delivery at another time, it is likely that a universally applicable normal blood pressure range does not exist for neonates even with the same gestational and postnatal age. Therefore only with appropriate monitoring of blood pressure, blood flow, and tissue oxygen delivery in each neonate can the normal blood pressure be defined for the individual patient and the given point in time. With this background information in mind, this chapter describes the information available on systemic and cerebral blood flow and oxygenation in relation to systemic blood pressure and the characteristic cerebral pathologies seen in the neonate, and the information focuses on the transitional period. By examining the pathologic processes in relation to blood pressure and flow, the chance of designing and providing timely and potentially effective treatment becomes more realistic. We also describe a paradigm for treatment of the pathologic processes underlying clinically evident brain injury in the preterm infant. However, it must be emphasized that only little evidence exists on the safety and effectiveness of the presently used approaches to treatment of neonatal hypotension.

Keywords

cerebral autoregulation, cerebral circulation, hypotension, neonate, neonatal shock, neurodevelopment, periventricular/intraventricular hemorrhage, white matter injury

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Neonatal hypotension can be defined by population-based normative data , by the principles of developmental cardiovascular physiology (autoregulatory, functional and ischemic blood pressure thresholds) or by the pathophysiology (morbidity and/or mortality).
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During the immediate transitional period, a given blood pressure value at a given point in time in a given patient may be associated with normal systemic and organ blood flow. However, depending on the underlying cardiovascular pathology and the patient’s ability to compensate, the same blood pressure value in the same patient at a different time point may be associated with impaired systemic and organ blood flow and thus oxygen delivery.
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Only an association but not causation has been documented between hypotension and brain injury/poor neurodevelopmental outcome. Therefore at present, one cannot infer that long-term neurodevelopmental outcomes will improve if hypotension is rigorously avoided.
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Treatment of neonatal hypotension improves the major hemodynamic variables (blood pressure, cardiac output, organ blood flow and oxygen delivery) but improvement in neurodevelopmental outcomes has not yet been documented.

With the evolution of neonatology over the past few decades, improved methods of monitoring and more effective interventions have been developed to identify and manage the respiratory, fluid and electrolyte, and nutritional abnormalities frequently encountered in very low-birth-weight (VLBW) infants. However, the ability to effectively and continuously monitor the hemodynamic changes at the level of systemic and organ blood flow and tissue perfusion is still limited. Yet the advances achieved with the use of targeted neonatal echocardiography and other bedside monitoring devices providing noninvasive, continuous systemic, organ and tissue perfusion and cerebral function monitoring have started to usher in a new era in developmental hemodynamics. The novel monitoring modalities include but are not restricted to electrical impedance velocimetry, continuous wave Doppler ultrasonography, near-infrared spectroscopy (NIRS), visible light spectroscopy, laser Doppler technology, and amplitude-integrated electroencephalography (EEG, aEEG). Yet with the improvements in hemodynamic monitoring and a better understanding of the principles of developmental cardiovascular physiology have come the realization that little is known about circulatory compromise and its effects on organ function, especially brain blood flow, blood flow–metabolism coupling, and long-term outcomes. Although we can continuously and reliably monitor systemic blood pressure in absolute numbers and a great number of proposed interventions exist for “normalizing” it, blood pressure is only the dependent component among the three hemodynamic parameters regulating systemic perfusion. Accordingly, blood pressure is determined by changes in the two independent variables, cardiac output and systemic vascular resistance (SVR). Therefore in addition to monitoring and maintaining perfusion pressure (blood pressure), the goal is to preserve normal systemic and organ blood flow and thus tissue oxygenation especially in the vital organs—the brain, heart, and adrenal glands. In this regard, when it comes to the brain, medicine is at an even greater disadvantage. For instance, measuring cerebral blood flow (CBF) is more complex than continuously measuring systemic blood flow (left ventricular output), which itself has remained a significant challenge. Assessment of systemic blood flow becomes even more complicated when shunting through the fetal channels (ductus arteriosus and foramen ovale) occurs during the first few postnatal days in the preterm neonate. Unfortunately, it is more complicated to detect clinical evidence of ischemia in the brain in a timely manner in the neonate. In addition, distinct regions of the brain have different sensitivity to decreased oxygen delivery. Accordingly, injury to the normally less well-perfused white matter might occur before other regions suffer damage. Alterations in normal brain activity and seizures are clear signs of a pathologic process, but they can be difficult to recognize, especially in the VLBW neonate; although the use of aEEG might be helpful in this regard. As for seizures, by the time they are present, irreversible injury may have already occurred. Most importantly, the clinician faces the formidable task of effectively supporting and protecting the enormously complex developmental processes that take place in the brain of the preterm infant during the postnatal transitional period and beyond. In addition, the understanding of how to manage hemodynamic disturbances that affect CBF, flow-metabolism coupling, brain function and structure, and ultimately neurodevelopmental outcome is limited.

The intent of this chapter is to review the information available related to the definition of systemic hypotension as well as the pathogenesis, diagnosis, and treatment of early cerebral perfusion abnormalities that have been shown to precede intracranial hemorrhage and periventricular white matter injury (PWMI) in the VLBW infant. Because CBF flow-metabolism coupling and cerebral oxygenation in this population is complex, the discussion is focused on the first postnatal days, during which the cardiorespiratory transition from fetal to extrauterine life occurs and most pathologic processes take place. The discussion focuses on some bedside modalities potentially useful for identifying changes in CBF and cerebral oxygenation. In addition, a paradigm is presented for the treatment of the pathologic processes underlying clinically evident brain injury in the VLBW infant based on the most up-to-date monitoring and clinical evidence. Unfortunately, there is sparse evidence related to the appropriateness and effectiveness of current approaches to treatment of neonatal hypotension and cardiovascular compromise. The goal is to provide the practitioner with guidelines for establishing the diagnosis and treatment of neonatal hypotension. Finally, although the understanding of both the normal and pathologic processes in the developing preterm brain is improving, a definitive, safe, and effective clinical approach remains elusive.

Definition of Hypotension

Hypotension, defined by population-based normative data , is present in up to 50% of VLBW infants admitted to the neonatal intensive care unit. Hypotension in the immediate postnatal period has historically been thought to be one of the major factors contributing to central nervous system injury and poor long-term neurologic outcome, including cerebral palsy in VLBW neonates. Indeed, an association between hypotension and brain injury and poor neurodevelopmental outcome is well documented and forms the basis of therapeutic efforts to normalize blood pressure. However, causation has not been demonstrated between hypotension and poor neurodevelopment and thus one cannot infer that long-term neurodevelopmental outcomes will improve if hypotension is rigorously avoided. Therein lies the conundrum often faced by the neonatologist: when to treat early cardiovascular compromise in the VLBW neonate, what medication to use, and how quickly to normalize blood pressure and CBF. Thus a prospective observational study of more than 1000 infants less than 28 weeks’ gestation showed that early postnatal hypotension was not associated with poorer outcomes. Furthermore retrospective studies have raised additional concerns by demonstrating an association between “treated hypotension” and poor neurodevelopmental outcomes. Of note, the use of the definition “treated hypotension” in these studies has introduced an additional bias by implying that, in addition to or independent of hypotension, the treatment might be a factor contributing to the described association. Although the implication of the potential negative effects of treatment of hypotension is plausible and thus needs to be prospectively studied, at present no conclusion can be drawn, especially because other investigators have reported essentially the opposite finding. Unfortunately, all prior studies were uncontrolled, either retrospective or observational in nature, and hypotension was treated. There is only one randomized controlled trial published to date that had a no-treatment arm. Owing to difficulties in obtaining informed consent in a timely fashion or refusal of enrollment by the attending neonatologist, these trials are not feasible to perform. Interestingly, a follow-up study to a randomized prospective trial comparing the effectiveness of dopamine and epinephrine in increasing blood pressure and CBF in hypotensive VLBW neonates during the first postnatal day found that neonates who responded to dopamine or epinephrine had long-term neurodevelopment outcomes comparable to those of age-matched normotensive controls. However, infants who did not respond to vasopressor-inotrope treatment had worse long-term outcome. However, as the primary outcome measure of the original study was not long-term neurodevelopmental outcome, the follow-up study was not appropriately powered to put this concern to rest.

It is clear that the relationship between a given mean blood pressure and associated brain oxygen delivery below which the risk for injury is increased remains unclear. Moreover, there is no clear evidence that increasing blood pressure to the normal range will normalize oxygen delivery. Mean arterial pressure (MAP) is considered by some to be less important than other indirect clinical indicators of decreased perfusion, such as capillary refill time (CRT), urine output, and lactic acidosis. This approach ignores the physiologic principle that a pressure gradient is necessary to drive flow (Poiseuille’s law). Simplistically, to provide blood flow to the brain, the systolic arterial pressure has to be higher than the intracranial pressure. Obviously, the dependent variables of systemic hemodynamics (cardiac output and SVR) determine blood pressure and thus tissue oxygen delivery. However, ignoring MAP itself, as implied by some, may not be prudent and even feasible. In summary, blood pressure should be considered as one of the markers of adequacy of circulatory function but not the only or primary marker . Indeed, low blood pressure implies impairment of vasomotor tone, low cardiac output, or both. Conversely, a normal blood pressure indicates either normal cardiac output and vasomotor tone or a compensated state, in which either cardiac output is increased to compensate for the low vasomotor tone or the vasomotor tone is elevated to compensate for the low cardiac output ( Fig. 1.1 ). In older children and adults, vital organs are relatively protected in the compensated phase of shock. Unfortunately, this may not be the situation in the preterm infant—hence the limitation of primarily relying on blood pressure monitoring in an effort to assess the adequacy of circulation.

In clinical practice, hypotension is usually defined as the blood pressure value below the 5th or 10th percentile for the gestational and postnatal age–dependent normative blood pressure values ( Fig. 1.2 ). Interestingly, findings of a recent study suggest that the normative values may actually be low; that is, physiologically normal blood pressure in VLBW infants may actually be higher than has been commonly accepted. Moreover, owing to the compensatory mechanisms, a certain blood pressure value in a given patient might be associated with normal oxygen delivery at one point in time while the same value may indicate true hypotension (abnormal tissue oxygen delivery) at another time. Accordingly, there is no consensus among neonatologists about the acceptable lower limit of systemic mean or systolic arterial blood pressure, and most units have different guidelines for the initiation of treatment of hypotension. From a pathophysiological standpoint, three levels of functional alterations of increasing severity can be used to guide the definition of hypotension ( Fig. 1.3 ). Findings of a small study underscore this point. However, it is important to keep in mind that no prospectively collected information is available on mortality and morbidity associated with the different proposed blood pressure thresholds.

First, the mean blood pressure associated with the loss of CBF autoregulation is the generally accepted definition of hypotension ( autoregulatory blood pressure threshold ). Indeed, there is considerable information in the literature indicating that CBF autoregulation is functional, albeit within a narrow range, in normotensive but not in hypotensive VLBW neonates in the immediate postnatal period ( Fig. 1.4 ). Also of interest is that CBF velocity increases in a pressure-passive fashion as systolic blood pressure is increased with dopamine during the first postnatal day. A study found that cerebral pressure passivity in the VLBW neonatal population was associated with an increased risk for periventricular/intraventricular hemorrhage (P/IVH). These findings implicate blood pressure and pressure passivity as risk factors for intracranial pathology.

Autoregulation is the ability of the arteries to constrict or dilate in response to an increase or decrease, respectively, in the transmural pressure to maintain blood flow relatively constant within a range of arterial blood pressure changes (see Fig. 1.4 ). However, in the neonate the vascular response has a limited capacity. In addition, and as mentioned previously, the autoregulatory blood pressure range is narrow in the neonatal patient population, with the 50th percentile of the mean blood pressure being relatively close to the lower autoregulatory blood pressure threshold. In other words, small decreases in blood pressure may result in loss of CBF autoregulation, especially in the VLBW infant. Available data suggest that the autoregulatory blood pressure threshold is around 28 to 29 mm Hg even in the extremely LBW (ELBW) neonate during the first postnatal day ( Fig. 1.5 ). However, this is rather arbitrary as it remains unclear at values around this range whether cellular function and structural integrity are affected, because increased cerebral fractional oxygen extraction (CFOE), microvascular vasodilation, and a shift in the hemoglobin-oxygen dissociation curve to the left can maintain tissue oxygen delivery at levels appropriate to sustain cellular function and integrity.

If blood pressure continues to fall, it will reach a value at which cerebral function becomes compromised ( functional blood pressure threshold ). Data suggest that the functional blood pressure threshold may be around 22 to 24 mm Hg in the VLBW neonate during the first postnatal days ( Fig. 1.6 ). However, caution is needed when interpreting these findings because the data were obtained in a small number of preterm infants.

Finally, if blood pressure decreases even further, it reaches a value at which brain tissue structural integrity becomes compromised ( ischemic blood pressure threshold ). On the basis of findings in immature animals, it is assumed that the ischemic CBF threshold is around 50% of resting CBF. Although it is unclear which blood pressure value represents the ischemic CBF threshold in the VLBW neonate during the first postnatal day, it may be at or below 20 mm Hg (see Fig. 1.3 ). It is important to emphasize that the situation is further complicated by the fact that these numbers represent moving targets for the individual patient influenced by his or her ability to compensate for decreases in blood pressure and oxygen delivery. In addition, other factors, such as the different sensitivity of brain structures to perfusion changes, arterial partial pressure of carbon dioxide (Pa co ₂) levels, the presence of acidosis, preexisting insults (interruption of placental blood flow [i.e., asphyxia]), and underlying pathophysiology (sepsis, anemia), all have an impact on the critical blood pressure value at which perfusion pressure and cerebral oxygen delivery cannot satisfy cellular oxygen demand to sustain autoregulation, then cellular function, and finally structural integrity.

In most units, continuous monitoring of blood pressure and assessment of indirect signs of tissue perfusion (urine output, CRT, and lactic acidosis) still form the basis for identifying the presence of cardiovascular compromise. As discussed earlier, though, “adequate” blood pressure may not always guarantee adequate organ perfusion in VLBW neonates, especially during the first postnatal day. Indeed, blood pressure only weakly correlates with superior vena cava (SVC) flow in VLBW neonates during the period of immediate postnatal adaptation. Of note, SVC flow has increasingly been used in the clinical practice as a surrogate for systemic blood flow in the VLBW neonate during the immediate postnatal period, when shunting through the fetal channels prohibits the use of left ventricular output to assess systemic blood flow. The finding that adequate blood pressure may not always guarantee adequate systemic blood flow in these patients may be explained, at least in part, by the notion that the cerebral vascular bed, especially of the 1-day-old ELBW neonate, may not be of high priority assignment yet and thus it will constrict, as do the vessels do in the nonvital organs, rather than dilate in response to a decrease in the perfusion pressure (see later text).

Pathogenesis and Diagnosis of Pathologic Cerebral Blood Flow

Fluctuations in CBF are implicated in the pathogenesis of P/IVH and PWMI in the VLBW infant. Both systemic and local (intracerebral) factors play a role in the pathogenesis of these central nervous system injuries and therefore are important to establish the underlying pathogenesis. In addition, the level of maturity, postnatal age, and intercurrent clinical factors (e.g., infection/inflammation, vasopressor-resistant hypotension) also need to be considered. In this section, we briefly discuss the monitoring parameters currently in clinical use (systemic arterial pressure and arterial blood gas sampling) and then delve into the emerging field of bedside monitoring of systemic and organ blood flow, especially CBF and brain activity. We review most of the existing technologies, including echocardiography and Doppler ultrasound, impedance electrical cardiometry (IEC), NIRS, and aEEG, and discuss the applicability and limitations of these modalities.

A logical place to begin the discussion on monitoring CBF in the VLBW infant is to ask, “What is normal CBF in the VLBW infant?” Several investigators have addressed this issue. It is clear from these studies that CBF is lower in preterm infants than in adults, corresponding to the lower metabolic rate of the preterm brain. A study using xenon 133 ( ¹³³Xe) clearance found that in 42 preterm infants with a mean gestational age of 31 weeks, CBF was 15.5 ± 7.2 mL/100 g/min during the first postnatal week, a value three to four times lower than that in adults. Interestingly, patients enrolled in this study who were receiving mechanical ventilation had lower CBF than their nonventilated counterparts and those supported by continuous positive airway pressure (CPAP) (11.8 ± 3.2 vs. 19.8 ± 5.3 and 21.3 ± 12 mL/100 g/min, respectively). CBF in this study was not consistently affected by postnatal age, gestational age, birth weight, mode of delivery, Pa co ₂, hemoglobin concentration, mean blood pressure, or phenobarbital therapy. In contrast, subsequent publications by the same group of authors investigating CBF reactivity in preterm infants during the first three postnatal days showed that, as expected, Pa co ₂and hemoglobin concentration significantly affect CBF in this patient population. However, the relationship between Pa co ₂and CBF appears to be also affected by postnatal age during the immediate postnatal period (see later text). Using positron emission tomography (PET) to measure CBF, a study found lower values for CBF in preterm and term neonates compared with those obtained by the use of ¹³³Xe clearance. More importantly, the authors reported that, in 1 term and 5 preterm infants with CBF between 4.9 and 10 mL/100 g/min, the term neonate and 3 of the preterm infants had normal neurodevelopmental outcome at 24 months. These data suggest that the “neurodevelopmentally safe” lower limit of CBF in the neonate is lower than predicted and may be between 5 and 10 mL/100 g/min. Finally, as mentioned earlier, because CBF is affected by many factors other than blood pressure, it is not possible to define the blood pressure value consistently associated with a decrease of CBF below the safe limit that results in ischemic brain injury.

Kluckow and Evans, using SVC flow as a surrogate for CBF, established normal values of SVC flow during the first 48 postnatal hours in well preterm neonates younger than 30 weeks’ gestation who were receiving minimal ventilatory support. However, it must be stated that the extent to which SVC flow is representative of systemic or CBF in preterm neonates during the first postnatal days is not understood. In a subsequent study that included sick preterm infants younger than 30 weeks’ gestation, the same group found that 38% of infants had a period of low SVC in the first 24 postnatal hours. The incidence of low SVC flow was significantly related to the level of immaturity, and more than 70% of low SVC flow occurred in very preterm neonates (< 27 weeks’ gestation). The sudden increase in the peripheral vascular resistance caused by the loss of the low-resistance placental circulation when the cord is clamped immediately after delivery, the complex process of cardiorespiratory transition to the postnatal circulatory pattern, and myocardial and autonomic central nervous system immaturity have all been proposed to contribute to these findings. Indeed, these factors may explain why many of these very preterm neonates struggle to maintain normal systemic blood flow during the first 12 to 24 postnatal hours. Of note is that using “physiologic” (delayed) rather than immediate cord clamping, immediate postnatal hemodynamic transition, and the incidence of associated cerebral pathologies have changed. Importantly, a proportion of the very preterm infants with extremely low SVC flow were found to have systemic blood pressures in the “normal” range (i.e., greater than or equal to their gestational age in weeks), a finding supported by subsequent studies of this group of researchers. Because normal blood pressure and decreased organ blood flow to nonvital organs are the hallmarks of the compensated phase of shock and because a portion of SVC flow represents blood returning from the brain, a vital organ, it is conceivable that that the proposed low-priority vessel (nonvital organ) assignment of the vascular beds of the forebrain (cerebral cortex and white matter) in the very preterm neonate during the immediate postnatal period explain these findings. This hypothesis, which is supported by studies in different animal models and, indirectly, in the human neonate, may explain, at least in part, why SVC blood flow may be decreased in some very preterm neonates who have normal systemic blood pressure. Most preterm neonates with documented low SVC flow in the first 24 to 48 hours who do not go on to have P/IVH or PWMI are more mature (28 weeks’ and beyond vs. 25–26 weeks’ gestation). Thus for preterm infants of less than 30 weeks’ gestation, preexisting low systemic blood flow (and CBF) may be necessary but not sufficient to cause intracranial pathology. Importantly, all patients studied had an increase in SVC flow by 24 to 36 hours, and all P/IVHs occurred after the SVC flow had increased. Findings of a later prospective observational study by our group using echocardiography and NIRS confirm and expand these observations. In this study, very preterm neonates who presented with lower systemic blood flow and higher cerebral vascular resistance during the first 12 postnatal hours were at a higher risk for the development of P/IVH. Importantly, the bleeding occurred only after cardiac output and brain blood flow had increased. In addition, lower cerebral tissue oxygenation levels detected by NIRS during the first 12 postnatal hours might identify the patients who will subsequently develop P/IVH. Taken together, these findings implicate an ischemia-reperfusion cycle in the pathogenesis of P/IVH in very preterm neonates during the immediate transitional period.

It is important to note that the methods used to assess systemic and CBF in VLBW neonates in the immediate transitional period have significant limitations. When SVC flow is used to assess systemic and CBF, the measurements are operator dependent owing to the uncertainties associated with the accurate measurement of vessel diameter and flow velocity. The fluctuations in vessel size during the cardiac cycle and the flow velocity pattern in the SVC are important factors contributing to these technical difficulties. In addition, the shape of the SVC, the lack of data on the magnitude of the contribution of CBF to SVC flow in the human neonate, and the lack of a documented association between Pa co ₂and SVC flow in this patient population call for caution in the interpretation of these findings.

Yet an association has been found between SVC flow and aEEG indices of oxygen utilization (continuity and amplitude) in the first 48 postnatal hours. A finding of this study also demonstrated that hypotension, either treated or untreated, was associated with decreased levels of brain activity as assessed by aEEG. This finding supports the previously referenced data indicating that blood pressure and brain oxygen utilization are inextricably linked.

In another study, CBF was measured in both the internal carotid and vertebral arteries and the sum of the flow in the four arteries supplying the brain was used to assess the changes in CBF volume in preterm infants of 28 to 35 weeks’ gestation over the first 2 postnatal weeks. Although the technique, again, has significant limitations, the findings suggest that a steep rise in CBF occurs from the first to the second postnatal day and that this pattern is independent of gestational age. Thereafter CBF continues to rise gradually ( Fig. 1.7 ). Because brain weight does not significantly increase during the first 48 postnatal hours, the investigators inferred that the observed increase in CBF during that period was secondary to increased cerebral perfusion per unit weight of tissue. On the other hand, the more gradual increase over the ensuing 2 weeks is likely due to a combination of both increased brain weight and increased perfusion. This study enrolled only healthy preterm infants with normal brains, whereas investigations in other studies included a group of preterm infants who were sicker and had a higher incidence of significant intracranial pathology. Nevertheless, the results in the two groups of patients are complementary as they provide evidence for a decreased CBF in the first postnatal day, followed by a significant increase by the second postnatal day. Although low CBF in the first postnatal day and the ensuing “reperfusion” appears to be a physiologic phenomenon likely occurring in all very preterm neonates, CBF is even lower in those who later develop P/IVH. Therefore the phenomenon of low CBF is also a necessary but not sufficient cause of intracranial pathology (P/IVH or PWMI) in this patient population. Although the vast majority of studies found low CBF on the first examination performed during the first few hours after birth, some have described a decrease in CBF at 12 hours compared with 3 to 6 hours after delivery. The reason for the discrepancy in the findings is unclear at present.

The ultimate goal is to improve neurodevelopmental outcome in preterm infants. In addition to the association between low SVC flow in the early postnatal period and P/IVH, low SVC flow in the early postnatal period is also independently associated with impaired neurologic outcome at 3 years of age. Therefore, infants most at risk must be identified in the immediate postnatal period. In addition to ultrasonography, NIRS and other monitoring modalities may be helpful in this regard. Indeed, and as mentioned earlier, preterm infants who develop P/IVH have a pattern of changes in cerebral regional tissue oxygen saturation and oxygen extraction that is different from those without risk for P/IVH. Thus combining different systemic and organ blood flow and tissue oxygenation monitoring technologies may be helpful in the early identification of infants at greater risk for the development of intracerebral pathologies.

It is clear from the large number of epidemiologic and hemodynamic studies, though, that the level of immaturity is one of the most important predisposing factors for the occurrence of more abrupt changes in CBF and the increased vulnerability during postnatal adaptation and for poor neurologic outcome. Therefore assessment of CBF during the first 24 to 48 postnatal hours in the most immature and vulnerable patients is important. However, owing to the technical difficulties associated with reliable and continuous assessment of CBF, clinical practice currently relies on indirect measures for diagnosis of changes in cerebral perfusion, especially because the sole reliance on blood pressure in the indirect assessment of CBF in this patient population during the first postnatal day is not appropriate.

In addition to blood pressure, monitoring of the indirect clinical indicators of tissue perfusion such as urine output, CRT, and acid-base status in the routine clinical practice remain important. Although these indirect clinical indicators by themselves are fairly nonspecific for evaluating systemic flow, using CRT and blood pressure together results in greater sensitivity. Indeed, when blood pressure and CRT are less than 30 mm Hg and 3 seconds or less, respectively, the sensitivity for identifying low systemic blood flow is 86%. In addition, avoidance of both hypocapnia and hypercapnia is of utmost importance because of their effect on CBF. However, and as mentioned earlier, the manifestation of the effect of Pa co ₂on CBF appears to be dependent on postnatal age. A recent study reported a gradual change in the relationship between Pa co ₂and middle cerebral artery mean velocity, a surrogate for CBF, from none on the first day to the expected positive linear pattern by the third postnatal day. Others have also described an attenuated relationship on the first postnatal day with an increase in the reactivity of CBF to carbon dioxide (CO ₂) during the following days.

Monitoring of Blood Pressure, Systemic and Organ Blood Flow, and Cerebral Function

Blood pressure is invasively and continuously monitored in most critically ill neonates using an indwelling arterial catheter and a calibrated pressure transducer. Available techniques more likely to be used for systemic blood flow and CBF monitoring are ultrasound (echocardiography and Doppler ultrasound), electrical impedance, and NIRS. As for continuous monitoring of cerebral function in neonates, aEEG has also been increasingly used at the bedside. We briefly discuss these modalities used for systemic and organ blood flow monitoring in the following sections with a primary focus on those that can be performed noninvasively at the bedside.

Doppler Ultrasound

Velocity of blood flow can be measured through the use of the Doppler principle, which states that the change in frequency of reflected sound is proportional to the velocity of the passing object (in this case, blood). The calculated velocity needs to be corrected for the angle between the vessel and the emitted sound beam (angle of insonation), and the straightforward idea is complicated by the fact that arterial blood is pulsatile and its speed varies within the vessel (i.e., it is faster in the center of the vessel). It is important to recognize that speed of blood (distance traveled per unit time) in a vessel means little by itself; we are interested in the absolute blood flow (volume per unit time). Thus volumetric measurements are crucial and can be obtained by the product of velocity time integral (VTI) and cross-sectional area of the vessel that the blood travels in. Investigators have used several different volumetric indices, including SVC, internal carotid artery, and vertebral artery flow, as previously discussed. The limitations of SVC flow measurements were discussed earlier. In general, major technical problems with volumetric measurements include but are not restricted to the small size of the vessels, the motion of vessel wall, and whether or not an angle of insonation of less than 20 degrees can be achieved. In addition to volumetric measurements of vessel blood flow, right ventricular and left ventricular outflow measurements have excessively been studied. However, both are fraught with pitfalls in the very preterm neonate in the immediate postnatal period, because the patent foramen ovale (PFO) and patent ductus arteriosus (PDA) represent shunts that confound measurements of the right ventricular and left ventricular flows, respectively. It is believed that right ventricular output may be a more reliable indicator of systemic blood flow during the immediate postnatal period with the fetal channels open, because shunting through the PFO is less significant than PDA shunting during the first 24 postnatal hours. Indeed, right ventricular output and systemic blood pressure have been correlated with EEG parameters (brain function) in VLBW infants in the immediate postnatal period. Ultrasound techniques are noninvasive and widely accessible in the intensive care setting and can be done at the bedside. The procedure itself minimally affects hemodynamic and physiological variables of the infant. However, all ultrasound measurements are noncontinuous, operator dependent, and have their significant limitations. As for the issues related to operator skills, centers using these methods to diagnose pathologic CBF in neonates must have a rigorous quality control system in place with neonatologists trained in functional echocardiography and available at the bedside at any time.

With regard to the limitations to the use of vascular Doppler ultrasonography in assessing organ blood flow, the most important limitation is the small size of the artery of interest (e.g., middle or anterior cerebral artery), which precludes accurate measurement of its diameter. As previously mentioned, the estimation of blood flow (Q) depends on assessment of mean velocity of the blood (V) and the vessel diameter (D) (Q = V[πD ²/4] × 60); any small error in measuring the diameter will translate into a significant error in estimating the actual blood flow. Therefore instead of directly measuring blood flow, investigators often use changes in various Doppler-derived indices, such as mean blood flow velocity or the pulsatility or resistance index, as surrogates for changes in blood flow. This approach is based on the premise that the vessel diameter remains constant despite the changes in blood flow. However, this concept in not universally accepted. Nevertheless, both animal and human studies have shown an acceptable correlation between these indices and other measures of blood flow.

Finally, although normative data for the Doppler ultrasonography‒derived indices for various vessels are available, the previously described limitations require caution in the interpretation of a single measurement. Rather, repeated measurements and the use of trends over time are thought to be more informative of the hemodynamic status and the changes in organ blood flow.

Impedance Electrical Cardiometry

IEC is a noninvasive and continuous bedside method of measuring beat-to-beat left ventricular output on the basis of detection of changes in thoracic electrical bioimpedance (Aesculon, Cardiotronic; La Jolla, CA) caused by the changes in the orientation of the red blood cells in the ascending aorta during systole and diastole normalized for the body mass of the patient. The method has been validated against thermodilution and other direct methods of cardiac output measurement and has shown good correlation in adults and children. Although its clinical utility in neonates is still untested, data from our group show a clinically acceptable precision and quantitation of left ventricular output comparable to echocardiography in term neonates. However, a recent study comparing magnetic resonance imaging (MRI) and IEC in adults found poor agreement between the two methods in estimating left ventricular output. In addition to the inherent limitations of MRI, in this study the IEC measurements were done before and after MRI and not simultaneously. Another recent study by our group, however, also found poorer correlation with MRI-derived values of cardiac output and its changes with those obtained by simultaneous IEC monitoring in adults during rest and exercise. These findings suggest that the absolute values obtained using IEC may not appropriately represent cardiac output. Yet because of its reproducibility, continuous beat-to-beat cardiac output measurements, and ease of application, IEC appears to possess clinical applicability when the measurements are trended over time. The recent publication of reference values for cardiac output measured by IEC in premature infants of different gestational age may be helpful if one considers IEC as a screening tool for the detection of infants at risk for low cardiac output. Further validation of this technique is needed, especially in the premature infant population, before the routine use of IEC can be recommended in the neonatal patient population. In conclusion, IEC remains an interesting approach with the ability to obtain continuous, beat-to-beat and noninvasively collected data in absolute numbers on stroke volume and cardiac output at the bedside in neonates, especially when trending changes in cardiac output and assessing the efficacy of therapeutic interventions.

Near-Infrared Spectroscopy

NIRS has received much attention since its first use in newborns in 1985, and numerous papers have been published describing its use and clinical relevance in neonatology. As absorption of light in the near-infrared range (600–900 nm) depends on the oxygenation status of chromophores such as hemoglobin and cytochrome aa3, the absorption during passage through brain tissue can be measured and oxygenation indices calculated. Different wavelengths of light can be used to assess different parameters, such as oxyhemoglobin, deoxyhemoglobin, and cytochrome aa3 oxidase. Through induction of a small but rapid change in arterial oxygen saturation in the subject, CBF can even be calculated using the Fick principle. This method assumes that during the measurement period, cerebral blood volume (CBV) and cerebral oxygen extraction remain constant. However, the technique may not be feasible in infants with severe lung disease, in whom no or very little change in oxygen saturation occurs with an increased fraction of inspired oxygen (F io ₂), and in infants with normal lungs in whom oxygen saturation is 100% when they breathe room air. To circumvent this problem, an injected tracer dye such as indocyanine green has been used instead of oxygen with comparable results. Some instruments use the tissue oxygenation index (TOI), which is the weighted average of arterial, capillary, and venous oxygenation and theoretically allows the measurement of regional cerebral hemoglobin oxygen saturation (rScO ₂) without manipulation of F io ₂or use of dye. However, this index also has significant potential for inaccuracy, with an intrameasurement agreement in a single subject as large as ‒17% to +17%. Indeed, reproducibility of NIRS measurements in general has been an ongoing issue for investigators, especially in the detection of focal changes in cerebral hemodynamics. This is a significant problem because focal hemodynamic changes are at least as likely as global changes to contribute to neuropathology. Despite these limitations, NIRS has been validated through comparison with ¹³³Xe clearance in human newborns. As the penetration depth of NIRS is around 2.5 cm, unless the patient is a very preterm neonate, rScO ₂is primarily assessed in the frontal lobes when the optodes are placed on the forehead.

For clinical use, an algorithm allowing for continuous monitoring of regional tissue oxygen saturation (rSO ₂) in absolute numbers has been developed for adult, pediatric, and neonatal use. More recently, newly developed MRI techniques that do not require respiratory calibration have allowed comparison of cerebral oxygen saturation measurements by NIRS and MRI in neonates. The agreement is reasonable with strong linear relation between the two methods. Although NIRS represents a practical solution and information on its use in neonates has been encouraging, accumulation of more data and prospective studies looking at both short- and long-term outcomes are needed to provide an evidence-based utilization of NIRS in neonatal medicine. A multicenter randomized clinical trial (SafeBoosC II [Safeguarding the Brain of Our Smallest Children II]) proposes a treatment guideline to reduce the burden of cerebral hypoxia or hyperoxia of extremely preterm infants by targeting a hypothesized “acceptable” rScO ₂range of 55% to 85% by use of NIRS monitoring during the first 3 postnatal days. Short-term outcomes have shown an overall 58% (95% confidence interval [CI] 35%–73%) reduction of hypoxia or hyperoxia burden in the NIRS group versus the control group (36.1% vs. 81.3% hours) using a preset treatment guideline. However, despite the decrease in cerebral hypoxia/hyperoxia burden, no significant differences in incidence of severe brain injury detected by cranial ultrasound and MRI, EEG (burst rates), or certain biomarkers of brain injury were found between the NIRS and control groups. Data collection for long-term neurodevelopmental outcomes is still underway. Limited animal data suggest that cerebral rSO ₂of 45% to 55% may be an important threshold below which ischemic brain injury likely occurs.

A recent case-control study comparing hypotensive preterm infants receiving moderate-high doses of dopamine with normotensive control subjects found no difference in the percentage time spent with cerebral saturation less than 50% in the first 3 postnatal days. However, patients who spent more than 10% of the time with saturation less than 50% had worse neurodevelopmental outcomes. In addition to the interest in absolute rScO ₂values, assessment of cerebral autoregulation in premature infants using NIRS has also become a focus of active research. Assuming a constant arterial oxygen saturation (Sa o ₂), hematocrit, metabolic rate, CBV, and arterial and venous blood distribution in the tissue, alteration in cerebral rSO ₂reflects changes in CBF. When coupled with mean arterial blood pressure measurement, cerebral autoregulation can be characterized. However, this is a challenging approach because maintaining a constant oxygen saturation in extremely premature infants is difficult in the clinical setting. In summary, before NIRS monitoring can be recommended to guide routine clinical care, well-designed, large, multicenter randomized control trials need to be completed.

Amplitude-Integrated EEG (Cerebral Function Monitoring)

Amplitude integrated EEG is one of the most accurate bedside methods to establish a neurologic prognosis in asphyxiated infants during the first several hours after birth. Accordingly, aEEG has been used to select candidates for enrollment in head-cooling neuroprotection trials. This technology uses either a single-channel EEG recording with biparietal electrodes or duo-channel EEG with four electrodes. Frequencies lower than 2 Hz and higher than 15 Hz are selectively filtered out, and the amplitude of the signal is integrated. The signal is then recorded semilogarithmically with slow speed, effectively compressing hours of EEG recording into shorter segments that reflect global background activity and major deviations from baseline (e.g., seizures). Studies have shown that aEEG correlates with conventional EEG and has the distinct advantage of being easily applied and interpreted by non-neurologists. In an earlier study, normal aEEG findings in the first 72 postnatal hours in asphyxiated term neonates have been found to be prognostic of normal neurologic outcome at 2 years of age. Coupled with early neurologic examination, simultaneous aEEG improved specificity and positive predictive value of abnormal results for abnormal neurologic outcome at 18 months of age. A growing interest for the utilization of aEEG in the preterm population has enabled gathering of normative data. Typical patterns of background activity for preterm infants have been established, and a number of studies exist that point to its applicability in this group. West and colleagues examined the relationships among echocardiographic blood flow findings, mean arterial blood pressure, and aEEG findings in preterm infants (<30 weeks’ gestation) during the first 48 hours after birth. They found that low right ventricle output, used as a surrogate for systemic blood flow owing to the shunting across the fetal channels at 12 hours of postnatal age, correlated with low aEEG amplitude, whereas low mean blood pressure (<31 mm Hg) correlated with low EEG continuity. However, there was no relationship between aEEG amplitude and SVC flow. Although preliminary in nature, this study at least succeeded in drawing attention to an association between a hemodynamic parameter in wide clinical use (blood pressure) and two more experimental modes of CBF monitoring (echocardiography and aEEG). Taken together with evidence that early aEEG in preterm infants can be helpful in predicting long-term neurodevelopmental outcome, it is reasonable to suggest that aEEG merits further study in the VLBW population, especially along with the use of NIRS, as a means of identifying infants at risk for low CBF and oxygen delivery and/or for pathologic fluctuations in CBF.

Summary of the Monitoring Methods Discussed

Methods capable of diagnosing altered CBF and the associated changes in brain function in the VLBW population in the first hours to days after delivery are still largely in the experimental arena. It is extremely unlikely that one monitoring parameter will be sufficient to encapsulate the status of CBF and oxygen delivery. Instead, and in addition to clinical assessment, a combination of a variety of technologies will likely prove helpful; these technologies range from conventional (heart rate, blood pressure, oxygen saturation, transcutaneous CO ₂) to advanced (Doppler ultrasonography, IEC, NIRS, aEEG) methods. Both systemic and CBF, as well as cerebral oxygen delivery and extraction, have to be evaluated simultaneously and continuously to enable the collection of in-depth information allowing for more informed, minute-to minute decisions about how, when, and what to treat. This goal has not been achieved, but it is likely that a number of these modalities will be incorporated into routine clinical use in the not too distant future.

Fig. 1.8 illustrates an example of a comprehensive, real-time, hemodynamic bedside monitoring and data acquisition system developed by our group.