Understanding the cardiovascular physiology and pathophysiology in a neonate during transition and beyond requires the availability of objective data that reflect both systemic and regional blood flow and oxygen balance at a given time. Complementing conventional hemodynamic parameters such as heart rate, blood pressure, and arterial oxygen saturation (SpO 2 ), this additional information can provide insights into complex physiologic interactions between the key components of circulation that determine oxygen demand-delivery coupling and potentially reveal preclinical indicators and trends that identify patients at risk for cardiovascular compromise. Comprehensive hemodynamic monitoring systems enable continuous and simultaneous acquisition of physiometric data in real time for subsequent analysis and processing using various applications including predictive mathematical modeling. Although still being used primarily in research settings, increasing use of such monitoring systems is the first step toward individualized hemodynamic management of high-risk patient subpopulations that could be identified early and would most likely benefit from a given intervention. To further enhance the capabilities of these systems, inclusion of genomic data potentially opens an entirely new era in hemodynamic research with implications for patient care in the near future.
Keywordsechocardiography, hemodynamic monitoring, hypotension, individualized care, near-infrared spectroscopy, organ blood flow, predictive modeling, systemic circulation
Accurate assessment of the hemodynamic status in critically ill neonates requires blood pressure measurements to be interpreted in the context of indirect (clinical signs) and direct (measurements and assessments) indicators of systemic circulation (cardiac output) and regional organ blood flow.
Further validation of emerging technological approaches to evaluate systemic circulation and regional blood flow in a continuous and noninvasive manner is necessary.
Comprehensive monitoring systems allow continuous and simultaneous collection of physiologic data on multiple hemodynamic parameters in real time. Inclusion of a motion-activated video-recording device enables analyzing objectively collected information in the context of the various clinical events taking place at the bedside.
Addition of the modules to assess functional status of a given organ allows correlation of the hemodynamic changes with functional activity of the interrogated organ (with a primary focus on the brain).
In a neonate, complex physiologic interactions such as baroreceptor reflex sensitivity, an indicator of the autonomic control of the circulation (heart and peripheral vascular resistance), and cerebral autoregulation can be reliably evaluated only using comprehensive monitoring systems.
Computational modeling using large amounts of the physiometric data obtained is the next step in identifying physiologic trends that predict the development of cardiovascular compromise. The development of algorithms then enables timely application of pathophysiology- and evidence-based interventions.
Relevant genetic information obtained via genome sequencing coupled with physiometric data may allow further stratification of patient subpopulations based on their individual risk of developing cardiovascular compromise and subsequent complications, such as periventricular/intraventricular hemorrhage, and allows prediction of the potential response to particular interventions. This approach will serve as the foundation of the development of individualized medicine in neonatology.
Recent advances in biomedical research and technology have allowed clinicians to obtain significantly more clinically relevant physiologic, biochemical, and genetic information that could be useful in the diagnosis and management of various conditions. It is fair to state that neonatology has become one of the rapidly evolving subspecialties at the frontier of this progress. However, the field of neonatal hemodynamics, although being extensively investigated in basic and animal laboratory and clinical research settings, remains inadequately understood. Accordingly, we continue to have difficulties in establishing reliable criteria for the diagnosis of the most common deviations from physiology, such as neonatal hypotension, especially during the period of immediate postnatal transition. This, in turn, leads to a paucity of established, evidence-based guidelines on when and how to intervene in a neonate presenting with these conditions. Thus we must recognize the significant limitations of our current understanding of a number of clinically relevant aspects of neonatal cardiovascular physiology and pathophysiology and acknowledge the existing vast differences in opinions on diagnostic criteria and treatment approaches in neonatal intensive care in general and neonatal cardiovascular pathophysiology in particular.
The next logical step in identifying individual patients with early signs of hemodynamic compromise is to develop and implement comprehensive hemodynamic monitoring systems that enable continuous and real-time monitoring and acquisition of multiple hemodynamic parameters of systemic and regional blood flow and oxygen demand-delivery coupling. The information obtained can then be used to design and execute clinical trials in subpopulations of neonates exhibiting common hemodynamic features and targeted by a given intervention. Only this approach will enable timely identification of the individual patient in the future in whom a trial-tested, individualized management plan can be used and the response to the pathophysiology- and evidence-based interventions monitored.
Limitations of Conventional Monitoring
Multiple studies have shown an association between severe cardiovascular compromise and increased morbidity and mortality in affected patients. Although there is some evidence for improved outcome in hypotensive preterm infants responding to vasopressor-inotropes with increases in blood pressure and cerebral blood flow, essentially none of the suggested interventions or medications used (dopamine, epinephrine, dobutamine, milrinone, or vasopressin) has been properly studied to determine the actual impact of the treatment on clinically relevant medium- and long-term outcomes.
The failure to identify effective interventions for the treatment of neonatal hemodynamic compromise stems from several unresolved challenges. The cardiovascular system of the newborn undergoes rapid changes during transition to extrauterine life, and these changes are greatly affected by multiple intrinsic and extrinsic factors. Such factors include, but are not limited to, individual variations in the degree of immaturity based on gestational and postnatal age, coexisting comorbidities including the need for positive pressure ventilation, the complex interactions between systemic and regional blood flow, and underlying genetic heterogeneity.
Another fundamental challenge is the lack of a pathophysiology- and evidence-based definition of neonatal hypotension (see Chapter 1 , Chapter 3 ). Measurements of blood pressure with or without the use of indirect clinical indicators of perfusion remain the major criterion in the assessment of the hemodynamic status and the need for interventions. Normative blood pressure values in preterm and term infants have been reported in population-based studies, and mean arterial blood pressure increases with increasing gestational and postnatal age (see Chapter 3 ). However, blood pressure within the normal range for a given gestational and postnatal age does not necessarily reflect normal organ blood flow. And, similarly, abnormally low blood pressure values do not automatically translate into compromised organ blood flow (see Chapter 1 , Chapter 3 ). So, for patients of the same gestational age and degree of maturity, the same blood pressure values can be associated with either adequate or compromised systemic and organ perfusion. More so, even for the same patient under different conditions and points in time, the same blood pressure values may represent adequate or compromised systemic and/or organ perfusion. The reason for such significant limitations of using the blood pressure alone as an indicator of hemodynamic compromise lies in the fact that blood pressure is determined by the interaction between systemic blood flow represented by effective cardiac output (CO) and systemic vascular resistance. Thus the same values of blood pressure, the dependent variable, can result from different combinations of the other two, independent, variables. In the early, compensated phase of shock, blood pressure remains within the normal range, whereas nonvital organ perfusion has, by definition, decreased. Because many pathophysiologic mechanisms may lead to inadequate organ blood flow, whether they affect effective CO, systemic vascular resistance, or both, failure to recognize these changes leads to delay in initiation of treatment, exhaustion of limited compensatory mechanisms, and a resultant progression to the uncompensated phase of shock with obvious signs of decreased organ perfusion and oxygen delivery. On the other hand, unnecessary treatment might also be started if the condition is thought to have reached the treatment threshold when, in reality, systemic and/or regional blood flow is maintained. In addition, identification of the primary pathophysiologic mechanism that could prompt appropriately targeted intervention becomes significantly more challenging when reliable information on the status of the macrocirculation and/or tissue oxygen delivery is not readily available.
Other conventional hemodynamic parameters (heart rate and SpO 2 ), even if continuously monitored along with blood pressure, as well as capillary refill time, urine output, and serum lactate levels, have significant limitations for timely and accurate assessment of both the cardiovascular status and the response to interventions aimed to treat the hemodynamic compromise. Therefore inclusion of targeted assessment of systemic blood flow and regional organ perfusion becomes paramount to overcome these limitations and identify at-risk patients in a timely manner and intervene appropriately.
Assessment of Systemic and Regional Blood Flow
Systemic Blood Flow
The essential component in bedside assessment of systemic perfusion is measurement of CO. Several diagnostic modalities are available for such measurements, with functional cardiac magnetic resonance imaging ( fc MRI) being now considered a “gold standard.” However, several factors, such as the need for expensive equipment, highly trained personnel, sedation, and transportation of the patient to MRI suite, as well as its noncontinuous nature, limit the use of fc MRI for routine bedside assessment. Accordingly, fc MRI remains mostly used in research settings (see Chapter 15 ).
Bedside functional echocardiography ( f ECHO) offers noninvasive, real-time, yet noncontinuous, assessment of CO in addition to other important parameters such as myocardial contractility, estimates of preload and afterload, etc. (see Chapter 10 , Chapter 11 , Chapter 12 , Chapter 13 ). Precision of f ECHO is within the acceptable range for technology used for clinical applications and is approximately 30%. It has increasingly become an integral part of routine bedside neonatal assessment ; however, to ensure accurate and reliable measurements, it requires appropriate training and sufficient practice. More so, a number of important limitations of f ECHO need to be accounted for when assessment of systemic circulation is performed at the bedside. Unlike in older children and adults when left ventricular output (LVO) can be used as a surrogate of systemic blood flow with confidence, transitional changes of the cardiovascular system in a neonate may significantly affect LVO because it will no longer represent only systemic blood flow. For example, in the presence of a hemodynamically significant patent ductus arteriosus ( hs PDA) when substantial left-to-right shunting takes place, the resultant increase in LVO represents both systemic and ductal (pulmonary) blood flow. Relying on LVO in such cases will lead to significant overestimation of systemic blood flow that can, in reality, be either within the normal range or decreased. Right ventricular output (RVO) has also been suggested for assessment of systemic perfusion. However, with significant left atrial overload from pulmonary overcirculation in the presence of a hs PDA, left-to-right atrial shunting via the patent foramen ovale (PFO) will result in an increased RVO. Thus RVO in such cases reflects both systemic venous return and transatrial left-to-right flow through the PFO. Alternatively, superior vena cava (SVC) flow, which is not affected by the presence of either interatrial or transductal shunts, has been studied and proposed as a surrogate of systemic perfusion. Although not without its own limitations, decreased SVC flow has been associated with adverse short- and long-term outcomes. Finally and of utmost importance, in any situation when congenital heart disease is suspected clinically or has been prenatally diagnosed, a formal echocardiographic evaluation must be performed and interpreted by a pediatric cardiologist.
Impedance electrical cardiometry (IEC) enables continuous and noninvasive assessment of CO using the changes in thoracic bioimpedance during the cardiac cycle (see Chapter 14 ). Beat-to-beat measurements of stroke volume (SV) and CO have been validated in term neonates without cardiovascular compromise, as well as in preterm neonates, including those requiring low-dose inotropic support and/or mechanical ventilation. The reported precision of the method was similar to that of f ECHO (approximately 30%). Preliminary normative data for CO measured by IEC in both preterm and term neonates, and the effects of PDA ligation on systemic perfusion, have also been published. However, in all three studies, CO data collection was noncontinuous.
Another, similar noninvasive technique of continuous monitoring of CO in preterm and term neonates has been studied recently. To measure CO, this technique uses the changes in bioreactance (i.e., electrical capacitive and inductive properties of the thorax) as reflected by the relative phase shift of an injected current. However, based on the consistent underestimation of LVO, the wide limits of agreement, and the increasing bias over time with continuous use, this technique seems to be inferior to f ECHO in its current form.
Organ Blood Flow
Near-infrared spectroscopy (NIRS) uses the principle of the different absorbency patterns of near-infrared light by oxyhemoglobin and deoxyhemoglobin to measure tissue oxygenation index or regional tissue oxygen saturation (rSO 2 ) (see Chapter 17 , Chapter 18 ). Thus NIRS also provides information on tissue oxygen extraction in vital and nonvital organs. Therefore it allows the indirect assessment of organ blood flow noninvasively and in a continuous manner. Indeed, with caution, it can be used as a surrogate of organ blood flow provided that SpO 2 , the metabolic rate for oxygen, the ratio of arterial-to-venous blood flow in the target organ, and hemoglobin concentration during the assessment period remain stable.
A growing body of evidence supports the clinical use of NIRS in neonates, particularly for assessment of cerebral tissue oxygen saturation (CrSO 2 ). A number of studies have reported on the changes in CrSO 2 in preterm and term neonates during transition and investigated the association between changes in CrSO 2 and adverse short- and long-term outcomes. Of note is that the earlier studies have significant limitations due to the noncontinuous assessment of CrSO 2 . This methodologic problem has, for instance, resulted in contradicting reports on the association between changes in CrSO 2 and the development of periventricular/intraventricular hemorrhage (P/IVH) in preterm neonates (see Chapter 6 , Chapter 7 ). Both increased mean CrSO 2 along with decreased mean fractional tissue oxygen extraction (FTOE) and, conversely, decreased CrSO 2 along with increased FTOE values have been reported in preterm neonates that developed P/IVH during the first few postnatal days compared with controls. When the systemic and cerebral hemodynamic changes were investigated in extremely preterm neonates, using intermittent assessment of cardiac function by f ECHO and mean velocity in the middle cerebral artery (MCA) by Doppler ultrasound along with continuous CrSO 2 monitoring, the identified early pattern of hemodynamic changes in preterm neonates later inflicted by P/IVH suggested a plausible pathophysiologic explanation for such discrepancies in the reported findings (see Chapter 7 ). Affected neonates demonstrated initial systemic and cerebral hypoperfusion followed by improvement in both systemic and cerebral blood flow as indicated by the increase in CO, MCA mean velocity, and CrSO 2 during the subsequent 20 to 44 hours and preceding detection of P/IVH. Of note is that partial pressure of arterial carbon dioxide (PaCO 2 ) also increased prior to detection of P/IVH. These observations support the hypoperfusion-reperfusion hypothesis as the major hemodynamic pathophysiologic factor in the development of P/IVH and underscore the advantages of continuous regional tissue oxygen saturation (rSO 2 ) monitoring in neonates using NIRS technology. Furthermore, findings of a number of studies investigating the changes in CrSO 2 in conjunction with other hemodynamic parameters and brain functional activity have enabled the assessment of cerebral autoregulation dynamics and its potential clinical implications in preterm and term neonates under different conditions (see later).
Peripheral Perfusion and Microcirculation
The observations on the gender-specific differences in vascular tone regulation and peripheral perfusion in preterm and term neonates and the findings that, in patients with sepsis or anemia, changes in microcirculation precede the changes in other hemodynamic parameters or laboratory values indicate the importance of the assessment of microcirculation in the overall evaluation of the neonate.
Perfusion index (PI), defined as the ratio of the pulsatile and nonpulsatile components of the photoelectric plethysmographic signal of pulse oximetry, has been used as a marker of peripheral perfusion. However, likely due to the high coefficient of variation of the measurements, the PI is not considered informative during early transition in both preterm and term neonates. In addition, whether the PI can be used reliably in the clinical setting for monitoring of perfusion in patients with hs PDA remains uncertain. Although, compared with neonates with a non- hs PDA or no PDA, some studies reported a significant difference in preductal and postductal PI values in patients with a hs PDA during the first days after delivery, others reported no effect of ductal flow and/or its persistence on PI. Moreover, the presence of the reported preductal and postductal gradient in both preterm and term neonates during the first several postnatal day seems to resolve by postnatal day 5.
Several other methods are currently available to assess peripheral perfusion and the microcirculation (see also Chapter 19 ). They include, but are not limited to, orthogonal polarization spectral (OPS) imaging, side-stream dark-field (SDF) imaging, laser Doppler flowmetry, and visible light technology. Videomicroscopy techniques (OPS and SDF) allow direct visualization of the microcirculation. However, their bedside use in neonates has been limited to intermittent assessments of peripheral perfusion rather than continuous monitoring. Although continuous recording of the images can be done, real-time assessment and interpretation remain challenging at this point, with motion and pressure artifacts posing a significant problem. A newer technique, incident dark-field imaging appears to be superior to SDF in image quality and accuracy of assessment of the microcirculation in preterm neonates but also bears the limitation of noncontinuous evaluation. On the other hand, laser Doppler flowmetry offers the capability of continuous monitoring and has been also used in the neonatal population. The main limitations of the technology include inability to evaluate absolute flow properties and thus allowing only assessment of the relative changes in flow over time, low temporal resolution requiring measurement times of approximately 1 minute and technical challenges (motion artifacts) to maintain proper probe position on the patient for an extended period of time. A newer laser-based technology, laser speckle contrast imaging (LSCI) addresses the issue of temporal resolution with significantly faster measurement times. However, similar to laser Doppler flowmetry, it provides only relative measurements of flux. In addition, LSCI has not been studied in the neonate yet. Assessment of the microcirculation using visible light technology has been reported. However, little is known about its utility in the neonatal population.
Table 21.1 summarizes the tools available for bedside monitoring of the various physiologic parameters discussed in this section.
|Purpose and Acquisition [C, I or C/I]
|Systemic perfusion (BP and CO)
|In conjunction with stroke volume gives flow status [C]
|Arterial line/cuff (oscillometry; Doppler-US)
|Perfusion pressure [C/I]
|Systemic, pulmonary (CO) and organ blood flow, cardiac function [I]
|Systemic blood flow (CO) and SV [C]
|Oxygenation on the arterial side [C]
|CO 2 status
|CO 2 diffusion through skin
|Potential effect on cerebral vasculature (changes in CBF) [C]
|Regional O 2 saturation
|Tissue oxygenation and (indirectly) organ perfusion [C]
|Microcirculation (oxygenation; blood flow velocity; capillary recruitment)
|Visible light technology
|Peripheral perfusion [C]
|Laser Doppler flowmetry
|Peripheral perfusion [C]
|OPS, SDF, and IDF
|Peripheral perfusion [I]
|Indirect assessment of perfusion
|Capillary Refill Time
|Systemic perfusion (indirectly) [I]
|Delta T (C-P)
|Systemic perfusion (indirectly) [I]
|Peripheral perfusion [I]
|Brain electrical activity
|Assessment of brain activity [C]
|Assessment of renal function [I]
Comprehensive Monitoring Systems
A growing body of evidence underscores the importance of, and the need for incorporating, multiple physiologic parameters when evaluating the hemodynamic status of neonates. Increasingly, investigators have combined data from different monitoring tools to improve their diagnostic and prognostic value. Such an approach frequently provides valuable insights into the underlying physiologic processes, as well as the pathophysiology, of the cardiovascular compromise that would not be possible with monitoring tools used in isolation. As an example, cerebral autoregulation (i.e., the ability of the brain to maintain cerebral blood flow during fluctuations of blood pressure within a certain blood pressure range [see Chapter 2 ]), has been studied using the interaction between the two aforementioned parameters (blood pressure and cerebral blood flow). Significant advances have been made in both studying cerebral autoregulation and improving our prognostic capability in preterm neonates, especially in those at risk for the development of P/IVH, and in term neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia. Inclusion of continuous monitoring of PaCO 2 , the most important and powerful regulator of cerebral blood flow, has the potential to provide additional information about the complex interactions between PaCO 2 , cerebral blood flow, and other hemodynamic parameters. This is of importance because significant alterations in PaCO 2 (both hypocapnia and hypercapnia) have been associated with adverse short- and long-term outcomes.
Currently, clinical and conventional physiologic data are collected and documented manually in the patient’s chart or recorded automatically from the bedside monitors to the patient’s electronic medical records. However, this information is typically documented on an hourly or bi-hourly basis only, intervals that are unacceptable for appropriate monitoring of the rapid and dynamic changes characteristic of the cardiovascular system. To be able to accurately assess the overall hemodynamic status, identify relevant changes in a timely manner, and understand the intricate interplay among the different hemodynamic parameters, these data need to be collected at much higher frequencies (sampling rates) and be time-stamped to other relevant clinical events. The development of comprehensive hemodynamic monitoring systems enables real-time, simultaneous, and continuous collection of physiologic data in a reliable and comprehensive manner for subsequent analysis and assessment of the complex interactions among multiple hemodynamic parameters that may change significantly in a matter of seconds or minutes. Such systems include various monitoring tools enabling concomitant evaluation of both systemic and regional perfusion and oxygen delivery and other physiologic parameters that play a role in cardiovascular regulation and adaptation along with monitoring the functional status of specific organs ( Fig. 21.1 ). Advances in biomedical technology and computer science have improved the capabilities of comprehensive monitoring systems to collect and store increasing sets of complex physiometric data. However, the caveats regarding their accuracy, feasibility, reliability, and need for validation across various subpopulations have to be emphasized. Finally and as previously discussed, the utility of the monitoring systems is determined by the comprehensiveness of the monitored hemodynamic parameters.
A previously described hemodynamic monitoring “tower” developed by the authors was the first step in the process to enable practical, continuous, and simultaneous monitoring and acquisition of neonatal hemodynamic data at high sampling rates in real time, initially designed for research applications. It integrates conventionally used technologies to continuously monitor heart rate, blood pressure, SpO 2 , transcutaneous CO 2 tension, and respiratory rate with other technologies such as IEC for beat-to-beat measurements of SV and CO, and NIRS for continuous monitoring of rSO 2 changes in vital (brain) and nonvital (kidney, intestine, and/or muscle) organs. The “tower” incorporates these various parameters onto a comprehensive patient monitor using conventional or VueLink modules (Phillips, Palo Alto, California). The continuous stream of measurements is then acquired through the analog output of the monitor via the use of an analog-to-digital converter and data-acquisition system onto a laptop computer. A motion-activated camera with the same time stamp is used to capture the bedside events that could affect the accuracy and interpretation of the collected data. This functionality aids in differentiating between true fluctuations of physiologic data versus equipment malfunction (lead disconnection, electrode/optode displacement) or other potential artifacts related to provision of routine clinical care and procedures. Another unique advantage of the “tower” is its ability to operate as a mobile, stand-alone unit that could be used at any bedside, space permitting.
Collection of all the data with a single monitoring device enables automatic data synchronization and avoids the need to match different time stamps so that simultaneous minute-to-minute changes and interactions between various parameters can be reliably analyzed. Relevant clinical events such as fluid bolus administration, titration of vasoactive medications or treatment of a PDA, transfusion of blood products, intubation/extubation, and change in respiratory support are manually documented by the bedside nurse on a dedicated flowsheet. Fig. 21.2 demonstrates an example of an approximately 1-hour and 10-minute period of processed patient data that was acquired using the hemodynamic monitoring “tower” when the clinicians’ assumption of the patient’s hemodynamic status was not fully supported by the data obtained by comprehensive hemodynamic monitoring. Fig. 21.3 demonstrates the hemodynamic changes that were observed during various events related to routine patient care and extubation. Retrospective review of the video data captured by the motion-activated camera during the study period enabled identification and accurate time-stamping of these events. Without the concomitant video component, proper interpretation of the physiologic data would have been challenging if not impossible.