Hypoxic-ischemic injury secondary to asphyxia is a common cause of brain injury in neonates, affecting 1 to 3 infants per 1000 live births. Infants with moderate to severe hypoxic-ischemic injury often have cardiovascular instability and myocardial dysfunction affecting organ perfusion and thus oxygen delivery, which can potentially result in further injury if not identified in a timely manner. Pulmonary hypertension can further complicate the postnatal course. Cerebral autoregulation, often severely impaired by the underlying pathophysiology, can further be affected by therapeutic hypothermia (TH) and rewarming, which in turn can lead to reperfusion injury to the brain. These hemodynamic complications might affect long-term outcomes.
As TH is now incorporated as a standard of care in infants with hypoxic-ischemic encephalopathy, studies to assess appropriate cardiovascular management before, during, and after TH would be of importance. It is plausible that mortality and immediate and long-term neurological outcomes might be further improved through integration of routine hemodynamic assessment and targeted management to minimize hemodynamic instability and improve tissue oxygen delivery. As for monitoring, clinician-performed cardiac ultrasound provides a platform to study the hemodynamic changes and follow the response to interventions in real-time. In this chapter, we review the impact of asphyxia and its treatment with TH on systemic and pulmonary hemodynamics and discuss the role of clinician-performed cardiac ultrasound in monitoring the hemodynamic changes and aiding the difficult process of decision-making.
Keywordscardiac function, hemodynamics, hypoxic encephalopathy, newborn, therapeutic hypothermia
Hypoxic ischemic (HI) injury occurs in two phases: the acute insult and the subsequent reperfusion injury.
Impaired cerebral blood flow/oxygen delivery leads to hypoxic-ischemic brain injury, while loss of cerebral autoregulation likely contributes to the insult.
Two-thirds of infants with moderate to severe HI injury have cardiac dysfunction, potentially contributing to tissue hypoperfusion.
Significant hemodynamic changes take place during provision of therapeutic hypothermia (TH) and rewarming.
TH causes bradycardia, decreases cardiac output, and increases systemic and pulmonary vascular resistance, which may lead to or worsen persistent pulmonary hypertension of the newborn.
Clinician-performed cardiac ultrasound provides more insight into the hemodynamic status of the neonate and aids in delivering pathophysiology-directed treatment.
There is insufficient evidence to guide the hemodynamic management of babies with HI injury.
Oxygen deprivation before or around the time of birth often results in hypoxia-ischemia (HI) induced brain damage or hypoxic-ischemic encephalopathy (HIE), which remains a common cause of neonatal brain injury across the world, affecting 1 to 3 per 1000 live births in the developed countries. Its incidence is much higher in developing countries, as high as 25 per 1000 having been reported. Despite our improving understanding of the pathophysiology of HIE and the advances in neonatal intensive care in general and in the treatment of moderate to severe birth asphyxia, HIE continues to be associated with significant mortality and long-term neurodisabilities in survivors. Ironically, even today, the definition of birth asphyxia remains imprecise.
Various pathophysiological mechanisms that contribute to HI-associated brain injury have been proposed. However, abnormal cerebral blood flow (CBF) and loss/impairment of cerebral autoregulation remain at the center of the HIE process in neonates. The disruption in CBF may be acute, chronic, or intermittent, and is most likely to occur as a consequence of interruption in placental blood flow and gas exchange when the fetus is compromised in the perinatal period. Impaired CBF results in hypoxia and anaerobic metabolism in the fetal brain, and overall impairments in tissue oxygen delivery, result in the development of fetal metabolic acidosis. Metabolic acidosis is a fairly consistent finding in neonates reflecting the degree of anaerobic metabolism and severity of hypoxia and/or ischemia during this process. The HI-associated neuronal brain injury is closely linked to the initial hypoperfusion and the ensuing reperfusion injury ( Fig. 28.1 ). There are two hemodynamic aspects to the pathological process. The first is the injury to the cardiovascular system itself, and the second is the deleterious effect of the impaired cardiovascular function on systemic and organ blood flow (including the CBF) in the postnatal period after the hypoxic/ischemic insult. The injury to the cardiovascular system results from myocardial ischemia and abnormal vasoregulation, as well as from the effects of pulmonary hypertension contributing to further decreases in cardiac output and systemic perfusion. Adrenal insufficiency secondary to immaturity, and the hypoxic/ischemic insult can decrease vascular tone and further exacerbate ischemic injury to the brain. Moreover, the treatment using therapeutic hypothermia (TH) and the ensuing rewarming process can also affect CBF and its autoregulation, as well as the distribution of blood flow in the brain, and potentially exacerbate the reperfusion injury.
The hemodynamic changes secondary to HI can start from fetal life and continue postnatally. The management of cardiovascular pathology in this group of infants is clinician-biased rather than evidence-based. In this chapter we discuss the underlying pathophysiological mechanisms, the principles of hemodynamic assessment and management, and how we can utilize current bedside assessment tools to adopt a more objective approach. We will focus on the hemodynamic changes in the asphyxiated infant and the effects of TH on the hemodynamic responses.
Pathophysiology of Hypoxic Ischemic Injury
The fetus exhibits both circulatory and noncirculatory responses to improve tissue oxygen delivery, especially to preserve cerebral perfusion. However, when the disruption of CBF reaches a certain level of severity and/or when the systemic and local adaptive mechanisms become exhausted, neuronal cell death starts. The pattern of neuronal injury depends on the level of the maturity and the severity of the insult. In term infants, severe HI causes selective damage to the sensorimotor cortex, basal ganglia, thalamus, and brain stem. However, in very preterm infants, periventricular white matter is particularly vulnerable to HI, resulting in a different pattern of brain injury characterized by motor, cognitive, sensory, and cortical visual deficits.
HI induced injury occurs in two phases:
during the time of the acute insult, and
during the recovery period, known as the reperfusion phase.
The significant reduction in CBF and oxygen delivery in severe cases of HI initiates a cascade of deleterious biochemical events at the cellular level. Hypoxia leads to anaerobic metabolism, an energy-inefficient state, resulting in rapid depletion of high-energy phosphate reserves such as adenosine triphosphate (ATP), and lactic acidosis. This directly affects neuronal cellular function and causes disruption of transcellular ion transfer, leading to intracellular accumulation of sodium, calcium, and water. Inappropriate membrane depolarization results in the release of excessive excitatory neurotransmitters, specifically glutamate, from the axon terminals. Glutamate then activates specific cell surface receptors, resulting in a further influx of sodium and calcium into postsynaptic neurons. Accumulation of calcium in cytoplasm is a consequence of both increased cellular influx and decreased efflux of calcium across the plasma membrane. Moreover, in selected neurons, intracellular calcium also induces the production of nitric oxide (NO), a potent free radical that easily diffuses to adjacent cells causing widespread NO toxicity in susceptible cells. Furthermore, there is also an excessive production of oxygen free radicals from increased fatty acid peroxidation.
The combined effect of cellular energy failure, acidosis, glutamate release, intracellular calcium accumulation, excessive production of oxygen free radicals, and NO neurotoxicity disrupts neuronal cell function and, if severe and/or long-lasting, leads to cell death by apoptosis. This process is multifactorial and the severity and duration of this insult determines the extent of cellular injury after HI.
Reperfusion Injury (Delayed Brain Damage)
Following resuscitation and circulatory restoration (if properly identified), cerebral perfusion and oxygenation are restored and the recovery phase begins. This phase is characterized by a secondary cerebral energy failure and often occurs 6 to 48 hours after the initial insult. During this phase, blood pH starts to normalize and the cardiorespiratory status often seems stable using “conventional” assessment. However, during this phase there is a decrease in the ratio of phosphocreatine/inorganic phosphate and the intracellular pH also remains acidic, which potentially contributes to further brain injury. Subsequently, acidosis improves, pH normalizes, and the concentration of phosphate metabolites returns to baseline. During the rewarming phase following TH, there is a sudden increase in CBF, potentially worsening the effects of the reperfusion, especially in preterm infants. Studies have shown poor outcome when CBF autoregulation remains impaired, especially during the reperfusion phase of HI.
The mechanism of secondary energy failure likely involves mitochondrial dysfunction secondary to extended reactions from the primary insults, and circulatory and endogenous inflammatory mediators contributing to ongoing brain injury. In infants, the severity of the secondary energy failure is correlated with adverse neurodevelopmental outcome.
The pathophysiology of HI, phases of brain injury and its management with TH in infants has been well characterized in the literature. However, the hemodynamic responses to HI and TH, which play an important role in the process, have not been well studied ( Fig. 28.2 ).
Fetal Cardiovascular Adaptation to Hypoxia-Ischemia
In experimental fetal animal models, initial HI decreases fetal systemic vascular resistance (SVR) by at least 50% to maintain CBF and oxygen delivery to a large extent. The decrease in fetal SVR persists until a normal or elevated mean arterial blood pressure is achieved. However, persistent hypoxemia from a severe or ongoing hypoxemic insult can lead to sustained systemic hypotension in the presence of maximal cerebral vasodilation. In such cases, CBF will be reduced. In adults, CBF thresholds to cellular injury have been identified, but the critical ischemic threshold for a developing brain in neonates remains unclear (see also Chapter 16 ).
The important cardiovascular manifestations of interruption of placental blood flow have been well described in fetal experimental studies. Circulatory failure (shock) develops in two phases: compensated and uncompensated.
Neuroendocrine compensatory mechanisms ensure redistribution of the initially only somewhat decreased cardiac output to preserve blood flow to the vital organs (brain, myocardium, adrenal gland) while blood flow to the nonvital organs such as kidneys, intestine, and muscles declines
Vasoparalysis with loss of cerebral autoregulation resulting in a pressure-passive cerebral circulation at maximum compensation
When the neuroendocrine compensatory mechanisms become overwhelmed by the ongoing and/or severe HI, systemic hypotension and critically low cerebral perfusion with reduced oxygen delivery, lactic acidosis, and HI tissue damage
The mechanisms involved in the redistribution of blood flow are complex and include peripheral vasoconstriction, neuroendocrine and endocrine factors, and local components.
Cardiovascular Effects of Hypoxia-Ischemia
Transient myocardial ischemia (and the resultant myocardial dysfunction), which may or may not be clinically symptomatic, occurs in two-thirds of asphyxiated infants. There is no doubt that this is also one of the more common causes of perinatal myocardial infarction.
The effects of HI insult on the cardiovascular system are complex, and it is very important to understand the principles of developmental cardiovascular physiology and pathophysiology in these sick infants. Both the primary insult and the ongoing redistribution of blood flow can lead to reduced myocardial perfusion potentially resulting in myocardial ischemia, especially in the sub-endocardial tissue and papillary muscles. The hemodynamic effects of myocardial ischemia may be further impacted by the immaturity of the neonatal myocardium, and decreased myocardial contractility secondary to acidosis and hypoxia. Hypoxia and acidosis are also potent pulmonary vasoconstrictors and hence increase the pulmonary vascular resistance (PVR), resulting in deleterious effects on the already impaired right ventricular (RV) function. Poor RV function and increased PVR affect left ventricular (LV) filling and function, and thus might impact systemic and cerebral blood flow. In addition, TH also increases PVR and SVR. As a consequence, cardiac function can deteriorate further, although hypothermia also results in reduction of the metabolic needs, and subsequently lower cardiac output and systemic oxygen delivery might suffice. Finally, neonates with HI insult often have associated morbidities such as meconium aspiration syndrome (MAS) and/or sepsis. These conditions themselves may have a negative impact on cardiac function ( Fig. 28.3 ).
The clinical consequences of the cardiovascular effects include low pulmonary blood flow (PBF) because of high PVR and thus increased RV afterload and RV dysfunction, especially when ductal flow is restricted or nonexistent. As mentioned earlier, the resulting decreases in pulmonary venous return lead to low systemic cardiac output and, if not compensated by peripheral vasoconstriction, systemic hypotension. If hypotension is treated with vasopressor-inotropes, systemic blood flow may further decrease if the response to the medication(s) is an overwhelming peripheral vasoconstriction. The impact of the clinical deterioration, the escalation of treatment, and their resultant effect on brain injury remain unknown.
The Cardiovascular System and Central Nervous System injury
The cerebral circulation is particularly sensitive to changes in partial pressure of carbon dioxide and oxygen ( Chapter 2 ). Hypercarbia and/or hypoxia induced by interruption of placental blood flow result in significant increases in CBF. Moreover, the resultant changes in regional blood flow vary widely among the different parts of the brain. For example, the cerebral white matter has a relatively limited vasodilatory response to hypoxia and/or hypercarbia compared with the brainstem and cortical structures.
In healthy infants, CBF remains constant over a relatively wide range of changes in systemic mean arterial blood pressure (see Chapter 2 for details). In animal models, the fetal autoregulatory curve differs from that of the adult. The curve is narrower, particularly at the upper elbow of the curve, and importantly, the normal mean arterial blood pressure in the less mature animal is only marginally above the lower elbow of the autoregulatory curve. In human preterm and term infants, the mean blood pressure value at the lower elbow of the autoregulatory curve, or the blood pressure threshold associated with neuronal dysfunction and then tissue injury are unknown.
Autoregulation is disrupted by hypoxia, hyperoxia, hypocarbia, hypercarbia, and/or acidosis. Severe disruption of autoregulation results in a pressure-passive cerebral circulation. In animal models, the role of the asphyxia-associated impaired CBF autoregulation in the pathogenesis of ischemic cerebral injury has been clearly described. If the same is true for humans, the clinical implications are of importance, as hypotension and decreased cardiac output result in decreases in CBF and thus secondary energy failure and neuronal injury. As expected, this process is more pronounced in the more vulnerable regions of the brain, such as the parasagittal cortex or periventricular white matter. However, in humans, this link between cerebral ischemia and cardiovascular dysfunction is not yet clear, and thus it is not known whether appropriate cardiovascular support and stabilization of CBF improve outcomes in asphyxiated infants.
Cardiovascular Effects of Therapeutic Hypothermia
TH improves outcomes in moderate to severe cases of HIE and is now part of standard care in term and near term infants (>35 weeks of gestation). The cardiovascular effects of TH may be more pronounced in infants with associated conditions such as sepsis and MAS. The direct effects of TH on the cardiovascular system include:
Moderate bradycardia which may decrease cardiac output
An increase in PVR, potentially resulting in the clinical presentation of persistent pulmonary hypertension of the newborn (PPHN) or worsening of PPHN in cases with preexisting PVR elevation
Resultant RV dysfunction and decreased RV output, leading to decreases in pulmonary venous return and thus LV filling and LV cardiac output
As a consequence of these effects of TH in an infant already compromised from severe HI, cardiorespiratory support may need to be escalated. This may involve the need for higher airway pressures on the ventilator. Unfortunately, this maneuver, especially in patients with normal lung compliance, may further impair venous return and hence decrease ventricular output. Introduction of vasopressor-inotropes, especially at inappropriately high doses, may impair myocardial perfusion and increase myocardial oxygen demand, potentially resulting in further deterioration of cardiac function ( Fig. 28.4 ).
Cardiovascular Effects of Rewarming After Hypothermia
As in the case of TH, the cardiovascular effects of rewarming have not been well studied. Accordingly, there is very little published data on the hemodynamic changes during rewarming in neonates. Rewarming decreases PVR and SVR and affects redistribution of cardiac output to the organs. It increases heart rate and cardiac output, although mean blood pressure may decrease or remain unaffected as a consequence of a decrease in diastolic blood pressure. Hence the physiological consequences of rewarming are likely to influence management, such as choice of vasopressor-inotropes/inotropes and fluid management, and might even impact clinical outcomes. In addition, rewarming affects metabolism and clearance of drugs, including cardiovascular medications.
Rewarming certainly has an effect on the cardiovascular status/hemodynamic stability in these sick babies. In addition, studies have shown that infants are more likely to have seizures during the rewarming phase. In a recent study involving 160 asphyxiated infants, 9% developed intra/periventricular hemorrhage during the rewarming phase. Therefore these infants remain particularly vulnerable during the rewarming phase and need to be monitored more closely for any hemodynamic instability. It seems to be a sensible approach to avoid large fluctuations in blood pressure and cardiac output and thus in CBF, especially in the sicker, more vulnerable infant on significant cardiovascular support.
The cardiovascular effects of TH and rewarming, and their subsequent impact on management, clearly needs further assessment in well-designed studies using clinician-performed cardiac ultrasound (CPU) and other advanced cardiorespiratory and neurocritical care monitoring techniques (see Chapter 21 ).
As discussed earlier, HI, TH, and rewarming all affect the cardiovascular system. These physiologic changes present with different clinical signs and symptoms, and have implications on the assessment and management of these infants.
Effect on Heart Rate and Cardiac Output
Hypoxic-ischemic insults often lead to compensatory tachycardia, although severe or terminal insults can lead to bradycardia. Due to the decreased metabolic demand and the direct effects of cooling itself, TH is associated with a decrease in heart rate in all infants, and there is a reduction in cardiac output in up to 62% of infants. The direct effects of cooling on heart rate presenting as sinus bradycardia are mostly due to the decreased repolarization of the sinoatrial node and the diminished influence of the sympathetic autonomic nervous system. It also induces pulmonary and peripheral vasoconstriction, which can affect ventricular filling and afterload, thereby further decreasing cardiac output. Vasopressor-inotrope and/or inotrope administration to combat hypotension and/or poor myocardial function, respectively, may lead to increases in heart rate and oxygen demand. Inappropriate dosing of these medications may cause excessive tachycardia and decreases in PBF and cardiac output, and adversely affect myocardial contractility.
Rewarming has the opposite effects on the cardiovascular parameters. During the re-warming phase, there is a sometimes sudden increase in the heart rate and cardiac output. These changes, especially if abrupt, may contribute to reperfusion injury in the brain and other organs. These effects can be more pronounced in infants already needing cardiorespiratory support.
Clinical Implications in Asphyxiated Infants With Sepsis and Persistent Pulmonary Hypertension of the Newborn
Hypoxic-ischemic insults can be associated with PPHN, and this may have significant clinical implications in these often critically ill infants. Hypoxia and TH can increase PVR, cause RV dysfunction, cause decrease in cardiac output, and subsequently lead to systemic hypotension and hypoperfusion. Sepsis, especially when associated with parenchymal lung disease, can have similar effects, but sepsis without parenchymal pathology also presents with tachycardia, increased oxygen demand, and systemic hypotension.
Clinical Assessment of the Asphyxiated Neonate
HI injury often exerts multisystem affects, including impairment of cardiovascular function. It may result in primary pump failure due to direct myocardial ischemic injury, abnormal vasoregulation, or both, and thus present with systemic hypoperfusion and hypotension. Disturbances of transition to extrauterine life and delayed resolution of the high PVR can manifest as maladaptation and pulmonary hypertension. The presence of clinical signs and symptoms of poor perfusion usually reflect the state of uncompensated shock and suggest the presence of HI organ damage of varied severity. It is therefore of importance to diagnose the hemodynamic disturbance early in its compensated phase. Clinician-performed cardiac ultrasound represents one of the essential diagnostic approaches in the care of these neonates. Its use may aid in appropriately targeting the treatment to the needs of the individual patient and could potentially lead to improvements in short- and long-term outcomes in this group of neonates. However, there is little evidence so far to support that this approach indeed results in better outcomes.
Immediate Assessment of Perfusion
The immediate assessment of perfusion in neonates with HI injury can be broadly grouped into assessment during the precooling phase and during TH. In both stages, the principles of assessment remain the same, but the findings should be interpreted according to the phase of the care of the infant.
The assessment of perfusion can be broadly classified into:
End organ perfusion
Furthermore, the assessment targets can be broadly grouped into:
Clinical assessment is routinely carried out, but there are inherent limitations as the signs and symptoms mostly become recognizable in the compensated phase of shock ( Chapter 1 ). Cardiac function and preload can be assessed by monitoring heart rate and jugular venous pressure, respectively. However, jugular venous pressure is very difficult to gauge in neonates, and hence it is difficult to assess preload clinically. In newborn infants, the cardiac output usually changes by variations in heart rate . As neonates receiving TH present with sinus bradycardia (see earlier), heart rate monitoring is of limited value to clinically assess changes in cardiac output in these infants. Heart rate variability has also been used for the staging of HIE and outcome prognostication (see Chapter 20 ). Severe HIE is reported to be associated with lower heart rate variability in the first 24 postnatal hours. In addition, the heart rate is affected by the temperature of the baby and the use of vasopressor-inotropes and inotropes, and hence it is a poor marker for bedside cardiac function.
The afterload can be assessed clinically by the blood pressure, but the choice of method may affect the measured values. Invasive blood pressure measurements are encouraged over noninvasive assessments, due to their suggested higher accuracy in critically ill patients ( Chapter 3 ). Blood pressure is affected by gestational and postnatal age, as well as by the severity of the acute insult and hypothermia treatment. Low systolic blood pressure is usually due to cardiac dysfunction. If low systolic blood pressure is recorded, it should be correlated with the requirements for oxygen. Normal oxygenation with low systolic blood pressure primarily reflects LV/RV systolic dysfunction. On the contrary, the finding of low systolic blood pressure and impaired oxygenation should alert the clinician to rule out PPHN with or without LV/RV dysfunction. Low systolic pressure may be seen during TH, but usually it is high enough to maintain adequate tissue perfusion due to the reduced metabolic demand. During TH, the diastolic blood pressure is usually maintained due to peripheral vasoconstriction. If diastolic blood pressure remains persistently low during TH, underlying causes such as sepsis should be ruled out. Mean arterial pressures alone should not be used for decision-making in infants with HIE, as it can delay identification of low systolic blood pressure.
The clinical signs of compensated shock (decreased urine output, prolonged capillary refill time, core-peripheral temperature difference) are of limited value in the neonate immediately following delivery ( Chapter 1 and Chapter 26 ). By the time metabolic acidosis and high lactate are present, shock has entered its uncompensated phase, and organ damage has become more likely. Finally, with active cooling, most of these clinical signs cannot be reliably used to assess perfusion.
The invasive assessments are useful for precise measurements but are either cumbersome or not available routinely on neonatal intensive care units. The exceptions are arterial blood gas measurements and continuous invasive blood pressure recording. The preload can be assessed using central venous pressure measurements. However, its accuracy is questionable at best. End-organ perfusion can be continuously assessed using mixed venous saturations to provide more accurate information on tissue perfusion, but this requires a central line that often is not available in babies on neonatal intensive care units. However, intermittent arterial blood gas analysis provides information on blood gas parameters that can be helpful for routine management of babies with HIE with or without pulmonary hypertension and/or maladaptation. The assessment of metabolic derangement through markers of end organ perfusion such as lactate concentration and the base deficit are helpful, but are late signs that are only present in the uncompensated phase of shock.
The interest in bedside noninvasive assessment of perfusion to assess various components of the hemodynamic status using various tools and techniques (see Chapters 14, 16 to 18 for details) and even a comprehensive approach ( Chapter 21 ) is now rapidly increasing. Some of these novel approaches, such as near infrared spectroscopy, are of special value for use in neonates with HIE.
Clinician-Performed Cardiac Ultrasound for Hemodynamic Assessment in Neonates With Hypoxic-Ischemic Encephalopathy
Clinician-performed cardiac ultrasound (US) has been increasingly used for the assessment of neonates with HIE, as it provides comprehensive information on the determinants of cardiac function and organ perfusion. With an increasing number of neonatologists available to utilize this bedside tool, in addition to providing information on the cardiovascular status and establishing the diagnosis of PPHN, with CPU the clinician can also help assess the response to treatment and more appropriately titrate the vasoactive medications. A number of assessments are available that can be used to assess loading conditions and cardiac function. The echocardiographic parameters for hemodynamic evaluation and pulmonary hypertension are summarized in Tables 28.1 and 28.2 , respectively. The details of echocardiographic techniques are discussed in Chapters 10 to 13 .