The transition from intrauterine life to extrauterine existence encompasses significant cardiorespiratory adaptations. These include rapid lung aeration and increase in pulmonary blood flow (PBF). Perinatal asphyxia and fetal growth restriction can severely hamper this transition. Hypoxia is the common denominator in these 2 disease states, with the former characterized by acute insult and the latter by utero-placental insufficiency and a chronic hypoxemic state. Both may manifest as hemodynamic instability. In this review, we emphasize the role of physiologic-based cord clamping in supplementing PBF during transition. The critical role of lung aeration in initiating pulmonary gas exchange and increasing PBF is discussed. Physiologic studies in animal models have enabled greater understanding of the mechanisms and effects of various therapies on transitional circulation. With data from sheep models, we elaborate instrumentation for monitoring of cardiovascular and pulmonary physiology and discuss the combined effect of chest compressions and adrenaline in improving transition at birth. Lastly, physiologic adaptation influencing management in human neonatal cohorts with respect to cardiac and vascular impairments in hypoxic-ischemic encephalopathy and growth restriction is discussed. Impairments in right ventricular function and vascular mechanics hold the key to prognostication and understanding of therapeutic rationale in these critically ill cohorts. The right ventricle and pulmonary circulation seem to be especially affected and may be explored as therapeutic targets. The role of comprehensive assessments using targeted neonatal echocardiography as a longitudinal, reliable, and easily accessible tool, enabling precision medicine facilitating physiologically appropriate treatment choices, is discussed.
Specific physiologic and structural adaptations allow the fetus to survive and thrive in the intrauterine hypoxic environment. These include secretion of fluid by the respiratory epithelial lining, distension of airways with fluid resulting in an expanded lung, right ventricular (RV) dominance, and pulmonary-to-systemic shunting through shunts (ductal and foramen ovale). The differential vascular resistance ratio favors the pulmonary over systemic and as a result, only 8% to 10% of total cardiac output passes through the high-resistance pulmonary circuit. Combined cardiac output at ∼30 weeks’ gestational age increases to 25% indicating gradual in utero adaptation toward extrauterine existence.1 At its most basic, although the partial pressure of oxygen in the placenta is low, it still maintains adequate oxygen delivery to the tissues (aided by the presence of fetal hemoglobin).2,3 Alterations in humoral mediators play important roles. These changes include a reduction of the vasoconstrictor thromboxanes, greater synthesis of nitric oxide (through endothelial nitric oxide synthase stimulation), and lower pulmonary vascular resistance (PVR).4 Increased secretion of vasodilatory prostaglandins (Prostaglandin I2 and Prostaglandin E2), a surge in catecholamines (consequent increased cardiac contractility and heart rate), and cortisol secretion (important for surfactant maturation) enables this transition.5
In this narrative review, we discuss recent advances in physiologic appreciation of the postnatal transition and resuscitation; specifically, we elaborate the specific role of animal studies in facilitating greater understanding of disease pathophysiology and the specific contributory role of cardiovascular performance in perinatal diseases states. Although a myriad of illnesses could affect cardiorespiratory transition, in this review, we focus on perinatal asphyxia and fetal growth restriction (FGR) because hypoxia is a hallmark characteristic of both. Whereas perinatal asphyxia represents acute hypoxia, FGR is an example of a “chronic” hypoxic adaptive state but with acute and chronic cardiorespiratory effects. Immediate neonatal circulation in asphyxiated infants is influenced by events leading to asphyxia (such as placental abruption–related blood loss or meconium aspiration), hypoxic-ischemic encephalopathy (HIE), and the treatment (therapeutic hypothermia [TH]). FGR deliveries are unique because the adaptive events like ventricular hypertrophy (followed by dilatation and globular cardiac shape) and thickened vasculature characterize important survival adaptations during fetal life. Postnatally, these translate into an inability to increase left ventricular (LV) stroke volume in the first week of life, potentially heightening the risk of circulatory instability.6
Perinatal Transition and Physiology-Driven Care
Birth is perhaps the greatest physiologic adaptation that humans undertake to successfully transition from fetal to neonatal life. Although most newborns make this transition with apparent ease that belies the enormity of the challenge, specifically, 1 in 5 Australian newborns (includes both preterm and term) requires assistance immediately after birth to help them breathe.7 The inability to breathe spontaneously at birth increases the risk of death and disability.
The transition to newborn life requires 2 major physiologic adaptations: (1) clearance of airway liquid to enable pulmonary gas exchange and (2) the circulation must transition from a fetal into a newborn phenotype. Aeration of the lung, whether it occurs via breathing or positive-pressure ventilation, triggers these physiologic adaptations by stimulating a ∼30-fold increase in pulmonary blood flow (PBF). During fetal life, PBF is low, with most RV output bypassing the lungs and flowing through the ductus arteriosus (fetal shunt) into the descending aorta.8 Because fetal PBF is low, it contributes little to LV venous return, which is different to adult circulation in which PBF contributes 100% of the LV venous return. Instead, in the fetus, it is largely derived from umbilical venous flow, which flows via the foramen ovale into the left atrium.8 Because venous return (preload) is a major determinant of ventricular output, the umbilical circulation not only provides oxygen for the fetus but it also maintains cardiac output.
At birth, umbilical cord clamping (UCC) separates the infant from its oxygen supply (the placenta) and abolishes umbilical venous return. This sudden loss in right-heart venous return leads to blunting of the Frank-Starling relationship and impairs RV performance. This causes cardiac output to decrease by ∼50% and remain low until the infant aerates its lungs which in turn stimulates a rapid increase in PBF.8 This large increase in PBF restores LV venous return, thereby maintaining cardiac output. Thus, lung aeration is essential for both pulmonary gas exchange and restoring cardiac output. The timing of UCC in and of itself has a profound impact on the transition at birth. In many studies, researchers have demonstrated benefits of delaying UCC in preterm and term infants,9–11 but most have examined delayed UCC for a specific period (>1 minute after delivery) without reference to the infant’s changing physiology at birth. Aeration of the lung before UCC, either through spontaneous breathing or respiratory support, allows PBF to increase before umbilical venous return is lost through UCC. As a result, the supply of venous return for the left ventricle immediately switches from umbilical to pulmonary venous return without any diminution in supply or cardiac output.12 We have termed this physiologic-based cord clamping because the timing of UCC is based on the newborn’s physiology, with successful transition indicated by increased PBF, rather than a set time.13 Studies in both preterm and near-term lambs as well as preterm human infants have revealed that allowing lung aeration before UCC maintains a stable cardiac output, blood pressure (BP), and cerebral perfusion and oxygenation.12,14–18 Possible benefits include protection of the newborn brain from fluctuations in BP and flow as well as preventing hypoxia, both major determinants of perinatal brain injury.
Pregnancy or perinatal complications affect a large proportion of infants. An understanding of how these can affect the normal cardiorespiratory transition at birth is critical before applying treatment recommendations. The results obtained in animal studies, with verification in human clinical trials, can potentially influence the management of healthy newborn infants worldwide.
Transitional Physiology in Animal Models of Compromised Pregnancy and Birth
Preclinical animal experiments provide an opportunity to appraise complex physiologic responses, revealing pathophysiological processes in response to fetal or neonatal compromise. Because of the invasive nature of these assessments, these would be difficult to perform in humans. In the sheep experimental model, perinatal compromise is induced by total occlusion of the umbilical cord and both discrete and whole-body changes monitored invasively and recorded in real time. Pressure and resistance changes within the systemic and pulmonary circulations provide key information and timing on the onset of respiration as well as movement of blood through the ductus arteriosus, ductus venosus, and the foramen ovale. Logistic challenges in the maintenance of recordings during the birthing process have resulted in most studies delivering sheep offspring via cesarean delivery. Large animal (sheep) models of fetal compromise allow comprehensive examination of the most common complications that may affect birth transition. This is, however, associated with higher costs, larger research teams, and the need for substantial equipment for translatable data acquisition. Experiment specific instrumentation, intervention, and outcomes studied in sheep models are described in Table 1.
Representative Samples of Preclinical Studies in Sheep to Assess Transition to Ex Utero Life
Reference . | Species . | Model . | %GA Induction . | %GA Transition . | Instrumentation . | Comments . |
---|---|---|---|---|---|---|
Asphyxia | ||||||
23 | Sheep | Decreased BP ∼22 mm Hg | 93 | 93 | CA catheter, CA blood flow | Benefits of model: Sheep models allow for instrumentation of the fetus before the birth transition for monitoring of both cardiovascular and pulmonary physiology. |
22 | Sheep | Decreased BP to ∼20 mm Hg | 93 | 93 | CA or FA catheter, JV catheter | |
25 | Sheep | Decreased BP ∼20 mm Hg | 93 | 93 | CA catheter, CA blood flow | |
26 | Sheep | Decreased BP ∼20 mm Hg | 93 | 93 | CA and JV catheters; CA and PA blood flow | |
21 | Sheep | Decreased BP to ∼25 mm Hg | 93 | 93 | CA catheter, CA blood flow | Main outcomes are to demonstrate that the environment of the fetus at the time of asphyxia (ie, in amniotic fluid versus air) can have dramatic influence on the cardiovascular outcomes and reveal that further preclinical asphyxia studies are required to inform resuscitation guidelines. Sustained inflations improved transition alone and in combination with oxygen. The combination of chest compressions and adrenaline improves transition at birth. |
24 | Sheep | Decreased BP ∼20 mm Hg | 93 | 93 | CA catheter, CA blood flow | |
27 | Sheep | Cardiac arrest for 5 min | 93 | 93 | CA and JV catheter, CA and PA blood flow | |
28 | Sheep | Cardiac arrest for 5 min | 93 | 93 | CA and JV catheter, CA and PA blood flow | |
FGR | ||||||
36 | Sheep | Single umbilical artery ligation | 69 | 85 | BA and JV catheter; CA and PA blood flow | Benefits of model: The SUAL model produces placental insufficiency and asymmetric FGR and can be induced as early- or late-onset FGR. The size of the fetal and neonatal lambs allows fetal monitoring and neonatal use of the same equipment used in NICUs. |
37 | Sheep | Single umbilical artery ligation | 69 | 85 | BA and JV catheter; CA and PA blood flow | Main outcomes: FGR lambs have lower LV output and carotid blood flow and increased systemic BP in the first min of life. The respiratory requirements of the FGR lambs are comparable with human infants posttransition, and they share similar cardiovascular adaptations. |
38 | Sheep | Single umbilical artery ligation | 69 | 85 | BA and JV catheter; CA and PA blood flow |
Reference . | Species . | Model . | %GA Induction . | %GA Transition . | Instrumentation . | Comments . |
---|---|---|---|---|---|---|
Asphyxia | ||||||
23 | Sheep | Decreased BP ∼22 mm Hg | 93 | 93 | CA catheter, CA blood flow | Benefits of model: Sheep models allow for instrumentation of the fetus before the birth transition for monitoring of both cardiovascular and pulmonary physiology. |
22 | Sheep | Decreased BP to ∼20 mm Hg | 93 | 93 | CA or FA catheter, JV catheter | |
25 | Sheep | Decreased BP ∼20 mm Hg | 93 | 93 | CA catheter, CA blood flow | |
26 | Sheep | Decreased BP ∼20 mm Hg | 93 | 93 | CA and JV catheters; CA and PA blood flow | |
21 | Sheep | Decreased BP to ∼25 mm Hg | 93 | 93 | CA catheter, CA blood flow | Main outcomes are to demonstrate that the environment of the fetus at the time of asphyxia (ie, in amniotic fluid versus air) can have dramatic influence on the cardiovascular outcomes and reveal that further preclinical asphyxia studies are required to inform resuscitation guidelines. Sustained inflations improved transition alone and in combination with oxygen. The combination of chest compressions and adrenaline improves transition at birth. |
24 | Sheep | Decreased BP ∼20 mm Hg | 93 | 93 | CA catheter, CA blood flow | |
27 | Sheep | Cardiac arrest for 5 min | 93 | 93 | CA and JV catheter, CA and PA blood flow | |
28 | Sheep | Cardiac arrest for 5 min | 93 | 93 | CA and JV catheter, CA and PA blood flow | |
FGR | ||||||
36 | Sheep | Single umbilical artery ligation | 69 | 85 | BA and JV catheter; CA and PA blood flow | Benefits of model: The SUAL model produces placental insufficiency and asymmetric FGR and can be induced as early- or late-onset FGR. The size of the fetal and neonatal lambs allows fetal monitoring and neonatal use of the same equipment used in NICUs. |
37 | Sheep | Single umbilical artery ligation | 69 | 85 | BA and JV catheter; CA and PA blood flow | Main outcomes: FGR lambs have lower LV output and carotid blood flow and increased systemic BP in the first min of life. The respiratory requirements of the FGR lambs are comparable with human infants posttransition, and they share similar cardiovascular adaptations. |
38 | Sheep | Single umbilical artery ligation | 69 | 85 | BA and JV catheter; CA and PA blood flow |
BA, brachial artery; CA, carotid artery; GA, gestational age; JV, jugular vein; PA, pulmonary artery; SUAL, single umbilical artery ligation; —, not applicable.
Perinatal Asphyxia
Acute, severe fetal hypoxia causes an adaptive cardiovascular response that aims to preserve blood flow to the brain and heart at the expense of nonessential organs.19 This results in an acidotic, hypoxic, and unresponsive newborn unable to successfully undertake independent transition. In the sheep model, asphyxia is commonly initiated by occluding the umbilical cord until systemic arterial pressure falls to ∼20 to 25 mm Hg,20–26 although some studies begin once the fetus is in full cardiac arrest.27 The heart rate response may be either decreased or increased depending on whether the fetus remained in utero or ex utero, respectively, during the asphyxia event.21,22 Cardiovascular and pulmonary responses are monitored in these experiments, with particular interest in highlighting the complex interplay between systems and organs.
Lamb studies have permitted concurrent monitoring of changes in pulmonary, femoral, and carotid artery blood flows during asphyxia and transition and have revealed that immediate UCC followed by ventilation caused a rebound tachycardia and hypertension that may be harmful to the brain. In contrast, physiologic-based cord clamping, in which cord clamping is delayed until the onset of ventilation, restored cardiac output and oxygenation in a manner similar to immediate cord clamping but was more protective for the neonatal brain by avoiding the rebound hypertension.15
Animal models also aid understanding of the effects of various resuscitation measures on body systems. A study in asphyxiated lambs revealed a significant relationship between expired or end-tidal carbon dioxide and the return of spontaneous circulation,27 with the latter being an important physiologic milestone for recovery of asphyxiated newborns. In further studies on resuscitation of near-term asphyxiated lambs, researchers found that an initial sustained inflation in combination with chest compressions and oxygen improved transition at birth.23,26,28 Sustained inflation delivered immediately at birth, however, may have neuropathological implications. It was shown to be associated with a compromise of the blood-brain barrier and potential brain injury in near-term asphyxiated lambs.24 These findings highlight the delicate balance between lung recruitment, intrathoracic pressure, and the adequacy of cardiac output. Although room air is the gas mixture of choice for initiation of resuscitation, current guidelines recommend empirical use of 100% inspired oxygen during chest compressions. Data from a lamb experimental model of asphyxia would suggest otherwise; specifically, no difference in carotid or PBF was noted, and the changes in Pao2 and cerebral oxygen delivery were similar in animals resuscitated with either 21% or 100% oxygen.29 Essentially, effective return of spontaneous circulation must be balanced with the risk of neuropathology. Further research is needed to appraise the role of sustained inflation and/or high oxygen use during transition in terms of potential brain injury versus benefits to cardiorespiratory transition. Hemodynamic changes during recovery after severe asphyxia in near-term lambs are summarized in Fig 1. We compared BP recovery after severe asphyxia in 2 near-term lambs that underwent either immediate cord clamping before advanced resuscitation (Fig 1A) or physiologic-based cord clamping (advanced resuscitation with an intact umbilical cord).30 These studies have greatly advanced the understanding of the impact of birth asphyxia on transition and are referenced in European31 and American32 resuscitation guidelines.
Comparison of BP recovery after severe asphyxia in near-term lambs. The mean BP is measured at end asphyxia (A) after return of cardiac output (R) and for 25 minutes after birth in asphyxiated lambs undergoing immediate cord clamping (A) or physiologic-based cord clamping (C). The dotted line indicates the time of UCC. The yellow shaded region indicates normal BP. Note the significant overshoot in BP in (A). This occurs because immediate cord clamping removes the low-resistance placenta (B), forcing blood to flow through a high-resistance systemic circulation resulting in a significant increase in BP. In contrast, delaying UCC for 10 minutes after return of cardiac output leaves the low-resistance placenta in the circulation (D), allowing blood to continue to flow through the low-resistance placenta, preventing a large increase in BP.
Comparison of BP recovery after severe asphyxia in near-term lambs. The mean BP is measured at end asphyxia (A) after return of cardiac output (R) and for 25 minutes after birth in asphyxiated lambs undergoing immediate cord clamping (A) or physiologic-based cord clamping (C). The dotted line indicates the time of UCC. The yellow shaded region indicates normal BP. Note the significant overshoot in BP in (A). This occurs because immediate cord clamping removes the low-resistance placenta (B), forcing blood to flow through a high-resistance systemic circulation resulting in a significant increase in BP. In contrast, delaying UCC for 10 minutes after return of cardiac output leaves the low-resistance placenta in the circulation (D), allowing blood to continue to flow through the low-resistance placenta, preventing a large increase in BP.
Medications are required in a proportion of newborn infants as part of resuscitation. Successful transition of an asphyxiated newborn improves with a combination of chest compressions and resuscitation medications, which augments coronary artery perfusion by inducing systemic vasoconstriction. Experiments on a well-established ovine model of perinatal asphyxia cardiac arrest closely mimicking the newborn infant provide important information that can guide future clinical trials.33 The vasopressor effects of epinephrine are critical for the restoration of spontaneous circulation as revealed by an increase in carotid arterial pressure and flow in asphyxiated near-term lambs.25 There is some evidence that vasopressin has promise as a resuscitation vasopressor in a neonatal porcine model of postnatal asphyxia (improved survival, lower postresuscitation troponin, less hemodynamic compromise after cardiac arrest).34,35 Because these investigations were conducted in piglets that had already undergone transition, further studies are required to determine their potential during the transition at birth. The dichotomous effects of the actions of vasopressin on V1 receptors, which induce vasoconstriction through calcium channels and potential favorable pulmonary vasodilator properties through nitric oxide pathways, make it suitable for the transitioning newborn. Especially, the potential for vasopressin to assist the rapid increase in cardiovascular function by increasing total peripheral resistance and diastolic pressures, but without increasing PVR, is worthy of further investigation.
FGR
The common mode of inducing FGR in animal models is single umbilical artery ligation at either 60% or 70% of ovine gestation. This results in early- or late-onset placental insufficiency and FGR.36 In a series of preclinical studies, researchers have investigated the unique challenges facing human growth-restricted fetuses via instrumentation at 80% gestation to record central and PBF and pressure changes during the transition. Data from FGR preterm lambs reveal that they have reduced LV output and reduced cerebral blood flow but higher systemic vascular resistance at birth.37–39 Preterm lambs also have a significantly altered cardiorespiratory response to surfactant.40 A more rapid improvement in compliance and tidal volume was observed in lambs appropriate for gestational age (AGA) (compared with FGR lambs) was noted.40 Data from lamb and rat models also reveal that chronic placental insufficiency alters perinatal pulmonary vasoreactivity and arterial structural vascular composition, preventing a fall in PVR at birth.41,42 In Sprague Dawley rats exposed to hypobaric hypoxia, hemodynamic and structural effects on pulmonary circulation were studied.43 Chronic hypoxemia induced muscularization of “resistance vessels” by way of proliferation of vascular smooth muscle.
Experiments on animal models may be helpful to accumulate preclinical evidence for potential therapies. In recent studies using sheep models, oxidate stress and deficiencies in the nitric oxide pathway have been targeted as key mechanisms underlying the cardiovascular and potentially respiratory morbidities seen in FGR.37,44,45 Inhaled nitric oxide has been investigated in preclinical models to improve cardiovascular function in the first hours of life with success.37 Although authors of additional studies have demonstrated benefits of antioxidants such as melatonin to improve cardiovascular function,46 it has not been investigated during the transition period. Hung et al47 recently examined whether daily administration of melatonin mitigates the pulmonary hypertension and vascular remodeling in chronically hypoxic rats. With the data, it was noted that melatonin treatment significantly attenuated pulmonary pressures, thickness of the pulmonary arteriolar wall, and oxidative and inflammatory markers in the hypoxic animals. In addition, a marked increase in the endothelial nitric oxide synthase phosphorylation in the lung was noted.47 Although these preliminary data suggest biological plausibility of its effects on pulmonary circulation, its effects on human transitional circulation are yet unexplored.
Cardiovascular Transition in Human Disease States
Birth is characterized by a rapid transition from a high-resistance–low-compliance fetal pulmonary circuit to one that is low-resistance high-compliance. In utero and perinatal events may hamper this orderly transition. In this section, we address common pathologies that influence perinatal transition in human neonates in which acute or chronic hypoxemia plays an important role.
HIE and TH
HIE affects ∼1 to 2 infants per 1000 live births.48 TH is standard management on the basis of several randomized trials, which have revealed lower mortality and lower neurodevelopmental impairment in survivors.49 Despite these remarkable advances, brain injury still occurs in ∼50% infants with HIE.49 Cardiovascular dysfunction (evidence of transient myocardial ischemia or hypotension requiring an inotrope for >24 hours) is commonly noted during the first 72 hours after birth.50 The incidence of hemodynamic instability ranged from 33% to 77% in infants receiving TH, compared with 25% to 83% in controls.51,52 Specific contributors to hemodynamic instability may include primary cardiac dysfunction, pulmonary hypertension, circulatory inadequacy (in case of abruption being the underlying cause), or impaired adrenal gland performance.53 Heart rate augmentation is the primary compensatory mechanism in neonates, with subsequent enhancement in myocardial performance based on the force-frequency relationship. Therefore, a low baseline resting heart rate in HIE makes assessment of circulatory inadequacy difficult. Traditional appraisal of hemodynamically stability has been focused on arterial pressure thresholds; however, given the variance in physiologic modulators in the setting of HIE, defining the “need” to treat and selection of the physiologically most appropriate therapy may require broader consideration. For example, assessment of volume status may be difficult because poor urine output, elevated lactate levels, and delayed capillary refill may reflect a state of hemodynamic disturbance, severity of HIE or the biological consequences of TH, and lower core body temperature. A nonjudicious approach to fluid resuscitation, outside of the setting of true hypovolemia, should be avoided because of the increased risk of subclinical heart dysfunction from which heart failure may ensue. Giesinger et al52 summarized the interrelationship between contributors to ischemic injury resulting from initial insult, TH, reperfusion injury on rewarming, and the impact of HIE on cerebral perfusion. Because tissue oxygenation depends on organ blood flow and oxygen content of the blood, complemented by the tissue’s ability to extract oxygen, comprehensive appreciation of the physiologic contributors to adverse cardiovascular health is essential.
Given the above complexities, targeted neonatal echocardiography may aid in ascertaining the incidence, severity, and nature of hemodynamic impairments. Commonly studied conventional echocardiography parameters are depicted in Table 2.48,54–56 Tissue Doppler imaging and speckle-tracking echocardiography are newer modalities, which provide quantitative measures of myocardial velocities and regional myocardial function, respectively.57–59 Historically, echocardiography research in HIE has been focused exclusively on lower cardiac output,48,55,60,61 presumed secondary to impaired LV systolic performance, oftentimes with maintained systolic BP.48 As the dominant ventricle prenatally, the right ventricle may be at a greater risk because of its dominant role in transitional circulation and increased vulnerability to coronary artery hypoperfusion.55,61,62 Hypoxia and acidosis contribute to significant pulmonary hypertension. In clinical trials of TH, ∼20% of asphyxiated infants in the control group and 25% in the hypothermia group were diagnosed with pulmonary hypertension.63 Combined with cardiac dysfunction, the frequent coexistence of pulmonary hypertension (and the side effect of increased PVR related to TH) causes poor PBF, ventilation-perfusion mismatch, and lower systemic preload, further reducing systemic output.64 HIE, whether in and of itself or compounded by the biological effects of TH (vasoconstriction and increased viscosity), may also hamper myocardial perfusion, evidenced by low coronary flow and raised cardiac troponin. This clinical phenotype has been associated with low cardiac output.55,61 Because metabolic demands are low, the aforementioned changes may simply reflect cardiac adaptation to the original insult and the ongoing therapeutics. Data characterizing the relationship between myocardial dysfunction and adverse neurodevelopmental outcomes are emerging. In the largest prospective observational study, Giesinger et al65 conducted longitudinal echocardiography as part of comprehensive multimodal neurohemodynamic evaluation in 53 infants with HIE who were administered TH. Both severity of cardiovascular illness and severity of neurologic insult were higher in neonates with adverse outcome. Of note, RV dysfunction (and not pulmonary hypertension or LV performance) was independently associated with an increased risk of mortality or abnormal MRI, after adjustment for both illness severity and magnitude of encephalopathy according to Sarnat staging. These findings were confirmed in a study of 33 infants with HIE who were administered TH; specifically, echocardiography in the first 6 hours (before initiation of TH) noted impaired RV function. Longitudinal echocardiography noted improved function between the cooling and the rewarming phases.66
Summary of Conventional Echocardiographic Parameters Used in Infants With HIE
Variable . | View . | Comment . |
---|---|---|
Heart function | ||
Fractional shortening (%) and ejection fraction (%) | Two-dimensional, parasternal long axis or short axis | Assesses LV systolic function |
May be affected by septal deviation | ||
mVCFc (circumferences) | Two-dimensional, parasternal long axis or short axis and apical 5-chamber view | Assesses LV systolic function |
Load independent | ||
Fractional area change (%) | Two-dimensional, apical RV 3-chamber view | Assesses global RV contractility |
TAPSE (mm) | m-mode, apical 4-chamber view | Assesses longitudinal RV contractility |
Myocardial performance index | PW, apical 4-chamber view | Combined measure of systolic and diastolic intervals |
Transmitral E/A ratio | PW, apical 4-chamber view | Assess LV diastolic function and compliance |
Isovolumic relaxation time (ms) | PW, apical 4-chamber view | Assess LV diastolic function and compliance |
Pulmonary hypertension | ||
TPV/RVETc | PW, oblique parasternal PA view | Surrogate of PVR |
Lower ratio = higher PVR | ||
Tricuspid regurgitation (m/s) | CW, apical 4 chamber | Pulmonary hypertension (4TRVmax2 + 5) |
Ductal shunt | PW, high parasternal view | Percent of time in cardiac cycle shunting right to left |
>30% is significant | ||
Cardiac output/systemic blood flow | ||
Biventricular cardiac output (mL/kg per min) | PW, oblique parasternal PA view and apical 5-chamber view | Stroke volume × heart rate |
Superior vena caval flow (mL/kg per min) | PW, subcostal | Surrogate of cerebral blood flowa |
Pulmonary venous flow (cm/s or cm) | Left atrial, crab view | Peak velocity/velocity time integral |
Need lower color scale to visualize flow | ||
Middle cerebral artery resistive index | PW, temporal view | (Peak systolic velocity − end diastolic velocity)/peak systolic velocity |
LV end diastolic volume (mm3) | Two-dimensional, parasternal long axis or short axis | Volume status |
Subjective, needing further quantification by other methods | ||
IVC distensibility (mm) | Two-dimensional, subcostal sagittal | Volume status |
Subjective, needing further quantification by other methods |
Variable . | View . | Comment . |
---|---|---|
Heart function | ||
Fractional shortening (%) and ejection fraction (%) | Two-dimensional, parasternal long axis or short axis | Assesses LV systolic function |
May be affected by septal deviation | ||
mVCFc (circumferences) | Two-dimensional, parasternal long axis or short axis and apical 5-chamber view | Assesses LV systolic function |
Load independent | ||
Fractional area change (%) | Two-dimensional, apical RV 3-chamber view | Assesses global RV contractility |
TAPSE (mm) | m-mode, apical 4-chamber view | Assesses longitudinal RV contractility |
Myocardial performance index | PW, apical 4-chamber view | Combined measure of systolic and diastolic intervals |
Transmitral E/A ratio | PW, apical 4-chamber view | Assess LV diastolic function and compliance |
Isovolumic relaxation time (ms) | PW, apical 4-chamber view | Assess LV diastolic function and compliance |
Pulmonary hypertension | ||
TPV/RVETc | PW, oblique parasternal PA view | Surrogate of PVR |
Lower ratio = higher PVR | ||
Tricuspid regurgitation (m/s) | CW, apical 4 chamber | Pulmonary hypertension (4TRVmax2 + 5) |
Ductal shunt | PW, high parasternal view | Percent of time in cardiac cycle shunting right to left |
>30% is significant | ||
Cardiac output/systemic blood flow | ||
Biventricular cardiac output (mL/kg per min) | PW, oblique parasternal PA view and apical 5-chamber view | Stroke volume × heart rate |
Superior vena caval flow (mL/kg per min) | PW, subcostal | Surrogate of cerebral blood flowa |
Pulmonary venous flow (cm/s or cm) | Left atrial, crab view | Peak velocity/velocity time integral |
Need lower color scale to visualize flow | ||
Middle cerebral artery resistive index | PW, temporal view | (Peak systolic velocity − end diastolic velocity)/peak systolic velocity |
LV end diastolic volume (mm3) | Two-dimensional, parasternal long axis or short axis | Volume status |
Subjective, needing further quantification by other methods | ||
IVC distensibility (mm) | Two-dimensional, subcostal sagittal | Volume status |
Subjective, needing further quantification by other methods |
CW, continuous wave; IVC, inferior vena cava; m-mode, motion mode; mVCFc, mean velocity of circumferential fiber shortening; PA, pulmonary artery; PW, pulse wave; RVETc, heart rate corrected right ventricular ejection time; TAPSE, tricuspid annular plane systolic excursion; TPV, time to peak velocity; TRVmax2, maximal velocity of tricuspid regurgitation.
Represents only a portion of venous return to the heart.
Although the relationship between cardiovascular and neurologic illness severity and outcomes is still inadequately understood, clinicians feel a compulsion to treat presumed low BP or low cardiac output state. Infants with HIE who develop hemodynamic instability are commonly administered inotropes on the basis of arterial pressure thresholds derived from small population studies in which BP is generally measured by noninvasive methods.67,68 Multicenter prospective cohort studies, powered to account for sex, racial, gestational, and birth weight variabilities, are better guides to normative values. The optimal thresholds for BP, cardiac output, and cerebral blood flow during the precooling period, after initiation of induced hypothermia and after rewarming, are unknown. Rapid increases in arterial pressure (and cerebral perfusion in a pressure-passive system) after initiation of inotropes or vasopressor drugs may theoretically increase the risk of reperfusion brain injury because it is unclear how much cerebral blood flow is optimal at different phases of the hypoxia-ischemia or reperfusion phases. In addition, nonjudicious use of vasoconstrictors may be detrimental to patients with heart dysfunction because they augment afterload, leading to lower cardiac output. Enhanced diagnostic precision, intermittent delineation of ambient physiology and frequent assessments of cerebral and/or cardiovascular hemodynamics may enhance choice (and need for) of cardiotropes. Targeted neonatal echocardiography reasonably provides the optimum diagnostic and longitudinal monitoring tool to delineate precise pathophysiology and refine therapeutic interventions in high-risk populations.69–71 Jain et al69 noted the value of targeted neonatal echocardiography in predicting cardiorespiratory instability after duct ligation. Low LV output at 1 hour postoperation was a sensitive predictor of systemic hypotension and the need for inotropes. Targeted neonatal echocardiography revealed an independent association between impaired RV performance (but not LV systolic performance) and the combined outcome of death and/or abnormal MRI in asphyxiated infants. The data indicated the importance of pulmonary circulation (and the right ventricle) as a potential therapeutic target.65 In another study on asphyxiated infants, targeted neonatal echocardiography was used to delineate how cardiac function evolved from the precooling phase, through 72 hours of TH, and then rewarming phase.66 In essence, the facility helps in the assessment of pathophysiology in critical disease states.
FGR and the Fetal Programming Perspective
FGR is defined as a birth weight <10th percentile for gestation and sex with reversed or absent antenatal Doppler recordings.72 Premature birth complicated by FGR exacerbates perinatal morbidity and mortality.73–75 Fetal programming initiates changes in physiology, metabolism, and structure (cardiac hypertrophy, increased sympathetic [and reduced parasympathetic activity] and reduced nephron endowment), which can affect transitional circulation.76 The causes of FGR are varied, but they are most often associated with placental insufficiency, resulting in an inadequate supply of oxygen and nutrients to the developing fetus.
In a cohort of FGR infants, placental vascular disease (histologic maternal and fetal vascular malperfusion and accelerated villous maturation) was an early clue of this maladaptation.77,78 Cord blood level of α-klotho (an antiaging protein produced by the placenta) is decreased in FGR infants and may be relevant in vascular-mediated accelerated placental aging.79 Other mediators and the putative clinical effects of a stiff vasculature are summarized elsewhere.80 This indicates vasculature as an affected organ; vascular ultrasound of fetal and neonatal vasculature has noted thickened systemic arteries.81,82 Recent data using high-resolution ultrasound reveal that pulmonary vasculature is similarly affected.80 FGR neonates also have a thicker pulmonary artery wall, reduced pulsatility, and greater RV myocardial performance index (indicating poor performance), compared with appropriately grown infants.80 In a cohort of preterm infants assessed in the initial 24 hours of life, the baseline PVR was higher in FGR infants compared with gestation-matched AGA infants.83 In response to surfactant replacement therapy, the cardiorespiratory transition (reduction in PVR and increase in PBF and reduction in fraction of inspired oxygen) was significantly impaired in FGR infants.83 In essence, this variable cardiorespiratory trajectory, being charted by in utero experiences, is relevant in perinatal transition as well as important pathogenic mechanisms for respiratory sequelae.83–85 Abnormalities in antenatal Doppler recordings also have a close relationship with cardiovascular transition to extrauterine life, making them a useful monitoring parameter.86 Alongside the vascular changes, the heart itself is affected in FGR infants. Alterations in cardiac shape and function (hypertrophied [dilated in later gestation] cardiomyopathy like hearts) are noted on human fetal studies.87 Similar changes in cardiac geometry and systolic and diastolic dysfunction have been noted in preterm and term FGR neonates in the first few days of postnatal life as well.88–90 Leipälä et al6 noted altered hemodynamic adaptation in preterm FGR infants compared with equally premature but AGA infants. An inability to increase cardiac output (despite a hypertrophied left ventricle) was noted, which could potentially increase the risk of circulatory failure during early adaptation.
Other than close monitoring and optimum timing of delivery, there is currently no disease-specific treatment of FGR. Although prevention, early diagnosis and close monitoring, and optimization of maternal nutrition are key, targets of intervention to improve FGR cardiovascular health must be tested in preclinical models to determine optimal timing and targets. Breastfeeding for >6 months improves cardiac geometry (less hypertrophy) and lower arterial thickness.91 Other targets include modulators of the renin-angiotensin system (decrease angiotensin II and increase angiotensin [1–7]) and antenatal melatonin (antagonizes oxidative injury and restores nitric oxide production).76 It is promising that the effects of melatonin on oxidative parameters in preterm respiratory distress syndrome and in those with chronic lung disease have shown beneficial effects.92,93 Whether it facilitates perinatal transition in human infants needs to be prospectively explored. In the immediate neonatal period, individualized management of FGR infants such as avoiding mechanical ventilation and administering surfactant through noninvasive means may be prospectively studied. Whether managing pulmonary vascular disease alters clinical outcomes should be studied prospectively.
Conclusions
The immediate transitional period after birth is characterized by major and interrelated changes in cardiopulmonary physiology that influence resuscitative and stabilization efforts. Optimization of lung recruitment positively affects the establishment of normal PBF and needs considering when determining the optimal timing of cord clamping. Infants with evidence of acute hypoxic-ischemic insult, during the birth process or immediately after birth, or infants with FGR secondary to chronic intrauterine hypoxia-ischemia are susceptible to abnormal cardiopulmonary adaptation, which may manifest as acute hemodynamic instability. Because of the limitations of routine clinical assessment, comprehensive targeted neonatal echocardiography is an essential longitudinal tool to enable enhanced diagnostic precision and facilitate more physiologically appropriate treatment choices. The relationship between hemodynamic disturbance and adverse neurologic outcomes warrants prospective investigation of at-risk phenotypes and novel treatment options.
Prof Sehgal conceptualized and designed the study and drafted the initial manuscript; Dr Allison, Prof Miller, Assoc Prof Polglase, Prof McNamara, and Prof Hooper drafted the initial manuscript; and all authors reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
References
Competing Interests
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
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