Chapter 56. Hemodynamics

An understanding of neonatal circulatory pathology is intrinsically linked to an understanding of circulatory adaptation to extrauterine life (see Chapter 43). In the fetal circulation, better oxygenated blood is returned from the placenta to the fetus via the umbilical vein. This blood is streamed by the ductus venosus across the right atrium, through the foramen ovale, and into the left atrium, facilitating delivery of the best oxygenated fetal blood to the brain and upper body. Blood returning via the vena cavae is streamed through the right side of the heart and into the descending aorta via the ductus arteriosus. This blood preferentially streams through the ductus because of arteriolar constriction and the high vascular resistance in the fetal lungs. The right-to-left ductal blood flow supplies the lower part of the body and also returns blood to the placenta via the umbilical arteries, which arise from the iliac arteries.

At birth, this blood flow pattern changes quickly. The lungs expand with the first breaths, the pulmonary arterioles dilate, right heart pressures fall, and blood pours into the pulmonary circulation to collect oxygen. The removal of the low-resistance placenta from the systemic circulation increases resistance and pressure on the left side of the circulation, while the pulmonary blood flow increases the left heart preload. The result is a dramatic increase in the workload of the left heart. The muscle in the wall of the ductus arteriosus constricts in response to rising oxygen levels, closing functionally within the first 24 hours after birth and structurally after several days to become a fibrous band.

During the last trimester, much of the fetal cardiopulmonary development is in preparation for the changes that have to occur at birth. Babies born prematurely have exquisite circulatory vulnerability during this period of the transitional circulation. More mature babies are also vulnerable if born in a compromised condition or if they become unwell shortly after birth.

Poor color, increased heart rate, prolonged capillary refill, and low urinary output suggest circulatory compromise. Blood measurements such as low pH and rising lactate can supplement the clinical assessments. These indicators are useful in identifying the baby with severe circulatory compromise, but they have limited accuracy for babies with lesser degrees of compromise.2

Blood Pressure

Blood pressure can be accurately measured and continuously monitored if there is intra-arterial vascular access. Because blood pressure is relatively easy to monitor, it has traditionally been the primary indicator of neonatal circulatory status, and much conventional circulatory support has focused on increasing the low blood pressure.3 Strong data exists for the importance of a normal blood pressure range4 (Fig. 56-1), but controversy arises over what constitutes an adequate blood pressure that is, the blood pressure below which organ injury can result.5 Further, an emerging body of evidence questions the accuracy of blood pressure as a gold standard for circulatory well-being.6-8 There is an association between low blood pressure soon after birth and ultrasound evidence of brain injury such as intraventricular hemorrhage and periventricular leukomalacia.9,10 A common assumption is that blood pressure equals blood flow, which has resulted in a focus almost entirely on blood pressure for the diagnosis and treatment of circulatory problems. However, because pressure is the product of flow and resistance, changes in either can affect blood pressure.

Measurement of Blood Flow

Accurate measurement of blood flow is much harder than measuring blood pressure, but it better predicts oxygen delivery. The 2 methods most widely used for both research and clinical blood flow estimates are Doppler echocardiography and near infrared spectroscopy.

Doppler Echocardiography

Blood flow is the product of mean velocity and vessel cross-sectional area. Blood velocity can be measured with Doppler (eFig. 56.1), and vessel size can be measured with ultrasound (eFig. 56.2), as long as the vessel is of a reasonable size (see Chapter 495). Flow measurements in neonates are usually limited to the great vessels close to the heart. The main pulmonary artery is used to measure right ventricular output. The ascending aorta is used for left ventricular output. Systemic venous return is measured via the superior vena cava. Doppler measures in the smaller vessels are usually limited to velocity, which may not accurately represent flow. The advantage of Doppler ultrasound is that it measures the hemodynamic variable that most closely represents oxygen delivery. The disadvantages are the need for special equipment and skilled personnel and the potential for significant intrinsic errors, particularly in vessel size measurement.11 Further, because of the complexities of the shunts in the transitional circulation, ventricular outputs may not represent systemic blood flow in newborns.12

Near Infrared Spectroscopy

Near infrared spectroscopy uses infrared light to measure oxygenated and deoxygenated hemoglobin and, from these measures, blood flow in the superficial tissues of the brain (and other organs). Organ blood flow is derived, using the Fick principle, from change in oxyhemoglobin in response to an increased inspired oxygen. Indices of tissue oxygenation can be derived from the ratios between oxyhemoglobin and deoxyhemoglobin. Although a useful research tool for understanding neonatal hemodynamics, near infrared spectroscopy has not been incorporated extensively into clinical practices.13

Ischemia is one component of the pathophysiology of a range of preterm complications, particularly those involving the brain. The preterm baby is essentially an exteriorized fetus whose cardiovascular system is adapted to the low resistance of the placental circulation. The preterm myocardium is immature with less contractile components than the myocardium of a term baby. The preterm heart may not adapt to the higher workloads of extrauterine life. Also, the fetal channels of the ductus arteriosus and foramen ovale are less likely to close in preterm babies, and the resultant left-to-right shunts may drain blood from the systemic back into the pulmonary circulation. Many preterm babies need ventilatory support, and positive pressure ventilation can compromise cardiac performance. Therefore, preterm babies in the intrapartum period and the first 24 hours after birth are vulnerable to circulatory compromise.

In the early hours after birth, low blood pressure and low systemic blood flow (SBF) can decrease cerebral blood flow (CBF) due to impaired cerebral autoregulation resulting in pressure-passive cerebral blood flow. Low blood pressure, SBF and CBF have been associated with ultrasound evidence of brain injury and adverse neurodevelopmental outcomes.6-8,14-17 Therefore, the relationships between SBF and CBF are a central focus in management of the preterm infant. Near infrared spectroscopy studies suggest there is a subgroup of preterm babies in whom autoregulation of CBF is compromised and who are at high risk for ultrasound evidence of brain injury.18,19 It is unclear whether absent autoregulation is the primary problem or is secondary to another insult.

Recent Doppler echocardiographic studies have focused on transitional hemodynamics in the heart with central measures of SBF. However, these measures can be confounded by left-to-right shunts through a patent ductus arteriosus or across a patent foramen ovale even in the early postnatal hours.6,12,20 Doppler measurements of superior vena cava (SVC) flow can be used to study the natural history of preterm SBF (upper body and brain).6,21 Low SVC flow occurs within the first 12 hours after birth in about 35% of babies born before 30 weeks, and flow improves by 24 to 48 hours.6 The magnitude of the low flow state correlates with the risk of intraventricular hemorrhage occurring as or after flow improves.6 There is also an association between lower average SVC flow in the first 24 hours after birth and poor 3-year developmental outcome.17

The causes of this low flow state are not known, but immaturity (lower gestational age) is the main risk factor. The preterm myocardium has a limited ability to respond to an increase in afterload,22,23 and the transition from the low-resistance intrauterine state to the high-resistance ex utero state may contribute to low SBF. The reduced capacity of the myocardium is further impacted by the requirement for positive pressure ventilation in many preterm infants, which is also known to compromise cardiac output.6 At the time of low SVC blood flow, babies are also more likely to have a larger patent ductus arteriosus (shunting blood out of the systemic circulation). Of clinical importance, there is only a weak relationship between blood pressure and SBF, whether measured by SVC flow or ventricular outputs.6-8 (Fig. 56-2), which indicates that peripheral vascular resistance must also decrease somewhat as flow increases, further compromising CBF.

This complex relationship with reduced myocardial capacity, low blood pressure and lost autoregulation that occurs in the preterm infant limits therapeutic options. Most practitioners attempt to maintain the blood pressure above an arbitrary level. Further therapeutic options will depend upon a better understanding of the factors that may improve autoregulation. Specific issues that may alter the preterm infant’s compensatory mechanisms are discussed below.

Hypovolemia

Hypovolemia is an uncommon cause of circulatory compromise in preterm and term infants. There is often no relationship between blood volume and blood pressure. Occasionally, hypovolemia results from acute fetal blood loss. Usually, it is associated with intrapartum blood loss or fetoplacental transfusion (eg, after early clamping of a nuchal cord). These babies usually have classic features of circulatory compromise with pallor, tachycardia, hypotension, and a typical appearance on echocardiogram of poorly filled ventricles.

Patent Ductus Arteriosus

Patent ductus arteriosus during the first week of life is associated with both lower systolic and diastolic blood pressures, and hence lower mean blood pressure,26 because the duct exposes the systemic circulation to the lower resistance of the pulmonary circulation throughout the cardiac cycle. Usually, patent ductus arteriosus is clinically silent during the first 3 postnatal days. Diagnosis with echocardiography is quick and easy (Fig. 55-1). In the very early transitional period, a larger ductal diameter is significantly associated with low SBF. Later (and contrary to popular belief) many babies will protect their systemic circulation well despite a patent ductus arteriosus.6,21 See Chapter 55 for further discussion.

Sepsis

Neonatal sepsis commonly presents with signs of circulatory compromise. In early-onset sepsis, the problems are probably a combination of the transitional hemodynamics and pulmonary hypertension associated with pneumonia. Severe shock associated with late-onset sepsis is usually associated with vasodilation and normal or high SBF (see eFig. 56.3).

Inotrope-Resistant Hypotension

Hypotension that is resistant to vasopressor support might seem to be associated with poor adrenocortical function.27,28 However, blunted cortisol responses are not consistently found in these babies, suggesting other etiologies. Inotrope-resistant hypotension is usually associated with vasodilation and normal or high SBF.29

For further discussion, see Chapters 50, 52, and 61.

Term Infants with Asphyxia, Persistent Pulmonary Hypertension, or Severe Respiratory Distress

Term and near-term babies with asphyxia, persistent pulmonary hypertension, or severe respiratory distress also have a high risk of low SBF in the first 24 hours. The incidence of low SBF decreases with increasing postnatal age.31,32 Contributing factors include the effect of high positive pressure ventilation, hypoxic-ischemic damage to the myocardium and the high resistance in the pulmonary circulation which may reduce pulmonary venous return, and thereby reduce cardiac output when the ductus arteriosus and foramen ovale are already closed in these more mature infants.31-33 A distended right ventricle may further impede left ventricle filling to reduce left ventricular output. Nitric oxide can increase cardiac output by decreasing pulmonary resistance and thereby decreasing the effect of right ventricular size on left ventricular filling (eFig. 56.4).

Circulatory Collapse

Sudden circulatory collapse in babies is rare but catastrophic. Although the problem is easily recognized, identifying the cause can be more difficult. Such babies are often assumed to be septic, which is probably the commonest reason for this presentation. However, other causes must be excluded. Congenital heart lesions with ductal-dependent systemic circulations, such as critical coarctation or hypoplastic left heart syndrome), are the most important diagnoses to exclude. However, other rarities, such as cardiac tamponade resulting from intravascular catheter eroding through the heart, can present unexpectedly. Many of these diagnoses are quickly apparent on echocardiography.

General Measures

Basic preventative strategies for circulatory support are important and easily overlooked. Antenatal steroids mediate their effects on both the respiratory and cardiovascular system. Babies born after maternal steroid treatment have higher blood pressure, have less need for inotropes, and are less likely to develop low systemic blood flow.16 Avoiding overventilation is also important because of the direct negative effects on the circulation of high intrathoracic pressure and because of the effects of low carbon dioxide in reducing CBF. Volume expansion with normal saline at 10 ml/kg over 20 to 30 minutes should be part of the initial approach to circulatory support in all inotrope strategies. Volume expansion should not be repeated unless there is a convincing response to treatment (falling heart rate and improving blood pressure) or there is strong clinical and/or echocardiographic evidence of hypovolemia. Too much volume replacement is as potentially harmful as inadequate volume replacement.

Volume expansion, dopamine, dobutamine, epinephrine, and, increasingly, hydrocortisone are the agents commonly used for neonatal circulatory support. Volume expansion restores normovolemia in the rare hypovolemic infant and increases preload and hence cardiac output in the normovolemic infant.

Clinical trials of volume expansion have been designed primarily to evaluate blood pressure rather than clinical outcomes. Routine volume expansion soon after birth does not change long-term outcomes in preterms.34,35,37

Inotropes increase systemic blood flow (SBF) by increasing cardiac rate and myocardial contractility or by reducing afterload. Some inotropes have predominantly vasoconstrictive (pressor) effects, which can improve preload and SBF by constricting the venous bed. Arterial constriction improves blood pressure, but too much constriction can reduce SBF by increasing afterload. Dopamine is a naturally occurring precursor to epinephrine and norepinephrine, which has dopaminergic, beta, and alpha effects. Each of these effects, respectively, is more likely to predominate as the dose increases. Over 10 mcg/kg/min, the alpha vasoconstrictive effects on blood pressure predominate, but in the very immature baby, these alpha effects may be apparent at lower doses. Dobutamine is a synthetic catecholamine with β-adrenergic effects, which tend to vasodilate, and cardiac α-adrenergic effects, which stimulate cardiac contractility and increase heart rate. Epinephrine has broad α-adrenergic and β-adrenergic effects and, like dopamine, will vasoconstrict at higher doses. Dopamine is more effective than dobutamine at increasing blood pressure, but dobutamine may be more effective than dopamine for improving cardiac output. Epinephrine has similar effects to dopamine on blood pressure and cerebral blood flow. There is no evidence that these interventions improve important clinical outcomes. Hydrocortisone increases blood pressure, but little is known about how it does so in the neonate.

Evidence for Volume Expansion in Neonates

Based on systematic review, routine early volume expansion in preterm babies does not improve outcomes.34 There is probably no advantage in using a colloid compared to a crystalloid. Volume expansion is not as good as dopamine at increasing blood pressure.35 There is less known about the effect of volume on organ blood flows. Studies have shown increases in left ventricular output36,37 or SVC flow38 with volume; however, these effects did not translate to an increase in cerebral blood flow in the study by Lundstrøm and colleagues.36 Volume expansion effects have been measured immediately after the volume was given, and sustained effects have not been evaluated. There is some evidence that the fluid used in volume expansion redistributes quickly out of the vascular compartment.

Evidence for Inotrope Use in Neonates

Although dopamine is better than dobutamine at increasing blood pressure, this treatment did not translate into better short-term outcomes.39 Epinephrine and dopamine have similar efficacy for increasing blood pressure.40 None of the studies have been powered or designed to evaluate clinical outcomes. Babies have been enrolled on the basis of blood pressure below a cutoff, and change in blood pressure was the hemodynamic outcome. Roze and colleagues41 measured an increase in left ventricular output in babies treated with dobutamine, while left ventricular output decreased with dopamine.

In the only randomized study of dopamine and dobutamine that enrolled babies on the basis of low blood flow,38 dobutamine increased systemic blood flow (SBF) better than dopamine, while dopamine increased blood pressure more. At 10 mcg/kg/min, there was no difference between the 2 drugs. In infants who received 20 mcg/kg/min dobutamine produced more flow benefit, while dopamine increased blood pressure without increasing flow. However, these physiological differences did not translate into any significant differences in outcome.42

SVC flow includes cerebral blood flow (CBF), but they are not equivalent. The effect of dobutamine on cerebral blood flow in preterm babies has not been studied. Using Xe clearance, Lundstrøm and colleagues36 showed that dopamine, while increasing left ventricular output and mean blood pressure, did not increase CBF. Seri and colleagues43 found no effect of dopamine on middle cerebral artery pulsatility index in a group of preterm babies with normal blood pressure but found clinical evidence of poor perfusion. In an open label observational study, Munro and colleagues19 used near infrared spectroscopy to show an increase in mean CBF when dopamine was given to preterm babies with a mean blood pressure below 30 mm Hg. In a double-blind randomized controlled trial, Pellicer and colleagues,40 also using near infrared spectroscopy, showed dopamine (at doses up to 10 mcg/kg/min) and epinephrine (at doses up to 0.5 mcg/kg/min) similarly increased cerebral intravascular oxygenation, which in turn was correlated with increases in mean arterial pressure.

Evidence for Hydrocortisone to Support Blood Pressure in Neonates

Much of the data on hydrocortisone is observational and relates to its use in inotrope-resistant hypotension. One randomized controlled trial showed hydrocortisone at 2.5 mg/kg had similar efficacy to dopamine for improving blood pressure in hypotensive preterm babies.44 There were no differences in other clinical outcomes. Noori and colleagues29 found increases in blood pressure, left ventricular output, and systemic vascular resistance with 2 mg/kg of hydrocortisone in 14 babies with inotrope-resistant hypotension. There is no information about the effects of hydrocortisone on CBF.

Blood Pressure Threshold Approach to Circulatory Support

If treatment is being guided mainly by blood pressure, then the intervention threshold must be determined. Two thresholds are often used for babies born before 30 weeks: Maintain mean blood pressure above 30 mm Hg9,19 or maintain mean blood pressure above the gestation (in weeks) of the baby. There is no outcome-based evidence for either approach.

Dobutamine increases blood pressure in many babies and seems better than dopamine for improving SBF.38,41 Therefore, within the first 24 hours after birth, when low SBF is common, it is logical to use dobutamine for babies whose blood pressure response is inadequate. For more consistent effects on blood pressure, dopamine or epinephrine should be the first choice. Despite similar hemodynamic effects, there is more clinical experience with dopamine. Using a vasopressor also risks raising afterload enough to compromise SBF. Increasing blood pressure may not always be the best approach to circulation control. Research demonstrates that some infants have dramatic increases in CBG in response to increased blood pressure. Hyperperfusion after hypoperfusion seems important in the pathogenesis of intraventricular hemorrhage.6 These risks can probably be minimized by starting with a low dose (5 mg/kg/min for dopamine or 0.1 mg/kg/min for epinephrine) and titrating in careful steps to a minimally acceptable blood pressure.

Blood Pressure and Blood Flow Threshold Approach to Circulatory Support

It seems logical to base therapy on a more complete understanding of the underlying cardiovascular hemodynamic than blood pressure alone can provide. This approach requires echocardiographic evaluation at 3 to 9 hours of age when infants are at highest risk for low SBF or whenever there are clinical signs of poor perfusion or hypotension. The 3 echocardiographic measures, in order of importance, are a measure of systemic blood flow (SVC flow or right ventricular output), the size and direction of ductus shunt, and an assessment for pulmonary hypertension.6,12,21 Intervention thresholds of 50 ml/kg/min for SVC flow and 150 ml/kg/min for right ventricular output are often sufficient. Pathologically low measures of these 2 variables would be less than 40 and 120 mL/kg/min respectively.6,21 Blood flow needs, as measured by velocity and vessel size, can be time consuming to derive. Large atrial shunts are uncommon in the first 48 hours. For clinical purposes, right ventricular output is a reasonably accurate marker of SBF in the early postnatal period. Velocity in the main pulmonary artery is the dominant determinant of right ventricular output, and measurement of the maximum velocity in the pulmonary artery (PA Vmax) provides a simple way to screen for low SBF (eFig. 56.5). If the PA Vmax is over 0.45 m/sec, low SBF is unlikely. If the PA Vmax is less than 0.35 m/sec, most babies have low SBF. Values between 0.35 and 0.45 m/sec are a gray zone where discriminatory accuracy is less good (eFig. 56.6). In practice, I recommend screening with PA Vmax and then doing full right ventricular output and/or SVC flow measures in those with a PA Vmax less than 0.45 m/sec.

In babies with a large patent ductus arteriosus (> 2 mm diameter in the first 6 hours, > 1.6 mm thereafter) and predominantly left-to-right shunts, consideration should be given to pharmacologic closure, particularly if the SBF or mean blood pressure is low. Otherwise, in babies with low SBF, treatment with volume and dobutamine starting at 10 μg/kg/min and increasing to 20 μg/kg/min depending on response is reasonable. If the mean blood pressure remains persistently below the gestational age despite dobutamine, dopamine at 5 μg/kg/min can be added and the dose titrated to achieve a minimally acceptable mean blood pressure.

After 24 hours of age, the SBF will likely be normal or high. If the blood pressure is low, a loss of vascular tone is likely and a pressor inotrope is the logical therapeutic choice. Dopamine can be initiated at 5 μg/kg/min and titrated to achieve a minimally acceptable blood pressure. There is no physiological reason that epinephrine should not be just as effective, but there is less clinical experience with epinephrine. If the SBF is normal and other markers of circulatory status are satisfactory, borderline low blood pressures can be tolerated (within 2 or 3 mm Hg of threshold).

Inotrope Resistance

There are 2 aspects to inotrope resistance. The first is the resistant hypotension discussed previously, and the second is the less well-recognized resistant low SBF, which may or may not be associated with hypotension. This low SBF resistance was observed in about 40% of the babies with low SBF and is not an uncommon finding in clinical practice.38 No reliable strategy to correct this low SBF state has been described. Epinephrine infusions and hydrocortisone have been tried but, anecdotally, neither seems very effective. SBF often spontaneously increases gradually between about 12 and 36 hours.

Except in the first 24 hours when low SBF is common, most babies with inotrope-resistant hypotension have vasodilation. The management of this resistant hypotension is empirical. Epinephrine infusions can increase blood pressure in babies already on maximum doses of dopamine, and hydrocortisone (at doses of 1–2 mg/kg) is being used. Considerably more is known about the hemodynamic effects of epinephrine than of hydrocortisone. However, the association between low cortisol levels and resistant hypotension provides an empirical logic for treatment of babies at risk of adrenal insufficiency with physiological doses of hydrocortisone. An approach with resistant hypotension will depend in the clinical situation. An epinephrine infusion can be tried before using hydrocortisone, but in the very premature baby, hydrocortisone may be given first. With the unresolved concerns about possible adverse neurological effects of early postnatal use of systemic corticosteroids, it seems wise to minimize the dose of hydrocortisone. A dose of 1 to 2 mg/kg hydrocortisone can be started and continued for 1 to 3 days depending on the response.46,47 Septic shock often causes vasodilation and can be very resistant to inotropes. Whether hydrocortisone should be used if there is suspected sepsis is open to question. This vasopressor-resistant loss of vascular tone is a feature of septic shock in older patients, and a variety of therapeutic strategies, including nitric oxide synthetase inhibitors and vasopressin, have been explored in this population.30 There has been no systematic study of these agents in the neonate.

How to Support the Circulation of the Term Infant

There are no clinical outcomes based on aggregated evidence. Diagnosis is clearly critical, and in hypovolemia or ductal-dependent cardiac lesions, treatment must be directed at the cause. The commonest situation is the term baby with severe pulmonary problems and/or persistent pulmonary hypertension. The same principles in relation to pressure and flow are applied, as discussed previously, and the effects of pulmonary vasoconstriction on systemic blood flow must be considered. In babies with pulmonary artery pressures, treatment with inhaled nitric oxide can be an effective circulatory support measure. With severe lung disease and/or persistent pulmonary hypertension of the newborn, vasopressors can constrict both the systemic and pulmonary vasculatures. Although not studied in term babies, dopamine has a balanced effect on both circulations with quite wide interindividual variation in preterm babies.48,49 There is some observational data that norepinephrine may have a preferential pressor effect on the systemic circulation with some vasodilatory effect on the pulmonary circulation.50

When the SBF is low, dobutamine may be the first choice, with dopamine or epinephrine added if the blood pressure remains low. If mean blood pressure is low and SBF is normal or oxygenation is borderline, dopamine or epinephrine may be better initial choices. Norepinephrine may have advantages in this situation. These are therapies that have been in routine clinical practice for over 25 years, yet there is no information if a primary goal, to reduce neurological morbidity, is achieved with their use.