Hemodynamic management in special circumstances

Key points

1.
Neonates with hypertrophic cardiomyopathy due to diabetes who have cardiovascular instability benefit from a strategy that avoids positive inotropy and high peak end-expiratory pressure and prioritizes left heart volume loading and increased left ventricular afterload.
2.
Neonates with pre-ductal arteriovenous malformations may have flow-mediated pulmonary hypertension and pseudocoarctation physiology if left-to-right ductal shunt (either due to natural decline in systemic vascular resistance or secondary to inhaled nitric oxide therapy) is added to the large intracranial shunt. Treatment for pulmonary arterial hypertension (e.g., inhaled nitric oxide) should only be considered for neonates who also have hypoxemic respiratory failure.
3.
Pulmonary arterial hypertension is more common in the transitional period for preterm infants. The frequency response to nitric oxide is comparable to term infants with acute pulmonary hypertension in the transitional period. The optimal starting dose, duration, and weaning schedule require further study.
4.
Neonates with congenital diaphragmatic hernia may have either a right heart (e.g., pulmonary arterial hypertension) or left heart (e.g., pulmonary venous hypertension) phenotype. The clinical manifestations may be similar. Echocardiography demonstration of the direction of atrial shunt prior to nitric oxide therapy may be advantageous.
5.
Twin-to-twin transfusion syndrome, particularly if not treated with in utero laser photocoagulation of affected vessels, may manifest as hypertrophic cardiomyopathy in the recipient twin and both twins may benefit from early echocardiography-based phenotypic delineation.

Introduction

There are several biological conditions that highlight important physiological concepts and require special attention when caring for an infant faced with cardiovascular compromise. As neonatologists, we generally treat a population of patients with structurally normal hearts but abnormal cardiovascular physiology. That is crucial because that makes up the bulk of clinical practice for each licensed independent practitioner every day; however, it is also important to consider how these principles may need to be adapted to other unique situations. In this chapter we will focus on the application of physiological principles to the management of the infant of a diabetic mother with hypertrophic cardiomyopathy, pre-ductal arteriovenous malformation, preterm arterial pulmonary hypertension (PH), congenital diaphragmatic hernia (CDH), and twin-to-twin transfusion.

Infants of diabetic mothers and hemodynamic management

Background

Diabetes mellitus is a common maternal morbidity, associated with higher body mass index, higher maternal age, and sedentary lifestyle, affecting 9–25% of pregnancies. The term “infant of a diabetic mother (IDM)” refers to neonates born to a woman with persistently elevated blood sugar during pregnancy. Infants of diabetic mothers, even with good glycemic control, are at five times increased risk of both morphological and functional cardiac changes because of characteristic fetal metabolic abnormalities such as hyperglycemia and hyperinsulinemia. . Fetal exposure to these conditions often contributes to neonatal morbidity, which may be transient or permanent and predispose to cardiovascular disease in adulthood. ^, Even asymptomatic infants may have subclinical functional impairment.

IDM and morphological changes

Congenital heart disease, including septal defects, transposition of the great arteries, persistent truncus arteriosus, and patent ductus arteriosus (PDA), is associated with maternal diabetes. Cardiomyopathy including hypertrophic obstructive cardiomyopathy, is identified in 13–44% of cases, with the greatest risk associated with maternal type 1 diabetes. ^, Hypertrophic cardiomyopathy is described as a combination of asymmetric septal hypertrophy and diastolic dysfunction. ^, These cardiac structural changes may be due to hyperglycemia, activating a cascade of cellular events and changes in gene expression. They have also been found to be associated with hyperinsulinemia and IGF-1, which promotes hypertrophy in cardiomyocytes, leading to decreased myocardial compliance. Asymmetric septal hypertrophy is typically due to a greater density of insulin receptors in this region as compared to other areas of the cardiac muscle. This may lead to left ventricular outflow tract (LVOT) obstruction and systolic anterior mitral valve displacement. Although good maternal glycemic control may improve heart development and mitigate the risk of increased ventricular thickness compared to infants of poorly controlled diabetic mothers, it does not eliminate the risk of septal hypertrophy.

Echocardiography can be utilized to demonstrate structural and functional changes commonly found in IDMs; specifically, it is useful to examine the interventricular septum and posterior wall thickness and measure left ventricular (LV) systolic and diastolic function. ^, Biomarkers such as cardiac-specific troponin I (cTnI) and N-terminal pro-brain natriuretic peptide (NT-pro BNP) may also be used to predict HOCM and LV dysfunction. cTnI is an inhibitory protein involved in cardiac muscle relaxation released in settings of myocardial injury. Serum levels are correlated with the degree of septal hypertrophy, which may be due to suboptimal coronary artery oxygen delivery to compensate for high myocardial oxygen demand.

IDM, transition, and functional impairment

IDM are at increased risk of respiratory distress syndrome because fetal hyperinsulinemia impairs surfactant production. ^, Lung disease may lead to secondary acute pulmonary hypertension (PH); however, animal studies have also shown increased muscularization of pulmonary arteries and fewer pulmonary vessels at birth, suggesting that a predisposition to pulmonary vascular disease may exist in the absence of lung disease. Maternal diabetes is also associated with chronic fetal hypoxia and polycythemia, which are risk factors for PAH at birth. ^, Katheria et al. demonstrated that even following well-controlled DM during pregnancy, the IDM is at risk of abnormal transitional hemodynamics. This was supported by lower right ventricular output compared to controls. These data are also consistent with the report by Seppänen et al., who showed that the closure of the ductus arteriosus and postnatal decrease in pulmonary artery pressure are delayed in IDMs when compared with control infants during the first postnatal days. The consequences of hypertrophic cardiomyopathy may include impaired systemic blood flow and hyperdynamic LV systolic function, which is often observed to coexist with diastolic dysfunction. However, even in the absence of hypertrophic cardiomyopathy, functional cardiac changes may be evident. As compared to well-controlled DM pregnancies and healthy controls, IDMs following poor control during pregnancy showed a significant reduction in LV global strain and strain rate. This suggests glycemic control influences the degree of impairment in myocardial systolic function, which persists at least through 6 months postnatal age. Additionally, persistence of the ductus arteriosus may be more prevalent among IDMs following poor glycemic control, which may have important implications for preterm IDMs. Interestingly, early functional impairment itself has been suggested to induce cardiac hypertrophy.

IDM and adult life

The potential benefit of evaluating fetal cardiac function may lie in its prognostic value for long-term cardiovascular health. Fetal studies have shown that in utero reprogramming of genes involved in metabolic processes can occur secondary to maternal diabetes, especially when associated with a high-fat diet. Several biochemical markers associated with adult cardiovascular disease have been identified as higher among IDMs than control infants. These include increased cellular adhesion molecules, markers of endothelial damage, and dysfunctional endothelial colony-forming cells. Elevated levels of angiotensin II, which potentiates stronger vasoconstriction in the presence of endothelin 1, and apoptosis of umbilical venous endothelial cells have been demonstrated in human IDMs. While limited longitudinal data specific to the heart is available, these findings may provide biological support to epidemiological studies suggesting a greater burden of cardiovascular disease among IDMs later in life.

Hemodynamic management of IDM with obstructive hypertrophic cardiomyopathy

In most instances infants with hypertrophic cardiomyopathy are asymptomatic and the hypertrophy resolves within months of birth as the stimulus for the insulin production disappears. ^, A subset of cases, however, develop cardiogenic pulmonary edema and/or shock with severe hypotension due to either LVOT obstruction and/or low LV preload resulting in a low cardiac output. Low cardiac output in these patients is associated with lower cerebral resistance to compensate for low flow through the carotid arteries. ^, Medication choices involve understanding of the physiology of hypertrophic cardiomyopathy. The most fundamental consideration is that hypertrophic muscle contracts well with often supra-normal systolic function but doesn’t relax well (impaired compliance), resulting in diastolic dysfunction. Practically, this translates into a problem of keeping the LV filled and a need for high LA pressure. During systole, the LV has the capacity to eject and may completely empty before the cavity pressure declines below aortic root pressure. Thus maintenance of high aortic root pressure is one strategy to maintain LV volume. The pattern of deterioration among patients with hypertrophic cardiomyopathy is predictable and should inform the urgency of treatment. The LV becomes underfilled and compensatory tachycardia reduces diastolic duration and further compromises stroke volume. The gradient to flow in the coronary arteries, from the hypotensive aortic root to the hypertensive coronary sinus, is not compatible with coronary blood flow, and the hypertrophic cardiac muscle has a high tissue oxygen demand. The result may be death from cardiac ischemia if prompt management is not instituted to correct the critically low coronary perfusion pressure and either restore LV filling or maintain right to left ductal shunting to support cardiac output. Once a patient becomes significantly hypotensive, emergent intervention should be instituted.

Pharmacologic Treatment of hypotension: The physiologic goal of treatment is to maintain a high filling pressure, optimize intracardiac volume loading, and avoid tachycardia. Therefore a liberal approach to use of crystalloid therapy is recommended. Intravenous vasopressin has been proposed as beneficial in the setting of hypertrophic obstructive cardiomyopathy physiology. Vasopressin has the potential to augment both cardiac preload and afterload due to effects on both free water absorption and systemic vasoconstriction while simultaneously avoiding tachycardia and excessive positive inotropy. The rationale behind this may be threefold; first , increased systemic vascular resistance (SVR) may increase a left-to-right ductal shunt, which may be beneficial in this population because the resultant increase in pulmonary blood flow may augment left atrial filling and improve cardiac output. In addition, enhanced left heart volume loading may prevent the premature and complete emptying of the left ventricle; second , higher afterload because of increased SVR results in reduced velocity of fiber shortening, limiting ejection time. As a result of incomplete emptying of the LV, there is greater end-systolic volume, which adds to preload to improve cardiac output; third , the anti-diuretic effect of vasopressin may increase circulating volume, and this may be beneficial in the acute phases of treatment. In a retrospective case series by Boyd et al, six infants with hypertrophic obstructive cardiomyopathy (five of whom were IDMs) were treated with vasopressin resulting in clinical and biochemical improvement, which warrants further investigation with a prospective randomized trial. Norepinephrine, although primarily an α-agonist, has some β1 activity and is not recommended due to the prevalence of tachycardia with NE use. Phenylephrine is used in adults and in anesthetic practice for treatment of shock due to obstructive cardiomyopathy, though there is limited experience with this agent in most neonatal intensive care units.

General cardiovascular care for patients with HOCM

The management of acute PH and/ or shock in the infant of a diabetic mother requires modification from routine neonatal intensive care strategies if significant septal hypertrophy is identified, particularly in the presence of LVOT obstruction. The most appropriate approach depends on the degree of obstruction to left heart outflow. If the dominant clinical concern is hypoxia and LVOT obstruction is mild or absent, treatment of PH with strategies that reduce pulmonary vascular resistance (PVR) such as inhaled nitric oxide (iNO) is the most appropriate. Conditions in which the left heart is preload compromised result in closer approximation of the septum and the mitral valve and therefore may exacerbate obstruction. This includes excessive mean airway pressure, particularly in the setting of high-frequency ventilation, where diastolic filling time may be limited. In addition, vasodilator drugs, such as milrinone, should be avoided. Positive inotropes (epinephrine, dobutamine, and dopamine) are contraindicated as more forceful contraction may worsen obstruction and, by inducing tachycardia, may reduce diastolic time, hence further limiting filling. For neonates with hypotension and moderate or severe LVOT obstruction, in whom adequate augmentation of LV filling is not possible, a strategy in which the PVR is kept elevated, and the right heart (via right-to-left ductal shunt) is temporarily used to supply systemic circulation may be the only way to accomplish adequate systemic blood flow. In this case prostaglandin E1 (PGE-1) to maintain ductal patency and avoidance of pulmonary vasodilators is warranted. Veno-arterial extracorporeal membrane oxygenation may be an alternative for neonates with refractory shock, though there is limited published evidence. ^, In the short term therapeutic hypothermia, which is associated with reduced HR, may be advantageous for these patients; however, this requires prospective study. The changes in heart rate, upon rewarming, in the setting of hypoxic-ischemic encephalopathy and therapeutic hypothermia, may negatively impact the physiology of these patients.

Chronic therapy for patients with hypertrophic obstructive cardiomyopathy

Long-term management may be required, though hypertrophic cardiomyopathy in infants of diabetic mothers is transient and typically resolves over 3–6 months. Beta-blockers may improve left heart filling based on their ability to reduce heart rate and for their negative inotropic properties. In the acute phase, however, beta-blockers can precipitate symptomatic PH crisis, which may adversely affect LA filling; therefore caution should be exercised. Calcium channel blockers (e.g., verapamil, diltiazem) may also be used to reduce myocardial stiffness. Drugs that reduce systemic afterload (e.g., nitrates, angiotensin-converting enzyme inhibitors, milrinone) should be avoided in this population as they may worsen LVOT obstruction. Diuretics should be used with caution when hypertrophic cardiomyopathy is severe enough to cause pulmonary edema as dehydration may compromise LV filling.

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