Neonatal cardiovascular drugs



Chapter 5: Neonatal cardiovascular drugs


Danielle R. Rios, Angelica Vasquez, Christopher McPherson




Introduction


There are a number of cardiovascular medications that are used in neonatology on a regular basis. An understanding of physiology can guide the clinician toward the selection of a specific medication based on mechanism of action that is necessary to manage the patient-specific disease state. Each medication will have a range of side effects that should be considered when choosing a medication therapy regimen, and even more so when utilizing this class of medications in critically ill neonates. Extrapolating data from older pediatric or adult patients must be done with caution considering the unique physiology of critically ill neonates. For example, the premature neonatal heart contains only 30% contractile tissue, in contrast to 60% in the adult heart.1 Additionally, expression of sarcoplasmic reticulum and t-tubules is low, while mitochondria are abundant, resulting in disorganized myocyte activity. These maturational differences are tolerated in the intrauterine environment dominated by low placental resistance. However, with exposure to ex utero systemic vascular resistance, the stress of illness, and inotropes or vasopressors, cardiovascular function may be impaired.


The adrenergic system and myocardial innervation both mature throughout gestation.2 This maturation is driven to some extent by stimulation, and fetal adrenoreceptors have a low threshold for provocation. In preterm neonates this manifests as “denervation hypersensitivity,” in which myocardial adrenoreceptors demonstrate maximal response to even small concentrations of catecholamine.3 Importantly, maturation is not uniform, as active alpha-1-receptors outnumber beta-1-receptors in early gestation.4 Consequently, agents with non-specific activity like dopamine have a different dose-response profile in premature neonates, term neonates, and older patients. Critical illness further complicates dose-response. Renal maldevelopment or maladaptation has implications on drug elimination with lower albumin binding leading to increased drug available for metabolism in the setting of less efficient renal clearance of active drug and metabolites. Hypoxic-ischemic encephalopathy complicates the consequences of bradycardia (induced by therapeutic hypothermia or medications like dexmedetomidine in the setting of existing cardiac dysfunction induced by hypoxia-ischemia) and tachycardia (induced by exogenous catecholamines in the setting of metabolic insufficiency and/or hypocalcemia compromising right ventricular performance).5 Additionally, decreased renal clearance in this population may exacerbate the therapeutic or adverse effects of pharmacologic interventions.6 In confluence, this complex milieu highlights the vital nature of optimizing diagnostic techniques and understanding the specific impacts of available pharmacotherapies.


This chapter will discuss the mechanism of action and therapeutic effects of cardiovascular medications used most commonly in critically ill neonates and infants based on predominant pathology grouping (Tables 5.1 and 5.2). We will not be discussing medication regimens for treatment of a hemodynamically significant patent ductus arteriosus (PDA), as these are discussed in detail in Chapter 17. Critical evaluation of available pharmacologic studies and randomized controlled trials was vital to generation of the content of this chapter. However, this evaluation highlighted the profound limitations of the available data. Therefore the information in this chapter should be interpreted in the context of emerging evidence.



TABLE 5.1




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CARDIOVASCULAR SUPPORT OF HEART FUNCTION

Receptors/Action Predominant Effects Dosing Range Common Clinical Use Comments
Predominant Inotropes
1. Dobutamine

Alpha-1-agonist


Alpha-1-antagonist


Beta-1, beta-2-agonist

↑ HR, inotropy


↓ /↔ SVR

2–20 mcg/kg/min

 RV dysfunction in PH or HIE, cardiac dysfunction in premature infants Improvement seen in premature infants at doses limited to 5–10 mcg/kg/min
2. Epinephrine

Alpha-1-agonist


Alpha-2 effects less prominent


beta-1, beta-2-agonist

↑ HR, inotropy


Vasodilation (muscle)


Vasoconstriction


↑ PVR = SVR

0.01–0.5 mcg/kg/min

 Septic shock with cardiac dysfunction, severe cardiac dysfunction Avoid in patients with hypertrophic cardiomyopathy
Inotropes With Vasodilator Effects
1. Milrinone

PDE-3 inhibitor

↓ SVR, PVR, inotropy, and lusitropy

0.25–1 mcg/kg/min

 Low cardiac output syndrome after cardiac surgery, PLCS, PH, CDH Caution in poor renal function or decreased renal clearance
2. Levosimendan

PDE-3 inhibitor

↓ SVR, PVR, inotropy

0.05–0.2 mcg/kg/min

 Patients requiring afterload reduction and inotropy Not available in United States or Canada
Primary Vasodilator
1. Sodium nitroprusside

Arterial and venous vasodilator

Vasodilation


↓ SVR

0.5–2 mcg/kg/min

 Hypertensive crisis Close monitoring needed to avoid severe hypotension and hypoperfusion
CARDIOVASCULAR SUPPORT FOR ACUTE AND/OR CHRONIC PULMONARY HYPERTENSION
Pulmonary Vasodilator
1. Inhaled nitric oxide

Selective pulmonary vasodilator

↓ PVR

1–20 ppm

 Acute and chronic PH Should be avoided in left-sided outflow tract obstruction and increased PCWP
Phosphodiesterase Inhibitor
1. Sildenafil

PDE-5 inhibitor

↓ PVR


↓/↔ SVR

Continuous IV: 0.4 mg/kg over 3 hours, then 1.6 mg/kg/day


IV: 0.4 mg/kg q6


PO: 0.5–3 mg/kg q6–8

 Chronic and occasionally acute PH Could contribute to worsened V:Q mismatch
Endothelin Receptor Antagonist
1. Bosentan

ETA and ETB blocker

↓ PVR

1–2 mg/kg BID

 Chronic PH Liver enzymes need to be followed closely
Prostacyclin Analogues
1. Epoprostenol

Pulmonary and systemic vasodilator

↓ PVR, SVR

Continuous IV: 50–80 ng/kg/min


Inhalation: 20–50 ng/kg/min

 Chronic PH and elevated PVR Abrupt discontinuation results in rebound PH
2. Treprostinil

Analogue of epoprostenol

↓ PVR, SVR

IV or subcutaneous infusion 2–20 ng/kg/min

 Chronic PH Optimal for prolonged subcutaneous infusion due to stability in solution and relatively long half-life
3. Iloprost

Analogue of epoprostenol

↓ PVR, SVR

Inhalation: 0.25–2.5 mcg/kg q2–6


Nebulization: 0.8 mcg/kg/h

 Chronic and occasionally acute PH Less basic pH compared to epoprostenol facilitates nebulized delivery; however, data limited in neonates
Prostaglandin E1
1. Alprostadil

Vasodilation of vascular and PDA smooth muscle

↓ PVR


↓/↔ SVR

0.01–0.1 mcg/kg/min

 CHD, PH with failing RV, acute PH Apnea seen more often in <2 kg BW, higher starting doses, and during the first hour of infusion
Soluble Guanylate Cyclase Stimulators
1. Riociguat

sGC stimulation

↓ PVR

0.5–2 mg up to TID

 Chronic PH Should not be used within 24 hours of sildenafil

BID, twice daily; CDH, congenital diaphragmatic hernia; ET, endothelin; HIE, hypoxic-ischemic encephalopathy; HR, heart rate; IV, intravenous; PCWP, pulmonary capillary wedge pressure; PDA, patent ductus arteriosus; PDE, phosphodiesterase; PH, pulmonary hypertension; PLCS, post-ligation cardiac syndrome; PO, per oral route; PVR, pulmonary vascular resistance; RV, right ventricle; sGC, soluble guanylate cyclase; SVR, systemic vascular resistance; TID, three times daily.



TABLE 5.2




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SUPPORT FOR SYSTEMIC HYPOTENSION

Receptors/Action Predominant Effects Dosing Range Common Clinical Use Comments
Predominant Vasoconstrictors
1. Vasopressin Arginine vasopressin, oxytocin, and purinergic receptors

↑ SVR


↓/↔ PVR


↓/↔ HR

0.1–1.2 mU/kg/min (0.006–0.072 U/kg/h)

 Vasodilatory shock, PH with preserved LV function, hypotension, hypertrophic cardiomyopathy Sodium levels must be monitored during use, prolonged therapy may result in polyuria and fluid imbalance upon discontinuation
2. Norepinephrine Alpha-1, alpha-2, beta-1> beta-2

↑ SVR


Minor inotropy, chronotropy

0.02–1 mcg/kg/min

 Sepsis and shock In presence of high oxygen concentrations, can induce pulmonary vasoconstriction
3. Dopamine CNS and peripheral dopaminergic, adrenergic (alpha-1, beta-1, beta-2), and serotonergic receptors

↑ HR


↑ PVR > SVR

2–20 mcg/kg/min

 Sepsis in setting of no PH Should be used with caution in premature infants due to the unpredictable nature of its effects
4. Phenylephrine Alpha-agonist

↑ SVR

0.1–0.5 mcg/kg/min

 “Tet spells” May cause severe bradycardia
Glucocorticoids
1. Hydrocortisone Genomic and non-genomic effects

Variable

LD: 1–2 mg/kg


0.5–1 mg/kg q6–12

 Adjunctive therapy for relative or absolute adrenal insufficiency and pressor-resistant hypotension when increased cell surface receptors required (e.g., adrenergic receptors) Concurrent use with indomethacin should be avoided
SUPPORT FOR SYSTEMIC HYPERTENSION
Dihydropyridine
1. Isradipine CCB

↓ SVR

0.05–0.15 mg/kg QID

 Acute hypertension Rapid onset of action
2. Amlodipine CCB

↓ SVR

0.05–0.3 mg/kg 1–2 times daily

 Chronic hypertension Slower onset of action and longer duration of effect
Angiotensin-Converting Enzyme (ACE) Inhibitors
1. Enalapril(at) Competitive inhibitor of ACE

↓ SVR

PO: 0.04–0.3 mg/kg/day div 1–2 times daily


IV: 5–10 mcg/kg q8–24

 Hypertension, LV diastolic dysfunction, congestive heart failure Use with caution in patients with impaired renal function or hypovolemia

ACE, angiotensin-converting enzyme; CCB, calcium channel blocker; HR, heart rate; IV, intravenous; LD, loading dose; PH, pulmonary hypertension; PO, per oral route; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance.


Cardiovascular support of heart function


When attempting to support heart function, a combination of inotropes and vasodilators may be utilized. Inotropes are medications that act primarily on the cardiac myocyte (Figure 5.1) to increase contractility, whereas vasodilators decrease wall tension leading to an improvement in stroke volume and cardiac output. In this section we will discuss two predominant inotropes, dobutamine and epinephrine; two inotropes with vasodilator effects, milrinone and levosimendan; and sodium nitroprusside, a primary vasodilator.


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Fig. 5.1Effects of medications on adrenergic receptors in the heart and peripheral vasculature. Source: (Adapted from Giesinger RE, McNamara PJ. Hemodynamic instability in the critically ill neonate: an approach to cardiovascular support based on disease pathophysiology. Semin Perinatol. 2016;40(3):174-188.)

Predominant inotrope


Dobutamine





  1. 1. Mechanism of action: Dobutamine is a synthetic catecholamine that is a racemic mixture of two parts (negative and positive isomers) and promotes direct stimulation of adrenergic receptors in the myocardium.7 The negative isomer is an alpha-1-receptor agonist and increases systemic vascular resistance (SVR) and myocardial contractility. The positive isomer is a beta-1- and beta-2-receptor agonist, which increases myocardial contractility and heart rate while decreasing SVR. It is also a potent alpha-1-receptor antagonist that blocks the effects of the negative isomer. The resulting effects of dobutamine are increased inotropy and chronotropy, with no effect on, or a decrease in, SVR.8,9
  2. 2. Dosing is via continuous infusion; the usual dosing range is 2–20 mcg/kg/min. Improved left ventricular (LV) performance in preterm infants is achieved at doses of 5–10 mcg/kg/min10–12 with changes in cardiac output within 20 minutes and improvement in systemic markers after 8–10 hours.13
  3. 3. Pharmacokinetics: Dobutamine is metabolized by the liver and excreted in the urine. The half-life is 3–36 minutes in preterm neonates.14
  4. 4. Examples of clinical use: Right ventricular (RV) dysfunction in the setting of pulmonary hypertension (PH) or hypoxic-ischemic encephalopathy, LV dysfunction following interventional closure of PDA, myocarditis, or asphyxia.
  5. 5. Adverse effects include tachycardia, arrhythmias, hypertension, and hypotension.12,15
  6. 6. Special considerations: Expression of α-adrenergic receptors is upregulated in preterm infants as compared to β-adrenergic expression, which may result in attenuated decreases in SVR when compared to term infants.8 Dobutamine has been shown to improve superior vena cava flow in preterm neonates when compared to dopamine.16

Epinephrine





  1. 1. Mechanism of action: Epinephrine is an endogenous hormone secreted by the adrenal medulla. It is a potent stimulator of both α- and β-adrenergic receptors and its effects on body organ systems are expressed in a dose-dependent manner. The cardiac and vascular beta-1- and beta-2-adrenoreceptors are primarily stimulated at low doses (0.01–0.1 mcg/kg/min), which leads to increased inotropy, chronotropy, and conduction velocity and peripheral vasodilation (primarily in the muscles).8 Doses >0.1 mcg/kg/min stimulate vascular and cardiac alpha-1-receptors leading to vasoconstriction and increased inotropy, while the alpha-2-receptor effects are less prominent.8 Epinephrine has been shown to increase coronary artery blood flow,17,18 cerebral perfusion,19 and SVR and pulmonary vascular resistance (PVR) in a 1:1 ratio20 or less21 with some dose-dependent variability. However, it has also been shown in high doses to irreversibly disrupt the myocardial sarcolemma and swell the mitochondria with calcium deposition in a neonatal animal model.22
  2. 2. Dosing is via continuous infusion with a usual dosing range of 0.01–0.5 mcg/kg/min.19,23
  3. 3. Pharmacokinetics: Epinephrine is metabolized in the liver and excreted in the urine as inactivated compound. Data characterizing the pharmacokinetics of epinephrine in neonates are limited; the half-life in adults is less than 5 minutes.
  4. 4. Examples of clinical use: Septic shock with cardiac dysfunction and diseases associated with severe cardiac dysfunction.
  5. 5. Adverse effects include tachycardia, lactic acidosis independent of improvement in hemodynamic status, and hyperglycemia requiring insulin seen in premature infants.19,23
  6. 6. Special considerations: In patients with acute PH caution is advised due to the potential increase in PVR and pulmonary artery pressure seen in animal studies.20 Epinephrine, as is true with all drugs with β-adrenergic activity and chronotropic effects, should be avoided in patients with hypertrophic cardiomyopathy.

Inotropes with vasodilator effects


Milrinone





  1. 1. Mechanism of action: Milrinone is a selective phosphodiesterase-3 (PDE-3) inhibitor that inhibits the degradation of cyclic adenosine monophosphate (cAMP).8 The increased concentration of cAMP leads to the multiple cardiovascular effects of milrinone, including vasodilation in the systemic and pulmonary vascular beds, inotropy through activation of contractile proteins, and a lusitropic effect by prolonging the relaxation period of the cardiac cycle.8
  2. 2. Dosing is via continuous infusion, with the usual dosing range being 0.25–1 mcg/kg/min. Loading doses ranging from 25 to 75 mcg/kg have been described in the literature24–26 but have been associated with hypotension, with some recommending avoidance.27 A normal saline bolus of 10–15 mL/kg administered during the first hour of infusion may assist in the prevention of low diastolic blood pressure (BP) due to vasodilation.28
  3. 3. Pharmacokinetics: Most of the circulating milrinone is not metabolized and is excreted unchanged in the urine. The mean half-life is approximately 4 hours in term neonates and 10 hours in preterm neonates.26,29
  4. 4. Examples of clinical use: Milrinone has been shown to improve hemodynamics in low cardiac output syndrome after cardiac surgery,30 post-ligation cardiac syndrome,28 PH,27,31 and congenital diaphragmatic hernia.32
  5. 5. Adverse effects include hypotension and arrhythmias; less commonly seen are thrombocytopenia, hypokalemia, and other laboratory value changes.24
  6. 6. Special considerations: Caution is advised in therapeutic situations associated with poor renal function or decreased renal clearance of medications. Patients with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia have been shown to exhibit profound hypotension with milrinone administration,6 likely due to vasodilation after accumulation from poor excretion. Clearance will vary based on gestational and chronological age.26,29 Additionally, it has been postulated in an animal model that PDE-4 is the predominant enzyme in fetal life leading to a potential delay in the inotropic effect for the first several days.33,34

Levosimendan





  1. 1. Mechanism of action: While levosimendan has not been approved for use in the United States or Canada, it is used in over 60 countries, including many in the European Union and Latin America. It enhances myocardial contractility by binding to troponin C, a cytosolic calcium-dependent interaction, thereby also improving LV diastolic function without promoting arrhythmogenesis or altering myocardial oxygen demand.8,35 Levosimendan also inhibits cardiac PDE-3 at higher doses8,35 and promotes vasodilation by activation of adenosine triphosphate (ATP)–sensitive potassium channels.8,35 Affected vasculatures include coronary, pulmonary, renal, splanchnic, cerebral, and systemic arteries as well as saphenous, portal, and systemic veins.35
  2. 2. Dosing: More studies are required to establish a safe dosing range in neonates and premature infants. Reported dosing range for continuous infusion is 0.05–0.2 mcg/kg/min with variable use of loading doses.
  3. 3. Pharmacokinetics: The metabolism of levosimendan results in active metabolites that are likely responsible for prolonged hemodynamic effects after discontinuation of continuous infusion.35 These metabolites are excreted in the feces and urine. Pharmacokinetic data on its use in neonates are not available; in adults the half-life of the parent drug is approximately 1 hour, while the active metabolite has a prolonged elimination half-life of 70–80 hours.
  4. 4. Examples of clinical use: Since the hemodynamic profile is similar to milrinone, levosimendan may be beneficial in patients requiring afterload reduction and inotropy (e.g., post-ligation cardiac syndrome).
  5. 5. Adverse effects include, as with any medications that cause vasodilation, hypotension. Further studies in neonates and infants are needed to delineate other potential adverse effects.
  6. 6. Special considerations: More data on its use in neonates and infants are required to evaluate potential effects and associations with clinical procedures (e.g., therapeutic hypothermia) and diagnoses (e.g., renal failure).

Primary vasodilator


Sodium nitroprusside





  1. 1. Mechanism of action: Sodium nitroprusside is a non-specific vasodilator (arterial and venous) with no direct effect on myocardial contractility or heart rate.36 It functions as a prodrug, reacting with sulfhydryl groups on erythrocytes, albumin, and other proteins to release nitric oxide (NO), which activates guanylate cyclase stimulating production of cyclic guanosine monophosphate (cGMP).36 Its main hemodynamic effect is reducing SVR, resulting in decreased afterload. The vasodilator properties lead to decreased ventricular filling pressures, reduced wall stress, and lower myocardial oxygen demand. Together, these result in increased cardiac output and systemic tissue oxygenation as long as coronary perfusion pressure is adequate.36
  2. 2. Dosing is via continuous infusion, with a usual dosing range of 0.5–2 mcg/kg/min, though maximum dosing as high as 10 mcg/kg/min has been reported for control of hypertensive emergencies.37 Doses higher than 1.8 mcg/kg/min and/or prolonged therapy have been associated with elevated cyanide levels.36,38
  3. 3. Pharmacokinetics: Sodium nitroprusside combines with hemoglobin, forming cyanide and cyanmethemoglobin. This process is rapid, with a half-life of approximately 2 minutes. Cyanide is then converted to thiocyanate in the liver and kidney, a process with limited capacity which can be overwhelmed in high doses, resulting in toxicity. Sodium nitroprusside is excreted in the urine as thiocyanate. The half-life of thiocyanate is approximately 3 days in adults with normal renal function.
  4. 4. Examples of clinical use: Hypertensive crisis (e.g., paradoxical hypertension following correction of coarctation of the aorta).39
  5. 5. Adverse effects include cyanide toxicity (especially in those who have hypoalbuminemia and hepatic impairment and those undergoing cardiopulmonary bypass or therapeutic hypothermia),40 hypotension, increased intracranial pressure,41 and methemoglobinemia.
  6. 6. Special considerations: Upon initiation of sodium nitroprusside, it is important to maintain close monitoring to avoid life-threatening hypotension and hypoperfusion, especially in populations at increased risk, such as premature infants.

Cardiovascular support for acute and/or chronic pulmonary hypertension (Figure 5.2)


The major goal of medication therapy in PH in the acute setting is to improve pulmonary blood flow, and, more often than not, fast-acting medications are utilized first-line (e.g., pulmonary vasodilator). In addition, there are likely to be secondary beneficial effects to RV function and cardiac output. In the chronic setting, while fast-acting agents may be utilized initially, more often than not, chronic medication therapy is required to affect pulmonary pressures. In both cases, evaluation, and support, when decreased, of both RV and LV heart function is still required.


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Fig. 5.2Pathways for medication effect and therapeutic benefit in acute and chronic pulmonary hypertension.

Pulmonary vasodilator


Inhaled nitric oxide





  1. 1. Mechanism of action: Inhaled nitric oxide (iNO) acts as a selective pulmonary vasodilator that relaxes vascular smooth muscle by binding to the heme moiety of guanylate cyclase, which leads to its activation and increased levels of cGMP.42 It improves oxygenation via reduction of PVR, improved ventilation/perfusion matching, and decreased right to left extrapulmonary shunting.43 These actions together improve pulmonary blood flow, which leads to improved pulmonary venous return and LV output.
  2. 2. Dosing is via inhalation, with a usual dosing range of 1–20 ppm, with starting doses ranging from 5 to 20 ppm. Doses >20 ppm are not recommended due to increased risk of methemoglobinemia and pulmonary injury from elevated nitrogen dioxide.43
  3. 3. Pharmacokinetics: iNO combines with oxyhemoglobin to produce methemoglobin and nitrate.42 The half-life of NO is 2–6 seconds in neonates.44 Nitrate is excreted in the urine.
  4. 4. Examples of clinical use: Acute or chronic PH.
  5. 5. Adverse effects include methemoglobinemia, which should be measured within 4–8 hours of initiation and periodically throughout administration, inflammation and lung tissue injury caused by nitrogen dioxide, and possible decreased platelet aggregation without increased bleeding time.42 In the presence of high concentrations of oxygen, it is possible that iNO may react with reactive oxygen species to form reactive nitrogen species (e.g., peroxynitrite) that can lead to cytotoxicity.42 Use in patients with LV systolic or diastolic dysfunction may increase pulmonary capillary pressure resulting in pulmonary edema. iNO should be avoided in patients with left-sided outflow tract obstruction (e.g., hypoplastic left heart syndrome) or those with excessive pulmonary blood flow (e.g., anomalous pulmonary venous return or vein stenosis, PDA).43
  6. 6. Special considerations: Echocardiography, prior to iNO use, should be considered to confirm features of PH (especially in premature infants),45 to determine RV and LV function, and to establish normal cardiac anatomy.43 Abrupt discontinuation of iNO may lead to worsening of oxygenation and/or rebound pulmonary hypertension; weaning is recommended.43,44

Phosphodiesterase inhibitors


Sildenafil





  1. 1. Mechanism of action: Sildenafil is a selective PDE-5 inhibitor in the smooth muscle of the pulmonary vasculature, which promotes increased cGMP and pulmonary vasculature relaxation.46 While sildenafil is more selective for the pulmonary vasculature, both pulmonary and systemic vasodilation may occur.
  2. 2. Dosing may be via intravenous (IV less commonly) or oral route. Recommended dosing for continuous infusion is 0.4 mg/kg load over 3 hours followed by 1.6 mg/kg/day.47,48 IV intermittent dosing is 0.4 mg/kg given over 1–3 hours every 6 hours.49 Oral dosing in neonatal case series of acute PH ranges from 0.5 to 3 mg/kg/dose q 6–8 hours.47,50,51 Chronic oral therapy is typically limited to a maximum dose of 2 mg/kg/dose, or 10 mg, orally every 8 hours.52
  3. 3. Pharmacokinetics: Sildenafil is metabolized in the liver by CYP3A4 (major) and CYP2C9 (minor) forming a major metabolite (desmethylsildenafil), which retains 50% of the activity of sildenafil. Elimination increases with increasing postmenstrual age (half-life of the parent compound ∼56 hours in term newborns with maturation to ∼48 hours by week 1 of age).53 Excretion is mainly as metabolites via feces and some urine. Clearance may be decreased in patients with hepatic or renal impairment.50
  4. 4. Examples of clinical use: Chronic and, less frequently, acute PH.
  5. 5. Adverse effects include hypotension and flushing. Due to risk of severe hypotension, concurrent use of riociguat (a soluble guanylate cyclase stimulator) is contraindicated and should not be given less than 24 hours apart. Caution is required with other vasodilators.
  6. 6. Special considerations: Pulmonary vasodilatory effects are not confined to well-ventilated portions of the lung, as is the case with iNO, which could contribute to worsened V:Q (ventilation:perfusion) mismatch.

Endothelin receptor antagonists


Bosentan





  1. 1. Mechanism of action: Bosentan blocks endothelin (ET) receptors, which induce vasoconstriction, on the endothelium and in vascular smooth muscle. While it blocks both ETA and ETB receptors, it has a slightly higher affinity for the A subtype receptor.54
  2. 2. Dosing is via the oral route with an initial dose of 1 mg/kg/dose twice daily, which may be increased to 2 mg/kg/dose twice daily if necessary.55,56
  3. 3. Pharmacokinetics: Bosentan is metabolized in the liver via CYP2C9 and CYP3A4 to one active and two inactive metabolites.54 Bosentan also induces both enzymes. The maximum concentration occurs at a median of 12 hours after administration of initial doses but this time decreases to a median of 7.5 hours by day 5 of therapy.55 It is mostly excreted in the feces as metabolites, with a small amount excreted in the urine as unchanged drug.54
  4. 4. Examples of clinical use: Chronic PH.
  5. 5. Adverse effects include hepatotoxicity and anemia requiring close monitoring of liver enzymes (baseline, then monthly) and hemoglobin (baseline, 1 and 3 months, then every 3 months).54
  6. 6. Special considerations: Bosentan is only available in the United States through a Risk Evaluation and Mitigation Strategy (REMS) program. It has been classified as a hazardous substance due to its associated risk of birth defects.54 Single gloving is recommended for administration of intact tablets or capsules. Double gloving, a protective gown, and eye/face protection are recommended for manipulating tablets and administration of oral suspension to neonates and infants. A suspension recipe has been shown to be stable for up to 1 month.57 Bosentan was shown to rapidly improve oxygenation index in the absence of iNO56 but was shown to have limited acute efficacy as an adjunct to iNO.55

Prostacyclin (analogues)


Epoprostenol




Treprostinil




Iloprost




Prostaglandin E1


Alprostadil





  1. 1. Mechanism of action: Alprostadil causes vasodilation by direct effect on vascular and ductus arteriosus smooth muscle.76
  2. 2. Dosing is via continuous infusion, with a usual dosing range of 0.01–0.1 mcg/kg/min.76 Higher initial doses (0.05–0.1 mcg/kg/min) may be required for patients with restrictive ductal flow, and once response is seen, the dose should be reduced to lowest effective dose (may be as low as 0.01 mcg/kg/min).
  3. 3. Pharmacokinetics: Alprostadil is mostly oxidized during a single pass through the lungs into an active metabolite, resulting in a half-life of less than 1 minute in neonates. Elimination occurs predominately as metabolites in the urine, with a small amount in feces.76
  4. 4. Examples of clinical use: Ductal-dependent congenital heart defects and acute PH in the setting of RV failure to offload the right heart.
  5. 5. Adverse effects include apnea, fever, flushing, and, less commonly, hypotension.76 Reversible cortical proliferation of the long bones is seen with prolonged treatment courses.77 Apnea is seen more often in neonates <2 kg at birth, with higher starting doses, and usually within the first hour of infusion.
  6. 6. Special considerations: Though alprostadil is most commonly used for maintenance of ductal patency in cases of congenital heart disease, it may play a role in disease states where a restrictive or closed ductus arteriosus is detrimental (e.g., acute PH with failing RV).78 Its pulmonary vasodilator effects may also be beneficial in acute PH and other disease states.79

Soluble guanylate cyclase stimulators


Riociguat





  1. 1. Mechanism of action: Riociguat sensitizes soluble guanylate cyclase (sGC) to endogenous NO and directly stimulates sGC independent of NO. This leads to increased cGMP levels and subsequently vasodilation.80
  2. 2. Dosing is via the oral route; pharmacological dose range studies in the neonatal and infant populations are not available; however, preliminary data is emerging.81 Suggested dosing range in adults is 0.5–2 mg/dose three times daily. Dosing should be titrated gradually to monitor for adverse effects; for instance, starting at 0.5 mg daily for 48 hours, then to twice daily for 48 hours. If tolerated, it can be increased to 0.5 mg three times daily, then to 1 mg three times daily, if necessary.
  3. 3. Pharmacokinetics: Riociguat is metabolized in the liver by CYP1A1, CYP3A, CYP2C8, and CYP2J2 into one active and other inactive metabolites. It is excreted in both urine and feces.80 The half-life in adults with PH is ∼12 hours.
  4. 4. Examples of clinical use: Chronic PH refractory to sildenafil.
  5. 5. Adverse effects include hypotension and bleeding.82 Use is contraindicated with specific PDE-5 inhibitors (e.g., sildenafil) and caution advised with non-specific PDE inhibitors (e.g., caffeine, theophylline). Riociguat should not be administered within 24 hours of a dose of sildenafil.
  6. 6. Special considerations: Riociguat is only available in the United States for neonates and infants through a REMS program. There is a paucity of data on its use in neonates and infants. Caution is advised in transitioning from sildenafil to riociguat, as clinical deterioration may be seen upon discontinuation of sildenafil even in non-responders. Up-titration of iNO or use of other pulmonary vasodilators (e.g., milrinone) may be of benefit during the wash-out period.

Support for systemic hypotension


Systemic hypotension is a common diagnosis in the neonatal intensive care unit (NICU), though its frequency varies considerably between institutions. The choice of medication will vary based on the presence or absence and degree of systemic perfusion, cerebral blood flow, heart function, pulmonary or systemic vascular resistance, and intra- or extra-cardiac shunt flow and direction. Commonly used medications in this setting include predominant systemic vasoconstrictors (i.e., dopamine, norepinephrine, vasopressin, and phenylephrine) and glucocorticoids.


Predominant vasoconstrictors


Dopamine





  1. 1. Mechanism of action: Dopamine is an endogenous catecholamine and a precursor of norepinephrine and epinephrine. It stimulates both central and peripheral nervous system dopaminergic and adrenergic (both alpha-1 and beta) receptors (Figure 5.1) while also having serotonergic effects.83 Approximately half of the cardiovascular effects are thought to be due to released norepinephrine, but low stores can lead to tachyphylaxis.83
  2. 2. Dosing is via continuous infusion into a large vein, reported dosing range of 2–20 mcg/kg/min, though in critically ill infants, receptor saturation is often seen by 8 mcg/kg/min.84,85 Low doses stimulate predominantly dopaminergic receptors (0.5–4 mcg/kg/min), medium doses additionally stimulate beta-receptors (beta-1 > beta-2; 2–10 mcg/min), and high doses additionally stimulate alpha-1-receptors (5–20 mcg/kg/min). Preterm neonates typically experience receptor effects at lower doses than term neonates, although high interpatient variability exists in the dose-response relationship regardless of gestational age; therefore, due to the unpredictable nature of its effects, dopamine should be used with caution in preterm infants.
  3. 3. Pharmacokinetics: Dopamine is irreversibly metabolized in the liver, kidney, and pulmonary endothelium and reversibly metabolized in the plasma. It is excreted in the urine as metabolites or unchanged drug.83 The mean half-life in critically ill newborns is 7 minutes.86
  4. 4. Examples of clinical use: Disease states with low SVR (e.g., septic shock) and no evidence of PH given potential risk of increased PVR.
  5. 5. Adverse effects include tachycardia, tachyarrhythmias, natriuresis, which may result in hyponatremia,85 increased oxygen consumption,87 increased pulmonary artery pressure and PVR,20 neutrophil apoptosis,88 and inhibition of thyrotropin.83 Dopamine is also associated with severe vasoconstriction after extravasation.83
  6. 6. Special considerations: Dopamine, as is true with all drugs with marked chronotropic effects due to β-adrenergic activity, should be avoided in patients with hypertrophic cardiomyopathy. Dopamine may be preferred over epinephrine, as a predominant vasoconstrictor in neonates, due to a lower incidence of transient tachycardia, lactic acidosis, and hyperglycemia.23

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Mar 3, 2024 | Posted by in Uncategorized | Comments Off on Neonatal cardiovascular drugs

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