Physiology of Blood Pressure in the Neonate
Neonatal Blood Pressure Support and Physiology of Blood Pressure
Caring for a critically ill neonate often requires the provider to consider the physiology, goals, complications, and pharmacologic methods of increasing a newborn patient’s blood pressure. Although various methods and medications are available to increase systemic blood pressure, few human data convincingly support the common practices for blood pressure support in adult intensive care unit, pediatric intensive care unit, or neonatal intensive care unit (NICU).1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11 This chapter describes the physiology of systemic blood pressure in the neonate, defines the pharmacologic target receptors, and presents the medications most commonly used to raise blood pressure.
Cardiac Output, Systemic Vascular Resistance, and Blood Pressure
Systemic blood pressure is determined by the product of cardiac output and systemic vascular resistance (SVR). Cardiac output is determined by the product of heart rate and stroke volume; stroke volume is determined by the preload, afterload, and contractility of the myocardium. Derangements in any of these parameters can produce hypotension in the neonatal patient. It should be noted, however, that simply increasing the blood pressure may not achieve the desired physiologic effect if the goal is to increase organ blood flow and oxygen delivery. Blood pressure and systemic blood flow are poorly correlated in the newborn,12,13 reflecting the importance of SVR in the neonate. Importantly, the neonate has unique physiology that must be understood when considering systemic blood pressure. Because of a relatively noncompliant myocardium, neonates are more dependent on heart rate to generate cardiac output than adults.14, 15, 16, and 17 Also unique to neonates are the transitional circulation immediately following birth, less-functional cerebral autoregulation mechanisms, the potential state of prematurity, and the ongoing maturation of the myocardium and vascular bed.18, 19, and 20
Defining Neonatal Hypotension
The definition of hypotension in the newborn continues to challenge the clinician. “Mean arterial pressure greater than or equal to gestational age” frequently is touted as a guideline for minimum acceptable blood pressure for a neonate, but few data exist to support this practice.21, 22, 23, 24, 25, 26, and 27 Clinicians often use both gestational age and birth weight as guidelines for estimating expected blood pressure in a neonate (Figures 82-1 and 82-2). In principle, the blood pressure must be adequate to deliver oxygen to the tissues and support delivery of nutrients to the organs (most importantly the brain and heart) while removing toxic waste products from cells. The inability to achieve adequate tissue oxygen delivery and waste removal defines neonatal shock. Blood pressure is clearly inadequate if organs are poorly perfused (eg, leading to acute kidney injury or necrotizing enterocolitis [NEC]) or if biochemical markers indicate inadequate perfusion (eg, elevated lactate or base deficit on blood gas analysis).
Linear regression of mean systolic (A) and diastolic (B) blood pressure vs birth weight in 329 newborns admitted to the neonatal intensive care unit on day of life 1. CL; confidence limit. (Reproduced with permission from Zubrow et al.25)
Linear regression of mean systolic (A) and diastolic (B) blood pressure vs gestational age in 329 newborns admitted to the neonatal intensive care unit on day of life 1. (Reproduced with permission from Zubrow et al.25)
The goal of managing neonatal hypotension should be to maximize oxygen delivery and minimize oxygen consumption, thereby providing the optimal oxygen supply/demand ratio. A detailed discussion of oxygen content, delivery, consumption, and extraction ratio is beyond the scope of this chapter.18,28 Although defining hypotension is difficult, data in the premature neonate have correlated hypotension with intraventricular hemorrhage, poor neurodevelopmental outcomes, and death, thus highlighting the importance of adequate tissue perfusion in these patients.1,27,29, 31, 32, 33, and 34 Further study of neonatal blood pressure and cerebral blood flow using superior vena caval flow measurement or near-infrared spectroscopy (NIRS) may help define what an “adequate” blood pressure is for a given newborn.26,35
Differential Diagnosis of Neonatal Hypotension
The differential diagnosis of inadequate tissue perfusion (including “hypotension” and “low-output states”) in the newborn is broad and varies based on the gestational age of the patient. The most common causes of shock and hypotension are hypovolemia (including placental hemorrhage or organ hemorrhage in the perinatal period); infection (sepsis, NEC); extreme prematurity; perinatal asphyxia; severe pulmonary disease (often with pulmonary hypertension); adrenal crisis/insufficiency; large left-to-right shunts (most commonly a large patent ductus arteriosus); and poor cardiac function (because of pump failure, arrhythmias, and obstructive congenital cardiac lesions, among others).6, 7, 8, and 9,11,22
Echocardiography is a noninvasive tool to assess cardiac structure and function in the hypotensive neonate. Cardiac pathology, such as left-sided obstructive lesions, a large patent ductus arteriosus, and poor myocardial contractility, can be delineated by an echocardiogram. These findings may lead the clinician to initiate inotropic agents sooner or modulate blood pressure in other ways when appropriate (eg, initiating prostaglandins in a ductal-dependent lesion such as critical aortic stenosis).
Treatment of hypotension (ie, blood pressure support) necessitates understanding the physiologic abnormality and the primary cause of the patient’s abnormal physiology. Maintaining intravascular volume (with saline or albumin infusions) is supported by physiologic principles, but it has not been shown to improve systemic blood flow compared to pharmacologic support.36,37 However, it is common practice to ensure adequate volume administration before initiating inotropes, and most inotropes and pressors require an adequate preload volume to augment blood pressure effectively. The remainder of this chapter focuses on the principles of pharmacologic management of hypotension.
PHARMACOLOGIC BLOOD PRESSURE SUPPORT
Inotropes and Vasopressors
The mainstays of pharmacologic treatment of neonatal hypotension remain inotropes and vasopressors, with the former defined as agents that increase the force of myocardial contraction and the latter defined as agents that increase blood pressure by constricting the arterial vasculature (ie, increasing SVR).2,3,9,10,38,39 (Vasodilators may also increase systemic blood flow, but they usually do not increase blood pressure and thus are not discussed here.) Inotropes are classified as sympathomimetics (eg, dopamine), phosphodiesterase inhibitors (eg, milrinone), and cardiac glycosides (eg, digoxin); their mechanism of action is to increase intracellular calcium concentration, thus increasing the force of myocardial contraction. Also frequently used are agents that increase heart rate (chronotropes), improve myocardial relaxation (lusitropes; phosphodiesterase inhibitors), and medications that work by other mechanisms to increase blood pressure (steroids, calcium, thyroid hormone). When initiating inotropes or vasopressors, the clinician must consider methods of monitoring intravascular volume status and the effectiveness of pharmacologic therapy. Blood pressure should be measured by an invasive arterial catheter (peripheral or umbilical) when a patient requires multiple interventions for the treatment of hypotension. Similarly, volume status should be measured with central venous access to confirm adequate cardiac preload.
Adrenergic Receptor Subtypes
To understand the actions of these medications, it is critical that the provider recall the receptor subtypes which are activated on the cell membrane. The relevant subtypes are the α1, β1, and β2 adrenergic receptors and the dopamine receptors.9,39, 40, and 41 The α1-adrenergic receptors, when activated in vascular walls, promote vasoconstriction; α1-stimulating medications elevate blood pressure by increasing SVR. The α1 receptor has also been found in the myocardium, and its activation increases cardiac contractility.42 Animal data also suggest that receptors in the right ventricle may differ from those in the left ventricle, thus promoting the specific targeting of right ventricular strain in clinical scenarios such as pulmonary hypertension.43 Activation of β1-adrenergic receptors promotes increased inotropy and chronotropy (without vasoconstriction); β1-stimulating medications increase blood pressure by increasing cardiac output. The β2-adrenergic receptors promote vasodilation in the cardiovascular system and bronchodilation in the lung. Dopamine receptor stimulation promotes dilation of the cardiac, gastrointestinal, and renal vascular beds via dopamine 1 (DA-1) receptors and of the peripheral vascular bed through dopamine 2 (DA-2) receptors. Stimulation of dopamine receptors can also induce norepinephrine release and act as a vasoconstrictor (see the discussion that follows). A summary of pharmacologic receptor subtype activity, mechanism of action, and hemodynamic effects for the most commonly used inotropes and vasopressors is included (Table 82-1).
Table 82-1Inotropes and Vasopressors: Receptors and Hemodynamic Effects ||Download (.pdf) Table 82-1Inotropes and Vasopressors: Receptors and Hemodynamic Effects
| ||Dose (μg/kg/min) ||α1 ||β1 ||β2 ||DA ||HR ||Systolic Function ||Diastolic Function ||Myocardial O2 Demand ||SVR ||PVR |
|Dopamine ||1–5 ||0 ||+ ||0 ||++ ||↑ ||Minimal change ||— ||Minimal change ||–/↑ ||– |
|Dopamine ||6–10 ||+ ||++ ||0 ||++ ||↑ ||↑ ||— ||↑ ||↑ ||–/↑ |
|Dopamine ||11–20 ||++ ||++ ||0 ||++ ||↑ ||↑ ||— ||↑ ||↑↑ ||–/↑ |
|Dobutamine ||1–20 ||0/+ ||+++ ||+ ||0 ||↑ ||↑ ||— ||↑ ||↓ ||–/↓ |
|Epinephrine ||0.01–1 ||++ ||+++ ||++ ||0 ||↑ ||↑↑ ||— ||↑ ||↑ ||–/↑ |
|Norepinephrine ||0.01–1 ||+++ ||++ ||0 ||0 ||↑ ||Some ↑ ||— ||↑ ||↑↑ ||–/↑ |
|Milrinone ||0.1–1 ||None (PDE inhibitor) || ||↑ ||Improved ||Minimal change ||↓ ||↓ |
|Vasopressors || || || || || || || || || || || |
|Phenylephrine ||0.1–2 ||+++ ||0 ||0 ||0 ||— ||— ||— ||— ||↑↑↑ ||— |
|Vasopressinb ||0.0003–0.008 ||+ ||None (stimulates ADH receptor) ||— ||— ||— ||— ||↑↑↑ ||? |
SPECIFIC AGENTS FOR BLOOD PRESSURE SUPPORT IN THE NEONATE
The pharmacologic agents for blood pressure support have been studied in human neonates; however, controversy still exists regarding which inotrope or vasopressor is preferred for a given patient. The following is a description of the primary mechanism of action, indications, side effects, and physiologic properties of the most commonly used blood pressure medications. Not described in this chapter are steroids, which have been studied in neonatal septic shock44, 45, 46, 47, 48, 49, 50, and 51 and are included in the Surviving Sepsis Campaign and guidelines for the management of pediatric and neonatal septic shock.52,53
Dopamine is a drug commonly used in neonates to treat hypotension from a variety of medical or surgical causes (especially postoperative cardiac).10,11,54,55 Dopamine’s effect on blood pressure is mediated via direct stimulation of β1 receptors on the myocardium along with the indirect effect of increasing norepinephrine, which stimulates α1 receptors.56, 57, and 58 In animal studies, neonatal myocardium has been shown to have more dopamine receptor sensitivity compared to adult myocardium.59,60
Frequently discussed is the dose-response curve of dopamine on the cardiovascular system.55,61 At doses of 1–3 μg/kg/min, the effects are primarily vasodilation of the cerebral, coronary, renal, and gastrointestinal vascular beds via stimulation of DA-1 receptors and dilation of peripheral vascular beds via DA-2 receptors. Doses in the range of 5–15 μg/kg/min are often referred to as “inotropic range” dosing because the stroke volume is increased with less effect on heart rate. As dosing increases in this range, there are increasing β1 (elevated heart rate) and α1 (elevated SVR) effects. Above 20 μg/kg/min, dopamine acts mainly on α1 receptors; it increases inotropy but may compromise blood flow by elevating vascular resistance in the kidney, periphery, and gastrointestinal system, among others.54,62, 63, 64, and 65
Dopamine can cause cardiac dysrhythmias (most commonly sinus tachycardia), vasoconstriction, tissue necrosis with extravasation, and immunosuppression with prolonged use. It has been shown to alter the production of prolactin by the hypothalamus.55 In select populations, dopamine has been shown to increase oxygen consumption more than oxygen delivery,66 and it may increase pulmonary artery pressure in premature newborns with a patent ductus arteriosus.67 Studies in premature and term neonates have compared dopamine to volume administration,68 dobutamine,35,65,69, 70, 71, 72, and 73 epinephrine,74,75 phosphodiesterase inhibitors,76,77 and steroids.78 These data suggest that dopamine augments blood pressure and may increase renal and mesenteric blood flow. However, based on current data, it cannot be recommended for use over other agents.
A large adult study recently compared dopamine to norepinephrine for the treatment of shock; although no difference in mortality was detected, dopamine resulted in significantly more side effects, such as cardiac arrhythmias.79 These data suggest that dopamine is effective at increasing blood pressure,11,55,57,62,72,80 but whether it improves mortality, morbidity, or neurodevelopmental outcomes is unclear.11,13,35,37,81
Dobutamine (1–10 μg/kg/min), a synthetic catecholamine, stimulates predominantly β1 receptors with very little α or β2 stimulation.2,3,6,7,10,11 Dobutamine, like dopamine, may exhibit a clinically significant dose-response curve. At doses less than 5 μg/kg/min in children, heart rate does not increase, but cardiac output and blood pressure increase, and left atrial pressure decreases. Heart rate increases at doses greater than 7.5 μg/kg/min.82 Dobutamine increases inotropy and heart rate and decreases SVR, thus increasing cardiac output and organ blood flow. Decreasing SVR may lower blood pressure; for this reason, dobutamine is mainly used for myocardial dysfunction without severe hypotension. Dobutamine also decreases ventricular filling pressure, pulmonary vascular resistance (PVR), and SVR more effectively than dopamine.83 Dobutamine does not stimulate norepinephrine release, which also differentiates it from dopamine.
Intestinal perfusion in preterm neonates increases with dobutamine infusion.62 Data in preterm neonates suggest that dobutamine may be superior to dopamine in increasing systemic blood flow71,72 (Figures 82-3, 82-4), but conflicting data suggest that dopamine increases blood pressure more effectively.13,69, 70, and 71 It remains unclear which inotrope is superior in the premature or term newborn in the NICU,7,13,71, 72, and 73 and neurodevelopmental outcomes appear similar after blood pressure support with both agents.35 Because dobutamine does not stimulate β2 receptors and has less chronotropic effect, indications for use include patients with systolic dysfunction and normal blood pressure and who are at risk for dysrhythmias. A study in children after cardiopulmonary bypass (CPB), however, revealed little reduction in SVR and significant tachycardia.84
Superior vena cava (SVC) flow, a surrogate for oxygen delivery to the brain, as measured in neonates receiving dopamine vs dobutamine (each at lower and higher doses). Only higher-dose dobutamine increased SVC flow. (Reproduced with permission from Osborn et al.72)
Superior vena cava (SVC) flow, a surrogate for oxygen delivery to the brain, as measured in neonates receiving dopamine vs dobutamine, each at high doses (E, F) and then with volume administration (G, H). High-dose dopamine and dobutamine increased SVC flow when administered with volume, illustrating the need for adequate volume resuscitation with inotrope administration. (Reproduced with permission from Osborn et al.72)
Epinephrine is a potent, endogenously produced adrenergic stimulator that strongly activates the β1 receptor and moderately activates the β2 and α1 receptors. Like dopamine, clinicians use the dose-response curve of epinephrine to affect these 3 receptors. At low doses (0.01–0.1 μg/kg/min), epinephrine increases blood pressure and heart rate by β1 stimulation, thus increasing cardiac output. The simultaneous α1 and β2 receptor stimulation results in little change to SVR at this dose. At higher doses (>0.1 μg/kg/min), epinephrine primarily acts as an α1-stimulating agent, increasing blood pressure by elevating SVR and increasing inotropy. In the lung, PVR is elevated, and bronchioles are dilated.
Epinephrine is primarily reserved for neonates with extended exposure to CPB with myocardial dysfunction or for patients with medical disease, such as sepsis, that is refractory to 1 inotrope.2,6,9, 10, and 11,85 It is also included in the algorithms for neonatal and pediatric resuscitations.86,87 Epinephrine has been studied in preterm neonates and is effective at increasing blood pressure, although the literature does not support its specific use compared to other inotropes.3,5,74,75,88
The use of epinephrine may be limited by side effects, which occur more commonly than with dobutamine or dopamine. These include tachycardia, ventricular dysrhythmias (especially in those with ischemia), hyperglycemia, lactic acidosis, increasing base deficit, tissue burns (if extravasated), and vasoconstriction, among others.5,74,88
Norepinephrine (0.01–1 μg/kg/min) is an endogenous catecholamine that stimulates α1 and β1 receptors, but unlike epinephrine, it does not have activity on β2 receptors.56 Therefore, administration of norepinephrine increases blood pressure by increasing SVR and, to a lesser extent, by increasing cardiac output. The unopposed increase in SVR and lack of β2-induced vasodilation make norepinephrine the preferred medication for patients with “warm” (septic) shock.52,53,89 Studies in adults have compared norepinephrine to other inotropes and vasopressors,3,89,90 and data suggest that norepinephrine may support blood pressure with a more favorable side effect profile compared to dopamine.79 Its use is limited in neonates and may be affected by concerns for NEC caused by intestinal vasoconstriction.9
Phenylephrine (0.1–2 μg/kg/min) is a pure α agonist that increases blood pressure by increasing SVR. There is minimal primary effect on inotropy or heart rate; however, vasoconstriction may not necessarily increase systemic blood flow and can result in reflex bradycardia. Phenylephrine has limited use in the NICU population and is reserved for patients in a low-SVR state such as warm septic shock or after anesthetic-induced vasodilation.91 A special indication for phenylephrine is in the setting of acute pulmonary hypertension, for which it can be used as an adjunct medication to increase SVR and right coronary artery perfusion pressure (when using a sedative and muscle relaxant for intubation, for example). Data from adults suggest it can be detrimental in the management of chronic pulmonary hypertension.92 Preferentially increasing SVR compared to PVR with phenylephrine is also useful in neonates with tetralogy of Fallot who experience hypercyanotic episodes (“tet spells”).18
The neonatal myocardium handles calcium differently from the adult because of the immature sarcoplasm reticulum in the neonatal cardiac myocyte.14,93 Neonates depend more on circulating ionized calcium to enter the cardiac myocyte and stimulate actin-myosin cross-bridge formation and contraction.16,19,94 For this reason, calcium chloride infusions (2–20 mg/kg/h) have been used to improve cardiac contractility. Ionized calcium levels are monitored with a goal to maintain levels of 1.1–1.3 mmol/L. Notably, excess calcium influx into the cardiac myocytes has been associated with myocyte necrosis and diastolic dysfunction.95, 96, and 97 In older children and adults, the mature sarcoplasmic reticulum stores calcium more effectively; exogenous administration of calcium chloride stimulates calcium receptors in the vascular endothelium and acts as a vasopressor.94 Therefore, in the adult, calcium administration increases SVR and is a pressor agent; in the neonate, it acts as an inotrope. Calcium administration is included in the guidelines for management of pediatric and neonatal septic shock.52
Vasopressin (0.0003–0.008 U/kg/min) is a nonadrenergic agent that stimulates vasopressin receptors and increases blood pressure by elevating SVR. In the adult and pediatric intensive care units, there may be a benefit when added to other inotropes to treat septic shock, although clinical trials have yielded conflicting results.52,89,90,98,99 Children have decreased arginine vasopressin levels following CPB,100 and vasopressin administration has been beneficial in hypotensive infants after cardiac surgery.101,102 Vasopressin has also been used in premature neonates with hypotension refractory to 1 or more inotropes/pressors.103, 104, 105, and 106 In patients susceptible to arrhythmias, vasopressin offers the advantage of increasing blood pressure with little chronotropic (β1) activity. However, in the failing myocardium, chronic vasopressin administration may increase afterload and lead to worsening cardiac performance.
Milrinone (0.1–1 μg/kg/min) is a synthetic phosphodiesterase inhibitor frequently used in patients with cardiac dysfunction, especially in the postoperative setting. By increasing intracellular cyclic AMP (adenosine monophosphate) levels, milrinone increases contractility, vasodilates the systemic and pulmonary vascular beds, and promotes cardiac diastolic relaxation (lusitropy). Because of its primary effects on contractility (increasing inotropy) and dilation of the vascular bed, milrinone is often referred to as an “inodilator.” Initial studies in adults revealed a reduction in myocardial oxygen consumption with the use of amrinone, a similar phosphodiesterase inhibitor.107
Studies of neonates after cardiac surgery indicated that milrinone attenuated the predictable decrement in cardiac output in the first 24 hours following exposure to CPB108, 109, 110, and 111 (Figure 82-5). Comparison of a phosphodiesterase inhibitor (amrinone) vs dopamine and nipride showed that amrinone provided a superior oxygen delivery/consumption ratio and higher cardiac output in neonates after repair of congenital heart defects.76,77 Neonates with persistent pulmonary hypertension may benefit from milrinone therapy, but there is insufficient evidence to suggest it should be used instead of inhaled nitric oxide.112,113
Systemic and pulmonary arterial (PA) pressures with loading and infusion doses of milrinone. Top: Mean arterial blood pressure decreased after the loading stage but did not decrease further at the infusion stage. Middle: Similar to mean systemic blood pressure, mean PA pressure decreased significantly after the loading dose of milrinone and remained lowered during the infusion stage as well. Bottom: Cardiac index. The baseline cardiac indices increased with the milrinone loading stage and increased slightly more at the infusion stage. The increase in cardiac index and decrease in systemic blood pressure result from a significant decrease in systemic vascular resistance (not shown). (Adapted with permission from Chang et al.108)
The safety and efficacy of milrinone in preterm neonates has not been established,114,115 and careful attention to renal clearance is warranted, as milrinone will accumulate in the setting of renal dysfunction.116 Milrinone has a longer half-life than other inotropes (2–3 hours) and a larger volume of distribution in neonates compared to adults.117,118 Neonatal clearance of the drug is less than 25% of that in children, indicating that neonates may require lower-dose infusions (eg, 0.25 μg/kg/min) for equal inodilator effect.117 Important side effects include thrombocytopenia, ventricular dysrhythmias, and abnormal hepatic enzymes.118
Triiodothrionine (T3) has been studied in specific neonatal populations to improve postoperative cardiac output and blood pressure. Neonates recovering from cardiac surgery were administered T3 and exhibited significantly increased blood pressure (with similar cardiac output) compared to placebo.119 Whether T3 has a role in other models of neonatal shock remains to be determined.
MECHANICAL SUPPORT: EXTRACORPOREAL MEMBRANE OXYGENATION AND VENTRICULAR ASSIST DEVICES
In the setting of continued inadequate oxygen delivery and tissue perfusion despite maximal medical therapy with inotropes or pressors, venoarterial extracorporeal membrane oxygenation (VA ECMO) is a final option to support severe circulatory failure. Ventricular assist devices (VADs) also provide a longer-term option for cardiac support in larger neonates (≥ 3.5 kg) who are candidates for cardiac transplantation. Of the VADs available in 2014 for implantation in pediatric patients, only the Berlin Heart EXCOR® was an appropriate size for neonates. Discussion of these devices is beyond the scope of this chapter, but the clinician should be aware of mechanical support options and contact a referral center with ECMO/VAD capabilities in the setting of persistent shock despite aggressive medical therapy.
Realizing that data regarding outcomes between specific inotropic infusions are limited, the clinician can use the physiologic principles described to support blood pressure with these pharmacologic agents. Further study is needed to understand which inotropes and pressors are most effective at reducing neonatal morbidity and improving outcomes, and continued clinical trials in the neonatal population are essential to an improved understanding of these medications.
et al.. Variations in prevalence of hypotension, hypertension, and vasopressor use in NICUs. J Perinatol
DJ. Use of inotropic and chronotropic agents in neonates. Clin Perinatol
et al.. Vasopressors for hypotensive shock. Cochrane Database Syst Rev. 2011;(5):CD003709.
et al.. Factors associated with treatment for hypotension in extremely low gestational age newborns during the first postnatal week. Pediatrics
M del C, Madero
et al.. Early systemic hypotension and vasopressor support in low birth weight infants: impact on neurodevelopment. Pediatrics
C. Hypotension and shock in the preterm neonate. Adv Neonatal Care
J. Controversies in the diagnosis and management of hypotension in the newborn infant. Curr Opin Pediatr
S. Diagnosis and treatment of neonatal hypotension outside the transitional period. Early Hum Dev
NV. Treatment of hypotension in newborns. Semin Neonatol
B. Use of catecholamines in pediatrics. J. Pediatr
I. Inotrope, lusitrope, and pressor use in neonates. J Perinatol
. 2005;25(Suppl 2):S28–S30.
N. Relationship between blood pressure and cardiac output in preterm infants requiring mechanical ventilation. J. Pediatr
N. The effect of inotropes on morbidity and mortality in preterm infants with low systemic or organ blood flow. Cochrane Database Syst Rev. 2007;(1):CD005090.
J. Maturation of the heart. Clin Perinatol
et al.. Developmental changes in myocardial contractile reserve in the lamb. Pediatr Res
HP. Noninvasive assessment of myocardial contractility, preload, and afterload in healthy newborn infants. Am J Cardiol
PA. Maturation and cardiac contractility. Cardiol Clin
AM. Congenital Diseases of the Heart: Clinical-Physiological Considerations. 3rd ed. New York, NY: Wiley-Blackwell; 2009.
et al.. Force frequency relationship of the human ventricle increases during early postnatal development. Pediatr Res
CP. Hypotensive extremely low birth weight infants have reduced cerebral blood flow. Pediatrics
et al.. Blood pressure ranges in premature infants. I. The first hours of life. J Pediatr
I. Pathophysiology of newborn hypotension outside the transitional period. Early Hum Dev
HS. Blood pressure measurements in the newborn. Clin Perinatol
. 1999;26(4):981–996, x.
DH. Normative arm and calf blood pressure values in the newborn. Pediatrics
B. Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study. Philadelphia Neonatal Blood Pressure Study Group. J Perinatol
M. Low superior vena cava flow and neurodevelopment at 3 years in very preterm infants. J Pediatr
N. Intra-arterial blood pressure reference ranges, death and morbidity in very low birthweight infants during the first seven days of life. Early Hum Dev
PT. The oxygen
delivery/consumption controversy. Approaches to management of the critically ill. Am J Respir Crit Care Med
. 1994;149(2 Pt 1):533–537.
et al.. Blood pressure, anti-hypotensive therapy, and neurodevelopment in extremely preterm infants. J Pediatr
. 2009;154(3):351–357, 357.e1.
JE. Influence of acidosis, hypoxemia, and hypotension on neurodevelopmental outcome in very low birth weight infants. Pediatrics
VM, de Vries
AG. Mean arterial blood pressure and neonatal cerebral lesions. Arch Dis Child
SK. Selective reduction of blood flow to white matter during hypotension in newborn dogs: a possible mechanism of periventricular leukomalacia. Ann Neurol
JP, du Plessis
et al.. Cerebral intravascular oxygenation correlates with mean arterial pressure in critically ill premature infants. Pediatrics
RWI. Blood pressure and cerebral haemorrhage and ischaemia in very low birthweight infants. Early Hum Dev
I. Low superior vena cava flow and effect of inotropes on neurodevelopment to 3 years in preterm infants. Pediatrics
N. Early volume expansion for prevention of morbidity and mortality in very preterm infants. Cochrane Database Syst Rev. 2004;(2):CD002055.
N. Early volume expansion versus inotrope for prevention of morbidity and mortality in very preterm infants. Cochrane Database Syst Rev. 2001;(2):CD002056.
DJ. The use of inotropic and afterload-reducing agents in neonates. Clin Perinatol
KJ. Hypotension and shock in the preterm infant. Semin Fetal Neonatal Med
RP. A study of the adrenotropic receptors. Am J Physiol
RJ. Regulation of adrenergic receptor responsiveness through modulation of receptor gene expression. Annu Rev Physiol
RM. Cardiac alpha 1-adrenergic drive in pathological remodelling. Cardiovasc Res
MA. Distribution of alpha1-adrenergic receptor mRNA species in rat heart. J Cardiovasc Pharmacol
et al.. Hydrocortisone
administration for the treatment of refractory hypotension in critically ill newborns. J Perinatol
et al.. A double-blind, randomized, controlled study of a “stress dose” of hydrocortisone
for rescue treatment of refractory hypotension in preterm infants. Pediatrics
et al.. Hemodynamic changes after low-dosage hydrocortisone
administration in vasopressor-treated preterm and term neonates. Pediatrics
P. Role of corticosteroids in neonatal blood pressure homeostasis. Clin Perinatol
. 1998;25(3):723–740, xi.
et al.. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med
et al.. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med
JS. Regional hemodynamic effects of dopamine
in the sick preterm neonate. J Pediatr
J. Peripheral vascular effects of noradrenaline, isopropylnoradrenaline and dopamine
. Br Med Bull
G. The haemodynamic effects of dopamine
and volume expansion in sick preterm infants. Early Hum Dev
et al.. Dopamine
increases L-type calcium current more in newborn than adult rabbit cardiomyocytes via D1
receptors. Am J Physiol Heart Circ Physiol
et al.. Age-associated reductions in cardiac beta1- and beta2-adrenergic responses without changes in inhibitory G proteins or receptor kinases. J Clin Invest
G. Impact on blood pressure and intestinal perfusion of dobutamine
in hypotensive preterm infants. Biol Neonate
GA. Effect of high-dose dopamine
on urine output in newborn infants. Crit Care Med
therapy promotes cerebral flow-metabolism coupling in preterm infants. Intensive Care Med
M. Left ventricular contractility in extremely premature infants in the first day and response to inotropes. Pediatr Res
et al.. Adverse effects of dopamine
on systemic hemodynamic status and oxygen
transport in neonates after the Norwood procedure. J Am Coll Cardiol
et al.. Dopamine
effects on pulmonary artery pressure in hypotensive preterm infants with patent ductus arteriosus. J Pediatr
AM. Randomised controlled trial of plasma protein fraction versus dopamine
in hypotensive very low birthweight infants. Arch Dis Child
. 1993;69(3 Spec No):284–287.CrossRef
V. Randomized, blind trial of dopamine
for treatment of hypotension in preterm infants with respiratory distress syndrome. J Pediatr
for hypotensive preterm infants. Cochrane Database Syst Rev
A. Assessment of therapy for arterial hypotension in critically ill preterm infants. Am J Perinatol
et al.. Dopamine
for cardiovascular support in low birth weight infants: analysis of systemic effects and neonatal clinical outcomes. Pediatrics
et al.. Cardiovascular support for low birth weight infants and cerebral hemodynamics: a randomized, blinded, clinical trial. Pediatrics
P. Amrinone versus dopamine
in neonates after arterial switch operation for transposition of the great arteries. J Cardiothorac Vasc Anesth
et al.. Amrinone versus dopamine-nitroglycerin after reconstructive surgery for complete atrioventricular septal defect. J Cardiothorac Vasc Anesth
et al.. The cardiovascular effects of dopamine
in the severely asphyxiated neonate. J Pediatr
pharmacokinetics and pharmacodynamics in pediatric intensive care patients. Crit Care Med
RM. Superiority of dobutamine
for augmentation of cardiac output in patients with chronic low output cardiac failure. Circulation
GA. Hemodynamic effects of dobutamine
after cardiopulmonary bypass in children. Crit Care Med
as an inotropic agent in septic shock: a dose-profile analysis. Crit Care Med
et al.. Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation
. 2010;122(16 Suppl 2):S516–S538.CrossRef
ME, de Caen
et al.. Part 10: Pediatric basic and advanced life support. Circulation
. 2010;122(16 Suppl 2):S466–S515.CrossRef
et al.. Experience with phenylephrine
as a component of the pharmacologic support of septic shock. Crit Care Med
AB. Management strategies for patients with pulmonary hypertension in the intensive care unit. Crit Care Med
M. Gene expression of SERCA2a and L- and T-type Ca channels during human heart development. Pediatr Res
DP. Cellular and molecular aspects of myocardial dysfunction. Crit Care Med
. 2001;29(10 Suppl):S214–S219.CrossRef
AM. Potential deleterious effects of inotropic agents in the therapy of chronic heart failure. Circulation
. 1986;73(3 Pt 2):III184–III190.
BH. Regulation of cardiac contraction and relaxation. Circulation
. 2000;102(20 Suppl 4):IV69–IV74.
et al.. Ca2+
- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. J Clin Investig
et al.. Intravenous arginine-vasopressin in children with vasodilatory shock after cardiac surgery. Circulation
. 1999;100(19 Suppl):II182–II186.
et al.. Arginine-vasopressin in neonates with vasodilatory shock after cardiopulmonary bypass. Eur J Pediatr
L. Arginine-vasopressin in catecholamine-refractory septic versus non-septic shock in extremely low birth weight infants with acute renal injury. Crit Care
BA. Effects of amrinone on myocardial energy metabolism and hemodynamics in patients with severe congestive heart failure due to coronary artery disease. Circulation
: systemic and pulmonary hemodynamic effects in neonates after cardiac surgery. Crit Care Med
et al.. Prophylactic intravenous use of milrinone
after cardiac operation in pediatrics (PRIMACORP) study. Prophylactic intravenous use of milrinone
after cardiac operation in pediatrics. Am Heart J
et al.. Efficacy and safety of milrinone
in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation
et al.. Postoperative course and hemodynamic profile after the arterial switch operation in neonates and infants. A comparison of low-flow cardiopulmonary bypass and circulatory arrest. Circulation
for persistent pulmonary hypertension of the newborn. Cochrane Database Syst Rev
improves oxygenation in neonates with severe persistent pulmonary hypertension of the newborn. J Crit Care
AJ. Pilot study of milrinone
for low systemic blood flow in very preterm infants. J Pediatr
D. Randomized trial of milrinone
versus placebo for prevention of low systemic blood flow in very preterm infants. J Pediatr
et al.. Population pharmacokinetics of milrinone
in neonates with hypoplastic left heart syndrome undergoing stage I reconstruction. Anesth Analg
et al.. A population pharmacokinetic analysis of milrinone
in pediatric patients after cardiac surgery. J Pharmacokinet Pharmacodyn
AM. Pharmacokinetics and side effects of milrinone
in infants and children after open heart surgery. Anesth Analg
et al.. A randomized, double-blind, placebo-controlled pilot trial of triiodothyronine in neonatal heart surgery. J Thorac Cardiovasc Surg