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Inotropic and Vasoactive Drugs in Pediatric ICU

Marco Piastra1,*, Ersilia Luca1, Sonia Mensi1,2, Federico Visconti1,2, Daniele De Luca1, Francesca Vitale1 and Domenico Pietrini1,2
1

Pediatric ICU and 2Institute of Anesthesia, Catholic University Medical School, Rome, Italy
Abstract: Circulatory failure recognition and treatment represents an important issue in critically ill infants and children. Early diagnosis and prompt institution of adequate treatment may be life-saving for pediatric patients with cardiocirculatory instability in the setting of intensive care. However, the hemodynamic status of the critically ill child is poorly reflected by baseline vital parameters or laboratory blood tests. A reliable tool for diagnosis and monitoring of evolution of both heart performance and vascular status is strictly needed. Advanced hemodynamic monitoring consists among others - of measuring cardiac output, predicting fluid responsiveness and calculating systemic oxygen delivery. Identification and quantifying of pulmonary edema has also been recently appreciated in pediatric critical care. In the last decade, the number of vasoactive drugs has increased, together with a better understanding of clinical application of both different monitoring devices and treatment strategies.

Keywords: Haemodynamic monitoring, heart failure, inotropes, pediatric shock, PICU, vasoactive drugs. INTRODUCTION Hemodynamic derangements are frequently encountered in PICU, representing the second main reason for intensive care requirement in infancy after respiratory compromise. All clinicians, even not intensivists, are in agreement that it is essential to treat extremely low blood pressure (BP) with evidence of poor circulation. However, there is uncertainty about which thresholds should be used to direct management of systemic BP. Conformly, conditions with decreased heart function can be suitable for inotropic treatment, i.e. agents increasing the strenght of cardiac muscle contraction. Deciding which inotrope to use and when and how long is complicated for several reasons. In fact, while BP is readily measured, it is much more difficult to measure the blood flow to key organs and districts. In this review we present both inotropic and vasoactive agents aimed at improving systemic and vital organs perfusion. The circulatory status depends on peripheral resistance, cardiac output and intravascular volume. Cardiac output depends on filling (preload), rhythm, contractility and rate. Afterload also affects the efficiency of the heart. Excessive afterload (systemic vasoconstriction) can arise in sepsis, but is more usually a feature of primary cardiac disease such as cardiomyopathy and will eventually reduce the cardiac output. HEMODYNAMIC MONITORING IN PEDIATRIC AGE Hemodynamic monitoring represents a cornerstone in the management of the critically ill patient, as it is used to identify cardiovascular insufficiency, its probable cause, and response to therapy. Still it is difficult to document the efficacy of monitoring because no device improves outcome
*Address correspondence to this author at the Pediatric ICU, institute of Anesthesia, Catholic University Medical School, Rome, Italy; Tel: +390630155203-5283-4250; Fax: +390630155283; E-mail: marco.piastra@rm.unicatt.it 1873-5592/12 $58.00+.00

unless coupled to a treatment that improves outcome. The primary goal of hemodynamic therapy is the prevention of inadequate tissue perfusion and inadequate oxygenation. Advanced cardiovascular monitoring is a prerequisite to optimize hemodynamic treatment in critically ill patients prone to cardiocirculatory failure. The most ideal cardiac output (CO) monitor should be reliable, continuous, noninvasive, operator-independent and cost-effective and should have a fast response time. Moreover, simultaneous measurement of cardiac preload enables the diagnosis of hypovolemia and hypervolemia and subsequent interentions. Over the 90ies there have been important advances in understanding pediatric septic shock and its management: J. Carcillo and co. described the mainstem importance of fluid replacement (1991) and then used invasive monitoring to assess haemodynamic status longitudinally in critically ill children with septic shock that did not respond to fluids [1]. Two thirds presented with low cardiac output needing inotropes (this can be described as cold shock). One fifth had vasodilation and a high cardiac output (this can be described as warm shock), and one fifth had low cardiac output and vasodilation. These patterns changed in some individuals from day to day. While this type of monitoring is not easily achievable in routine practice, it does illustrate the patterns that clinicians will encounter. INFLUENCING THE CIRCULATION: HEMODYNAMIC SUPPORT Schematically, the circulation depends on peripheral resistance, cardiac output (CO) and intravascular volume. Cardiac output output depends on filling (preload) and several other factors. In fact, CO is the product of heart rate and cardiac stroke volume (SV). SV depends on preload, afterload, and contractility. The relation between SV and preload is reflected by the Frank-Starling curve. Blood pressure there 2012 Bentham Science Publishers

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fore is easy to measure, but it is the resultant of SV and systemic vascular resistance. Afterload also affects the efficiency of the heart and may represent a target of pharmacological modulation. Excessive afterload (systemic vasoconstriction) can arise in sepsis, but is more usually a feature of primary cardiac disease such as cardiomyopathy and will further reduce the cardiac output. As a result, a low blood pressure can be caused by a low CO, a low systemic vascular resistance, or both. Addressing BP with vasoactive agents without a reliable diagnosis of the underlying circulatory derangement may be very harmful and can precipitate an ongoing cardiac dysfunction. This issue is very relevant for critically ill children and adults. Vasoactive and inotropic agents main characteristics are summarised in (Table 1). CATHECOLAMINERGIC AGENTS Cathecolamines are the drugs of choice in circulatory shock because they are effective and easy to titrate with a short half-life; they act on various adrenergic receptors see (Table 2), their specific activity depending on dose. Beta-adrenergic stimulation increases essentially cardiac output, by combined increase in stroke volume and heart rate, it also decreases vascular tone and increases hepatosplancnic blood flow. Alpha-adrenergic receptor stimulation results in vasocostrictive effect and increases cerebral and coronary perfusion pressure. Dopamine-1 (DA-1) receptor agonism results in selective vasodilation primarily in renal and mesenteric beds, while DA-2 receptors stimulation causes norepinephrine release from sympathetic nerve endings, inhibition of prolactin release and antinausea effect. Stimulation of both DA receptors can decrease bowel peristalsis thus inducing ileus. Catecholamines represent the traditional approach to increasing BP also in a hypotensive neonate, infant and child. Epinephrine and norepinephrine are long established. Both may produce significant tachycardia (which reduces the time available for cardiac filling, thus reducing preload, reduces the time for perfusion of the coronary arteries and increases myocardial oxygen demand). Dopamine and dobutamine can also be used. Norepinephrine has strong vasopressor properties, although it also has some beta-adrenergic effects enabling to maintain cardiac output. Dopamine is an immediate precursor of NEPI which acts on alpha and beta-adrenergic and dopaminergic receptors as well. Previously, its interesting profile changing accordingo to dose accounted for the popularity of the drug, as low doses (1-4 mcg/kg/min) act primarily on the beta-adr and DA-1 receptors. Incresing Dopamine dose, beta-adrenergic effects increase while alphaadrenergic effects increase even more. Above 20 mcg/kg/min usually dopamine effects do not increase further. However, there is a substantial interindividual variability, depending on the messenger (NEPI) nervous terminations stores. Main side effects include tachyarrhythmias induction. Mostly in newborn and early infancy a relative dopamine resistance has been described, possibly in association with norepinephrine stores consumption in sympathetic nerve endings; as a consequence, norepinephrine may still increase blood pressure when dopamine increasing dose is failing or insufficient response is achieved. Dopamine has been also used in neonatal and pediatric ICUs for a long time at a renal dose for its renal protective effect, and still rep-

resents the first vasoactive agent to be introduced in shock protocols. Regarding renal protective effect, though DOPA can increase renal blood flow and diuresis in animal studies and in healthy subjects, there have been conflicting results in critically ill patients [2]. Dobutamine is a beta-adrenergic agent that remains the gold standard inotropic agent in the treatment of septic shock. In the Surviving Sepsis Campaign, dobutamine is recommended as the first-line therapy for myocardial dysfunction as suggested by elevated cardiac filling pressures and low-cardiac output (grade 1C). Fluid resuscitation is a prerequisite for all inotropes, but mostly for dobutamine; in fact, it may lower BP in those without adequate volume resuscitation. Preliminary data in adults suggest that combination of metoprolol and milrinone may be beneficial for septic cardiomyopathy, representing a future field of research Phenylephrine Previous findings suggest that a delayed administration of phenylephrine replacing norepinephrine in septic shock patients causes a more pronounced hepatosplanchnic vasoconstriction as compared with norepinephrine. In a prospective, randomized controlled trial, 32 septic shock patients were randomly allocated to treatment with either norepinephrine or phenylephrine infusion [3]: no differences were seen in cardiopulmonary performance, global oxygen transport and regional hemodynamics between phenylephrine and norepinephrine in the hemodynamic support of septic shock. This study suggests there are no differences in terms of cardiopulmonary performance, global oxygen transport and regional hemodynamics when phenylephrine was administered instead of norepinephrine in the initial hemodynamic support of septic shock. CLINICAL APPROACH TO SHOCK The hemodynamic management of shock is aimed at maintaining oxygen delivery above a critical threshold and increasing mean arterial pressure (MAP) to a level that allows appropriate distribution of cardiac output to achieve adequate individual organ perfusion. Vasoactive therapy in the treatment of shock aims to increase oxygen delivery or increase organ perfusion pressure or both. Vasoactive drugs should be used judiciously, with a goal-directed approach. Whilst the traditional agent of choice has been dopamine, a more recent strategy is to titrate norepinephrine to a MAP goal of normal perfusion pressure for age (i.e., Systemic Perfusion Pressure =MAP-CVP) and to titrate dobutamine to a central venous oxygen saturation goal of 70%. It means that NEPI act mainly on perfusion, whereas dobutamine improves cardiac function. For shock refractory to first-line inotrope, the American practice parameters suggest a clinical classification to guide treatment. Cold shock (presumably due to low cardiac output) should be treated with epinephrine. Warm shock (presumably high cardiac output with low systemic vascular resistance (SVR)) should be treated with norepinephrine. Septic shock invariably involves vasodilation, but it is not limited to vasodilation: the overall incidence of global left ventricular hypokinesia in patients with septic shock and no prior cardiac history has been described as 60% [5]. Global left ventricular hypokinesia is more frequent in septic

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Table 1.

Inotropes and Other Agents that Have Been Cited in the Text

Agent

Pharmacology

Physiological Effect

Dose Range Neonates: 5-20 g/kg/min PICU starting dose: 3-5 g/kg/min, maximum dose 20 g/kg/min May have an effect at 1 g/kg/min in healthy children

Comments Associated with vasoconstriction so requires a long line or central line; may be started on peripheral venous access in emergency condt (Septic shock guidelines 2007)

Dopamine

D1, D2, 1, 2 Agonist

Increases contractility and vascular resistance. At lower doses, dopamine is claimed to be a vasodilator (acting on dopaminergic and then -receptors), but at higher doses it has a greater effect on vasoconstriction Affects contractility without increasing vascular resistance. Dobutamine has a greater action on -receptors, producing vasodilation, tachycardia and chronotropy. Increases contractility (with increased vascular resistance at higher doses). Theoretically, EPI acts more on the -receptors than on the
receptors and so should increase BP by increasing cardiac rate and contractility. Dopamine and dobutamine are less potent and have less peak effect than EPI or norepinephrine. All may produce tachycardia. Higher doses lead to receptor desensitisation but can be used sometimes.

Dobutamine

Predominant 1 Agonist

Neonates: 5-20 g/kg/min PICU starting dose: 3-5 g/kg/ min, maximum dose 20 g/kg/min

Can be infused via peripheral line

Epinephrine

1,
2, 1, 2 Agonist

Neonates: 100-300 ng/kg/min Others: 0.1 titrated up to 1.5 g/kg

Associated with vasoconstriction so requires a long line or central line

Norepinephrine

1,
2, 1 Agonist

Norepinephrine has a proportionally greater action on the
-receptors and so increases BP by vasoconstriction

Neonates: 20-100 ng/kg/min initially, up to 1.0 g/kg/min as base. Others: 20-100 ng/kg/min initially, up to 1.0 g/kg/min as base. Higher doses lead to receptor desensitisation bolus: 5 to 20 mcg/kg/dose every 10 to 15 minutes as needed. manteinance: 0.1 to 0.5 mcg/kg/min titrated to effect.

Associated with vasoconstriction so requires a long line or central line

Phenilephrine

1,
2, 1 Agonist

Pure alpha-agonist vasoconstrictor

Vasopressin

ADH Agonist in Arterioles

May replace basal vasopressin levels in cases of severe hypotension Vasopressin analogue with increased half-life

0.018-0.12 units/kg/h May be used Uncertainty about role as rescue as rescue treatment or primary treatment 0.04 mg/kg stat, then 0.02 mg/kg 6 hourly or drip 0.5-0.75 g/kg/min

Terlipressin PDE III inhibitor PDE III inhibitor

Milrinone

Inotropic and vasodilating effect

Enoximone

Inotropic and vasodilating effect

5-20 g/kg/min 0,1 g/kg/min increment gradually if requie every 15-30 minutes to max 1,6 g/kg/min 0,01 g/kg/min (range 0,005-0,03 g/kg/min) 0,3 mg/kg in 6 ml/kg 5% dex and give 1,5 ml/kg/hr for 10 minutes, then 0,24 ml/kg/hr for 24 hr. In neonates: 2.5 mg/kg 6 hourly Older ch: 1 mg/kg 6 hourly

Risk of hypotension

Fenoldopam

D1 Agonist

Renal and peripheral vasodilation

Nesiritide

Renal

B-type natriuretic peptide

Levosimendan

CalciumSensitizer

Inotropic effect independen from beta-receptor stimulation May increase beta-receptor sensitivity to cathecolamins

Hydrocortisone

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Table 2.
Target

Vasoactive Agents Receptors and Their Location.

Receptor Location

Main Actions
Vasoconstriction- increase in arterial pressure
Decreased blood flow (increased after load)

Alpha adrenergic

Arterioles

Decreased heart rate (baroflex)
Increased cerebral blood flow
Decreased renal and hepatosplenic blood flow
Increased force of contraction

Conducting system of heart Beta adrenergic Heart muscles Arterioles in heart and skeletal muscle

Increased heart rate
Vasodilatation
Increased Hepatosplenic blood flow
Increased cellular metabolism

Receptors Alpha1 Alpha2

Arterioles Arterioles: mainly coronary and renal Conducting system of heart

Constriction Constriction Increase heart rate Increase in contractility Vasodilatation Increase in heart rate Increase in contractility Vasodilatation Vasodilatation Vasodilatation

Beta1

Atrial and ventricular muscle Arterioles in heart and skeletal muscle Conducting system of heart

Beta2

Atrial and ventricular muscle Arterioles in heart and skeletal muscle

D1 D2

Postsynaptic receptor in peripheral vasculature Presynaptic receptor in peripheral vasculature

shock than previously known and can be unmasked by norepinephrine treatment. Hemodynamic treatment should be tailored in order to address the leading mechanism [6]. In clinical practice, add-on inotropic support is otherwise advisable when a vasocostrictive agent is needed. In fact, paradoxical left ventricular septal wall motion, consistent with left ventricular dysfunction has been found in virtually all children with septic shock [7]. Alternative Vasoactive Agents Fenoldopam a pure D1 agonist- has been described in adults for treatment of oliguria/anuria and for renal perfusion and protection, whereas few pediatric data are available up to now. A recent study assessed the effects of fenoldopam on urine output and potential deleterious changes in hemodynamics or serum creatinine in children [8]: Fenoldopam increases urine output in select critically ill pediatric patients without requiring escalation of inotropic support without adverse hemodynamic effects or alterations in serum creatinine. It has been used in comparison with the renal dose of dopamine in a recent study on adults [9]. In critically ill patients, a continuous infusion of fenoldopam at 0.1 microg/kg/min did not cause any clinically significant hemo-

dynamic impairment, thereby improving renal function compared with renal dose dopamine. In the setting of acute early renal dysfunction, before severe renal failure has occurred, the attempt to reverse renal hypoperfusion with fenoldopam apperars more effective than with low-dose dopamine. The use of fenoldopam in newborns has been described mostly in the setting of cardiac surgery: in fact Fenoldopam may improve urine output in neonates who are failing to achieve an adequate negative fluid balance despite conventional diuretic therapy after cardiac surgery and cardiopulmonary bypass [10]. However, a prospective study gave conflicting results [11], as well a review regarding neonatal ICU patients [12]. Vasopressin Vasopressin is an endogenously released stress hormone that is important during shock. It acts as a pure vasoconstrictor via a receptor to platelet-derived growth factor. The rationale for its use in the ICU is that there is a vasopressin deficiency in vasodilatory shock and that exogenously administered vasopressin can restore vascular tone [13]. Although low-dose vasopressin did not reduce mortality compared with norepinephrine among septic shock patients, vasopressin is well tolerated and may be beneficial in pa-

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tients having less severe septic shock. This study also confirmed the deficiency of endogenous vasopressin levels in septic shock and that infusion of 0.03U/min restored serum vasopressin levels to an appropriate level for shock [14]. An RCT of vasopressin in shocked children showed no improvement in outcome and a higher (albeit insignificant) mortality in the treatment group [15]. In clinical practice it is available the vasopressin analogue terlipressin: it may also be used as a continuous i.v. drip (starting dose 0.04 mg/kg, further doses 0.02 mg/kg q6hrs). The half-life of terlipressin is 6 h, and the duration of action is 210 h, compared with them short half-life of vasopressin (6 min) and duration of action (3060 min). The disadvantage terlipressin has over vasopressin is that once a bolus of terlipressin is given, its effects cannot be reversed easily, as with a continuous infusion of vasopressin. Vasopressin is not available in some countries. Hydrocortisone and Vasopressor Interaction with Corticosteroid Treatment In adults, the Corticosteroid Therapy of Septic Shock (CORTICUS) study prospectively tested for a difference in mortality between septic shock patients treated with corticosteroids vs. placebo [16], reporting no difference in survival. However, the results confirmed the known corticosteroid potentiation of adrenergic signaling pathways. That is, the need for catecholamine vasopressors was reversed more rapidly in the hydrocortisone-treated group. Then, though corticosteroids did not decrease mortality of patients having septic shock, and cannot be recommended, hydrocortisone may have a role among patients who are vasopressor unresponsive. In pediatrics, a relative adrenal insufficiency has been described in patients undergoing meningococcal septicaemia and septic shock. In pediatric patients requiring high levels of hemodynamic support, in the absence of a corticotrophin stimulation test, steroid supplementation appears both feasible and advisable [17, 18]. NON CATHECOLAMINERGIC INOTROPIC DRUGS Phosphodiesterase Inhibitors Phosphodiesterase inhibitors are called inodilators, because they are thought to improve both contractility and cause vasodilation. Both of these effects may be useful in some septic children. Specific phosphodiesterase inhibitors, such as milrinone and amrinone, improve cardiac output without troublesome hypotension in short trials of septic children. As well as these effects, the phosphodiesterase inhibitors may improve ventricular relaxation a luseotropic effect which can improve ventricular filling and so cardiac output. Diastolic dysfunction is increasingly recognised to be important. Enoximone (Perfan) represent another component of the PDI family, though its use in critically ill patients is limited by a marked hypotensive effect. Recently, milrinone has emerged as one of the most useful second line agents. Milrinone [Corotrop, Primacor) is a phosphodiesterase-3 inhibitor with inotropic, lusitropic, and vasodilating properties independent of alpha and beta receptors [13, 18]. Its direct myocardial effect is related to the increase in intracellular cyclic adenosine monophosphate with a subsequent increase in intracellular calcium levels and increased sensi-

tivity of the actinmyosin complex to calcium, leading to increased contractility. Outside the cardiac surgery setting, in volume-resuscitated pediatric patients with septic shock, when administered in addition to catecholamines, milrinone will further improve cardiovascular function [19]. Levosimendan A new agent, levosimendan, has been shown to improve cardiac function in adults with heart failure [20, 21]. Levosimendan is a calcium sensitizing agent. It produces potent inotropic actions by sensitizing myocardial troponin C to calcium and exerts vasodilator effects through stimulation of the adenosine triphosphate- sensitive potassium channels of systemic, pulmonary, and coronary vascular smooth muscle cells. LS use in pediatric patients was first reported in 2004 [22, 23]. In 2006, Namachivayam et al. retrospectively defined LS as safe in children with severe myocardial dysfunction, reporting a substantial reduction of catecholamines dosage in 15 children with end-stage or acute heart failure treated in a Pediatric Intensive Care Unit [24]. Further clinical reports in children with LCOS have been recently published. All these reports involve both young infants [25, 26] and premature newborns [27] in postoperative setting. Recently, LS use in newborn affected by both cardiac failure and pulmonary hypertension has been described at our institution [28]. Calcium Ionised calcium is an important component and may be significantly different from total calcium concentrations (given abnormalities in pH or serum albumin). Calcium may improve contractility and increases vascular tone. Treating a low ionised calcium may be of benefit, especially in younger children with sepsis. Children with meningococcal sepsis may have particularly low concentrations of calcium. Nesiritide Nesiritide (Natrecor, Scios, Fremont, CA) though not an inotropic agent, is a recombinant form of human B-type natriuretic peptide that was approved by the U.S. Food and Drug Administration in 2001 for the treatment of acutely decompensated CHF in adults, is well tolerated and results in improved hemodynamics and patient symptoms [29]. Preliminary reports suggest that natriuretic hormone infusions cause physiologic improvements in adults with acute lung injury and asthma but not in those with acute renal failure. A review on the diagnostic-therapeutic indications of nesiritide has been published recently [30]. Vasoactive-Inotropic Index (VSI) A composed index has been proposed after the Wernovsky Inotropic Index accounting for both inotropic and vasopressor drugs, with the aim to precisely define the hemodynamic need of the pediatric patient [31]. Definitely, it could disclose the amount of cardiovascular support in the first 48 hrs after congenital heart surgery with cardiopulmonary bypass predicts eventual morbidity and mortality in young infants (Table 3).

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Table 3.

Vasoactive Inotropic Score

Wernovsky IS = dopamine dose (ug/kg/min)

[14] + dobutamine dose (ug/kg/min) + 100 x epinephrine dose (ug/kg/min) VIS = IS + 10 x milrinone dose (ug/kg/min) + 10,000 x vasopressin dose (U/kg/min) + 100 x norepinephrine dose (ug/kg/min) [16] [17] [18] [15]

CONFLICT OF INTEREST Declared none. ACKNOWLEDGEMENT Declared none. REFERENCES

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Received: December 02, 2011

Revised: December 27, 2011

Accepted: December 27, 2011

PMID: 22512389