inotropic and vasoactive drugs in pediatric icu

900 Current Drug Targets, 2012, 13, 900-905

1873-5592/12 $58.00+.00 © 2012 Bentham Science Publishers

Inotropic and Vasoactive Drugs in Pediatric ICU

Marco Piastra1,*

, Ersilia Luca1, Sonia Mensi

1,2, Federico Visconti

1,2, Daniele De Luca

1,

Francesca Vitale1 and

Domenico Pietrini

1,2

1Pediatric 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 cardiocircula-

tory instability in the setting of intensive care. However, the hemodynamic status of the critically ill child is poorly re-

flected 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 oth-

ers - 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. Decid-ing which inotrope to use and when and how long is compli-cated for several reasons. In fact, while BP is readily meas-ured, 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 vol-ume. 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 iden-tify cardiovascular insufficiency, its probable cause, and response to therapy. Still it is difficult to document the effi-cacy 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: [email protected]

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, nonin-vasive, operator-independent and cost-effective and should have a fast response time. Moreover, simultaneous meas-urement of cardiac preload enables the diagnosis of hypo-volemia 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 de-scribed as ‘warm shock’), and one fifth had low cardiac out-put and vasodilation. These patterns changed in some indi-viduals 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: HEMODY-

NAMIC SUPPORT

Schematically, the circulation depends on peripheral re-sistance, cardiac output (CO) and intravascular volume. Car-diac output output depends on filling (preload) and several other factors. In fact, CO is the product of heart rate and car-diac 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-

Inotropic and Vasoactive Drugs in Pediatric ICU Current Drug Targets, 2012, Vol. 13, No. 7 901

fore is easy to measure, but it is the resultant of SV and sys-temic vascular resistance. Afterload also affects the effi-ciency of the heart and may represent a target of pharmacol-ogical modulation. Excessive afterload (systemic vasocon-striction) 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 hepato-splancnic 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 end-ings, inhibition of prolactin release and antinausea effect. Stimulation of both DA receptors can decrease bowel peri-stalsis thus inducing ileus.

Catecholamines represent the traditional approach to in-creasing 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 proper-ties, although it also has some beta-adrenergic effects ena-bling 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 interest-ing 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 Do-pamine dose, beta-adrenergic effects increase while alpha-adrenergic effects increase even more. Above 20 mcg/kg/min usually dopamine effects do not increase fur-ther. However, there is a substantial interindividual variabil-ity, depending on the messenger (NEPI) nervous termina-tions stores. Main side effects include tachyarrhythmias in-duction. Mostly in newborn and early infancy a relative do-pamine 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 dys-function 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 re-suscitation. Preliminary data in adults suggest that combina-tion 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 vaso-constriction as compared with norepinephrine. In a prospec-tive, randomized controlled trial, 32 septic shock patients were randomly allocated to treatment with either norepineph-rine 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 car-diopulmonary performance, global oxygen transport and regional hemodynamics when phenylephrine was adminis-tered 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 al-lows 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 Per-fusion 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 im-proves cardiac function. For shock refractory to first-line inotrope, the American practice parameters suggest a clini-cal classification to guide treatment. Cold shock (presumably due to low cardiac output) should be treated with epineph-rine. 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

902 Current Drug Targets, 2012, Vol. 13, No. 7 Piastra et al.

Table 1. Inotropes and Other Agents that Have Been Cited in the Text

Agent Pharmacology Physiological Effect Dose Range Comments

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

Neonates: 5-20 μg/kg/min PICU

starting dose: 3-5 μg/kg/min,

maximum dose 20 μg/kg/min

May have an effect at 1 μg/kg/min

in healthy children

Associated with vasoconstric-

tion so requires a long line or

central line; may be started on

peripheral venous access in

emergency condt (Septic shock

guidelines 2007)

Dobutamine Predominant 1

Agonist

Affects contractility without increasing vascular

resistance. Dobutamine has a greater action on

-receptors, producing vasodilation, tachycar-

dia and chronotropy.

Neonates: 5-20 μg/kg/min PICU

starting dose: 3-5 μg/kg/

min, maximum dose 20 μg/kg/min

Can be infused via peripheral

line

Epinephrine 1, 2, 1,

2 Agonist

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 increas-

ing cardiac rate and contractility. Dopamine and

dobutamine are less potent and have less peak

effect than EPI or norepinephrine. All may pro-

duce tachycardia. Higher doses lead to receptor

desensitisation but can be used sometimes.

Neonates: 100-300 ng/kg/min

Others: 0.1 titrated up to 1.5 μg/kg



central line

Norepineph-

rine

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 ini-

tially, up to 1.0 μg/kg/min as

base. Others: 20-100 ng/kg/min

initially, up to 1.0 μg/kg/min as

base. Higher doses lead to recep-

tor desensitisation



central line

Phenilephrine 1, 2, 1

Agonist Pure alpha-agonist vasoconstrictor

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.

Vasopressin ADH Agonist

in Arterioles

May replace basal vasopressin levels in cases of

severe hypotension

0.018-0.12 units/kg/h May be used

as rescue treatment

Uncertainty about role as rescue

or primary treatment

Terlipressin Vasopressin analogue with increased half-life 0.04 mg/kg stat, then 0.02 mg/kg 6

hourly or drip

Milrinone PDE III

inhibitor Inotropic and vasodilating effect 0.5-0.75 μg/kg/min

Enoximone PDE III

inhibitor Inotropic and vasodilating effect 5-20 μg/kg/min Risk of hypotension

Fenoldopam D1 Agonist Renal and peripheral vasodilation

0,1 μg/kg/min increment gradually

if requie every 15-30 minutes to

max 1,6 μg/kg/min

Nesiritide Renal B-type natriuretic peptide 0,01 μg/kg/min (range 0,005-0,03

μg/kg/min)

Levosimendan Calcium-

Sensitizer

Inotropic effect independen from beta-receptor

stimulation

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.

Hydrocortisone May increase beta-receptor sensitivity to

cathecolamins

In neonates: 2.5 mg/kg 6 hourly

Older ch: 1 mg/kg 6 hourly


Table 2. Vasoactive Agents Receptors and Their Location.

Target Receptor Location Main Actions

Alpha adrenergic Arterioles

Vasoconstriction- increase in arterial pressure

Decreased blood flow (increased after load)

Decreased heart rate (baroflex)

Increased cerebral blood flow

Decreased renal and hepatosplenic blood flow

Beta adrenergic

Conducting system of heart

Heart muscles

Arterioles in heart and skeletal muscle

Increased force of contraction

Increased heart rate

Vasodilatation

Increased Hepatosplenic blood flow

Increased cellular metabolism

Receptors Alpha1 Arterioles Constriction

Alpha2 Arterioles: mainly coronary and renal Constriction

Beta1


Atrial and ventricular muscle


Increase heart rate

Increase in contractility

Vasodilatation

Beta2


Atrial and ventricular muscle


Increase in heart rate

Increase in contractility

Vasodilatation

D1 Postsynaptic receptor in peripheral vasculature Vasodilatation

D2 Presynaptic receptor in peripheral vasculature Vasodilatation

shock than previously known and can be unmasked by nore-pinephrine treatment. Hemodynamic treatment should be tailored in order to address the leading mechanism [6]. In clinical practice, add-on inotropic support is otherwise ad-visable when a vasocostrictive agent is needed. In fact, para-doxical 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 hemody-namics or serum creatinine in children [8]: Fenoldo-pam 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 criti-cally 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 com-pared 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 im-prove 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 vasoconstric-tor via a receptor to platelet-derived growth factor. The ra-tionale for its use in the ICU is that there is a vasopressin deficiency in vasodilatory shock and that exogenously ad-ministered vasopressin can restore vascular tone [13]. Al-though low-dose vasopressin did not reduce mortality com-pared with norepinephrine among septic shock patients, vasopressin is well tolerated and may be beneficial in pa-

904 Current Drug Targets, 2012, Vol. 13, No. 7 Piastra et al.

tients having less severe septic shock. This study also con-firmed 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 2–10 h, compared with them short half-life of vasopressin (6 min) and duration of action (30–60 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 infu-sion of vasopressin. Vasopressin is not available in some countries.

Hydrocortisone and Vasopressor Interaction with Corti-

costeroid Treatment

In adults, the Corticosteroid Therapy of Septic Shock (CORTICUS) study prospectively tested for a difference in mortality between septic shock patients treated with corticos-teroids 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 rap-idly in the hydrocortisone-treated group. Then, though corti-costeroids did not decrease mortality of patients having sep-tic shock, and cannot be recommended, hydrocortisone may have a role among patients who are vasopressor unrespon-sive. 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 feasi-ble and advisable [17, 18].

NON CATHECOLAMINERGIC INOTROPIC DRUGS

Phosphodiesterase Inhibitors

Phosphodiesterase inhibitors are called inodilators, be-

cause 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 in-

hibitors 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 compo-

nent of the PDI family, though its use in critically ill patients

is limited by a marked hypotensive effect. Recently, milri-

none has emerged as one of the most useful second line

agents. Milrinone [Corotrop™, Primacor™) is a phosphodi-

esterase-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 intracel-

lular cyclic adenosine monophosphate with a subsequent

increase in intracellular calcium levels and increased sensi-

tivity of the actin–myosin 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 mus-

cle 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 dys-

function, 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 clini-

cal reports in children with LCOS have been recently pub-

lished. All these reports involve both young infants [25, 26]

and premature newborns [27] in postoperative setting. Re-

cently, LS use in newborn affected by both cardiac failure

and pulmonary hypertension has been described at our insti-tution [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 na-

triuretic 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]. Pre-

liminary 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 Wer-

novsky 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 cardiopul-

monary bypass predicts eventual morbidity and mortality in young infants (Table 3).


Table 3. Vasoactive Inotropic Score

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

+ 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)

CONFLICT OF INTEREST

Declared none.

ACKNOWLEDGEMENT

Declared none.

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Received: December 02, 2011 Revised: December 27, 2011 Accepted: December 27, 2011

PMID: 22512389

inotropic and vasoactive drugs in pediatric icu

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