Cual Inotropico

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Which inotrope?Shirley Friedman

Joe Brierley

Abstract ‘Which inotrope?’ for the sick child is a question that suggests the exis-

tence of ready answer. But, with critically ill children the ‘answer’ is

context specific. What is the clinical situation? Is the predominant prob-

lem systolic myocardial impairment post cardiopulmonary bypass,

decreased systemic vascular resistance in sepsis or diastolic dysfunction

in restrictive cardiomyopathy? What about age and ethnicity? In fact the

optimal reply relies on factors which medical science has not yet entirely

elucidated e such as genomic/genetic and developmental variations in

inotrope receptor distribution and function and the underlying variability

in host responses to varying clinical situations.

Overall, the evidence base to guide inotrope use in children is sparse,

and extrapolations from adult medicine and physiology predominate. In

daily practice a combination of experience, ‘usual regimes’ and local clin-

ical practice guidelines e often derived from resuscitation courses or in-

ternational guidelines provide identifiable standards for inotrope use.

Inotropes are vasoactive drugs, and the choice of drug and dose is

tailored to the haemodynamic, or blood flow/circulatory, state of the pa-

tient and frequently adjusted depending on effect.

This review provides a background to these agents and offers sugges-

tions to help decision-making regarding their use.

Keywords children; haemodynamics; inotropes; shock

What are inotropes?

In general terms inotropy is the condition of contractility of the

myocardium and inotropes are substances that increase the force

or energy of ventricular muscle contraction. Inotropes are often

used in the care of critically ill children to improve cardiac output

(CO) and so to increase oxygen delivery (DO2) to tissues.

No inotrope exerts its effect entirely by altering myocardial

contraction all have other effects e whether on systemic or

pulmonary vascular resistance (SVR or PVR), heart rate or ven-

tricular relaxation. Furthermore, the relative effects depend on

blood concentration and often unresolved issues in host vari-

ability, such as receptor distribution.

The choice of ‘which inotrope’ ought to be determined by the

specific therapeutic goal, which should seldom be an elevation in

systemic blood pressure alone. Manipulating hemodynamics in

acutely unwell children should be directed at optimizing DO2 to

vital tissues, to treat or prevent shock.

Cardiovascular system

Cardiovascular system failure is one of the commonest organ

failures in the critically ill child. It is associated with shock, the

state in which either cellular DO2 or utilization is insufficient to

meet metabolic demand. This mismatch between tissue meta-

bolic requirements and DO2 stems from three main, often co-

existing, mechanisms: increased metabolic demand; primary

circulatory failure of DO2 and other nutrients delivery to the

tissues and an inability to utilize delivered oxygen at cellular

level. Although decreasing metabolic demand can be useful,

medical treatments overwhelmingly address the second mecha-

nism of circulatory failure, with optimization of CO and global/

regional perfusion.

There are a few basic haemodynamic terms which are useful

to consider when addressing circulatory failure:

Cardiac output (CO) is the blood flow ejected by the heart in one

minute, and divided by body surface area gives cardiac index

(CI). It is the product of stroke volume (SV) and heart rate (HR)

so: CO ¼ SV HR.

SV is directly related to preload (volume status, atrioventric-

ular synchrony) and myocardial function which is dependant on

both ventricular systolic and diastolic function. It is inversely

related to afterload (increased by outflow tract obstruction or

increased SVR).

In children, decreased preload due to volume loss is a

commonly encountered cause of shock for example from diar-

rhoea and vomiting, sepsis or poor fluid intake.

Because blood pressure is affected by SVR and CO (a version

of Ohm’s law) knowing BP in isolation cannot tell us CO without

knowing SVR: BP ¼ CO SVR.

Multiple neural, humoural and chemical factors regulate SV,

HR and SVR.

However, it is not uncommon for this regulation to fail e.g.

vasodilated septic shock and inotrope choice may be aided by

understanding their likely action on the physiological derange-

ment: Drugs influencing heart rate are known as chronotropes,

whilst lusitropy pertains to ventricular diastolic relaxation. Va-

sopressors increase vascular tone and therefore systemic

vascular resistance whereas vasodilators reduce it and inodila-

tors possess both inotropic and vasodilator effects.

As all drugs have more than one effect, perhaps vasoactive

drug is a better term than inotrope per se.

Although shock states are categorized according to the main

aetiological process (Table 1), there is both an overlap between

the various mechanisms and frequent changes in the predomi-

nant pathophysiological manifestation as shock evolves.

Recognition and assessment of shock

Recognition of shock is well covered in resuscitation courses

(ALSG), however before discussing vasoactive drugs it is

important to understand how cardiovascular system failure is

quantified and assessed.

In children presenting with circulatory compromise, heart

rate, blood pressure, capillary refill and core-peripheral

Shirley Friedman MD is PICU Senior Physician in the Pediatric Intensive

Care Unit “Dana-Dwek” Children’s Hospital, Souraski Medical Center,

Tel-Aviv. Israel. Conflicts of interest: none.

Joe Brierley FRCPCH is Consultant Paediatric Intensivist in the Paediatric

and Neonatal Intensive Care Unit, Great Ormond Street Hospital for

Children NHS Trust, London, UK. Conflicts of interest: none.

OCCASIONAL REVIEW

PAEDIATRICS AND CHILD HEALTH 23:5 220 2013 Published by Elsevier Ltd.

http://dx.doi.org/10.1016/j.paed.2013.02.004




temperature gradient can be readily assessed and repeated. As

children deteriorate the effects of haemodynamic compromise on

end organs can be assessed e such as decreased urine output and

conscious level.

Clearly adequate volume expansion is an important primary

step in the shocked child. However, a recent randomized trial of

fluid without inotrope in children in a low resource (non-PICU)environment showed volume expansion to be harmful.

Optimization of preload with volume resuscitation is still

generally recommended in a UK setting, but early concurrent

inotrope therapy, as suggested by the last iteration of the inter-

national ACCM haemodynamic guidelines is recommended.

Further studies are urgently needed to clarify optimum fluid-

therapy in shock.

Targets

In paediatric shock compromised DO2 is often the primary

problem rather than oxygen extraction, as in adults. Therefore,

tissue perfusion seems an especially important parameter toquantify in children in shock. However, to date there is no ‘tissue

perfusion monitor’ in widespread use, Near infrared spectros-

copy and microcirculation assessment devices show promise, but

it is not clear how they will ultimately contribute to circulatory

optimization of the shocked child.

BP is the most commonly measured haemodynamic param-

eter in PICU despite being an inaccurate measure of DO2. In

children hypotension is a late event in the cascade of shock,

unsurprising to those taught it is a pre-terminal sign in resusci-

tation courses. Whilst not strictly true e children in vasodilated

shock can maintain relative hypotension for a time e this ‘truism

underpins an important biological fact: children have pristine

systemic vasculature compared to adults and can readily

compensate for changes in myocardial performance with either

vasodilation, or pronounced vasoconstriction. However, in re-

ality, it is far from established whether vascular or myocardial

derangements are the primary pathophysiological alteration in

paediatric shock. In children the concept of measuring haemo-

dynamic parameters e

such a CO e

has not received as wide-spread acceptance compared with adult ICU, possibly due to the

risks of the initial measurement devices.

Whilst the International Pediatric Consensus definition for

sepsis and organ dysfunction permit definition of cardiovascular

system dysfunction as hypotension despite fluid resuscitation,

the ALSG and the American Academy of Critical Care Medicine

focus other parameters to target early resuscitation against:

decreased mental status, decreased urine output, capillary refill

time (CRT) more than 2 second, mottled cool extremities and

diminished pulses in ’cold’ shock and brisk CRT and bounding

pulses for ’warm’ shock.

However, for post 60 minute/PICU on-going care optimization

of perfusion pressure (mean arterial pressure central venouspressure) in ‘catecholamine-resistant shock’ is advised. Later a CI

between 3.3 and 6.0 l/min/m2 is advised if shock is not reversed.

Lactate, which accumulates during anaerobic metabolism, is

one of the biomarkers used to assess global tissue metabolism

and lactate clearance is a widespread resuscitation target in

shock. However certain drugs such as Adrenaline or inborn

metabolic derangements as well as deranged local waste removal

from tissues also influence lactate levels.

Central venous oxygen saturation (CVC-O2) is another global

measure of circulatory performance with low levels suggesting

increased tissue oxygen extraction due to poor circulation.

Normalization of CVC-O2 has been used in influential adult and

Classification of shock

Decreased oxygen

delivery

Reduced blood flow Hypovolemic shock Blood/plasma loss Haemorrhage

Dehydration

Cardiogenic shock Reduced myocardial

contractility

Myocarditis

Cardiomyopathy

Ischaemia

Increased afterload Obstruction to the left or right

ventricle outflow tract

Increased systemic or pulmonary

vascular resistance

Decreased ventricular

filling

Reduced volume

Decreased filling time- tachycardia

Altered distribution

of flow

Anaphylactic shock

Spinal/neurogenic shock

Septic shock

Decreased oxygen

content

Acute hypoxaemic

respiratory failure

Decreased Hb carrying

capacity

Carbon monoxide poisoning

Decreased oxygen

extraction

Inability to utilize

delivered oxygen

Septic shock Mitochondrial disfunction

Endothelial dysfunction

Dissociative shock Mitochondrial dysfunction Cyanide poisoning

Table 1

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paediatric studies as a target for shock therapy. Improved sur-

vival was demonstrated in these studies when this target was

included in therapy goals, however central venous saturation

may be falsely high in situations where the O2ER is severely

impaired such as mitochondrial disease.

How do inotropes work: back to medical school

Inotropes largely mediate their actions via stimulation of a1, b1,b2 adrenoceptors and Dopaminergic receptors varyingly distrib-

uted throughout the tissues (Table 2).

The paediatric evidence base for the use of vasoactive agents is

sparse, so there is a paucity of data regarding developmental

pharmacodynamics and the myriad adverse effects. Some adverse

effects are secondary to an agent’s haemodynamic profile, such as

regional vasoconstriction leading to tissue ischaemia; others are a

consequence of interactions with cellular energy metabolism and

the inflammatory response mechanism.

Adrenergic, dopaminergic and vasopressin receptors e

distribution and effect

b1-adrenoceptor stimulation increases myocardial contrac-

tility via Ca2þ-mediated actinemyosin complex binding with

troponin-C, and increases heart rate through Ca2þ channel

activation.

b2-adrenoceptor stimulation causes vasodilation due to

relaxation of vascular smooth muscle cells following

increased Ca2þ uptake by the sarcoplasmic reticulum.

a1-adrenoceptors stimulation on arterial vascular smooth

muscle cells leads to smooth muscle contraction, and an

increased SVRD1 and D2 dopaminergic receptor stimulation in the renal and

splanchnic vascular beds results in respective vasodilation via

activation of second-messenger systems.

V1-V1a stimulation in vascular smooth muscle causes

vasoconstriction.

However, whilst genetic variations in adrenoceptors distribution

are being explored in both hypertension and asthma, little is

known about how this influences inotrope efficacy.

The drugs themselves (finally)

Endogenous inotropes and vasoactive agents

Adrenaline (epinephrine in American): adrenaline is an endog-

enous catecholamine secreted by the adrenaline gland which is an

agonist to all adrenoceptors. It causes a wide array of

Summary of adrenergic, dopaminergic and vasopressin receptors characteristics

Receptor type Affinity to effectors Distribution Effect

a1 AD ¼ NA

High dose Dopamine

Arteriolar smooth muscleþþ

Including large coronary arteries

Vasoconstriction

a2 AD > NA

High dose Dopamine

Arteriolar smooth muscleþ

Including large coronary arteries

Vasoconstriction

Arteriolar endothelium Vasodilatation

b1 AD < NA Myocardiumþþ Inotropy [

Conduction system Chronotropy [

Large and small coronary arteries smooth muscleþþ Vasodilatation

Arteriolar smooth muscleþ (splanchnic,

pulmonary and skeletal)

Vasodilatation

b2 AD > NA Myocardiumþ Inotropy [

Conduction system Chronotropy [

Large and small Coronary arteries smooth muscleþ Vasodilatation

Arteriolar smooth muscleþþ (splanchnic,

pulmonary and skeletal)

Vasodilatation

D1 Dopamine Postsynaptic peripheral vasculature Vasodilatation

Myocardium Inotropy

Kidney Diuresis

Natriuresis

D2 Dopamine Presynaptic in peripheral vasculature Vasodilatation

Myocardium Inotropy

Kidney Diuresis

Natriuresis

V1 Vasopressin V1a e Vascular smooth muscle Vasoconstriction

V1be adenohypophysis Modulation of function

V2 Vasopressin e high

affinity

Cortical collecting tubule Increased water permeability

Vascular endothelium Release of von Willebrand factor and factor 8

The þ signs define the relative distribution of the receptor and the extent of its effect in various tissues.

Table 2

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cardiovascular, metabolic, endocrine and immunological effects.

In the cardiovascular system low dose adrenaline infusion (0.05

e0.1 mcg/kg/min) mainly affects cardiac b1 receptors which re-

sults in increasedcontractility, heart rate and coronary blood flow,

but also a theoretically detrimental increase in myocardial oxygen

requirement. At these doses there is also b2 receptor-activated

vasodilatation that decreases both SVR and PVR, contributing to

improved CO. Between 0.1 mcg/kg/minute and 1 mcg/kg/minutea receptor mediated vasoconstriction is counterbalanced by b2-

receptor mediated vasodilatation, but at greater doses vasocon-

striction predominates potentially compromising organ perfusion,

for example in severe septic shock adrenaline decreases

splanchnic blood flow in comparison with NA.

Adrenaline has considerable non-haemodynamic effects:

hyperglycaemia is induced by inhibition of insulin release,

stimulation of glucagon release and hepatic glycogenolysis and

gluconeogenesis; lipolysis raises plasma free fatty acid levels and

b2 receptor activation mediates increased lactate secondary to

increased oxygen consumption (Levy et al. 417e21). In the im-

mune system, b2 receptor stimulation induces leucocytosis from

the marginal pool although adrenaline is also associated with latephase immunosuppression. Adrenaline has also been shown to

be pro-thrombotic inducing release of factor 8 and von Wille-

brand factor and also promoting platelet aggregation.

Whereas low dose adrenaline can be safely administered

through a peripheral intravenous line central or even intra-

osseous access is recommended for high dose adrenaline because

of the risk of extravasation and tissue necrosis due to local

vasoconstriction (ACCM ref). The overall recommended dose

ranges between 0.05 and 2 mcg/kg/minute.

Noradrenaline (Norepinephrine): noradrenaline is a potent a1

and b1 agonist with minimal effects on b2 receptors and so the

main cardiovascular effect is vasoconstriction, leading toincreased SVR and blood pressure. The expected cardiac b1

adrenoceptors mediated chronotropic effect is blunted by

increased blood pressure induced vagal responses, so that

although SV increases CO is relatively unchanged. Although

coronary blood flow is increased owing to b1 mediated vasodi-

latation and increased BP, splanchnic, cutaneous, pulmonary

and renal blood flow decreases with increasing concentration of

NA. Cerebral blood flow is preserved as the distribution of

adrenoceptors in the CNS vasculature is minimal.

Whilst noradrenaline has fewer non-haemodynamic effects

than adrenaline, causing only a modest rise in serum glucose and

no lactate increase, it does increase bacterial iron uptake and

hence growth rate. A recent prospective study of adults withseptic shock demonstrated noradrenaline to be inversely associ-

ated with IL-8 and TNF-a levels and hence less proinflammatory

than adrenaline.

Noradrenaline should be administered through a central

venous access due to possible extreme vasoconstriction. The

infusion rate is 0.05e2 mcg/kg/minute.

Dopamine: dopamine, a precursor of noradrenaline and adren-

aline acts as a neurotransmitter in the nervous system and as a

humeral factor when secreted from the adrenal gland. It agonizes

both dopaminergic and adrenergic receptors, although the latter

requires higher plasma concentration due to lower affinity.

Dopaminergic receptors in the kidneys, mesenteric vascula-

ture and coronary arteries are activated by infusion rates up to

5mcg/kg/minute leading to vasodilatation with improved coro-

nary, renal and splanchnic blood flow, and increased CO. A

direct effect on renal tubules leading to diuresis and natriuresis

has been argued, though others consider this secondary to

increased CO per se.

At infusion rates 5e

10 mcg/kg/minute b-adrenoceptor medi-ated inotropy and chronotropy lead to improved CO and higher

systolic BP.

With infusions exceeding 10 mcg/kg/minute (maximum 20

mcg/kg/minute) a adrenoceptor-induced vasoconstriction pre-

vails, causing increased SVR to the extent that CO and regional

blood flow may be compromised. Furthermore, increased

arrhythmia has been reported during Dopamine treatment in

septic shock.

Extra-haemodynamic effects include suppression of growth

hormone, thyroid stimulating hormone and prolactin release in

addition to lymphocytic apoptosis, immunosuppression and an

overall proinflammatory cytokine profile. Due to this dopamine

use in adult practice has decreased, though it remains acommonly used agent in paediatric practice.

A diluted solution can be safely given peripherally before

central access is secured.

Vasopressin: vasopressin is a hormone released from the pos-

terior pituitary in response to stimuli from chemical, osmotic and

baroreceptors and exerts its effect on V1 and the higher affinity

V2 receptors. In the normovolaemic state circulating vasopressin

has little effect on vascular tone, but helps to maintain BP during

hypovolaemia. The haemodynamic effects of vasopressin are

mediated throughV1 receptors causing significant vasoconstric-

tion and increase in SVR. The resulting decrease in splanchnic

blood flow is so substantial that vasopressin is used to treat GIbleeding. Through the stimulation of V2 receptors, vasopressin

triggers water absorption in the kidneys and procoagulant factors

release from the endothelium. Increased levels of vasopressin

have been demonstrated in haemorrhagic shock however, there

is evidence that this compensatory response is blunted in septic

shock.

Vasopressin should be administered through central venous

access in a dose that ranges from 0.01 to 0.12 units/kg/h.

Exogenous inotropes and vasoactive agents

Dobutamine: dobutamine is a synthetic catecholamine binding

b1 and b2 receptors in 3:1 ratio, with some a receptor agonism. It

is available as a compound of two isomers, the (þ

) isomer is apotent b1 agonist and a1 antagonist and the (-) isomer a weak b1

antagonist and a strong a1 agonist. Due to the opposing a effects

inotropy predominates, but with increased myocardial oxygen

demand and marked chronotropy, which can limit ventricular

filling time and therefore use in septic shock. The main indication

is short term cardiac support in cardiogenic and septic shock

with infusion rates 5e20 mcg/kg/min, which may be given

dilute via a peripheral vein.

Phenylephrine: phenylephrine is an extremely potent selective

a1 agonist, leading too vasoconstriction with increased SVR and

BP but occasional reflex bradycardia and significantly reduced

OCCASIONAL REVIEW






splanchnic blood flow. It is used to restore vascular tone in spi-

nal/neurogenic shock and can be given as an intravenous bolus

or continuous infusion titrated to response.

Phosphodiesterase inhibitors: milrinone is a potent selective

inhibitor of phosphodiesterase III that causes an increase in

cAMP and PKA levels in a non-receptor dependant fashion.

Milrinone is an inodilator causing enhanced inotropy, lusitropyand to a lesser extent chronotropy along with vasodilatation of

the pulmonary and systemic vasculature. As a result of the

decrease in the afterload to both ventricles there is no significant

increase in the cardiac oxygen demands despite the increase in

contractility and rate. The use of milrinone is widespread in

cardiac intensive care to treat heart failure and post cardiac

surgery. In general paediatric critical care it may be used to treat

pulmonary hypertension and as an adjunctive medication in

cardiogenic shock to support the failing heart and in ’cold’

septic shock with reasonable BP to improve the peripheral

perfusion and CO. Adverse effects include hypotension,

arrhythmia, and thrombocytopaenia (rare) and impaired liver

enzymes.Milrinone is administered in a continuous infusion ranging

from 0.25 to 1 mcg/kg/minute. Due to long half-life a loading

dose (20e50 mcg/kg) may be administered depending on blood

pressure. Milrinone may be administered through a peripheral

venous access, but must be used with caution in renal impair-

ment as it undergoes renal excretion.

Enoximone is a PDEIII inhibitor with greater affinity to b1

cAMP hydrolysis inhibition consequently exerting its inotropic

effect mainly in the myocardium with minimal vasodilatation.

Levosimendan: levosimendan binds to troponin-C and acts as a

myofilament calcium sensitizer and opens ATP-dependant po-

tassium channels. It is an inotropic and also vasodilates bothcoronary and peripheral vessels. Levosimendan has minimal ef-

fect on myocardial oxygen consumption and does not interfere

with diastolic relaxation (Tavares et al. S112eS120). In adult in

cardiogenic shock after myocardial infarction there is haemody-

namic benefit but to date no demonstrable survival benefit in

either cardiogenic shock or acute heart failure. In adult septic

shock Levosimendan improves ejection fraction, SV, CI, urine

output and gastric mucosal perfusion compared with dobutamine

and has been shown to improve both right ventricular perfor-

mance and mixed venous oxygen saturation.

In the children Levosimendan is at least as effective as mil-

rinone after congenital cardiac surgery.

A loading does of 6e

12 mg/kg over 10 minutes is followed byan infusion of 0.05e0.2 mg/kg/minute, with a haemodynamic

effect within 5 minutes.

Selection of inotropic and vasoactive agents in shock

Traditionally in paediatric septic shock the first and most crucial

step is timely adequate volume resuscitation, with repeated bo-

luses of 20 ml/kg of isotonic fluids given until clinical parameters

such as peripheral perfusion and heart rate improve. With this

approach adequate fluid resuscitation is a prerequisite for ino-

trope therapy. Arguably, the FEAST study e which demonstrated

increased mortality in developing world population with lone

administration of fluids in septic shock e confirmed the ACCM

guidelines suggestion that early inotropes during fluid resusci-

tation are warranted.

In definite cardiogenic shock judicious fluid management is

needed due to the risk of causing pulmonary oedema with severe

left ventricular dysfunction. In fact this approach, mindful of the

Starling curve of the LV, may well offer optimal resuscitation in

all shock, although the skill to quantify SV at the bedside is not

widespread. However, if the problem is predominantly diastolicdysfunction, e.g. tamponade, fluid resuscitation remains impor-

tant but ought to be administered in a specialist cardiac centre.

It is also of note that acidosis, frequently encountered in shock

states, results in decreased adrenoceptor responsiveness: hence

correction of acidosis should be considered to optimize cate-

cholamine effect.

A recent Cochrane review demonstrated no mortality differ-

ence between different vasopressors in adult and paediatric hy-

potensive shock, either alone or in combination. However, given

the knowledge of the therapeutic properties and adverse events

of the various vasoactive and inotropic agents, the dynamic na-

ture of shock and the differences between adult and paediatric

shock states it is sensible to tailor the haemodynamic support tothe individual patient.

Septic shock: sepsis, SIRS and septic shock are now well defined,

with septic shock basically haemodynamic compromise compli-

cating a severe infection. It is characterized by circulatory organ

system failure in the presence of systemic inflammatory response

syndrome, immune dysregulation, microcirculatory de-

rangements, and end-organ dysfunction. The major pathophysi-

ological abnormalities are vasoconstriction or dilation together

with inflammation and increased microvascular permeability

leading to leucocyte accumulation in tissues remote to the

infective source. All these derangements affect the pharmacoki-

netics and pharmacodynamics of vasoactive drugs. The meta-bolism and clearance of drugs may be altered due to

redistribution of flow resulting in splanchnic hypoperfusion in

addition to the altered cellular metabolism secondary to the

‘cytokine storm’. The volume of distribution of any infused drug

is also affected by increased capillary permeability. Sustained

activation of adrenoceptors in sepsis can result in down-

regulation and desensitization of both a and b receptors as

well as reduced generation of new adrenoceptors, all worsened

by any endotoxins that downregulate adenylatecyclase.

As a result any recommended vasoactive dose should be regar-

ded as a starting point with titration to individual response neces-

sary. Furthermore, the manifestation of shock in children evolves

over time, with the haemodynamic pattern changing necessitatingfrequent reassessment and change of vasoactive agents.

Children often present in "cold" shock with decreased CO

with often increased SVR, rather than in the adult pattern of high-

output vasodilatation.

Dopamine or low dose adrenaline can both be safely adminis-

tered via peripheral cannula and therefore are the first line vaso-

active agents recommended to reverse shock by the ACCM. Above

10 mcg/kg/min of Dopamineavasoconstrictive effects prevail and

counteract positive inotropy if shock persists after 10 mcg/kg/min

dopamine the addition of another agent is recommended. In

normotensive septic shock dobutamine may be considered as the

initial agent.

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If the shock persists (catecholamine resistant shock), steroids

should be administered if a potential steroid deficiency is sus-

pected. Adding a third agent should be considered according to

the evolution of the shock. In normotensive "cold" shock with

low CO, the circulation may improve by administering an ino-

dilator such as milrinone or a direct vasodilator to decrease SVR.

Hypotensive "cold" shock may benefit from titrating adrenaline,

dobutamine and noradrenaline. Noradrenaline may be used earlyin hypotensive "warm" shock to increase SVR or as a counter

measure to milrinone-induced hypotension.

In most adults with septic shock, and some children, the

haemodynamic presentation is "warm shock" with low SVR,

hypotension and increased CO. Noradrenaline is the recom-

mended first line agent in adults in fluid refractory vasodilated

shock with reduced 28-day mortality compared to Dopamine

probably due to less arrhythmic events and relative lack of

proinflammatory effect. Paediatric practice is mixed, though NA

used is increasing.

In refractory vasodilatory paediatric shock administration of

vasopressin improves the haemodynamic state, although urine

output and creatinine can be reversibly compromised andthrombocytopenia can occur.

Enoximone and Levosimendan may be added as well in shock

states refractory to catecholamines and vasopressors.

Cardiogenic shock: excluding cardiac surgery patient cardio-

genic shock in the PICU is most often due to myocarditis, dilated

cardiomyopathy (DCMP) and arrhythmia. Arrhythmia is treated

with rate and rhythm control measures, not least because ino-

tropes can be detrimental. In myocarditis/DCMP inotropes and

vasodilators are the main agents used, though increased

myocardial oxygen consumption can be a problem. For cardiac

tamponade whilst aggressive fluid therapy to restore right ven-

tricular filling pressure is useful, evacuation of pericardial fluid isthe mainstay of treatment.

In low CO state with reasonable BP, In low CO state with

reasonable BP, Dopamine and dobutamine at a dose up to 10

mcg/kg/minute results in improved contractility along with a

reduction in SVR hence providing relief of myocardial work. Low

dose AD will also have positive inotropic effect while causing

vasodilation, though low diastolic pressure can impair coronary

perfusion. Milrinone can improve diastolic function and provide

positive inotropy whilst reducing SVR and PVR without

increased myocardial oxygen demand.

In hypotensive cardiac shock titration of Dopamine, AD, or

even judicious NA can be used to achieve positive inotropy and

vasoconstrictor support whilst adequate preload is restored.

Neurogenic shock: neurogenic/spinal shock results in profound

hypotension secondary too sympathetic denervation of the

vasculature and heart. There is extreme vasodilatation, with

some decreased inotropy and chronotropy. Initial fluid resusci-

tation to ensure adequate circulatory volume is recommended

before inotrope use with NA recommended due to strong a

mediated vasoconstriction as well as some inotropy and chro-

notropy whereas AD or Dopamine even at high doses do not

adequately reverse peripheral vascular failure. Alternatively, a

combination of an inotrope with a potent vasoconstrictor such asPhenylephrine can be used.

Failure of shock reversal

If shock cannot be reversed mechanical support may be indi-

cated, depending on the chance of eventual reversal of the

pathophysiology.

Conclusion

Selecting the appropriate vasoactive agent in any shock state is

influenced by many variables. The dynamic evolution of the

shock and its effects on the pharmacodynamics and pharmaco-

kinetics of the different agents, the vast array of non-haemody-

namic effects exerted by various agents along with the lack of evidence from randomized control trials in the paediatric popu-

lation contribute to the complexity of shock treatment. The key

message is to start with a reasonable agent given the manifes-

tation of shock at presentation, and to then frequently reassess

and alter the haemodynamic support as necessary. A

FURTHER READING

Brierley J, Carcillo JA, Choong K, 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 2009; 37: 666e

88.Ceneviva G, Paschall JA, Maffei F, Carcillo JA. Hemodynamic support in

fluid-refractory pediatric septic shock. Pediatrics 1998; 102: e19.

de Oliveira CF, de Oliveira DS, Gottschald AF, et al. ACCM/PALS haemo-

dynamic support guidelines for paediatric septic shock: an outcomes

comparison with and without monitoring central venous oxygen

saturation. Intensive Care Med 2008; 34: 1065e75.

Goldstein B, Giroir B, Randolph A. International pediatric sepsis

consensus conference: definitions for sepsis and organ dysfunction in

pediatrics. Pediatr Crit Care Med 2005; 6: 2e8.

Lemson J, Nusmeier A, van der Hoeven JG. Advanced hemodynamic

monitoring in critically ill children. Pediatrics 2011; 128: 560e71.

MacLaren G, Butt W, Best D, Donath S, Taylor A. Extracorporeal membrane

oxygenation for refractory septic shock in children: one institution’sexperience. Pediatr Crit Care Med 2007; 8: 447e51.

Nichols D. Rogers handbook of pediatric intensive care. Woltors Kluwer,

ISBN 078178705X; 2008.

OCCASIONAL REVIEW




Cual Inotropico

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