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Hypotension and shock in the preterm infant

Keith J. Barrington*

McGill University, NICU, Royal Victoria Hospital, 687 Pine Ave W, Montreal, Quebec H3A 1A1, Canada

KEYWORDSHypotension;Inotrope;Preterm infant;Shock

Summary Between 16% and 98% of extremely preterm infants receive treatment for hypo-

tension in the first few days of life. This enormous variation has arisen because of a lack of re-

liable information to create an evidence base for intervention. This review article provides the

unique characteristics of the neonatal cardiovascular system, and addresses the definitions of

hypotension and shock in the preterm infant, the indications for treatment and appropriate

therapies in individual cases.

The treatment of shock and hypotension in the preterm infant may be the area of neonatol-

ogy where there is the greatest intervention/data imbalance; more babies receive moretreatments with less supportive evidence than in virtually any other domain.

Treatment of hypotension in infants with good perfusion is probably unnecessary and may be

harmful, but the assessment of adequate perfusion remains problematic. Infants with inade-

quate oxygen delivery to the tissues may benefit from treatment, but which treatments are

effective are unknown. It is essential that better evidence be available to create a rational ba-sis for intervention.

2007 Elsevier Ltd. All rights reserved.

Introduction

Large numbers of very premature infants receive cardio-vascular support in the first few days of life. The proportionreceiving such support varies dramatically between in-stitutions,1 with a maximum of 98% receiving therapy forhypotension in some neonatal intensive care units (NICUs).

The variations between NICUs are not accounted for byvariations in patient characteristics, but seem to result en-tirely from patterns of practice.1 Many neonatologists treatpremature infants solely on the basis of the numericalblood pressure (BP) value,2 while others require additionalclinical signs before intervening. Why are there such dis-crepancies? What do we really know about the diagnosis,

management and outcomes of hypotension in the preterminfant? The preterm infant is a unique patient, born duringdevelopment of the cardiovascular system, which makes itessential to have a basic understanding of some of the ma-jor aspects of developmental cardiovascular physiology.

The unique characteristics of the neonatal

cardiovascular system

At the subcellular level, the newborn myocardium differssubstantially from the mature myocardium, particularly inthe lack of sarcoplasmic reticulum3 and a poorly formed orabsent t-tubule system. The myofibrils are shorter andmore rounded, with a much higher number of mitochondria,and are relatively disorganised.4 The myocardium containsmuch more fibrous non-contractile tissue and has reducedsympathetic innervation.5 Despite these limitations, the

* Tel.: 1 514 934 1934x34876; fax: 1 514 843 1741.E-mail address: [email protected]

1744-165X/$ - see front matter 2007 Elsevier Ltd. All rights reserved.doi:10.1016/j.siny.2007.09.002

a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / s i n y

Seminars in Fetal & Neonatal Medicine (2008) 13, 16e23
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neonatal myocardium operates at a very high functionallevel, with a much higher cardiac output than older individ-uals, and is therefore working at near maximal capacity withvery little contractile reserve.6 There is a very limitedability to increase cardiac output in response to drugs orchanges in loading conditions,6 and an elevated sensitivityto increased afterload,7 which commonly leads to decreasesin cardiac output.8 Many of the drugs used for cardiac sup-

port increase afterload; this effect may lessen the cardiacoutput responses to any positive inotropic effect. If after-load is increased sufficiently, cardiac output may falldespite a positive inotropic intervention, the so-calledinotropic/afterload imbalance.

Responses to catecholamine agents

Most inotropic medications used in the newborn are cate-cholamines; responses to these drugsare receptor-mediated.The receptors were initially divided into a- and b-receptors,and more recently into a1-, a2-, b1- and b2-receptors, andtheir subtypes. Thea1-receptors are post-synapticand linked

to phospholipase C through a stimulatory G-protein; they arefound both in the myocardium and in the vasculature.Stimulation of a1-receptors causes an increase in the inotro-pic state of the heart, as well as an increase in vascular tone,leading to increases in BP and increases in afterload. Thea2-receptor is a pre-synaptic receptor involved in theregulation of norepinephrine release and mediates an in-crease in vascular tone. b1-receptors are present mostlyin the heart, increase cyclic AMP levels through a G-protein-dependent pathway and increase both heart rate and theinotropic state of the myocardium. b2-receptors largelycause vasodilation and bronchodilation; they may mediatean increased heart rate, partly through reflex action andpartly through a minor direct action.

Specific dopaminergic receptors consist of five geneti-cally different receptors, which fall into two groups, thed1-like (consisting of the d1 and d5 receptor), and the d2-like (consisting of the d2, d3 and d4 receptors). The d1-likereceptors are largely post-synaptic and G-protein-depen-dent, coupled to adenyl cyclase and phospholipase C. Theymediate vasodilation in the circulations of the kidneys,bowel, myocardium and brain.9 The d2-like receptors areboth pre- and post-synaptic and inhibit adenyl cyclase ac-tivity. Limited physiological effects on tubular function ofthe kidney have been described.

Adrenergic receptor ontogeny

At birth, there are limited a-receptors and little sympa-thetic innervation of the myocardium. However, those thatare present may exhibit so-called denervation hypersensi-tivity, whereby they are maximally stimulated by smallconcentrations of catecholamines.5 The haemodynamic ef-fects, which result from stimulation of these receptors,are minor, because of the aforementioned limited capacityof neonatal myocardium to increase its inotropic state. Incontrast, the density of b-adrenoceptors, which is low atages equivalent to extreme preterm delivery, appears to in-crease during the later part of gestation10 and the density ofthe b-receptors at term gestational age is actually increased

compared to older subjects. Similar to the responses to a-adrenergic agents, b-receptor stimulation in the newbornhas a limited effect on myocardial contractility.11

In the developing peripheral vasculature, there appearsto be fewer b2-receptors12 but many active a1-receptors.Thus, vasoconstriction from a1-adrenoceptor stimulationcan cause marked increases in systemic vascular resistance.The increases in vascular resistance and BP evident from

controlled and uncontrolled experience with inotropesdemonstrate that these receptors must be active in the pre-term human infant. Administering the selective a1-agonistphenylephrine causes major increases in vascular resis-tance; despite a-adrenergic stimulation of the myocardium,the increase in afterload leads to a decrease in cardiac out-put and there results a minor increase in BP.13

The development of the dopaminergic receptor appearsto be more complex in that the d1-receptors are present inthe renal circulation of the newborn mammal, but selec-tively stimulating these receptors appears to have noeffect.9,14 This is probably because the dopaminergic recep-tor is not linked to post-receptor events,9 even though thepost-receptor mechanisms are intact, in what appears to

be a lack of linkage of the d1-receptor to the stimulatoryG-protein. In the bowel, however, a decrease in mesentericvascular resistance is detectable with high doses of the se-lective d1-agonist, fenoldopam.14 The pattern of matura-tion of these receptors in other regional circulations, suchas the coronary or cerebral circulations, is not known.

Catecholamines

Dopamine

Dopamine stimulates a1-receptors, a2-receptors, b1-

receptors and specific dopaminergic receptors. The myththat low-dose dopamine in the newborn causes selectiverenal vasodilation, medium-dose dopamine causes generalvasodilation and inotropy, and high-dose dopamine causesvasoconstriction must be dismissed. This information wasderived from studies in healthy adult dogs and is clearly notgeneralisable to critically ill newborn infants.15 Dopaminehas little or no b2 activity16 and has not been demonstratedto cause b2-mediated vasodilation.16 At the b1-receptor,dopamine is 30e40 times less potent than either epineph-rine or norepinephrine. Thus, dopamine primarily has a1 ef-fects, some a2 effects and dopaminergic effects.

Dopamine pharmacokinetics is very variable in thenewborn; the same administered dose may produce serum

concentrations varying by as much as 100-fold.17 This re-sults from variable clearance, probably because of variableactivity of the three different enzyme systems metabolisingdopamine. There are also variations in receptor density andaffinity, which lead to marked inter-individual variations inactions of dopamine and of all of these drugs, for that mat-ter. The same pharmacokinetic variability probably appliesto the other inotropic agents, which have, however, beenstudied much less.

Toxicities

Dopamine is an important neurotransmitter. Althoughsystemically administered dopamine does not cross the

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bloodebrain barrier in large quantity, the anterior mediumeminence of the hypothalamus and the pituitary are out-side of this barrier. The d2-receptors are important inendocrine regulation; systemically administered dopamine,even at very low doses, has profound endocrine effects.Thus, during dopamine therapy, prolactin productioncompletely stops, growth hormone pulses disappear andthyrotropin-releasing hormone production is inhibited,

leading to a reduction in thyroxine and triiodothyronine(T3).18 Low levels of thyroxine and T3 are associated withpoor neurodevelopmental outcome of preterm infants. Do-pamine is sometimes administered over many days in thiscritical phase of brain development. It seems unlikelythat the suppression of thyroid function, which is a conse-quence, is beneficial to the infant (although it has notbeen proven to be harmful). Other catecholamines in ther-apeutic use have no action at the dopamine receptor.

Dopamine also stimulates the same receptors in thecarotid body leading to a decrease in ventilation andrespiratory drive.19 Dopamine may also impair T-cell func-tion20 and increase energy expenditure and lipolysis.21

Dobutamine

Dobutamine was synthesised with the intention of creatinga selective b1-agonist. However, its functions are actuallyquite complex, with the two stereoisomers of dobutamine,both present in the clinical product, having various degrees ofaction at both a- and b-receptors. Overall, dobutamine is aneffective inotropic agent, which also causes vasodilation andcauses mild tachycardia. At very high doses of dobutamine,BP may sometimes increase22 and there may also be an in-crease in systemic vascular resistance, probably because ofthe stimulation of the a-receptor by the () enantiomer.

ToxicitiesFew toxic effects have been associated with dobutamine;infants may become excessively tachycardic during dobut-amine therapy, but a reduction in dose is usually all that isrequired. Dobutamine also appears to have metaboliceffects. A study in lambs suggested that any potentialbenefit of increased oxygen delivery to the tissues wasoffset by an increase in tissue metabolic rate.23 There ap-pear to be no studies that have examined the relative in-creases in oxygen delivery and oxygen consumption duringinotrope therapy in the human newborn.

Epinephrine

Epinephrine stimulates a1-, a2-, b1- and b2-receptors andcauses vasodilation at very low doses, an inotropic actionthat appears to increase as the dose increases, and beginsto cause significant vasoconstriction at high doses.24 At veryhigh doses, the vasoconstriction is sufficient to overcomethe inotropic benefits and cardiac output may begin tofall.25 Thus, epinephrine at low doses will probably increasecardiac output and at moderate doses will likely increaseBP as well, but studies in humans are limited.

Toxicities

Epinephrine directly impacts lactate metabolism, causingan increase in lactate production and a decrease in lactate

metabolism, leading to increased serum lactate concentra-tions.26 At higher doses, there may be an impairment ofbowel blood flow and oxygen delivery to the gut, as seenin some studies of septic adults and in acutely instrumentedpiglets at a dose of 3.2 mg/kg/min.26 This is presumably ana-mediated effect and does not seem to be occur at lowerdoses.

Norepinephrine

Norepinephrine has not been studied much in neonatalmodels, presumably because of its lower affinity for the b2receptor. Norephinephrine is therefore more likely to causevasoconstriction compared to epinephrine. For this reason,it has been widely used in adults for gram-negative sepsisand warm shock, in whom improvements in tissue oxygendelivery and urine output may result.27 Since vasodilatedseptic shock is not commonly seen in the newborn, norepi-nephrine probably has a limited place.

Non-catechol inotrope/pressor agents

Agents that block the action of phosphodiesterase III havebeen used in adults and older children with some effect.The drugs increase intracellular cAMP, which leads to bothinotropic effects and vasodilation. However, in neonatalmammalian models, class III phosphodiesterase (PDE) in-hibitors have minimal effects, no effect, or even negativeinotropic effects, perhaps because of a developmentalimbalance between class III and class IV PDE in neonatalsarcoplasmic reticulum. The effects on the preterm humanmyocardium are unknown and clearly cannot be predictedfrom animal studies. In contrast, vasodilation has beennoted in limited neonatal studies.28 Milrinone may haveother adverse effects. In dogs, milrinone at 1 mg/kg

produced lesions in the left ventricle and the right atrium.Similar lesions have been noted with other inotropes orpressors; they may occur whenever myocardial workloadis increased, as this may exceed any increases in myocar-dial oxygen and substrate supply.

Other agents undergoing extensive evaluation in oldersubjects, such as levosimendan, are completely unstudiedin the newborn. Given the brief review of developmentalcardiovascular physiology above, it is clear that very care-ful evaluation of any agent is required before using it in thenewborn infant.

The definition of hypotension and shock

Hypotension

Blood pressures are normally lower in more immatureinfants. Normal BP is also lower immediately after birth,progressively increasing thereafter.29 Hypotension could bedefined statistically by taking the mean minus two standarddeviations at each postnatal and postmenstrual age. Hypo-tension, as defined statistically, in the majority of infants isstill associated with normal systemic blood flow30 and lowsystemic vascular resistance. Hypotension could also bedefined as an unsafe BP, i.e. a BP below which outcomesare worse. More valuable still would be an operational

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definition, i.e. a threshold pressure, below which interven-tion has been shown to improve outcomes.

We recently performed a systematic review to look forevidence that a particular BP threshold was associated withan increase in poor outcomes.31 There does appear to bea broad association between lower BP and an increase in ul-trasound-diagnosed brain injury. However, it is not possibleto determine at what BP threshold this occurs, or whether

the effect is independent of treatment. In many studies,the normal values were constructed after excluding infantswho received treatment for hypotension, while the infantswho received treatment were then included when ascer-taining the risk of hypotension. In some studies, the sameBP threshold was applied for infants of all gestationalages, but the most immature infants, at greatest risk ofpoor outcomes, have the lowest BP; therefore, this kindof analysis will show an artefactual association betweenhypotension and brain injury. In numerous studies, thesame BP threshold was applied at all postnatal ages; asBP normally increases spontaneously in the first week oflife, infants who have a BP below a threshold on, for exam-ple, day 7, are much more severely hypotensive than those

whose BP is below the same threshold on day 1. Suchmethods of data analysis generate biases that cannot beovercome by multivariate statistical manipulation of thedata. The definition of hypotension, therefore, remainselusive.

Shock

Shock is a pathological state in which tissue oxygen deliveryis inadequate to meet demand. Thus, the occurrence ofshock depends on systemic blood flow, the oxygen contentof the blood and oxygen demand. The balance betweenoxygen delivery and oxygen demand is difficult to assess inthe clinical situation. Measurements of flow are only onepart of this equation. In animal models, the mixed venouspartial pressure of oxygen (PO2) is the single best measure-ment to indicate the adequacy of oxygen delivery to satisfydemands. However, this measurement is almost neveravailable in the premature infant. Right atrial PO2 or oxy-gen (O2) saturation, which is limited even in the absenceof shunts because of incomplete mixing, may be contami-nated in the newborn by inter-atrial shunting.

Evaluation of shock in the newborn infant

The diagnosis of shock is suggested by the appearance ofprolonged capillary filling, reduced strength of peripheral

pulses, cool skin, lethargy, oliguria, increasing lactate con-centrations and a progressive anion-gap acidosis. Directmeasurement of systemic blood flow must take into accountthe common occurrence of shunts in the newborn. Leftventricular output, for example, equals pulmonary bloodflow (plus or minus any net foraminal shunting), unless theductus arteriosus is shown to be closed. Either pulmonaryarteryflow (ifnet foraminal shuntingis minimal)as a measureof total systemic blood flow, or selectivemeasurementof theflow in the superior vena cava, can give valuable informationabout systemic perfusion.30 Measurements which take intoaccount thebalance betweensupply and demand include se-rum lactate concentration,26,32 and decreased intracellular

pH as determined by gastric tonometry, currently being in-vestigated in the newborn.

Clinical signsThe relative sensitivity of any of these clinical or laboratoryfindings for detecting shock as defined above is unknown.Capillary filling has been correlated with systemic bloodflows in preterm infants33; there is a statistically significant

correlation, but a great deal of scatter. Urine output is nor-mally low on the first day of life and the use of oliguria as anestimate of renal perfusion is therefore problematic. It islikely that no single clinical sign of decreased perfusion isimportant by itself, but the overall assessment of the infantby an experienced individual does appear to identify infantswith poor outcomes.34

Serum lactate concentrations and outcomesThe relationship between absolute serum lactate concen-trations and an increasing trend in concentrations are bothassociated with adverse outcomes.32 In term and preterminfants, these factors can be used for prediction of mortal-

ity and there is an association between neurological out-comes and peak serum lactate concentration.35 However,routinely measuring serum lactate, which in order to be ac-curate should be obtained from a freely running blood sam-ple, sent on ice and analysed immediately, has not beendemonstrated to improve outcomes.

Intracellular pH by gastric tonometryIn many studies in adults and older children, intracellularpH as estimated by gastric tonometry has been shown to beassociated with short-term outcomes. As yet, humanneonatal data are limited,36 but the data suggest that thismay become a useful tool in the future. Randomised studies

to demonstrate whether outcomes are improved arewarranted.

Flow measurementsOxygen demand is different among categories of patients;hypoxia suppresses oxygen demand in the newborn,37

whereas oxygen demand may be increased in sepsis.38 Oxy-gen extraction at the tissue level may also be impaired incertain pathological states. For these reasons, low systemicblood flow, as an isolated variable in preterm infants, doesnot e by itself e define shock. However, this may be irrel-evant if it could be shown that outcomes are improved bymeasurement of flows and treatment according to lowflow states. Direct measurements of systemic blood flow,

championed by the group in Sydney, have been used toshow that low flows correlate with outcomes.39 However,does knowledge of flows allow more appropriate therapyand therefore improve outcomes? Although a reasonablehypothesis, this has not been proven and is amenable toclinical studies.

Hypotension without shock: treatmentworse than the disease?

It is unclear whether infants who are hypotensive, but haveadequate tissue oxygen delivery, require any treatment.



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Our systematic review mentioned above also addresseda second question: are there any reliable data to demon-strate that routine treatment of infants with statisticallylow BP improves outcomes? We were unable to find anyreliable evidence that treatment of low BP decreases braininjury or improves any other clinically important outcome.

In many NICUs, preterm infants with numerically low BPare routinely treated, and in fact are easily the largest

group of preterm infants who receive cardiovascular sup-port. Such infants will frequently receive one or severalboluses of fluid followed by dopamine (or occasionallyadditional catecholamines) followed by glucocorticoids ifthey do not respond. One common approach is to attemptto maintain the BP of all infants above a mean of30 mmHg,40 intervening with albumin, dopamine, dobut-amine and then glucocorticoids when this threshold is notreached. A mean BP of 30 mmHg is above the 50th percen-tile for infants of 25 weeks gestation at 3 h of age, and thusthe majority of infants in such units must receive interven-tion, despite no evidence of benefit and substantial risk ofharm. Presumably such infants are treated because of datafrom a prospective observational study,41 which demon-

strated a statistical association between a mean BP below30 mmHg and brain injury in preterm infants (nZ 9 withmajor intraventricular haemorrhage (IVH) or periventricu-lar leukomalacia). However, using the same threshold forinfants at different gestational ages will artefactuallyshow an association, as the more immature infants (whoare at greater risk of severe IVH) are more likely to bedeemed hypotensive. The commonest approach is to main-tain the BP above the gestational age in weeks.2 This ig-nores the usual spontaneous increase in BP over the firstfew postnatal days and there are no published data to sup-port this definition of hypotension.

Data from the Canadian Neonatal Network show sub-

stantial and statistically significant variations in IVH fre-quency among NICUs.42 These variations remained aftercorrection for multiple demographic factors and severityof illness. After further correction for the use of pressoragents and bicarbonate, all differences between NICUs dis-appeared. Another analysis of this dataset,43 which tookthe lowest recorded BP into account, showed that infantswho had a BP below their gestational age, or had a BP be-low the 10th percentile, had a slightly increased chanceof having a severe IVH, but this risk also disappeared aftercorrection for the use of pressors. Furthermore, the infantsin the database who had treatment with pressors, despitea BP that was never hypotensive according to these twocriteria, had a higher frequency of severe IVH than hypo-

tensive infants who were not treated. One potentialexplanation for this finding is that it is the treatment of hy-potension rather than hypotension, itself, which is harmful.

Fluid boluses

Fluid boluses are the usual first intervention in infants witha low BP;2 they are presumably given in the belief that suchinfants are hypovolemic. However, in most hypotensiveinfants, circulating blood volumes are normal and there islittle or no response to volume administration.44 Hypovole-mia rarely occurs, for example as a result of twinetwin

transfusion or following external haemorrhage; concealedhaemorrhage from feto-matenal bleeding is very uncom-mon at early gestational ages.

Fluid boluses in non-hypovolemic infants may not bebenign. In an observational study, Goldberg et al.45 foundan increase in the incidence of IVH in preterm infants re-ceiving rapid volume expansion. Adverse neurological out-comes have also been reported in preterm infants

receiving colloid infusion.46

Multiple fluid boluses are asso-ciated with increased mortality in the preterm infant.47

Furthermore, the amount of sodium contained in a singlefluid bolus is within the range shown in two randomised tri-als to increase bronchopulmonary dysplasia when given inthe first days of life.48,49

There is, therefore, no physiological justification to givefluid boluses to hypotensive preterm infants and no empir-ical evidence to support the practice, with observationaldata showing an association with worse outcomes.

Inotrope/pressor agents

Despite the treatment of many thousands of preterminfants with dopamine, the haemodynamic responses tothis agent, the clinical risk/benefit ratio and the long-termconsequences of its use are uncertain. Randomised trialshave shown that the increase in BP with dopamine is usuallyaccompanied by a decrease in left ventricular output,a decrease or no change in right ventricular output andsuperiorvena caval flows,50e53 and no improvement in con-tractility54 or cerebral perfusion.55 Thus, the main mecha-nism of the action of dopamine on BP appears to bevasoconstriction.56 Dobutamine in clinical studies is moreeffective at increasing systemic perfusion, but does not re-liably increase BP.53,57 Epinephrine has also been studiedvery little in prospective trials,52,58 and, although BP and

systemic flow appear to be increased, clinical outcomeshave not been shown to be superior to other treatments.

Glucocorticoids

Glucocorticoids are now prescribed to almost 10% of verylow birthweight infants for the management of hypotension,as shown in a recent prospective evaluation of postnatalglucocorticoid use.59 This has occurred despite potentialshort-term adverse effects and the lack of any data onlong-term follow-up. A randomised controlled trial (RCT)of dexamethasone versus placebo60 (nZ 17) found that, inboth groups, there was a significant increase in BP at 4 h

following infusion and that the duration of epinephrineuse was significantly shorter with dexamethasone. However,no improvements in clinical outcomes were shown. Nget al.61 randomised preterm infants with a mean arterialpressure below their gestational age (despite receiving atleast 30 mL/kg of normal saline and at least 10 mg/kg/minof dopamine) to 3 mg/kg/d of hydrocortisone for 5 days.The babies receiving hydrocortisone had a slightly faster in-crease in their BP, but no clinical difference in outcomeswas found. The use of glucocorticoids for prevention ortreatment of hypotension cannot be recommended unlessprospective RCTs demonstrate that clinical outcomes areimproved.

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Permissive hypotension

Many infants who are hypotensive have normal systemicblood flows, are clinically well perfused and can havea good short-term outcome without intervention.62 Thereappears to be no justification from the literature for thecommon practice of routinely intervening with potent andpotentially harmful therapies because a baby has a BP

less than the gestational age. Such an approach leads toa very high proportion of extremely preterm infants receiv-ing these interventions, up to 98% in some NICUs.1

For years in our NICU, we have only intervened forhypotension when infants showed clinical signs of poorperfusion. With such an approach, about 16% of extremelylow birth weight infants receive treatment. Infants who areclinically well perfused, but with lower than average BPs,have good short-34 and long-term outcomes without therapy.

Is there any risk to permissive hypotension? Whencerebral vasodilation is maximal, at low BP, it is possiblethat fluctuations in BP could put the cerebral circulation atrisk. This possibility makes it essential that prospectiveRCTs are performed to determine the appropriateness ofintervention for hypotension.

Shock without hypotension

When cardiac output is low, peripheral vasoconstriction willmaintain BP up to a certain limit; thus, shock can occurwithout hypotension. One common cause for shock is sepsis,but the haemodynamic features of sepsis in the humanneonate have not been well described. In newborn infants,the pathophysiology, bacteriology, haemodynamic responses,effects of manipulation of cardiac-loading conditions, toxic-ities of medications,and potential complications aredifferent

than in adults. The haemodynamics of sepsis in adults may bequite different and better models may be neonatal animalsinfected with the sameorganisms.63 In experimental newbornpiglets with sepsis induced by the Group B streptococcus, theearly changes consist of a rapid fall in cardiac output accom-panying an early and progressive pulmonary hypertensionand normal systemic BP, which is maintained by vigorous pe-ripheral vasoconstriction.64 As cardiac output falls further,there is hypotension in the pre-terminal phase. These changesare in contrast to those in adults with gram-negative sepsis,who frequently have increased cardiac output and are vasodi-lated and hypotensive, so-called warm shock. The vasodila-tion is largely a result of overproduction of nitric oxide in theperipheral circulation.

Adults with septic shock have improved outcomes withearly goal-directed therapy.65 Optimising therapy with thegoal of achieving a mixed venous oxygen saturation targetof 70% required more inotropes, more transfusions and ear-lier fluid boluses. Studies of goal-directed therapy in new-born infants with suspected septic shock are warranted.In view of the difficulty of obtaining mixed venous bloodin a newborn, different goals will have to be used. Treat-ments that may be appropriate for the septic adult maybe completely inappropriate for newborn infants, who usu-ally exhibit cold shock.

For infants who are shocked but normotensive, patho-physiologically appropriate therapy would be directed to

increase cardiac output while attempting to decreasesystemic and pulmonary vascular resistance. This wouldsuggest a preference for dobutamine, with low-dose epi-nephrine possibly being a reasonable alternative. Possiblyother vasodilators may have a role. Some infants with thishaemodynamic profile have persistent pulmonary hyper-tension of the newborn; decreasing pulmonary vascularresistance with inhaled nitric oxide may improve right

ventricular function, and therefore aid in the treatmentof shock, even when the infant is not hypoxic.64 If sepsis isthought likely, fluid boluses could be considered, perhapsafter institution of dobutamine or low-dose epinephrine.

Adults with septic shock have improved outcomes whenphysiological stress doses of corticosteroids are added totheir therapy. In contrast, outcomes with high-dose gluco-corticoids are substantially worse. In some studies, bothglucocorticoids and mineralocorticoids have been used.Whether glucocorticoids have a role in septic shock orother forms of shock in the newborn are unknown, andwhat dose should be used is also unknown.

Hypotension with shock

Infants who are both hypotensive and in shock will probablyhave very high morbidity and mortality. Pathophysiologi-cally appropriate therapy should be directed at increasingsystemic perfusion, while attempting to avoid the adverseeffects of increased afterload on myocardial function. Thissuggests that epinephrine may be the optimal single therapyand that close monitoring of cardiac function and bloodflows may help in determining the appropriate manipula-tions. Infants who are in shock and hypotensive are likely torequire higher doses of epinephrine, and possibly norepi-nephrine could be considered, but the effects on afterloadand potential decrease in systemic perfusion must be

closely monitored. Direct measurements of systemic bloodflow can help to make the therapy more rational and aid inensuring that increases in therapy actually improve flows.Consideration of fluid boluses and stress-dose glucocorti-coids may be reasonable, especially if sepsis is likely, buthave as yet not been definitively studied.

Summary

Interventions for different categories of patients should beindividualised. There is little reliable information on anappropriate response to infants with hypotension or differ-ent categories of shock. Although there are data suggesting

that some commonly used interventions increase BP, thereis little information about the effects on systemic flows andtissue oxygen delivery, little information about effects onoxygen demand, and almost no reliable information on theeffects of intervention on clinically important outcomes.

Infants who are hypotensive without shock probablyrequire no treatment, but only close observation and reas-sessment at frequent intervals. There is no reasonablerationale for the administration of fluid boluses to suchinfants, and dopamine and other vasoactive drugs may domore harm than good. Glucocorticoidsare poorly studied andcarry substantial risks. Permissive hypotension should bestudied prospectively.



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Studies investigating appropriate goals and goal-directedtherapy in neonates with shock are required in order tomake evidence-based recommendations. Meanwhile, path-ophysiology-based recommendations have been made, withthe understanding that such recommendations may beproven incorrect when evidence based on clinical outcomesbecomes available.66

It is essential that prospective controlled evaluations of

cardiovascular interventions for all of these categories ofpatients be performed, with the focus on clinically impor-tant outcomes.67 Measuring BP or flows or any other surro-gate outcomes is inadequate; effects on survival, braininjury and developmental sequelae are essential in futureinvestigations of these potent and toxic therapies. Only inthis way can we ensure that future cohorts of preterm in-fants will receive treatment that is safe, effective andbeneficial.

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Research directions

Prospective studies to evaluate appropriate crite-ria for intervention in extremely preterm infantsare required.

If appropriate criteria for intervention can be de-fined, then comparative studies randomly examin-ing fluid boluses versus no boluses, and variousinotrope/vasopressor agents are required.

The role, benefits and toxicities of the use of glu-cocorticoids for treatment of hypotension must bedefined by adequate prospective controlled trials.

Practice points

Cardiovascular physiology in the neonate is so dif-ferent that responses to interventions cannot beextrapolated from adults.

Many infants who are hypotensive by statisticaldefinitions have normal tissue oxygen delivery.

Infants who are hypotensive by statistical defini-tions and well perfused may not require anyintervention.

Infants who are in shock require individualised as-sessment and intervention.

22 K.J. Barrington


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