Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

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Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal

Transcript of Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Page 1: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Treating Hypotension and Shock in the Newborn

Keith J Barrington

CHU Sainte Justine, Montreal

Page 2: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.
Page 3: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Disclosure

I have no relevant financial relationships with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in this CME activity.

None of the medications that I will discuss are labelled for neonatal use.

Page 4: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Hypotension in Preterm Infants

Common practice in the NICU, to treat preterm infants with a mean arterial blood pressure in mmHg < gestational age in weeks, regardless of clinical signs,

Many receive a fluid bolus (or 2 or 3 or 4) and then dopamine.

If the blood pressure remains « low » then dobutamine is added, and/or hydrocortisone.

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Other hemodynamic interventions

Infants with asphyxia Infants with PPHNBabies with septic shock

– Often receive multiple interventions to support the circulation.

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Violette day 1

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Cardiovascular function in the newborn

Ultrastructural:Cellular:Metabolic:Functional:Vascular:

Factors are different in the neonate

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Ultrastructure Adult & Neonatal myocyte from

the rabbit. Far fewer contractile elements. More mitochondria. Increased non

contractile elements in cells. Disorganised orientation of

myofibrils. Altered shape of cells….relatively

short and round. Characteristic banding not clearly

apparent. Decreased sarcoplasmic reticulum. Relationship of SR to sarcomere

not developed. T-tubules not fully developed.

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Ventricular compliance in the newborn

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Cellular mechanismsExcitation/contraction coupling is normally

triggered by an influx of Ca into the cells.Ca initially enters across the sarcolemmal

membrane and then causes a secondary release of Ca from SR. (Ca induced Ca release).

SR in the newborn is decreased in concentration and functionally immature.

In the newborn the lack of SR means that all the calcium crosses the sarcolemma.

Ca induced Ca release is absent at birth.

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Metabolic Neonatal myocardium utilises glucose as a substrate in

preference to fatty acids. Adult myocardium uses fatty acids, in particular palmitic

acid.

– Change from neonatal to adult pattern of substrate utilisation occurs during first week.

Greater resting myocardial blood flows and oxygen consumption.

Less depression of contractility during acidosis.

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FunctionalDespite all these limitations, neonatal hearts

generate high cardiac outputs and have extraordinary performance.

Newborn lambs for example generate 400 ml/kg/min, and stroke volumes of 2 ml/kg cf adult sheep who have Q of 100 ml/kg/min and SV of 1 ml/kg.

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Functional Neonatal hearts are functionally immature and are

operating at such a relatively high performance that:– There is little contractile reserve. – Frank Starling curve is flatter in newborns. – Newborns normally operate near flat portion of the curve.– Neonatal hearts are intolerant of afterload.– The right ventricle is more markedly affected by increased

afterload, but the left doesn’t do very well either.

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Effect of afterload: neonatal lamb

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Catecholamine receptors The catecholamines stimulate a variety of receptors which

are usually categorized as 1, 2 , 1 , 2 , DA1 and DA2. Traditionally, dopamine is said to stimulate DA receptors

at low concentrations, receptors at moderate concentrations, and receptors at high concentrations.

In reality: Dopamine has virtually no effect at the receptor, and

very little at the 1 receptor

Enormous variation in serum concentrations are obtained by the same administered dose of drug, as much as 100 fold variations may be seen.

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Sympathetic innervation Cardiac sympathetic innervation is incomplete at birth. The various adrenoceptors appear at differing periods of

ontogenesis. The pattern of their appearance is not well defined. receptors increase in density in late gestation. High cardiac output at birth may partly be mediated by the

presence of many functional receptors. Further stimulation of these receptors in early life, e.g. with

isoproterenol, does not much increase cardiac function. receptors may appear prior to the receptor.

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Myocardial adrenoceptors Dopamine receptors are present in the mature

coronary circulation but not in myocardium. Frequently stated that dopamine’s inotropic effects are

due to release of endogenous norepinephrine from sympathetic nerve endings (tyramine-like effect).

Dopamine therefore may have indirect and effects on the myocardium.– Rapid tachyphylaxis

The incomplete innervation of the neonatal heart means that this effect is of little importance in the newborn.

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Newborn hearts are not small adult

Hearts!

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Vascular catecholamine receptors

There is much less information regarding the rates of appearance and maturation of vascular adrenoceptors.

1 receptors are present in neonatal peripheral circulation and respond to 1 stimulants such as phenylephrine.

1 receptors appear to be relatively lacking in the pulmonary circulation of the lamb.

Vascularreceptors are next to appear. DA receptors probably largely become active

during postnatal life.

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Immature subjects react differently

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Topics

PPHNSeptic ShockCardiogenic ShockHypotension in the ELGAN

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What is PPHN

Many infants with hypoxia and PHN do not have detectable R-L shunts at either the foramen ovale or ductus arteriosus1.

The most severely hypoxic infants are more likely to have such shunts,

Documented R-L shunts not required for PHN diagnosis in any of the iNO studies.

– In 1 study PHN= Echo estimated peak systolic PA pressure > 35 mmHg

– Abnormal, but will it cause left to right shunting?

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What is PPHN?

If no detectable extrapulmonary shunt then what causes hypoxia?

Hypoxia in infants without extrapulmonary shunt is due to ventilation perfusion mismatch. i.e. underventilated areas of perfused lung.

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Hypoxic respiratory failure

Under-ventilated perfused areas of lung are sometimes referred to as ‘intrapulmonary shunts’, (literally true when atelectatic areas of lung are perfused)

Intrapulmonary shunting does not require suprasystemic PA pressures.

Majority of infants with “PPHN” and abnormal chest x-ray have moderate elevations of PA pressure, problems in oxygenation are commonly due to major ventilation perfusion mismatch

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Why does this matter?

If R-L ductal shunting is prominent, then interventions to selectively elevate systemic pressures may decrease shunting (although they may not improve systemic O2 delivery!)

If oxygenation problems are due to VQ mismatch, then pushing up the systemic pressures with vasoconstrictors is likely to only decrease systemic O2 delivery.

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Goals of treatment

Intact survival (obviously!) Maintain or Improve oxygen delivery to vital organs

– Improve systemic perfusion– Improve VQ matching

• Elevate systemic pressures Interrupt process of PHN

– Dilate pulmonary circulation– Specific interventions

Minimize iatrogenic injury

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Oxygen delivery

Volume of blood ejected from left ventricleOxygen content of that bloodNet shunting across the ductus

– Net left to right shunting will DECREASE O2 delivery

– Net right to left shunting will INCREASE O2 delivery

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Intracardiac shunts

Foraminal shunting depends on inter-atrial pressure gradients

Atrial pressures largely dependent on ventricular end-diastolic pressures

Therefore depend on ventricular function (compliance, preload, contractility)

Improving right ventricular function will decrease right to left inter-atrial shunting

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So What works?

For what therapies are there good data, from prospective trials, demonstrating improved clinically important outcomes:– iNO

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Inhaled Nitric Oxide

Improves survival without ECMO for term infants with respiratory failure and an OI greater than 25

True whether or not an echocardiogram has confirmed PHN

Why would it work if there is not definite PHN? Improves VQ matchingDecreases RV afterload

– Improves RV function

Page 31: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.
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My research assistants

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Inhaled NO

3 day old piglets with meconium aspiration with a closed duct

Rapid increase in systemic PO2 after iNO– Improved VQ match

• Barrington KJ et al Pediatric Pulmonology 1995.

Page 34: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Inhaled NO

Piglets with infusion of killed GBS Remained normoxic, but developed severe pulmonary

hypertension (which never exceeds systemic pressure!) Majority die within 6 hours Progressive reduction in cardiac index

With inhaled NO treatment, PA pressures fall, cardiac index maintained for 6 hours

No effect on oxygenation Piglets survive

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Page 36: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Best uncontrolled data

Steinhorn et al: prospective cohort study of clinical responses and pharmacokinetics of intravenous sildenafil in 36 term neonates with OI > 15

Page 37: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Other uncontrolled data

Case Series and case reports• Prostanoids

– Iloprost

– epoprostanol

• Endothelin antagonists– Bosentan

• Magnesium

• Adenosine

Page 38: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Where are we now?

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What probably doesn’t work

Systemic tolazolineHyperventilationBicarbonate infusion

Paralysis– deafness

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Adverse effects of Hyperventilation

Hyperventilated piglets with or without added CO2– Isolate effects of respiratory alkalosis from

mechanical effects

Progressive systemic hypotension, increase in the PVR/SVR ratio

Exaggerated increase in the PVR/SVR ratio after 4 hours of respiratory alkalosis

Page 41: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Jundi et al 2000

In the hyperventilated normocarbic group: no changes

Page 42: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Adverse effects of hyperventilation

Decreases cerebral perfusionAssociated with hearing loss and neurologic

injury in follow-up studies of infants who survived

Induces hypocalcemia, and myocardial dysfunction

Page 43: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Adverse effects of Bicarbonate

Worsens intracellular acidosisNo evidence of beneficial effectMulti-center observational study

demonstrated:marked variation in use of bicarbonate

between centers, Centers that used more bicarbonate had more

infants progress to needing ECMO

Page 44: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Cardiovascular support

What improves oxygen delivery?What affects PVR?What affects SVR?

In human neonates with PPHN, very difficult to answer

Page 45: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Cardiovascular Support

Prospective comparative trials– Clinically important outcomes

• None– Short term physiologic outcomes

• None

Before and after trials of individual agents– A few!

Observational studies

Animal data

Page 46: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Dopamine, animal data

Stimulates α1, α2 and β1-receptors and specific dopaminergic receptors,

Generally, dopamine elevates both systemic and pulmonary artery pressures

Because neonatal myocardium is very sensitive to increased afterload, cardiac output often falls

Extremely high dopamine doses may increase SVR more than PVR, but are probably dangerous

No renal vasodilatory effect– Coronary vasoconstriction

Little evidence of increased oxygen delivery with dopamine No evidence of improved clinical outcomes

Page 47: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Dopamine and renal perfusion:chronic piglet model

Pearson RJ, Barrington KJ, Jirsch DW, Cheung PY. Dopaminergic receptor-mediated effects in the mesenteric vasculature and renal vasculature of the chronically instrumented newborn piglet. Crit Care Med 1996 Oct;24(10):1706-12.

Dopamine dosage (g/kg.min)

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Page 48: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

The Pituitary and the blood brain barrier.

The pituitary and the anterior hypothalamus are outside of the barrier

Dopamine is an important neurotransmitter with endocrine effects

Page 49: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Effects of stopping dopamine

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Dopamine and thyroid suppression in the newborn

Filippi L, Cecchi A, Tronchin M, Dani C, Pezzati M, Seminara S, et al. Dopamine infusion and

hypothyroxinaemia in very low birth weight preterm infants. Eur J Pediatr 2004 Jan;163(1):7-13.

Page 51: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Low dose dopamine = Pituitary dose dopamine

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Epinephrine, animal data

Stimulates α1, α2, β1 and β2 receptorsSome evidence that Systemic pressure

increase more than pulmonary In standard doses, beta effects predominate

(up to 0.2 mcg/kg/min?), high doses will cause vasoconstriction

Improves renal perfusion in hypoxic animals

Page 53: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.
Page 54: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Norepinephrine

Largely α effects : little β activity(some β1) Seems to cause an NO mediated vasodilatation

in certain models of neonatal pulmonary hypertension

Pre/Post study in 18 newborns with hypoxic respiratory failure, increased saturations, systemic flow and blood pressure, and increased LPA flow

• Pierre Tourneux et al, Pulmonary Circulatory Effects of Norepinephrine in Newborn Infants with Persistent Pulmonary Hypertension J Pediatrics 2008.

Page 55: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Dobutamine, animal data

Little effect on baseline PA pressuresSome evidence of pulmonary vasodilatation

(and systemic) if baseline is elevatedAt high doses PA pressures may increase in

hypoxic piglets

Page 56: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Dobutamine response BP only increased at 50

g/kg.min (Cheung and Barrington 1998)

Cardiac output increased at 5 g/kg.min and above.

Vasodilatation seen at 5 g/kg.min and above.

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Page 57: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Milrinone, neonatal animal data

Specific phosphodiesterase III inhibitor Increases contractility and vasodilates in

mature modelsEffects in neonatal animal models variable,

may decrease, have no effect, or slightly increase contractility.

Page 58: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Immature subjects react differently

Page 59: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Oxygen may be toxic at term also!

Lakshminrusimha, 2008, normal lambs

Page 60: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Lambs with PPHN (antenatal DA ligation), resuscitated with 100%, 50% or 21% O2

Pulmonary vascular responsiveness examined afterward

Initial PVR dropped faster during those ventilated with 100% O2

Pulmonary vasculature was more reactive to hypoxia, and less responsive to NO after O2 resuscitation

Page 61: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.
Page 62: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Human Data?

There is no relevant data from human studies to determine whether maintaining higher than normal systemic or alveolar oxygenation is beneficial or harmful

Based on the available physiologic data the best approach is to give enough oxygen to achieve systemic normoxia

Aiming for higher than normal values risks pulmonary oxygen toxicity, risks impeding pulmonay vasorelaxation

Page 63: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Still with me?

Page 64: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Summary

Oxygen to achieve normoxia Respiratory support to optimize lung volume,

ventilation, surfactant... Avoid hyperventilation, bicarbonate, paralysis Cardiovascular support with epinephrine (or

norepinephrine? VERY LIMITED DATA) Nitric oxide to reduce RV afterload, improve VQ

matching Sedation if required, ? Fentanyl Research to determine whether any of this is true! And to evaluate sildenafil and other therapies

Page 65: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Generally:

Most babies with PPHN will eventually improve and survive

Therefore any uncontrolled study will seem to show benefit

EVEN IF THE STUDIED INTERVENTION IS INEFFECTIVE

It is vitally important to have controlled trials Why are there so few?

The NO studies showed that we are capable of performing such studies

Page 66: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

A Plea!

Controlled prospective studies in PPHN are possible

They are essential if we are to progress beyond our current state of knowledge

Page 67: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

What are the hemodynamic changes in Septic Shock in the newborn?

Probably different between G +ve and G-ve infections

May not be much different to older children, with vasodilatation in the G-ve, but vasoconstriction and early cardiac dysfunction in the G+ve

Page 68: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

What is ‘functional hypovolemia’ and how should we treat it?

Do all babies with septic shock require large volumes of fluid?– Recent RCT showed worse outcomes with

volume administration in children with early septic shock

Page 69: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Which inotrope/vasopressor for septic shock?

In adults, norepinephrine gives best hemodynamic profile, – little evidence of any difference in clinical

outcomes.

A ‘one size fits all’ approach is probably inappropriate

Individualization of the treatment makes more sense.

Page 70: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Septic Shock

30 newborn infants with refractory septic shock

Substantial improvement in blood pressure, urine output and pH within 2 hours of starting norepinephrine

2 deaths during acute phaseLong term outcomes poor

Page 71: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Septic Shock

Late onset sepsis – more often G-ve, vasodilatation, hypotension– Consider norepinephrine, ?hydrocortisone

Early onset sepsis– Variably G+ve, or –ve– Consider epinephrine, ?hydrocortisone

Page 72: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Current Canadian Practice:Hypotension in the ELGAN

120 questionnaires to neonatologists 79% final response – Respondents: 77% from units with > 50

VLBWs pa/ 43% with > 100 VLBWs pa. Criteria for diagnosing hypotension:

– 74% use both BP<GA (or another criterion) and clinical signs to define hypotension.

– 26% use BP alone, (most common, BP<GA)

Page 73: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Responses to Questionnaire: Therapeutic Options

Volume 1st-- 97%Dopamine is 1st drug --92%Three main patterns of treatment

– volume, dopamine, steroid (37%) – volume, dopamine, dobutamine(28%) – volume, dopamine, epinephrine (16%)

14% have protocols in place

Page 74: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Inotropes

Dopamine: starting dose range 2.5-10 g/kg/min – maximum dose 10-30

• The maximum dose for 7 respondents is the initial starting dose for 17 others.

Dobutamine: starting dose range 2-10 g/kg/min – maximum dose 10-20

Epinephrine: starting dose 0.01-0.1 g/kg/min– maximum dose 0.3-4.0

Page 75: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Steroid usage for BP

Usual corticosteroid administered is hydrocortisone (98%).

Initial doses varied 0.1–5 mg/kg/doseTotal daily doses range from 0.4-15

mg/kg/day.

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IVH frequency among VLBW infants, Synnes et al 2001

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Factors known to be associated with IVH

Prematurity Respiratory SupportHypocarbia Illness severity (SNAP-PE)OutbornNot receiving antenatal steroids

Page 78: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Adjusted Odds Ratios Synnes et al 2001

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Data of the CNN

Objective: Compare frequency of diagnosis of hypotension, using 4 different criteria, and the effects of that on relation between hypotension and IVH.

Methods: The highest and lowest BP are prospectively recorded for database, n= 16,007

1735 of the infants < 28 wks had head ultrasound data.

Results: 14.7% < 28 wks had severe IVH (Gd 3 or 4). Elevated BP- no apparent relationship with IVH.

Page 80: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

BP<Gestational age

Frequently used rule for hypotension, BP (mmHg) < GA (wk), defined 48% of <28wk as hypotensive at some time during day 1.

15.9% of the infants (<28 wk) with lowest recorded mean BP on day 1 < gestational age had a severe IVH.

13.3% of the infants not hypotensive by this rule had severe IVH.

Statistically significant (p < 0.05): not very useful! Multivariate analysis, including use of inotropes and

SNAP-PE score → no relation between “hypotension” and IVH: OR 1.19, p=NS.

Page 81: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Watkins charts

Using Watkins charts (10%les) 42,5% of the infants <28 wk classified as being hypotensive– Why not 10%? Cross sectional not longitudinal data, rapidly

changing variable More strongly associated with severe IVH (16.5% vs

11.4%): – Association disappeared after correction for use of inotropes.

Normotensive infants who received inotropes, (n=150) more severe IVH (17.9%) than hypotensive infants who did not receive inotropes (5.9%).

Page 82: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

The effects of hypotension

Are the adverse outcome effects of hypotension really the adverse effects of its treatment?

Alternative explanations:– SNAP does not represent all of the increased risk of

IVH?– Other factors associated with both IVH and inotrope

use? The association between inotrope usage and IVH

appears fairly robust.

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Mean BP of preterm infants. Watkins et al 1989.

20

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Is hypotension related to survival or long term outcomes?

Systematic review of the literature, examining 100’s of references, found 16 studies that looked carefully at this issue

The answer… Maybe! The majority of studies have shown some correlation

between lower BP and poor outcomes BUT Systematic biases in many of them:

– For example: same BP used as threshold for all infants (Miall-Allen et al 30 mmHg)

– If you use the same threshold for everyone, the more immature babies will be more likely hypotensive, and they have the worse outcomes

Page 85: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Does treatment of hypotension improve outcomes?

Fluid Boluses compared to no intervention

Cochrane review – Various fluids: including saline, albumin, plasma substitutes or

blood. – 5 studies compared volume to no treatment in patients without

cardiovascular compromise. – No controlled trials comparing the use of fluid boluses to no fluid

boluses in preterm infants with cardiovascular compromise, specifically hypotension.

– Therefore there is no level 1 or 2 evidence to support the use of volume for treatment of hypotension in the premature newborn with hypotension.

Page 86: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

?Benefits of fluid boluses

1 short term physiologic study (abstract only) 10 mL/kg 5% albumin to hypotensive preterms, ↑BP 2.7 mmHg LVO↑ ± 20% no effect on RVO– I.E. ductal shunting increased, but no effect on systemic blood flow.

Another uncontrolled study: 20 mL/kg of 10% albumin ↑ BP 4 mHg. ↑ LVO, (RVO not measured), left atrial and ventricular distension (but not right) after bolus, – also suggests that ductal shunting increased.

Osborn measured SVC flow and RVO in infants with low blood flow, (not necessarily hypotensive, mean BP 26 vs 30). With saline bolus 22% ↑ RVO – Infants all immediately started on an inotrope so duration of effect

unclear.

Importance of measuring both LVO and RVO

Page 87: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

LVO & RVO

Page 88: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

?Harms of fluid boluses

Potential for pulmonary, cardiovascular and CNS complications. – The volume of fluid administered during the first few days of life

in the preterm correlates with subsequent development of BPD. This correlation has been confirmed by a prospective

controlled trial which demonstrated improved survival and decreased bronchopulmonary dysplasia rates in preterm that were randomized to low fluid intakes versus those given a more liberal fluid intake.– In this study sodium intake was also different between groups

Goldberg found an increase in the incidence of IVH in preterm infants receiving rapid volume expansion.

Page 89: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

?Harms of fluid boluses

Greenough reported adverse neuro. outcomes in patients who received colloid infusion.

Multiple fluid boluses associated with increased mortality in the preterm infant.

The amount of sodium contained in a single fluid bolus is within the range shown in 2 randomized trials to increase BPD

Page 90: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

?Benefits of Inotropes

There are 4 trials of dopamine use in the preterm with untreated controls, in none were clinically important outcomes reported, and in none was hypotension required as an entry criterion.

Cuevas investigated routine use of low-dose dopamine in ventilated preterm infants, and showed no significant effect on renal function.

Systematic review concluded: No evidence that low dose dopamine has favourable effects on renal function, including urine flow and creatinine clearance, or clinical outcomes.

3 studies, investigating effects of dopamine on renal dysfunction due to indomethacin therapy, subject of a Cochrane Systematic Review,

no evidence of renal protection from dopamine during indomethacin therapy.

Page 91: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Hmmmm

Page 92: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

?Harms of inotropes: dopamine

Other catecholamines in therapeutic use have no action at the dopamine receptor.

Dopamine also stimulates the same receptors in the carotid body leading to a decrease in ventilation and respiratory drive. Dopamine impairs T-cell function.

Dopamine increases energy expenditure and lipolysis.

Page 93: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

?Harms of inotropes: dobutamine

Few toxic effects described Infants may become excessively tachycardic

during dobutamine therapy, reduction in dose is usually all that is required.

Dobutamine has metabolic effects, – study in lambs showed that any potential benefit of

increased oxygen delivery to the tissues was offset by an increase in tissue metabolic rate which “utilized” most of the increased amounts of oxygen delivered to the tissues.

No studies of this in the newborn human.

Page 94: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

?Harms of inotropes: epinephrine

Epinephrine directly impacts lactate metabolism – ↑ in lactate production and ↓ in lactate metabolism, leads to ↑ in

serum lactate during epinephrine treatment. At higher doses there may be an impairment of bowel

blood flow and oxygen delivery to the gut, this has been seen in some studies of septic adults.

Also occurred in acutely instrumented piglets during both normoxia and hypoxia, dose of 3.2 g/kg.min. – Presumably mediated effect, may not occur at lower doses.

Page 95: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Milrinone

Phosphodiesterase III inhibitors increase intracellular cAMP: inotropic effects and vasodilatation.

In neonatal models PDE III inhibitors have minimal effects, no effect, or even negative inotropic effects. – developmental imbalance between class III and class IV

Phosphodiesterase in neonatal sarcoplasmic reticulum. Negative inotropic effects in neonatal puppies become

positive in 1st few days after birth. The effects on preterm human myocardium are unknown

Page 96: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Milrinone

Vasodilatation may occur in newborn mammals (limited studies).

In dogs treatment with milrinone at 1 mg/kg produced lesions in the left ventricle and the right atrium.

Similar lesions noted with other inotropes; may occur whenever myocardial workload is increased, as this may exceed any increases in myocardial oxygen and substrate supply.

Page 97: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Benefits of glucocorticoids

Probably increase blood pressure:Gaisssmaier et al compared dexamethasone

versus placebo in hypotensive infants starting on an epinephrine infusion.

Both groups (total n=17) significant increase in BP at 4 hours: duration of epinephrine use significantly shorter in the steroid treated group.

Page 98: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Benefits of glucocorticoids

Two studies (abstracts) compared hydrocortisone versus placebo. – 1st randomized 26 “hypotensive” LBW neonates (all on dopamine at 20

g/kg/min) to receive 5mg/kg/day of hydrocortisone in 4 doses: those who received hydrocortisone had a more rapid increase in BP: placebo babies also had a sustained increase in BP. There was no difference in the incidence of IVH.

– 2nd randomized 24 neonates <1250 grams “hypotensive” on 1st day of life to hydrocortisone 20mg/kg/day in 4 doses or placebo. There was a statistically significant reduction in the amount of inotrope required. No difference noted in IVH rate, and no long-term data presented.

More recent study: randomized preterm infants with mean BP < GA, all receiving ≥ 10 g/kg/min of dopamine after ≥30 mL/kg of normal saline, to 3 mg/kg/d of hydrocortisone for 5 days.

Hydrocortisone infants had slightly faster increase in BP, but no clinical differences in outcomes

Page 99: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Harms of glucocorticoids

Too many slides needed! Short term

• Hyperglcemia• GI perforation• GI bleeding

Medium term• Decreased growth• Decreased brain growth• Cardiac hypertrophy• Increased sepsis, bacterial and fungal

Long term• Impaired neurodevelopment, especially motor function

Page 100: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Treatment of Hypotension

So why do people treat?« Hypotension impairs cerebral perfusion »« CBF is pressure passive… »Of course if you go to your family Doc for

a checkup you aren’t likely to be at significant risk of brain injury with life long consequences! (But you are at risk of complications from intervention)

Page 101: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Are any treatments of hypotension better than others?

Comparisons of two fluids Comparisons of 2 different fluids have been performed in 4 trials.

– 1 compared FFP to albumin in patients with systolic BP < 40 mmHg: no difference in the increase in systolic BP 1 and 4 hours post infusion, no clinically important outcomes were presented.

– No long-term data were presented.

Three other trials have compared 5% albumin to normal saline. – One found no difference in treatment failure or P/IVH or mortality. – Another found that the blood pressure increase was greater with colloid

than crystalloid, but no clinical outcomes were reported. – The third found no difference between fluids but no data on morbidity and

mortality were presented.

Page 102: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Comparisons of two inotropes

5 studies compare the effects of dopamine versus dobutamine in hypotensive babies

Cochrane review concludes dopamine more likely to increase BP than dobutamine but no evidence of a differential effect on clinical outcomes. – 3 had data on mortality, 3 had data on PVL and

2 had data on severe IVH, none of which were significantly different between the two drugs.

Page 103: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Comparisons of two inotropes

Further study compared dopamine to dobutamine in cases of low systemic flow during 1st twelve h.

42 patients initially received a 10ml/kg normal saline bolus followed by one inotrope or the other. Dopamine increased BP whereas dobutamine increased SVC flow. There was no difference in mortality or other clinically important outcomes

In 4 studies comparing dopamine to other inotropes blood flows have been measured. – All 4 showed when dopamine given in sufficient doses to increase BP

LVO decreased, by about 20%. In contrast dobutamine increased LVO in two of these studies and SVC flow in the other and epinephrine increased LVO and RVO.

– Only Roze et al reported clinically important outcomes, not different between groups.

Page 104: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Comparisons of 2 treatment modalities.

Cochrane review comparing early volume bolus with dopamine use. Two small randomized unblinded studies: both used albumin. Conclusion: dopamine was more successful than albumin at correcting

low BP, but no data on clinically important outcomes. – Lundstrom only enrolled preterm babies with a mean BP 29 to 40 mmHg. – Measured LVO (Doppler) and CBF (intravenous xenon clearance). Blood

pressure was increased 20% by dopamine, LVO was increased by 16% and cerebral blood flow was not significantly affected.

– I.E. systemic and cerebral vascular resistances were increased by dopamine, RVO not measured, therefore effects on systemic perfusion uncertain.

1 trial compared dopamine with hydrocortisone in hypotensive preterms. No significant difference in improvements in hypotension, no clinically important differences in the short term.

Page 105: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.
Page 106: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Why are preterm babies « hypotensive »

Most babies with BP lower than average have acceptable SVC flows

Some babies with « normal »BP have low flow Most babies with BP<20 mmHg have low flow. Most « hypotensive » babies have normal flow,

but low resistance: do they need any treatment?

Page 107: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Copyright ©2004 BMJ Publishing Group Ltd.

Osborn, D A et al. Arch. Dis. Child. Fetal Neonatal Ed. 2004;89:F168-F173

Figure 3 Scatter plot of mean blood pressure (BP) against superior vena cava (SVC) flow for all observations. Reference lines represent SVC flow of 41 ml/kg/min and mean BP of 30 mm Hg.

Page 108: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Where are we now?

Page 109: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Hypotension or shock?

DO2/VO2

Blo

od P

ress

ure

Page 110: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Results of retrospective cohort study

118 patients were admitted 2000-2003. BP data were available on 107, 53% of patients had BP < GA.

17/118 ELBW infants received treatment for Hypotension: – 11 received only an epinephrine infusion, – 4 had only a single fluid bolus (saline 10 ml/kg), and – 2 had a fluid bolus followed by epinephrine infusion.

4 other Hypotensive infants received only a blood transfusion, over 2 hr, as therapy.

Page 111: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

NormotensivePermissive

hypotensionTreated

Hypotension

Hypotensive, transfusion only

Number 52 34 18 4Necrotizing

enterocolitis, n (%)

4 (8%) 3 (9%) 2 (11%) 2 (50%)

Surgical NEC, n 1 1 1 0Isolated GI

perforation, n 2 0 1 0

IVH 3 or 4, n 2 4 5 2

Cystic PVL, n 1 0 0 0

Mortality, n 10 4 13* 2Survival without

severe IVH, cystic PVL, surgical NEC, or GI perforation, n (%)

40 (77%) 26 (76%) 4* (22%) 1 (25%)

Page 112: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Results

Overall survival of ELBW was 73%6% of the ELBW infants received a fluid

bolus9% of the ELBW infants received inotropes

Page 113: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Results

Recent publication shows:– Up to 98% of ELGA infants receive fluid boluses, often

multiple times

– Up to 78% of ELGA infants receive inotrope infusions, often dopamine

– Many ELGA infants are receiving steroids to elevate blood pressure.

Our data suggest that most of those babies would do well without intervention.

Page 114: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Hypotension without shock

Infants who are hypotensive but clinically well-perfused probably have adequate tissue oxygen delivery

They have good clinical outcomesThey probably do not need any intervention

Page 115: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Shock

Infants with poor perfusion have poor outcomes May benefit from intervention, but very little data to guide

therapy If BP is adequate a vasodilator that supports cardiac

function might be the best idea– Dobutamine, low dose epinephrine

If BP is low then cardiac support and BP support both may be needed– Moderate dose epinephrine, ?combinations

Fluid boluses and stress-dose glucocorticoids might have a role in the presence of shock, especially when due to sepsis, but supportive data entirely based on adult studies– Bacteriology, Hemodynamics, complications completely different

Page 116: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.

Conclusion

Very little good data to support evidence based guidelines

Hypotensive babies who are well perfused may not need any treatment– As they are treated so frequently in some centers we need good

prospective trials to prove whether or not there is a benefit. Babies with poor perfusion do badly, individualizing the

interventions, by measurements of relevant physiologic endpoints such as blood flow, serum lactate etc. may help us to improve care.

Page 117: Treating Hypotension and Shock in the Newborn Keith J Barrington CHU Sainte Justine, Montreal.