Comparisons of two inotropes

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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.
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.
Other hemodynamic
interventions
 Infants with asphyxia
 Infants with PPHN
 Babies with septic shock
– Often receive multiple interventions to support
the circulation.
Violette day 1
Cardiovascular function in the
newborn
 Ultrastructural:
 Cellular:
 Metabolic:
 Functional:
 Vascular:
Factors are different in the neonate
Ultrastructure
 Adult & Neonatal myocyte from
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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.
Ventricular compliance in the
newborn
Cellular mechanisms
 Excitation/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.
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.
Functional
 Despite 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.
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.
Effect of afterload: neonatal
lamb
Catecholamine receptors
 The catecholamines stimulate a variety of receptors which
are usually categorized as a1, a2 , b1 , b2 , DA1 and DA2.
 Traditionally, dopamine is said to stimulate DA receptors
at low concentrations, b receptors at moderate
concentrations, and a receptors at high concentrations.
 In reality:
 Dopamine has virtually no effect at the b2 receptor, and
very little at the b1 receptor
 Enormous variation in serum concentrations are obtained
by the same administered dose of drug, as much as 100
fold variations may be seen.
Sympathetic innervation
 Cardiac sympathetic innervation is incomplete at birth.
 The various adrenoceptors appear at differing periods of

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ontogenesis.
The pattern of their appearance is not well defined.
b receptors increase in density in late gestation.
High cardiac output at birth may partly be mediated by the
presence of many functional b receptors.
Further stimulation of these receptors in early life, e.g.
with isoproterenol, does not much increase cardiac
function.
a1 receptors may appear prior to the b receptor.
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 a and b effects
on the myocardium.
– Rapid tachyphylaxis
 The incomplete innervation of the neonatal heart
means that this effect is of little importance in the
newborn.
Newborn hearts are
not small adult
Hearts!
Vascular catecholamine
receptors
 There is much less information regarding the
rates of appearance and maturation of vascular
adrenoceptors.
 a1 receptors are present in neonatal peripheral
circulation and respond to a1 stimulants such
as phenylephrine.
 a1 receptors appear to be relatively lacking in
the pulmonary circulation of the lamb.
 Vascular b receptors are next to appear.
 DA receptors probably largely become active
during postnatal life.
Immature
subjects
react
differently
Topics
 PPHN
 Septic Shock
 Cardiogenic Shock
 Hypotension in the ELGAN
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?
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.
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
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.
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
Oxygen delivery
 Volume of blood ejected from left ventricle
 Oxygen content of that blood
 Net shunting across the ductus
– Net left to right shunting will DECREASE O2
delivery
– Net right to left shunting will INCREASE O2
delivery
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
So What works?
 For what therapies are there good data, from
prospective trials, demonstrating improved
clinically important outcomes:
– iNO
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 matching
 Decreases RV afterload
My research assistants
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.
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
Best uncontrolled data
 Steinhorn et al: prospective cohort study of
clinical responses and pharmacokinetics of
intravenous sildenafil in 36 term neonates
with OI > 15
Other uncontrolled data
 Case Series and case reports
• Prostanoids
– Iloprost
– epoprostanol
• Endothelin antagonists
– Bosentan
• Magnesium
• Adenosine
Where are we now?
What probably doesn’t work
 Systemic tolazoline
 Hyperventilation
 Bicarbonate infusion
 Paralysis
– deafness
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
Jundi et al 2000
 In the hyperventilated normocarbic group:
no changes
Adverse effects of
hyperventilation
 Decreases cerebral perfusion
 Associated with hearing loss and neurologic
injury in follow-up studies of infants who
survived
 Induces hypocalcemia, and
 myocardial dysfunction
Adverse effects of
Bicarbonate
 Worsens intracellular acidosis
 No evidence of beneficial effect
 Multi-center observational study
demonstrated:
 marked variation in use of bicarbonate
between centers,
 Centers that used more bicarbonate had
more infants progress to needing ECMO
Cardiovascular support
 What improves oxygen delivery?
 What affects PVR?
 What affects SVR?
 In human neonates with PPHN, very
difficult to answer
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
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
% change in blood pressure
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.
% change in renal artery flow
Pearson RJ, Barrington KJ,
20
10
0
-10
-20
-30
-40
-50
% change in renal vascular resistance
Dopamine and
renal perfusion:
chronic piglet
model
40
30
20
10
0
-10
-20


100
80
60
40
20
0
-20
-40

2
4
8
16
32
Dopamine dosage (g/kg.min)
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
Effects of stopping dopamine
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.
Low dose dopamine
= Pituitary
dose dopamine
Epinephrine, animal data
 Stimulates α1, α2, β1 and β2 receptors
 Some 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
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.
Dobutamine, animal data
 Little effect on baseline PA pressures
 Some evidence of pulmonary vasodilatation
(and systemic) if baseline is elevated
 At high doses PA pressures may increase in
hypoxic piglets
Cardiac Index
(mL/kg.min)
Dobutamine
response
 BP only increased at 50
*
*

*
*
Systemic blood pressure
mean, (mmHg)
Baseline 5
Systemic vascular resistance
index (mmHg/mL/kg.min)
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.
300
280
260
240
220
200
180
160
140
120
10
20
50
100
95
90
85
80
75
70
65
*
Baseline 5
10
20
50
0.6
0.5
* * * *
0.4
0.3
0.2
Baseline 5
10
20
50
Dobutamine dose (g/kg.min)
Milrinone, neonatal animal
data
 Specific phosphodiesterase III inhibitor
 Increases contractility and vasodilates in
mature models
 Effects in neonatal animal models variable,
may decrease, have no effect, or slightly
increase contractility.
Immature
subjects
react
differently
Oxygen may be toxic at term
also!
 Lakshminrusimha, 2008, normal lambs
 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
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
Still with me?
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
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
A Plea!
 Controlled prospective studies in PPHN are
possible
 They are essential if we are to progress
beyond our current state of knowledge
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
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
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.
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 phase
 Long term outcomes poor
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
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)
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
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
Steroid usage for BP
 Usual corticosteroid administered is
hydrocortisone (98%).
 Initial doses varied 0.1–5 mg/kg/dose
 Total daily doses range from 0.4-15
mg/kg/day.
IVH frequency among VLBW infants,
Synnes et al 2001
Factors known to be
associated with IVH
 Prematurity
 Respiratory Support
 Hypocarbia
 Illness severity (SNAP-PE)
 Outborn
 Not receiving antenatal steroids
Adjusted Odds Ratios
Synnes et al 2001
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.
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.
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%).
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.
Mean BP of preterm infants. Watkins et al
1989.
40
38
10 %ile of mean BP
36
500g
600g
700g
800g
900g
1000g
1100g
1200g
1300g
1400g
1500g
34
32
30
28
26
24
22
20
3
12
24
36
48
60
Age (hrs)
72
84
96
Is hypotension related to
survival or long term
outcomes?
 Systematic review of the literature, examining 100’s of
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
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 (MiallAllen 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
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.
?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
LVO & RVO
?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.
?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
?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.
Hmmmm
?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.
?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.
?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 a mediated effect, may not occur at lower doses.
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
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.
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.
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
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
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)
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.
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.
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.
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.
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?
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.
Osborn, D A et al. Arch. Dis. Child. Fetal Neonatal Ed. 2004;89:F168-F173
Copyright ©2004 BMJ Publishing Group Ltd.
Where are we now?
Blood Pressure
Hypotension or shock?
DO2/VO2
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.
Normotensive
Permissive
hypotension
Treated
Hypotension
Hypotensive,
transfusion
only
Number
52
34
18
4
Necrotizing
enterocolitis,
n (%)
4 (8%)
3 (9%)
2 (11%)
2 (50%)
Surgical NEC, n
1
1
1
0
Isolated 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*
2
Survival without
severe IVH,
cystic PVL,
surgical NEC,
or GI
perforation, n
(%)
40 (77%)
26 (76%)
4* (22%)
1 (25%)
Results
 Overall survival of ELBW was 73%
 6% of the ELBW infants received a fluid
bolus
 9% of the ELBW infants received inotropes
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.
Hypotension without shock
 Infants who are hypotensive but clinically
well-perfused probably have adequate tissue
oxygen delivery
 They have good clinical outcomes
 They probably do not need any intervention
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
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.
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