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DCC - How does it work: Transfusion, Hemodynamics, Stem Cells

or Hands Off?

Dr Martin Kluckow MBBS FRACP PhD CCPU

Professor, Neonatology Royal North Shore Hospital &

University of Sydney, Australia

Cardiovascular Resuscitation Deferred cord clamping

The first step in neonatal transition? ??Delaying resuscitation and worsening clinical outcomes

Early Cord Clamping §  Introduced into clinical practice without any trial §  Little historical or physiological rationale §  Reduce maternal PPH, less medication,

polycythemia/jaundice in baby §  Assumed infant better off with cord clamped and

being able to be resuscitated if needed (?in preterms too)

§  Vs the clinical benefits of DCC

Later cord clamping Potential mechanisms of benefit §  Placental transfusion §  Prevention of low systemic blood flow §  Sequencing of the transition §  Stem cell transfer §  Less intervention at birth

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PT – Does it really occur? Is it simply volume transfer?

In Favor §  Early placental drainage/

labeling studies §  Weight gain §  ñ Hematocrit §  Less blood T/F, inotropes §  Longer term iron studies

Against §  Euvolaemia §  ?Placental restoration –

vasoconstriction in the infant

§  None in LSCS/GA lambs §  Hematocrit change due to

some other effect

Conditions to allow PT

Lungs aerate

Placenta

RightHeart

Le0Heart

Upperbody

Lungs

Lowerbody

Ductus arteriosus

Foramen Ovale

=

the RITCHIE CENTRE

mimr-phi institute

Umbilical arteries Umbilical vein

•  Time •  Gravity •  Contractions •  Oxytocics •  Breathing/Crying •  Lung open •  LSCS/NVD •  UA vs UV flow

NET Flow into baby X X

In-utero Balanced Flow

Placental transfusion Umbilical vessel flow influence

Ultrasound assessment of flow prior to cord clamping(midwife decision) in 30 term infants

§  Flow often stopped at different times in UA/UV §  Pulsatility did not always mean flow §  Breathing/Crying a significant influence on flow §  Spontaneous breathing may inhibit flow (CPAP)* – closes off UV

*Brouwer et al In Press, Boere et al. Arch Dis Child 2014

Time Arterial flow Venous flow No flow at birth 17% 10% Flow stopped before cord clamped 40% (Avg 4:22 min) 57% (Avg 4:34 min) Flow continued until cord clamp 43% (Avg 5:16 min) 33% (Avg 5:13 min)

Later cord clamping = Placental transfusion

§  111 term infants – serum albumin labelling/placental drainage

§  Distribution between baby and placental circuits §  Birth 67/33 % §  1 min 80/20 % §  3 min 87/13 %

§  20% transferred

Yao et al Lancet 1969

67%

33%

80%

20%

87%

13%

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Later cord clamping Placental transfusion

§  46 Preterm infants in RCT ICC vs DCC(30 sec delay). §  Blood volume (biotin label) measured at 4 hrs

Aladangady et al. Pediatrics 2006

Placental transfusion Role of infant position

§  Infant position relevant to the placenta ?important determinant of transfusion volume

§  Multicenter trial - infant weight at birth & after 2 mins delay to cord cut, almost 400 babies

§  RCT at vaginal introitus or on mothers abdomen §  Mean weight gain in introitus position 56 gms (n=197),

chest/abdomen 53 gms (n=194) §  No difference §  Overall PT of 15mls/kg in 3.5kg infant

Vain et al. Lancet April 2014, Polgalse et al PAS 2015

Sheep studies Role of position/gravity

§  Anaesthetised newborn lambs– placed 10cm above or 10cm below the placenta

§  Minor variations in umbilical blood flows (often acute), no change in blood volume in either position overall

§  Lung inflation had more effect on blood flows

Polglase et al. Arch Dis Child 2016

Placental transfusion Role of uterine contraction

§  DCC studies have not reported timing of oxytocic administration

§  In lamb studies oxytocin with increased uterine contractions results in decreased UA and UV flow*

§  Clinical trials in humans - Vain 2019 (In Press) §  No difference in weight with oxytocin at birth vs post

DCC in infants receiving 3 min deferral of clamping

*Stenning et al ADC 2016 , Vain et al. Lancet April 2014

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Another way to assess possible hypovolaemia?

RA LA

RV LV

DUCT

Lungs

RV Output

LV Output

Body

= Systemic blood flow + PDA

= Systemic blood flow + PFO

SVC Flow

Superior Vena Cava flow (SVC flow)

Kluckow & Evans ADC 2000

Normal range

Low SVC flow: Relationship to grade 3 IVH.

IVH IVH

IVH IVH

0 10 20 30 40 50 60 70 80 90

0 12 24 36 48 Postnatal Age (hrs)

SVC

Flo

w (m

l/kg/

min

)

Kluckow & Evans Arch Dis Child 2000

Low SVC flow: Delayed Cord clamping êIVH.

Rabe et al Cochrane review 2012

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Delayed Cord clamping No longer protective of IVH.

Fogarty et al AJOG 2017

Severe intraventricular haemorrhage 11 trials / 2300 patients RR 0.87 [0.59, 1.27] Intraventricular haemorrhage - any 19 trials / 2871 patients RR 0.87 [0.75, 1.00] 13% vs 10%.

Hooper & Kluckow 2018

Study N Mean GA

Weeks

Intervention ICC SVC Flow (mL/kg/

min)

DCC SVC Flow (mL/kg/min)

Age (Hrs)

Meyer, 2012

30 26 DCC 30-40s 52 (42-100) 91 (81-101)* 16

Sommers,2012

51 28 DCC 41s vs 5s 89 ± 24 112 ± 30* 6

Popat, 2016

266 28 DCC 60s 92 ± 35 95 ± 41 3-6

Katheria 2016

125 28 DCC vs VDCC 86 ± 32$ 83 ± 26# <12

Hemodynamic effects of DCC

Later cord clamping Keeping the transition in sequence

Hooper, Polglase, Bhatt et al J Physiology 2013

Who in the audience has clamped the umbilical cord

of an apnoeic preterm infant?

the RITCHIE CENTRE

mimr-phi institute

RightHeart

Le0Heart

Upperbody

Lungs

Lowerbody

Newborn/Adult Fetus Placenta

RightHeart

Le0Heart

Upperbody

Lowerbody

Ductus arteriosus

Pre-ductal arteries

Foramen Ovale

X X

Lungs

Time (mins)

DA bl

ood f

low (m

L/min)

-400

-200

0

200

400

600

PBF (

mL/m

in)Le

ft pulm

onary

arter

y

0

50

100

150

200

250

300

0 12020 40 60BCO ACO

0 12020 40 60BCO ACO

Figure 2

a

bb

bc

c

d

eed

d

d

aa

bb

c

d

dd

cbc

Time (mins)

Cardiovascular transition at birth (modified from Prof Stuart Hooper)

Loss in venous return

reduces CO

LV Preload

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Ventilating before cord clamping

Lungs aerate

Placenta

RightHeart

Le0Heart

Upperbody

Lungs

Lowerbody

Ductus arteriosus

Foramen Ovale

X X

the RITCHIE CENTRE

mimr-phi institute

2] Avoid pressure/flow surge

1] Maintain venous return and cardiac output

3] *Avoid SpO2 drop

Ventilation before cord clamping stabilises the cardiovascular transition at birth

the RITCHIE CENTRE

mimr-phi institute

Clamp Clamp Vent Vent Vent Vent Clamp Clamp

Later cord clamping Role of lung inflation

§  Key initial event in transition: lung inflation resulting in a fall in pulmonary vascular resistance

§  Conversely, early clamping of the cord in a non breathing preterm infant may result in §  Sudden pressure surge in the systemic circulation(SVR↑) §  Reduced venous return to the left heart §  Reflex bradycardia

§  Inflation/ventilation of lungs PRIOR to cord clamping appears to prevent these changes

Dawes et al. J Physiol 1953, Bhatt et al J Physiology 2013

§  Earliest transfer of stem cells between mother and fetus is potentially during DCC - may confer long term protective effects against age related disorders

§  Early UCC may reduce the transfer of stem cells and increase risk of adverse outcomes

§  Cord blood transfusion is allowed to end physiologically in most placental mammals (ie. No cord clamping)

§  Are human infants being deprived of this?

Sanberg et al. PMC 2014

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§  Outcome of some placental transfusion trials have shown lower sepsis rates in in the transfusion arm

§  Mercer study showed reduced blood culture proven late onset sepsis in DCC group(3% vs 22%, p 0.03) – all infants with LOS had ICC.

§  APTS and subsequent meta-analysis did not support this §  Growing interest in umbilical cord blood collection for stem

cells (banking)

Stem cell transfer Clues?

Mercer et al, Pediatrics 2006

Cord blood banking & DCC

§  Umbilical cord blood is a well established stem cell source §  Can be used for public donation use or private/family use Single Centre study from USA Cord blood units(CBU) from 1210 mothers (collected from ex-utero drainage of placenta) §  Birth to clamp(BTC). DCC defined as BTC time >30secs §  Measured total nucleated cells(TNC) and weight/volume of

CBU collected vs BTC time

Umbilical cord stem cell transfer

Ciubotariu et al, Transfusion 2018

BTC time of more than 60 seconds resulted in §  A 10 fold decrease in successful recovery of CBU from

22% to 2.4% (p < 0.001). §  Significantly lower TNC counts (p < 0.0001). §  A significant increase in CBUs with volume less than 40

mL(not useable).

Umbilical cord stem cell transfer

Ciubotariu et al, Transfusion 2018

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Umbilical cord stem cell transfer

Ciubotariu et al, Transfusion 2018

§  DCC of >60 sec, by reducing the CBU collectable by ex-utero drainage, likely results in a significant transfer of stem cells to the baby – BUT none of the studies actually test this!

§  Are we “stealing” stem cells from the baby by either undertaking ICC or cord blood collection for stem cells?

Summary DCC Potential mechanisms of benefit § Placental transfusion § Prevention of low systemic blood flow § Keeping the transition in sequence –

inflate lungs before cord clamp § Stem cell transfer (theoretical) § ?Less intervention at birth - time for

spontaneous breathing and transition

Resuscitation:

...“To revive from apparent death or from unconsciousness”

? The RESUSCITATION team

Suction Cold mask application

Attempt intubation

=Vagal stimulation Apnoea & Bradycardia

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<32 weeks - % breathing by intervention (secs) N= 150

0 10 20 30 40 50 60 70 80 90

100

1-5 6-10 11-15 16-20 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60

DCC V-DCC

Katheria et al J Pediatrics 2016

30% 95%

Per

cent

bab

ies

Time (secs)

Later cord clamping -> increased numbers of very preterm infants

breathing by clamp time

Duration of DCC 30-45 sec vs 60-75 sec

Song et al. PLOS One 2015

Prospective observational study, 353 infants, Nursery outcomes

Resuscitation: Supporting the transition

Defer cord clamping

More spontaneous breathing Glottis open….

Less vagal influence/intubation An unexpected outcome of DCC

Research areas §  Transfusion/Blood volume vs timing

§  Both important – how to quantitate? Expired CO2/Weight §  Determinants of the placental transfusion

§  Time, Breathing, Umbilical vessel flows, Delivery mode. Position?, Oxytocin?

§  Stem cell transfusion – more research needed §  Resuscitation vs supporting the transition

§  Stimulate spontaneous breathing vs stimulate vagal reflexes? §  Clamp cord after lung inflation established §  Resuscitation if needed with intact cord ?Asphyxia

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Conclusions DCC § TIME based clamp point

§  Arbitrary, Not Physiological

§ PHYSIOLOGY based clamp point § Cord vessel flow § Measured transfusion (weight?) §  Breathing established/inflation of lungs

Conclusions DCC § TIME based clamp point

§  Arbitrary, Not Physiological

§ PHYSIOLOGY based clamp point § Cord vessel flow § Measured transfusion (weight?) §  Breathing established/inflation of lungs

*Ritchie Centre at MIMR led by Stuart Hooper and Graeme Polglase *Hemodynamics research group led by Nick Evans in Sydney *Investigators and collaborators of the APTS trial led by Prof William Tarnow-Mordi

martin.kluckow@sydney.edu.au