Transitional and Neonatal Circulation

Patrick J McNamara

Professor of Paediatrics & Physiology

Senior Associate Scientist, University of Toronto

Laying the Foundation [1920-60]

• Nutrition

– Breast milk for all

• Respiratory control

– “mechanical ventilation”

• Temperature control

– “The incubator”

Defining the Specialty [1960-2000]

State of Knowledge

Research Gaps

NEONATAL HYPOTENSION

Controversial 1. When is hypotension “pathological”2. Define contributing factors3. “state-specific” approach to treatment

PATENT DUCTUS ARTERIOSUS

Controversial 1. Natural history of PDA 2. Investigating relationship of shunt volume to

neonatal outcomes3. Identification of targeted population

PPHN IN PREMATUREINFANTS

Controversial 1. Natural history of pulmonary vascular disease2. Evaluating the role of RV performance 3. Investigation of a targeted population

MAP > GESTATIONAL AGE

Mean BP the driver of Clinical Decision Making

Case I Case II

26 week (850 g) preterm – 3 hours old

Vitals BP 30 / 18 (22)

Heart rate 160

BP 38 / 26 (32)

heart rate 160

Investigations pH 7.1, Bxs -11

Lactate 5.2 mmol/l

pH 7.19, Bxs -11

Lactate 5.2 mmol/l

Likelihood of

cardiotrope

High Low

When is low defined?

20 UK pediatricians (2 of them neonatologists)

The brain’s defense against ischemic injury…

Use of antihypotensive therapies in extremely preterm infants. Pediatrics. 2013;131(6):e1865–e1873. (21)

Cerebral autoregulation: ”the physiological mechanisms that maintain blood flow at an appropriate level during changes in blood pressure”.

Tsuji 2000 Pediatr Tyszcuk 1998 Paediatrics

Inconsistent Relationship:Arterial Pressure & Cerebral Perfusion

Blood pressure alone does not explain brain injury!

• 13 studies [1985-1999] to interrogate the BP → WMI relationship

• YES: 4 studies [N = 348, median 92 (IQR: 33, 131)]

• NO: 9 studies [N = 1495, median 67 (IQR: 34, 632)]

• Variable methodology:• “Hypotension” definition (mean < GA, mean < 30mmHg)

• Duration of low BP to be considered “exposed”

• Type of measurement (arterial, cuff)

• No consideration of etiology; typically “early”

MRI: Axial T2; diffuse cystic PVL with multiple areas of WM hemorrhage; 31 week neonate with severe hypotension 2° septic shock.

**Therapy for hypotension associated with risk of NDI/death; independent of “disease severity” as assessed by this logistic regression model.

Mean BP does not predict Cardiac Output

LVO

MBP [mmHg]

10 20 30 40 50 60 70 80

mls

/kg

/min

]

0

200

400

600

800

1000

MBP vs LVO_POST

r = 0.07

SVC flow

MBP [mmHg]

10 20 30 40 50 60 70m

ls/k

g/m

in]

0

100

200

300

400

500

r = 0.25

McNamara et al, 2007

↓FLOWN BP

N FLOW↓ BP

Flow BP

19% ↓ ↓

20% N ↓

22% ↓ N

Metabolic Homeostasis

Cellular Metabolism

Oxygen Delivery

HemoglobinAnemia

Hemorrhage

Oxygen SaturationLung disease

Shunts

Cardiac OutputHeart Ratearrhythmia

PreloadVolume status

Diastolic function

Pericardial effusion

ContractilityCatecholamines, sepsis

Cardiomyopathy, acidosis

AfterloadSVR, pericardial “P”

BP

SVR

Oxygen

Consumption

Basal MetabolismPain, sedation, anxiety

thermogenesis

WorkBreathing, growth, trauma

catabolism, fever

How do we optimize cardiovascular care?

PRECISION OF MONITORINGCHOICE OF THERAPIES

“Right” therapy for the “right” patient at the “right” time

The Changing NICU

Cost-effectiveness

Optimal Outcome

What is Targeted Neonatal Echocardiography?

• Extension of the clinical examination - not confined to organs (Assessment phase)

• Relate physiologic and hemodynamic data to the clinical problem (Integration phase)

• Response to intervention (Response)

Case Scenario

• Term infant born by Em C/S [Difficult delivery – failed forceps]

• Apgar 11 , 35 , and 410

• Cord pH 7.02 (v), 7.04 (a)

• Intubated -10 mins for low SpO2 (50-70%)

• Therapeutic hypothermia (passive) initiated at referral hospital

• Received 20 mls/kg saline for low BP

Assessment

BP 71/45 (54) HR 140 /min

SpO2 Pre-94 / Post76

HFOV: FiO2 0.7 MAP 10 cmH2O

ABG: 7.19/57/47/21/-9 Lactate 6.4 mmol/L

CXR unremarkable

Clinical Impression

• PPHN secondary to HIE

• Maintain pre-ductal SpO2 > 95% & post-ductal SpO2 > 85%

[FiO2 1.0 delivered]

• Commence iNO if FiO2 remains > 75%

• TnECHO requested

PVR

PV

return

SVR

BALANCING CIRCULATION

• Severe global LV systolic and diastolic dysfunction

– Ejection fraction 19% (systolic function)

– LV output 60 mls/min/kg

• R-L transductal shunt essential [PVR>SVR]

Approach

• Maintain permissive elevation of PVR• Post-ductal SpO2 > 75% acceptable• Wean oxygen

• Low-dose dobutamine 5 mcg/kg/min

• Monitor 4-limb BP, urinary output, ABG closely

Course

• Weaned to room air - 2 hours

• Improvement in urinary output, plasma lactate and arterial pH - 6 hours

• Off inotropes - 24 hours

• Normalization of LV contractility - 48 hours

• Adjust rapidly from intrauterine to postnatal physiology.

• Knowledge of physiologic norms essential [LIMITED DATA]

Complexity of Cardiovascular Transition – inherent vulnerability

↓RV

AFTERLOAD

↑ LAPRELOAD

↑ LV AFTERLOAD

I: PVR takes 2 weeks to normalize and less sensitive to rising paO2 in normal range

II: Premature Myocardium is Developmentally Regulated and Vulnerable

Systolic

• Immature myocardium/less compliant (70 % non-contractile tissue)

Romero 1983 Ped Res

• Inotrope-responsiveness lessRomero 1979 Ped Res

• Diastolic vulnerability

Impaired early filling and low E waves !Riggs 1989 JACC, Reed Circulation 1986

Van Hare 1990 Circ Research

Rowland 1995 Am J Card

III: Immature myocardium susceptibile to afterload

PRELOAD AFTERLOAD

Clinical appraisal

TnECHO

Decision

HEMODYNAMIC CONSULT: Do we treat the PDA?

CUMULATIVE EVIDENCE FROM > 5O RCTS SAYS “NO BENEFIT”

Challenge I: Variable Role of the Ductus Arteriosus

• Transitional Physiology

• PPHN

• Duct dependent CHD

• Systemic-pulmonary shunting

PVR

PV

return

SVR

SEVERE RV DYSFUNCTION

Pulmonary blood flow dependent on L-R ductal shunt

Challenge II: Diameter Assessment

• Measurement error [Operator]

• Measurement error [Equipment]

• Measurement error [Location]

• Variability in architecture

• Size is NOT STATIC or UNIDIMENSIONAL

SHUNT VOLUME

PBF

PV

return

SBF

Determinants (Poiseulle)

F = 𝜋 𝑃𝑟𝑒𝑠𝑠𝑢𝑟𝑒 𝐷𝑖𝑓𝑓 𝑟4/ 8 (viscosity) (length)

Vessel Diameter

Vessel Architecture

Trans-Ductal Pressure gradientViscosity

N=200 Ductal Diameter Ductal diameter/kg Ductal Diameter/LPA

Echo Marker r2 β coef r2 β coef r2 β coef

Desc Aorta Diast flow Reversal 0.24 1.57* 0.06 0.56* 0.09 2.84*

Celiac Artery Diast flow Reversal 0.21 1.43* 0.03 0.44* 0.05 1.95*

LVEDD 0.19 0.18* 0.002 0.01 0.03 0.18**

LVO 0.17 68.58* 0.05 23.2* 0.06 107.35*

IVRT† 0.16 -5.58* 0.1 -0.31* 0.12 -1.35*

Pulm Vein D‡ 0.15 0.09* 0.05 0.03* 0.1 0.19*

LA:Ao ratio 0.14 0.06* 0.04 0.02* 0.06 0.11*

Mitral E/A† 0.08 0.04* 0.05 0.02* 0.06 0.10*

Relationship of PDA diameter to Indices of Shunt Volume

Ductal Evaluation

PDA – size, flow direction

& quality

Pulmonary Overcirculation

- LA:Ao, E:A ratio, IVRT

- ASD size & flow

- LPA diastolic flow

-Pulm Venous Vmax

Systemic Hypoperfusion

- LVO or LVO:SVC flow

- Desc Ao Doppler

- End-organ Dopplers

(MCA, celiac, renal)

Toronto PDA EVALUATION – SHUNT VOLUMEHARM

NO IMPACT

BENEFIT

R-L FLOW

NEUTRALSHUNT

L-R mod/high

volume

Clinical appraisal

TnECHO

Decision

HEMODYNAMIC CONSULTATION

Low SpO2 75%

iNO non-responder

Challenge II: Acute Pulmonary Hypertension

Failure of normal postnatal adaptation with persistent high PVR leading to

right ventricular failure and pulmonary:systemic channel shunting

Challenges

1. Failure to recognize this is a problem with RV Afterload

2. Echocardiography limited to subjective appraisal of pressure and function

RV pressure

• RVSP – TR jet

• PDA shunt

• Septal wall motion

• PAAT:RVET ratio

RV Function

• Subjective

• RV fractional area change

• TAPSE

• Tissue Doppler / Strain

Impact of PH

- RV output

- Pulm vein S/D Vmax

-LV function & output

Toronto PH EVALUATION HARM

BENEFIT

CHD

NORMAL

Acute PH

I: Tricuspid Regurgitation dependant on RV function

Bernoulli Equation [RVSP = 4 Vmax2 + Right Atrial Pressure]

(i) Normal patients: TR absent or trivial (< 2 m/sec)

(ii) Underestimates RVSP if RV dysfunction

II: Transductal flow not always present

Bidirectional → Near systemic (Calculate % R-L using

time interval or VTI)

Right to Left → Suprasystemic

L → R

R → L

III: Septal Wall Motion impacted by LV pressure

Septum Convex Septal Flattening Septal Bowing

Normal ½ to 2/3 systemic Systemic or above

RV

LV

(i) False negatives if Systemic Hypertension

(ii) Impacted by RV vs LV systolic function

IV: Reliability of RV Assessment

Purna et al 2017 ePAS

All (n=60) Controls (n=30) PH (n=30)

RV Dilation

All 0.14 (0.02), p<.001 0.12 (0.04), p=.004 0.12 (0.03), p<.0001

Expert 0.15 (0.06), p=.003 0.13 (0.02), p<.001 0.17 (0.07), p=.009

Novice 0.13 (0.05), p=.003 0.22 (0.07), p=.002 0.02 (0.06), p=.38

Septal Curvature

All 0.2 (0.02), p<.001 0.08 (0.03), p=.004 0.22 (0.03), p<.0001

Expert 0.23 (0.05), p<.001 0.09 (0.08), p=.13 0.23 (0.08), p=.001

Novice 0.21 (0.05), p<.001 0.06 (0.07), p=.18 0.29 (0.07), p<.0001

RV dysfunction

All 0.3 (0.03), p<.001 0.11 (0.05), p=.01 0.33 (0.04), p<.0001

Expert 0.31 (0.06), p<.001 0.13 (0.01), p=.1 0.32 (0.08), p<.0001

Novice 0.35 (0.06), p<.001 0.06 (0.1), p=.3 0.4 (0.08), p<.0001

Reliability of qualitative assessment of RV dilation, septal flattening and RV systolic function

Purna 2017 E-PAS

Novel Methods of Assessment of RV Contractility

TAPSETricuspid annular plane systolic

excursion

RV fractional area

change [3C][RVEDA-RVESA]/RVEDA

Peak Longitudinal Strain[Speckle Tracking]

Insights during Normal Transition:RV adaptation continues for first 36 hours

Jain et al. 2016 JASE

Insights in PPHNTAPSE < 6 and Increased Risk of Death or ECMO

Jain et al 2017, in submission

* vs. Stage I# vs. Stage II

* #

*vs. Stage I

*

Normal Normal

Insights in Hypoxic Ischemic EncephalopathyAbnormal RV function in patients with brain injury

Giesinger et al E-PAS 2017

After adjustment for severity of encephalopathy lower TAPSE [OR = 0.57 (0.34, 0.95)] and lower RV FAC [OR = 0.79 (0.67, 0.94)] independently associated with poor outcome

Predictors of Death/Abnormal MRIAbnormal

(n = 17)

Normal

(n=29)

P

Cord arterial pH 6.86 (0.12) 6.96 (0.15) ns

APGAR score at 5 min 2.5 (3.0) 4 (1.9) ns

Sarnat III 10 1 0.004

SNAPPE-II score 24h 60 [52, 85] 37.5 [33, 53] 0.001

FiO2 at 24h 0.21 [0.21, 0.50] 0.21 [0.21, 0.21] ns

iNO 6 (35) 4 (14) ns

Inotropes at 24h 11 (64) 6 (21) 0.004

LVO 99 (33) 125 (30) 0.01

Ejection Fraction 67 (6) 66 (8) ns

LV pLS - global 19 (2.4) 20 (1.9) ns

TAPSE 5.3 (1.4) 7.2 (1.7) <0.001

RV FAC 0.24 (0.04) 0.34 (0.08) <0.001

RVO 98 (48) 123 (29) 0.03

Putative Cardiovascular Contributors to Brain Injury

Is treatment of abnormal hemodynamics of benefit or harm?

Impact of TnECHO on Clinical Practice: Prospective observational study.

Giesinger 2017, in submission

Acute Hemodynamic

Instability[Hypotension and/or

Acute Pulmonary Hypertension]

Clinicalassessment

& plan

TnECHOConsult

Change in Management

Plan

Avoidance of Therapy 14%

Escalation of vasopressor/inotrope

36%

Change in Therapeutic Strategy

43%

93%

Scientific Framework: Re-engaging Cardiovascular Physiology

Mechanism of Disease

Reliability of Investigative TechniquesDefine Normal Physiology

& Heart Function

Predictive models: Population at Rick

Pharmacological Appraisal of Relevant Therapy

Targeted Treatment Trials

In conclusion……

• Mean BP > GA is probably too simple.

• A holistic assessment is critical - ‘right’ drug at ‘right time’ in ‘right patient’ once we understand normal.

• TnECHO evaluation may help define the physiology and refine treatment selections

• ECHO assessments need to be standardized, comprehensive with quality assurance

Acknowledgements…

Thank you to:

The Toronto TnECHO team and the members of the Canadian National Targeted Neonatal Echocardiography Collaborative

Does low blood pressure = Low blood flow?

Agent Advantages Cautions

iNO ↓ PVR; ↑ pulmonary blood flow & venous return to LA

R → L ductal shunt may be needed if:• severe LV dysfunction • septal hypertrophy

Dobutamine α1 & β1 ↑ stroke volume May cause hypercontractile state if under-filled or hypertrophic LV; may lack potency

Epinephrine Potent inotrope and vasopressor Proportional ↑ PVR and SVR; may exacerbate HRFLong term use associated with ↑lactate, glucose; potential for sarcolemmal rupture

Vasopressin Potent ↑SVR without ↑ PVR (↑ release of endothelial NO in lung)

Negative inotropic properties; caution if normal LV function is not established

Hydrocortisone ↑ Sympathetic response; ↑ other catecholamine activity; treat adrenal dysfunction

Delayed onset of action by 2-6h

Prostaglandin ↑ Systemic blood flow if PHTN or severe LV dysfunction; ↓RV wall stress

May exacerbate hypotension via vasodilation

Ductal Evaluation

PDA – size, flow direction

& quality

Pulmonary Overcirculation

- LA:Ao, E:A ratio, IVRT

- ASD size & flow

- LPA diastolic flow

-Pulm Venous Vmax

Systemic Hypoperfusion

- LVO or LVO:SVC flow

- Desc Ao Doppler

- End-organ Dopplers

(MCA, celiac, renal)

COMPREHENSIVE PDA EVALUATION – SHUNT VOLUME

HARM

NO IMPACT

BENEFIT

R-L FLOW

NEUTRAL SHUNT

L-R mod/high

volume

Giesinger RE, McNamara PJ. Hemodynamic instability in the critically ill neonate: An approach to cardiovascular support based on disease pathophysiology. Semin Perinatol. 2016 Apr;40(3):174-88

The Systolic BP – Stroke Volume & Heart Rate

DISEASE RECOMMENDED MECHANSIM

PDA DobutamineFlow modulation strategies

Augment cardiac outputManipulate PVR

PPHN iNOVasopressin

Pulmonary vasodilationSystemic Vasoconstriction

PPHN + RV dysfunction EpinephrineVasopressinProstaglandin E2

Augment systolic performancePulmonary VasodilationSupport coronary perfusion pressure

Septic Shock - vasodilator DopamineVasopressinNorepinephrine

Systemic vasoconstriction

Septic Shock- cardiogenic Epinephrine Augment systolic performance and cardiac output

LV Dysfunction Epinephrine Augment systolic performance and cardiac output

SeptalHypertrophy/HOCUM

VasopressinNorepinephrine

Augment filling pressuresSupport ooronary perfusion pressure

Dealing with Numerical Bias

• Competence• Quality of images and standardized approach

• Training

• Common sense• Do the numbers fit with the clinical concern?

• Integrative approach

• Comprehensive• Variability of individual measurements minimized

• Longitudinal evaluation

Possible causes Therapeutic Approach (mechanism)

PPHN 1.Reduce PVR e.g. iNO, milrinone (may inotropy)2. Improve atrial filling pressure (preload) e.g. fluid bolus, vasopressin (may ↓ PVR)3. Enhance myocardial systolic performance e.g. dobutamine, epinephrine4. Consider PGE1 infusion if RV dysfunction and DA closed or restrictive

Septic (Cold) shock 1. Improve myocardial systolic performance e.g. dobutamine, epinephrine (may ↑ preload) 2. Optimize treatment of sepsis

Cardiogenic shock 1. Check heart rhythm (rule out arrhythmia)2. Improve myocardial systolic performance e.g. dobutamine, epinephrine

Possible causes Therapeutic Approach (mechanism)

Systemic hypovolemia 1.Optimize filling pressures (preload) - fluid boluses (max 2 of 10mls/kg each) ± colloid2. Increase SVR once adequate volume given e.g. vasopressin, dopamine

Warm shock 1.Optimize filling pressures (preload) - fluid boluses (max 2 of 10mls/kg each) 2.Increase SVR (e.g. dopamine, norepinephrine, vasopressin (may increase atrial filling pressure)

PDA 1. Ductal closure strategies e.g. NSAID, acetaminophen, surgery2. Flow limitation strategies e.g. permissive hypercapnia, PEEP3. Enhance LV systolic function e.g. dobutamine

Cause Physiology Therapeutic algorithmA. Progression of severity after an initial period of low systolic APPPHN LV dysfunction &/or

loss of vascular tone 1. Improve atrial filling pressure (preload) e.g. fluid bolus, vasopressin (unless LV dysfunction on TnECHO)2. Enhance myocardial systolic performance e.g. dobutamine, epinephrine

Cardiogenic shock

Worsening LV function (? impending arrest)

Enhance myocardial systolic performance e.g. dobutamine, epinephrine

B. Progression of severity after an initial period of low diastolic APHypovolemia or warm shock

Myocardium unable to compensate or progression to cardiac dysfunction

1.Optimize filling pressures (preload) - fluid boluses (max 2 of 10mls/kg each) 2.Increase SVR e.g. dopamine, norepinephrine, vasopressin (if no LV dysfunction)

PDA Large volume shunt + myocardium unable to compensate

1. Flow limitation strategies e.g. permissive hypercapnia, PEEP2. Enhance LV systolic function e.g. dobutamine, dopamine (if critical DAP)

C. Both systolic & diastolic low at presentation (profound hypotension)Manage as severe warm shock with LV dysfunction if no echo available(rule out adrenal insufficiency)

See above + early hydrocortisone

Pathophysiology:± cardiac systolic dysfunction

Define type of hypotension(Please refer to table of normal values)

No improvement by 4 hours of age ORWorsening hypotension ORDeveloping signs of shock

Observe if Postnatal age < 4 hours AND hypotension mild

Signs of shockProlonged CRT (>3-4 seconds)Poor peripheral pulsesArterial lactate > 2Significant metabolic acidosis (base deficit > 8)Oliguria/anuria

Are there signs of shock?

Systemic Hypotension

Special ConsiderationsWean mean airway pressure to lowest needed provided no worsening of oxygenationConsider hydrocortisone if hypotension unresponsive to 2 therapeutic agentsEarly TnECHO consult is advisable for refractory hypotension Carefully evaluate infant and investigate/treat underlying cause of hypotension (e.g. acute blood loss, sepsis, SIRS, adrenal insufficiency, arrhythmia, electrolyte disturbances)Avoid use of cardiovascular agents which have chronotropic or inotropic effects in IDM patientsCaution with use of milrinone in neonates with HIE or where borderline mean or diastolic AP

Systolic < 3rd centile AND Diastolic < 3rd centileSystolic AP < 3rd centile

Pathophysiology: ↓ LV stroke output

Pathophysiology:↓ SVR

Diastolic AP < 3rd centile

YesNo