Transitional and Neonatal Circulation - MCA …...Transitional and Neonatal Circulation Patrick J...
Transcript of Transitional and Neonatal Circulation - MCA …...Transitional and Neonatal Circulation Patrick J...
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Transitional and Neonatal Circulation
Patrick J McNamara
Professor of Paediatrics & Physiology
Senior Associate Scientist, University of Toronto
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Laying the Foundation [1920-60]
• Nutrition
– Breast milk for all
• Respiratory control
– “mechanical ventilation”
• Temperature control
– “The incubator”
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Defining the Specialty [1960-2000]
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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
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MAP > GESTATIONAL AGE
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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
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When is low defined?
20 UK pediatricians (2 of them neonatologists)
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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”.
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Tsuji 2000 Pediatr Tyszcuk 1998 Paediatrics
Inconsistent Relationship:Arterial Pressure & Cerebral Perfusion
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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.
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**Therapy for hypotension associated with risk of NDI/death; independent of “disease severity” as assessed by this logistic regression model.
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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
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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
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How do we optimize cardiovascular care?
PRECISION OF MONITORINGCHOICE OF THERAPIES
“Right” therapy for the “right” patient at the “right” time
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The Changing NICU
Cost-effectiveness
Optimal Outcome
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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)
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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
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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
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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
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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]
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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
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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
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• 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
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I: PVR takes 2 weeks to normalize and less sensitive to rising paO2 in normal range
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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
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Van Hare 1990 Circ Research
Rowland 1995 Am J Card
III: Immature myocardium susceptibile to afterload
PRELOAD AFTERLOAD
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Clinical appraisal
TnECHO
Decision
HEMODYNAMIC CONSULT: Do we treat the PDA?
CUMULATIVE EVIDENCE FROM > 5O RCTS SAYS “NO BENEFIT”
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Challenge I: Variable Role of the Ductus Arteriosus
• Transitional Physiology
• PPHN
• Duct dependent CHD
• Systemic-pulmonary shunting
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PVR
PV
return
SVR
SEVERE RV DYSFUNCTION
Pulmonary blood flow dependent on L-R ductal shunt
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Challenge II: Diameter Assessment
• Measurement error [Operator]
• Measurement error [Equipment]
• Measurement error [Location]
• Variability in architecture
• Size is NOT STATIC or UNIDIMENSIONAL
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SHUNT VOLUME
PBF
PV
return
SBF
Determinants (Poiseulle)
F = 𝜋 𝑃𝑟𝑒𝑠𝑠𝑢𝑟𝑒 𝐷𝑖𝑓𝑓 𝑟4/ 8 (viscosity) (length)
Vessel Diameter
Vessel Architecture
Trans-Ductal Pressure gradientViscosity
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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
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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
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Clinical appraisal
TnECHO
Decision
HEMODYNAMIC CONSULTATION
Low SpO2 75%
iNO non-responder
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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
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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
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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
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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
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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
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IV: Reliability of RV Assessment
Purna et al 2017 ePAS
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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
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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]
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Insights during Normal Transition:RV adaptation continues for first 36 hours
Jain et al. 2016 JASE
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Insights in PPHNTAPSE < 6 and Increased Risk of Death or ECMO
Jain et al 2017, in submission
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* 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
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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
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Putative Cardiovascular Contributors to Brain Injury
Is treatment of abnormal hemodynamics of benefit or harm?
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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%
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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
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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
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Acknowledgements…
Thank you to:
The Toronto TnECHO team and the members of the Canadian National Targeted Neonatal Echocardiography Collaborative
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Does low blood pressure = Low blood flow?
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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
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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
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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
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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
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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
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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