Pressures are rising sir!

Hye is it
PPHN ?

Mohit Sahni
Consultant Neonatologist, Neonatal Cardiologist,
Neonatal developmental Follow up (Bailey III)
How many among us have used iNO ?

Yes
 Who thinks Nitric Oxide (iNO)
is a wonder drug ?
(Conditions apply)

Yes
 Outline
PPHN

Pathophysiology

Approach to therapeutic intervention

Role of iNO

Alternative pulmonary vasodilators

Local experience & Protocol

 Scenario
Labour and Delivery:
Term infant, NVD, Thin MSL
Vigorous at birth
APGAR 8, 9

At 1 hr nurse noted baby to be dusky, with rapid

breathing

Vitals:
SpO2 55% in room air Temp 36.6 C
HR 146/min CRT 5-6 sec
Faint murmur MBP = 36 mmHg
Mod retractions RR 60/min

SpO2 -Pre69% & Post 50% in FiO2 100%

 Scenario
Intervention:
Intubated [CMV 24/6,
50/m, Ti 0.35s]
FiO2 100%, SpO2 85 / 69%
Art Gas: 7.01/79/35/16/
-12
 PPHN
Failure of normal postnatal adaptation with
persistent high PVR (pulmonary vascular
resistance) leading to --

Right ventricular failure and

Pulmonary systemic channel shunting

Fetal circulation Neonatal circulation
(Parallel) (Series)
 High PVR- Ductal Shunt

Pressure Pressure

PVR
 Background
PPHN
1: 500 - 1500 live births

1 - 4 % of Level 3 NICU admissions

Variable mortality (20%)

High morbidity : Cognitive delay (30%), hearing loss

(19%) neurodevelopmental impairment (48%)
 Pulmonary Hypertension

Reversible Irreversible

Pulmonary
Pulmonary Non-pulmonary hypoplasia

Hypoxia (HIE) Alveolar capillary

dysplasia
Vein of Galen
Early Late
Pulmonary Pulmonary
overcirculation interstitial
RDS BPD
lymphangiectasia
Neuromuscular
TTN PIE
Drug (i.e. NSAID, Surfactant
MAS
SSRI) apoprotein B
Pneumonia
deficiency
 PPHN - Pathogenesis
Reactive: Increased pulmonary
vascular smooth muscle
contraction
Hypoxia
Perinatal insults
May be due to over circulation
eg: PDA etc
Eisenmenger syndrome

Fixed: Pulmonary vascular

remodeling
 ROP
PVL
BPD

Hypoxanthine

Cardiac /
Xanthine
renal
OXYGEN FREE damage
O2 Oxidase RADICALS

Fe, OO-

Lipid
Apoptosis Hydroxyl radical peroxidation
Necrosis
DNA breakage
 Clinical assessment
Baby have respiratory distress

Difference of 10-15 % in Pre and Post ductal

SpO2

Hyperoxia test

Other predisposing factors

Clinical assessment ALONE does not allow
accurate evaluation of the nature of the
cardiovascular compromise
 Physiologic Approach
Treat the problem not the consequences

Optimize lung recruitment

Effective pulmonary vasodilation

Achieve normal cardiac output and blood

pressure
 Desireable Effects

Improve Right
Ventricular Function

Pressure Pressure

60 45

25 40
PVR
 Mean Airway Pressure & Blood flow

Mirro 1987 J Pediatr Laubscher 1996 Arch Dis Child

 Oxygen & PPHN
Pulmonary vasodilator

paO2 target range?

> 95% vs 90-85%

Merits of post-ductal SpO2 monitoring?

 Oxygen Paradox
Hypoxia-ischaemia

Hypoxanthine
O2 Cell Injury
Oxygen free
Radicals

Reperfusion
Oxygen Saturation Target
Target pre-ductal SpO2 [88-94%] and paO2 [50-
80 mmHg]

No evidence to support SpO2 > 95% or paO2 >

80 mmHg

Cautious approach to pre-post ductal gradient

(?? > 75% acceptable if lactate, pH, urinary output normal)
Right Heart Compromise
High Mean Airway Pressure

Alveolar expansion

Compromised SVC flow Pulmonary vascular resistance

Pulmonary blood flow Impaired RV performance

Left Heart Compromise
High Mean Airway Pressure

Compromised pulmonary Transmitral flow

venous return LV stroke volume

Pulmonary edema Low cardiac output state

 Cardiotropic Drugs in PPHN?

Physiologic Considerations:
Impaired RV contractility and pulmonary blood flow
Pressure loaded RV
Compromised left heart preload and low cardiac output
Hypercontractile LV
 Which Inotrope you start 1st in PPHN ?

Dopamine

Dobutamine

Milrinone
Goal is maintenance of effective tissue perfusion

Target normal systolic and diastolic blood pressures

Ensure adequate cardiac output state (urinary
output, pH, lactate)

Dobutamine is preferable for neonates with

hypotension
and signs of a
low cardiac output (RV or LV) state
 Effect on Systemic perfusion

Included if SVC flow < 40 mls kg-1

Osborn 2002 J Pediatr

Dopamine and PVR

Cheung & Barrington 2001 CCM

 Cardiotropic agents:

Inodilators milrinone, dobutamine

Vasopressors dopamine, epinephrine,

vasopressin
 Treatment
Gold standard treatment
iNO

Adjunctive Pulmonary
vasodilation therapy
Milrinone, Sildinafil etc.
Inhaled Nitric Oxide

Selective pulmonary vasodilation

Bronchodilator activity

Surfactant stimulation
iNO and Death/ECMO

Barrington, & Finer 2008

Effect on Oxygenation

Kinsella 1999 Lancet

SURVEY CANADA / AUSTRALASIA
(McNamara, Sahni M et al)
Kumar 2007 J Perinat
Author Population Dose Time Intermed. CLD CNS
outcomes
Kinsella <34 wks 5 ppm D 0-7 a:A ratio
1999 a : A < 0.22
(n=80)
Schrieber <34 wks 10 ppm D1 N/A severe
2003 <3d 5 ppm D 1-7 IVH/PVL
(n=207)
Van Meurs < 34 wks 5-10 ppm D 0-3 N/A
2005 OI > 10 >1kg: < 1kg:
(n=420)
Hascoet <34 wks 5 ppm clin a:A response
2005 a : A < 0.22 45%
(n=415)
Mestan 2005 <34 wks 10 ppm D1 N/A delay &
<3d 5 ppm D 1-7 disability
Ballard < 32 wks 20 ppm D7-21 O2 duration
2006 < 1250 g 10, 5, 2 Early disch.
(n=582)
Kinsella < 34 wks 5ppm D1-21 N/A
2006 < 48 hrs old 750-999g
(n= 793) 500-1250g
Does iNO alter the likelihood of brain injury?
 Treatment exercise:
Have 24 wks sick with high Pul pressures on
ECHO and high Fio2 need

Have 32 wks with 100 Fio2 CDH on HFOV

Have Ex 23+4 wks now 52 days old Severe CLD

on HFJV and Fio2 80 %
WHOM You will Rx iNO
 Need for Adjunctive therapy

30-40% patients iNO non-responders

NINOS 1997 NEJM

Escalating costs of iNO treatment

Short (peroxynitrate generation) & long-term

(altered DNA structure) side effects of iNO
treatment
Role in Preterms
Other Pulmonary Vasodilators
Sodium
Nitroprusside
Arginine
Prostacyclin

NO Nitrosothiols

Adenylate Guanylate
Cyclase Cyclase
Milrinone Sildenafil
-ve
cAMP cGMP
-ve
PDE III PDE IV

Pulmonary -agonist
Phenoxybenzamine
Vasodilation
Other Pulmonary Vasodilators
 Milrinone - Oxygenation
Oxygenation index inhaled Nitric Oxide

60
25

p<0.001 p<0.001
50
20

40

15
# #
#

ppm
#
OI

30

10
20
# # # #
# #
5
10

0 0
0 10 20 30 40 50 0 10 20 30 40 50

Time [ hours] Time [hours]

FiO2, MAP and pO2 Sahni M et al, PAS 2010.

base deficit & lactate

Local Experience
 Protocol
Guidelines for inhaled Nitric Oxide therapy
Indications:
Term/ Near term newborn 34 weeks of gestation in the first
week of life with ECHO evidence of high pulmonary pressures
and the heart is structurally normal.
Requiring FiO2 > 60% and oxygenation Index (OI) >25 on two
consecutive arterial blood gases (ABG), taken at least 20 mins
apart.
Start the iNO at a dose of 20 ppm
Obtain ABG within 30 minutes of initiating iNO
 Protocol
No change in Ventilatory parameters and pharmacological Rx
in 30 mins
Positive response
Defined on the basis of an increase in PaO2 above baseline 30
mins post delivery of prescribed dosage as follows:
Full response : PaO2 change > 20mmHg
Partial response: PaO2 change 10-20 mmHg
No response : PaO2 change <10 mmHg
If a full response is determined clinically , maintain iNO at 20
ppm until weaning criteria are met.
If a partial or no response is obtained discontinue iNO
 Protocol
Weaning of iNO:
Clinically stable and Fio2 <60%, consider weaning iNO

Reduce the iNO by 5 ppm every 4 hours until 5 ppm is

reached

At 5 ppm, consider a stepwise reduction of iNO by 1 ppm

every 4 hours until discontinuation is possible.

At any point in the weaning process there is significant

deterioration in oxygenation and a change in FiO2 > 10%, stop
weaning iNO and return to the previous iNO dosage.
 Summary I
PPHN is about elevated PVR and impaired myocardial
performance

Consider impact of oxygen and mechanical

ventilation

Consider tolerating postductal SpO2 > 75%

iNO is an effective pulmonary vasodilator but issues

related to toxicity, lack of response and cost are
concerning
 Summary II
Evidence for Adjunctive therapy (milrinone /
sildenafil) promising

Consider cardiotropic support to optimize cardiac

output (but not to induce systemic hypertension or
raise postductal SpO2)

Avoid vasoconstricting agents that increased

pulmonary vascular resistance
Acknowledge :
Dr.Afif
Dr. EL Khuffash
Patrick McNamara

Dr. Patrick McNamara