Gentle Ventilation in Infants with Pulmonary Hypertension€¦ · F. Neurologic; PV-IVH, PVL, Sensorineural hearing loss G. Pulmonary Hypertension H. Chronic Lung Disease (BPD) I

Gentle Ventilation in Infants with

Pulmonary Hypertension

Jen Wung, MD

Professor of Pediatrics

Columbia University College of Physicians and Surgeons

Morgan-Stanley Children’s Hospital Of New York

New York, NY

Disclosures

Off-Label Usage: None

Interests: None

7th Bubble CPAP and Non-Invasive

Respiratory Management of the Neonate

Conference & Workshop

The George Washington University School of

Medicine and Health Sciences

Washington, DC.

December 9 & 10, 2017

Gentle Ventilation in Infants

with Pulmonary Hypertension

Jen-Tien Wung, M.D., FCCM

Neonatal Intensivist

Professor of Pediatrics

Columbia University Medical Center

New York (CHONY)

I have no conflict of interest to disclose.

Persistence of fetal circulation

PPHN - Causes

•Perinatal asphyxia, MAS

•Congenital heart diseases

•Pulmonary hypoplasia, CDH, Oligohydramion

•RDS

•GBS or other sepsis

•Premature ductal closure secondary to maternal drug therapy (NSAIDs)

•Maternal use of selective serotonin-reuptake inhibitor (SSRI, fluoxetine) in late pregnancy

•Alveolar capillary dysplasia (Misaligment of PVs)

•Idiopathic

•Iatrogenic

Normal Lung(left) vs PPHN Lung (right)

There is smooth muscle hypertrophy of the pulmonary

arteriole (PA) and narrowing of the arteriolar lumen in PPHN

Misaligment of pulmonary Vessels

Diagnosis of PPHN

•Case history

•Oxygen requirment out of proportion to the severity of lung

disease (chest X-xay)

•Pre- / Post- Oxygen Saturation discrepancy

•EKG (RV hypertrophy)

•Echocardiography

•Cardiac Catheterization - Gold standard

•Biochemical Marker: B-type natriuretic peptide (BNP),and

N-terminal proBNP(NT-proBNP)

Echocardiographic Estimation of PA presssure

➢TR jet flow

Modified Bernouli equation: Systolic PAP = 4 × (TR peak jet

velocity)2

+ RA pressure

➢Septal flattenning, Interventricular septum at end-systole

RV pressure/Systemic pressure: round <50%,

Flat = 50-100%, Bowing to LV ≥100%

➢RA enlargement, RV hypertrophy / dilation, thick RV wall,

dilated PA, ↑ velocity PV regurgitation,

↓ acceleration time of RV ejection to PA

PPHNManagement in 1980’s

“Full Artillery” Approach

1. FiO2 100%

2. IMV 50 – 100/min.

PIP 25 – 45 cm H2O to achieve PaCO2 < 25 mmHg

3. Muscle relaxant

4. Tolazoline

5. To achieve mean BP 45 – 50 mmHg: Dopamine 2-20 g/kg/min

and/or Dobutamine 5-30 g/kg/min

6. NaHCO3 1 meg/kg/hr to keep pH > 7.55

Hyperventilation

• Overventilation impedes venous return, decreases pulmonary blood flow, oxygenation, cardiac output and blood pressure

• Increases pulmonary vascular resistance. The capillaries are stretched and their caliber are reduced

• Increases lung injury (barotrauma, volutrauma, and biotrauma).

• Shifts O2-hemoglobin dissociation curve to the left due to alkalosis

• Decreases cerebral blood flow.

• Causes hearing loss.

Management of PPHNColumbia Approach

• Treating the underlying disease

• Continuous monitoring of pre- & post-ductal O2 saturation

• Mechanical Ventilation: 1. Conventional ventilation 2. PTV (SIMV +/- PS, A/C) 3. HFPPV 4. HFV (HFO)

• No hyperventilation, induction of alkalosis or neuromuscular blockade

• Pulmonary vasodilator-- INO (for pre-ductal oxygen saturation < 90%). If no response, milrinone, inhaled iloprost or I.V. sidenafil may be added.

• ECMO as last resort

MAP: MAP at referral hospital, MAP1: baseline MAP

following admission and before INO therapy, MAP2:

MAP within 24 hours of INO therapy

Journal of Perinatology 2002; 22: 435

10

15

20

MAP MAPI MAP2

MEAN AIRWAY PRESSURE

CM

H2O

*

*

*p<0.01

0

20

40

60

O I - A O I - B

oxyg

en

ati

on

in

de

x

*

Oxygenation index before (OI-A),

and after starting INO therapy (OI-B)Journal of Perinatology 2002; 22: 435

*p<0.001

CHONY Kinsella NINOS Davidson Clark

N 112 107 114 114 126

Gestation (wks) 40 (med) >34 >34 >37 >34

Baseline O.I. 50.7 2.6 49.3 3.4 43.0 17.6 24 9 37+24

PaO2 (mm Hg) 32.7 1.3 40.3 1.7 46.8 15.5 59 16 72+64

PH 7.26 0.2 7.41 0.02 NA 7.50 0.11 7.45+0.1

PaCO2 (mm Hg) 51.9 2.2 35.5 1.3 NA 30 9 35+13

INO (hours) 45 (med) 75.5 1.1 40 (med) 58 <96

Ventilator days 6.69 0.3 9 1 11.6 7 9.2 7.4 11+7

Nonresponders (ECMO+deaths)

25% 30-60% 46% 29.8% 40%

ECMO 17.9% 39% 38%

Mortality 8% 15% 14% 8% 8%

➢ IMV (CMV) or

➢HFPPV (rate 100, P 20/1, Ti 0.3 seconds

➢PTV (SIMV +/- PS, A/C, NAVA )

➢Inhaled nitric oxide

➢ HFV (HFO)

➢ ECMO

Mechanical Ventilation

Conventional

• Pressure-Limit

❖For small child or

❖large air leak with small endotracheal tube

❖Watch chest excursion

• Volume-limit

❖ Tidal volume 4-7 ml/kg

❖ Compressed volume 1 ml/H2O/L

(>> tidal volume 6 ml/kg)

Infant Ventilators

Conventional

• Flo-Disc MVP-10

• Healthdyne(PremieCare, Infant Star-200)

• Infant Star-500, Star Sync, Infant Star-950

• V.I.P.Bird Gold, V.I.P. Bird Sterling

• Bear Cub 750PSV

• Servo 300

• Draeger Babylog 8000, Servo i

• Servo n, Servo u, Babylog VN500, Avea, Puritan Bennett 840

MVP-10 Babylog 8000

Servo i

Servo n

Infant VentilatorBasic Simplified Schematic

1. O2 blender. 2. flowmeter. 3. heated humidifier.

4. manometer. 5. exhalation valve. 6. PEEP/CPAP control.

7. PIP control. 8. solenoid valve/ timer.

Infant VentilatorParameters

• FiO2

• Flow rate

• IMV rate

• Inspiration Time (Ti)

• Peak Inspiratory

Pressure (PIP)

• Positive end expiratory

Pressure (PEEP)

Mechanical Ventilation Complications associated with endotracheal intubaton

1.Hypoxia, bradycardia

2.Esophageal perforation

3.Increased airway resistance

4.Obstruction of endotracheal tube (ETT)

5.Malposition or dislodged ETT

6.Nasal septum damage (nasotracheal tube)

7.Aquired palatal groove (orotracheal tube)

8.Vocal cord injury. Unilateral → dysphonia, Bilateral → aphonia

9.Subglottic edema

10.Subglottic stenosis

11.Tracheomalacia, Tracheal stenosis

12.Release of plasticizer (DEHP)

Mechanical VentilationComplications associated with Positive Pressure

Ventilation :

A. Cardiovascular Effects

1. The abolition of the "thoracic pump" mechanism, decrease of venous return and cardiac output

2. "Tamponade" of the heart

3. Interference with pulmonary blood flow

B. Acute lung injuries ( barotrauma, volotrauma, biotrauma, atelectasis)

C. Airleaks

D. Uneven Ventilations, V/Q mismatch

E. Acid-base Imbalance

F. Neurologic; PV-IVH, PVL, Sensorineural hearing loss

G. Pulmonary Hypertension

H. Chronic Lung Disease (BPD)

I. Cor Pulmonary

J. VAP (ventilator associated pneumonia)

Effect of lung volume on pulmonary vascular resistance

when transmural pressure of the capillaries is held

constant. At low lung volumes, resistance is high

because extra alveolar vessels become narrow.

At high volumes, the capillaries become stretched as

the caliber is reduced.

Froese, et al., Anesthesiology, 1974

Paralyzing the diaphragm

is asking for trouble!

Gattinoni, et al., Critical Care Medicine, 1991

It is not good to spend all day

laying on your back!

The Best Mode of Ventilation is

Spontaneous Breathing

Spontaneous breathing improves lung

aeration in oleic acid-induced lung injury

Anesthesiology 2003;99:376-384

Wrigge H, Zinserling J, Neumann P, et al

Spontaneous breathing affects the spatial ventilation and

perfusion distribution during mechanical ventilatory

support

Crit Care Med 2005; 33:1090-1095

Newmann P. et al

Spontaneous breathing during APRV

(airway pressure release ventilation) is

associated with better ventilation and more

pulmonary blood flow to dependent lung

regions located close to the diaphragm

IMV Ti PIP PEEP FiO2 pH PaCO

2

PaO2

Before

transfer

80 0.4 35 5 1.0 7.41 44 33

After

transfer

40 0.6 30 5 1.0 7.30 55 31

After

reversal*

25 0.6 30 5 1.0 7.34 53 68

*TcPO2 rises (arrow) with spontaneous breathing after

pavulon reversal

➢A large body of evidence indicates that physiologic rhythms

are characterized by spontaneous variability. Heart rate,

respiratory rate, and blood pressure amplitude are all variable

and clearly affect each other.

➢In fact, therapeutic interventions with life-support systems

diminish or eliminate spontaneous physiologic rhythms.

Elimination of these inherent spontaneous rhythms may be

detrimental and contribute to the morbidity and mortality

associated with such life-support systems.

➢Specifically, mechanical ventilation may be improved if

normal physiologic variation is reproduced.

➢Using a computer-controller, the onset, duration, rate and

volume of the ventilator inspiratory cycle could be varied and

influence alveolar recruitment and thereby produce better

oxygenation

.

.

A large body of evidence

indicates that physiologic

rhythms are characterized by

spontaneous variability. Heart

rate, respiratory rate, and blood

pressure amplitude are all

variable and clearly affect each

other.

➢In fact, therapeutic interventions

with life-support systems diminish or

eliminate spontaneous physiologic

rhythms.

➢Elimination of these inherent

spontaneous rhythms may be

detrimental and contribute to the

morbidity and mortality associated

with such life-support systems.

➢Specifically, mechanical ventilation

may be improved if normal

physiologic variation is reproduced.

➢Using a computer-controller, the

onset, duration, rate and volume of

the ventilator inspiratory cycle could

be varied and influence alveolar

recruitment and thereby produce

better oxygenation

Biologically Variable or Naturally Noise

Mechanical Ventilation Recruits

Atelectatic Lung

W.Alan, C. Mutch,et. al

Am J Respir Crit Care Med 2000; 162: 319-23

Stochastic resonance -The addition of noise

to input signal (variable PIP) to amplify

output (PaO2) in a nonlinear system

PaO2 PaCO2 Shunt% Crs MAP Vt

ml/kg

Vbv 502 35 9.7 1.15 15.7 14.7

Vc 381 48 14.6 0.79 18.8 13.2

Vs 309 50 22.9 0.77 18.9

Vbv: biologically variable MV,

Vc: monotonously control MV,

Vs: Vc plus sigh

Biologically Variable Ventilation

➢Improves lung mechanics, gas exchange,

inflammatory mediators, and histological

evidence of lung injury in ARDS.

➢Recruits atelectatic and poorly areated

lung regions.

Graham M.R. et al, Crit Care Med 2011;39:1721-1730

Stochastic Resonance

is most simply described as

the addition of noise to an input signal

to enhance output in a nonlinear system

Stachastic Resonance

Overdistention may be regionalEven a “normal” VT can create regional overdistention

Mechanical Ventilation Using Conventional Infant

Ventilators

Four Techniques

1. Conventional technique (IMV < 41/min.)

2. High Frequency Positive Pressure Ventilation (HFPPV)

3. Prolonged inspiratory time with inspiratory pressure plateau (reverse I/E ratio)

4. Synchronization (IMV rate between 40 and 100/min to synchronize with patient's spontaneous respiration)

Parameter• FiO2 (1)

• Flow rate (2)

• IMV rate (8)

• Ti (8)

• PIP (7)

• PEEP (6)

Conventional VentilationFiO2

To keep PaO2 50 – 70 mmHg

Acceptable O2 Saturation around 90%

(Alarm limit 85 – 95%)

Conventional VentilationFlow

• Usually 5 – 8 lpm

• Enough to reach PIP within Ti

• Minimum flowrate to prevent rebreathing CO2 :

minute ventilation (200ml/kg) × 2.5 plus air leak

Conventional Ventilation(<40/min)

IMV Rate

• Usually start at 20 – 40/min

• To keep PaCO2 40 – 70 mmHg

• To avoid excessive labored spontaneous

breathings


Ti

• Usually 0.5 seconds

(about 2 time constant,

T.C. = C x R)

Tc=C× R

Tc = c× R

Tc =C x R


PIP

• Usually start at 20 cmH2O (15 cmH2O for

preemie)

• To have adequate chest and/or abdominal

excursion


PEEP

• Usually 5 cmH2O

• To increase for deep inspiratory retraction

due to low FRC

• To decrease for lung hyperinflation

Conventional Technique

Settings1. Flow rate 5 - 8 LPM

2. FiO2 to keep PaO2 50-70 mmHg

3. IMV rate

• Usually started at 20-40/min.

• Avoid excessive labored breathing

• Maintain PaCO2 40-70 mmHg

4. Inspiration time (Ti) 0.5 seconds

5. Peak inspiratory pressure (PIP)

• Adequate chest excursions

• Usually started at 20 cmH2O for term infant and 15 cm H2O for preemie

6. PEEP 5 cmH2O


Improvement

• Decrease IMV rate by 2-5/min for PaCO2 <50 mmHg

• Decrease PIP by 2-5cmH2O for excessive chest excursion

• Decrease FiO2 by 1/10 for PaO2>60mmHg

• Usually no change for flow rate, Ti or PEEP


Deterioration

• R/O ET tube obstruction, pneumothorax, underventilation, overventilation, etc.

• For PaCO2>70mmHg or excessive labored breathings, increase IMV rate (up to 40/min)

• For hypoxemia,

➢ Increase PIP if chest excursion is inadequate

➢ Increase PEEP for severe inspiratory retractions

➢ Increase FiO2

Indications for a Trial of HFPPVOn Conventional Technique:

1. PaO2 < 50 mm Hg with an FiO2 100%

2. PaO2 is very labile

3. PIP > 30 cm H2O to achieve visible chest excursions

4. PaCO2 > 70 mm Hg or excessive labored

spontaneous breathing with IMV rate up to 40/min.

5. Pulmonary interstital emphysema (P.I.E.)

High Frequency Positive Pressure Ventilation

(HFPPV)

Setting

1. IMV 100/min.

2. Ti 0.3 sec. (Te 0.3 sec)

3. Flow rate (>6 LPM)

4. PIP is usually the same as conventional

settings

5. PEEP 1 (to prevent intrinsic high PEEP)


Ventilators

Four Techniques

3. Prolonged inspiratory time with inspiratory pressure plateau (called reverse I/E ratio in the past)

• Inspiration time (Ti): 0.5 -1.0 seconds

• For infants with severe parenchymal lung disease, e.g. severe RDS, congenital pneumonia, etc.

• Replaced by HFO


Ventilators

Four Techniques

4. Synchronization

• IMV rate between 40 and 100/min to synchronize with patient's spontaneous respiration

• Ti: 0.5 seconds or I:E ratio = 1, whichever is shorter

• Replaced by patient triggered ventilation (SIMV, A/C, PS or NAVA)

“Agitation”

“Fighting with respirator”

Patient is telling us something is wrong

“Agitation”

“Fighting with respirator”

• Looking for the cause

• Suctioning of the endotracheal tube

• Nasotracheal intubation

• Mild sedation if necessary

• Best sedation is a clear airway and

television set

Ramsay Sedation Scale

1. Agitated, anxious, restless

2. Cooperative, oriented, tranquil

3. Drowsy, respond to commend

4. Sleepy, easy arousal

5. Sleepy, difficult arousal

6. Sleepy, not arousal

Ramsay et al Br Med J 1974;2:656-9

Sedation Analgesia

----------------------------------------- --------------

Amnesia Hypnosis Anxiolysis

----------------------------------------------------------

Selective α2 adrenoreceptor agonist

Dexmedetomidine (precedex)

Loading :1 ug/kg over 10-20 minutes

Maintenance: 0.2 – 0.7 ug/kg/hr (max. 24 hours)

Tolerance,withdrawal, and physical

dependence of children in PICU after

long-term sedation and analgesia

Joseph P. Tobias

Crit Care Med 2000; 28: 2122-32

Neuromuscular blocking agents

Undesirable side effects1. Loss of spontaneous respiration and increase of respirator

settings which cause barotrauma and volotrauma

2. V/Q mismatch

3. suppression of cough reflex resulting in secretion retention and atelectasis

4. Immobility leading to peripheral edema, peripheral nerve injuring, muscle atrophy, contractures, skin breakdown/stasis ulcer, deep vein thrombosis and pulmonary embolism

5.Inability or limitation of doing a thorough neurological examination

6. Autonomic and cardiovascular changes

7. Inappropriate use of sedatives and analgesics

8. Prolonged paralysis or weakness

9. Myopathy, particularly if corticosteroids are concurrently used.

The act of breathing depends on rhythmic discharge from the respiratory center of the brain. This discharge travels along the phrenic nerve, excites the diaphragm muscle cells, leading to muscle contraction and decent of the diaphragm dome. As a result, the pressure in the airway drops, causing an inflow of air into the lungs

Central nervous system

↓

Phrenic nerve

↓

Diaphragm excitation

↓

Diaphragm contraction

↓

Chest wall and lung expansion

↓

Airway pressure drop, flow reversal --→ PTV

Patient Triggered Ventilation

Beware of

• :Sensor: It may not working properly and need calibration.Watch sensitivity level. Avoid autocycling due to water condensation or heart beat in VLBW.

• Tidal volume: Part from spontaneous breathing and part from respirator. Pay attention to airleakage and hypoplastic lung.

• A/C mode: May need to adjust Ti. May not synchronized with high respiration rate.

• Narcotic and sedative suppress respiratory effort

IMV SIMV A/C PS

Flowrate Flowrate Flowrate Flowrate

FiO2 FiO2 FiO2 FiO2

IMV rate SIMV rate Patient,

Backup rate

Patient,

Backup rate

Ti Ti Ti Insp. cycle off

PIP PIP PIP Support P.

PEEP PEEP PEEP PEEP

Sensitivity Sensitivity Sensitivity

Sync. Synchronization Sync.

Readjust Ti and PEEP Readjust PEEP

SIMV + PS

88

Patient Ventilator Interaction

Nature 1999

Central nervous system

↓

Phrenic nerve

↓

Diaphragm excitation --→ NAVA

↓

Diaphragm contraction

↓

Chest wall and lung expansion

↓

Airway pressure drop, flow reversal --→ PTV

NAVA (Neurally Adjusted Ventilatory Assist)

91

Edi Catheter positioning procedure

Position and Edi signal

92

Asynchrony

Even with current technology the most sensitive

triggers will exhibit lag time = Asynchrony.

Formula for estimating peak pressures during

NAVA:

Ppeak est.=NAVA level X (Edipeak – Edimin) + PEEP

* NAVA level is the factor by which the Edi signal

is multiplied to adjust the amount of assist

delivered to the patient

Implement NAVA Mode

High Frequency Ventilation

⚫ Defined by FDA as a ventilator that delivers

more than 150 breaths/min.

⚫ Delivers a small tidal volume, usually less than

or equal to anatomical dead space volume.

⚫ While HFV’s are frequently described by their

delivery method, they are usually classified by

their exhalation mechanism (active or

passive).

HIGH FREQUENCY VENTILATION

Types of Ventilators

• HFPPV (High Frequency Positive Pressure Ventilation, infant respirator, rate 60 - 150)

• HFFI (High Frequency Flow Interrupter, Infant Star, rate ~ 22 Hz)

• HFJV (High Frequency Jet Ventilator, Bunnell Life Pulse, 7 Hz)

• HFO (High Frequency Oscillatory Ventilator, SensorMedics 3100A, rate ~ 15 Hz )

• HFCWO (High Frequency Chest Wall Oscillator)

AIRWAY PRESSURE WAVEFORMS

HFJV

HFOV

HFJV

HFOV

CV

MAP

seconds0.80.60.40.2

10

15

20

5

Tra

ch

ea

l P

res

su

re

cm

H

2O

Time

0

0

PRESSURE WAVEFORM COMPARISON

LifePulse HFJV-Model 204

➢Rate: 4-11Hz, usually 7Hz

➢Inspiration: active

➢Expiration: passive

➢A jet is produced by

opening and closing of a

control valve

➢Tidal volume > anatomical

deadspace

➢Microprocessor –controlled

➢Feedback control (peak pressure and gas temperature)

➢Patient box contains pressure transducer and pinch valve

➢Lifeport ET tube adaptor

LifePort ET tube adapter

ET Tube Connector

Jet Port Cap

Jet Injection Port

15-mm Connector

Pressure Monitoring Line

LifePort Adapter

Jet

Port

Inspired gas is

injected down

the ETT in high

velocity spurts.

PIP is measured

here and filteredto estimate PIP

at the tip of ETT.

Pressure

Monitoring

Port

HFJV in Tandem with CV

Jet CV

LifePort adapter

Ventilation Oxygenation

PEE

P

Valve

Jet Flow 1 Lpm

CV Flow 5 Lpm

PIP Rate PIP Rate

HFJV

Bunnell Life Pulse- (3)

Operator-selected parameter:

➢Conventional ventilator required for FiO2, IMV

rate (0-10,) PIP and PEEP

➢Jet: PIP

rate 420/min (4 – 11 Hz)

Ti 0.02 seconds

➢Oxygenation: PIP, PEEP, FiO2

➢Ventilation: Jet PIP

HFJV vs. HFOVWhen is the Jet the HFV of choice?

• Air Leak Syndromes

• Excessive Secretions

• Hemodynamic Compromise

• When HFOV Fails(e.g., non-homogenous lung diseases)

(e.g., Ptx, PIE)

(e.g., pneumonias)

Operator-selected parameter:

▪FREQUENCY(10 – 15 HZ)

▪INSPIRATION TIME (33%)

▪MEAN AIRWAY

PRESSURE (MAP)

▪AMPLITUDE

▪BIAS FLOW RATE

▪PISTON CENTERING

▪FIO2 (ATTACHED OXYGEN

BLENDER)

How to begin!

for infant

• Start with mean airway pressure 0-4 cmH20 above

CMV mean airway pressure(disease dependent)

✓ Monitor SaO2 to maintain SaO2 to 88 -93%

✓ If SaO2 does not increase within the first 5 – 10

minutes, increase mean airway pressure by 1-2

cmH20.

• Start with the power setting at 2.5 and monitor

chest wiggle to umbilicus.

• Inspiration time 33%

Respiratory Distress of NeonatesFour Categories

➢Diffuse homogeneous lung diseases e.g. RDS,

pneumonia, ARDS

➢Nonhomogeneous lung diseases e.g. MAS,

focal pneumonia, BPD

➢Lung hypoplastic syndromes e.g.

hypoplastic lung, CHD, Potter’s Syndrome

➢Airleak syndromes e.g. P.I.E.,

pneumothorax, bronchopleural fistula

SensorMedics 3100Astrategies for diffuse homogeneous lung disease

➢ Initial settings: Bias flow: > 6 LPM MAP: 1 – 2 cm H2O above conventional MAP F: 10 – 15 Hz Ti: 33% Amplitude: chest vibration

➢ Adjustment: MAP: 1 cm H2O increment till no PaO2 improvement

Chest X-ray: Rt. diaphragm at T 9 Amplitude for PaCO2

Avoid lung overexpansion & cardiovascular decompensation

➢ Weaning: decrease FIO2 till 60% then decrease MAP, decrease MAP if lung hyperinflation or cardiovascular decompensation

SensorMedics 3100AStrategy for Airleak Syndrome

➢MAP = conventional MAP reduce MAP if

possible

➢Increase FIO2 for low PaO2

➢F: 10 Hz

➢Amplitude to keep PaCO2 at 50’S

➢Continue for 48 hrs after airleaks resolved and then resume

RDS strategy

SensorMedics 3100AStrategies for:

Nonhomogeneous Lung Diseases and Lung Hypoplastic Syndrome

➢To improve PaO2 at lowest possible MAP

➢MAP = conventional MAP to decrease MAP if possible

➢F: 10 – 15 Hz

➢Ti: 33%

➢Amplitude: chest vibration

OXYGENATION:

➢Conventional ventilator: FiO2, PIP, PEEP, Ti

➢HFO: MAP, FiO2

VENTILATION:

➢Conventional ventilator: MV = Vt F

where F is IMV rate, Vt is PIP – PEEP

➢HFO : MV = Fa Vtb

where a is estimated as 0.75 to 1.24 and b is between

1.5 and 2.2 (About MV = F x Vt2)

Vt is related to amplitude

Patient on HFOV. O2 sat. increase with

spontaneous breathings

Shunt Oscillation

HFO

• Very sensitive to increase of airway resistance

• Less sensitive to Nonhomogeneous compliance

Left lung collapsed

(lower compliance)Left lung opened

on HFO

HFV versus CMV -1

Reference Device N BW(kg) CLD Rate

Carlo ’87 HFJV 41 1.48 No difference

HIFI ’89 HFOV 673 1.10 No difference

Carlo ’90 HFJV 42 1.42 No difference

Clark ’92 HFOV 83 1.10 30% vs 65% 30d

10% vs 38% 36w

Ogawa’92 HFOV 92 1.20 No difference

Pardou’93 HFFI 24 1.30 No difference

HFV versus CMV -2

Reference Device N BW(kg) CLD Rate

Gerstman’96 HFOV 125 1.50 24% vs 44% 30d

Wiswell

’96

HFJV 73 0.90 No difference

Keszler

’97

HFJV 130 1.00 67% vs 71% 30d

20% vs 40% 36w

Rettwitz-Volk

’98

HFOV 96 1.10 No difference

Thome’99 HFFI 284 0.88 No difference

HIGH FREQUENCY VENTILATION Concern of the

trials

✓The results are contradictory

✓Masking of investigators is not possible

✓ Most of these trials have been performed by investigators who have extensive experience in HFV

✓A standardized approach for HFV versus a non-standardized approach for CMV

✓Only studies in which there is a relatively high rate of BPD in CMV group have demonstrated a lower incidence of BPD in HFV group

HIGH FREQUENCY VENTILATION Indication -

Prophylactic

✓In animal experiments, HFV cause less lung trauma

than conventional ventilation

✓Whether this is also true in human preterm infants is

still uncertain

✓The findings of clinical trials are contradictory

✓There remain concerns that HFV may be associated

with a high rate of brain injury

HFV as a primary mode of ventilation is not recommended

HIGH FREQUENCY VENTILATION Indication - Rescue

✓Most of the evidence of benefit is short term

and in term babies

✓No clear evidence to support a rescue role in

preterm babies

✓Indications should be considered on a case by

case basis

P P H NVasodilator Therapy

• tolazoline (priscoline)

• epinephrine (0.1 ug/kg/min)

• prostaglandin E1 (0.1 ug/kg/min)

• magnesium sulfate

• inhaled nitric oxide (after 5/1994)

• milrinone I.V.

• sidenafil P.O., or I.V

• inhaled iloprost

.

P P H Ntolazoline (priscoline)

• Infuse into upper extremity or scalp

vein

• Test dose: 1 mg/kg

• Maintenance: 1mg/kg/hr

Vasodilator TherapyInhaled Nitric Oxide

Phosphodiesterase type 5 inhibitor (PDE5):

sildenafil

Prostacycline:

inhaled iloprost

inhaled treprostinil ( lasting >3 hrs )

flolan


milrinone

Endothelin receptor antagonist:

bosentan

Ambrisentan

Nitric Oxide Pathway

GTP cGMP Relaxation

guanylyl cyclase

NO or NO donor

X Sildenafil(Type 5 phosphodiesterase inhibitor)

Ca++

Schematic of NO uptake and

mechanism for pulmonary vasodilatation

PPHN PPHN + INO

PPHN + Nipride PPHN + INO

Inhaled Nitric Oxide

•Selective pulmonary vasodilator

•The gold standard therapy for PPHN

INOmaxTM

Dosage

• The recommended initial dose is

20 ppm.

• Dose reduced as tolerated to 5 ppm

after a sustained improvement in

oxygenation (24 to 48 hours).

• Duration is usually 2 to 6 days

Methemoglobin Concentration-Time ProfilesNeonates Inhaling 0, 5, 20 or 80 ppm INOmaxTM

Methemoglobin Concentration - Time Profile

Davidson et al. Pediatrics 1998;101:325-334

Inspired NO2 level - Time Profile

Davidson et al. Pediatrics 1998;101:325-334

INOmaxTM

Weaning

20ppm →15ppm →10 ppm →

5 ppm →( 4 --->3 -->2 -->1 ) → 0

INOmaxTM

Discontinuation

• INOmaxTM discontinued when the infant is

stable on 5 ppm, and FiO2 <60%

• About half of patients require an increase of

FiO2 (20 - 40%) for a few hours after weaning off

INOmaxTM

Discontinuation

of INO (1)

Note the stability of mean

blood pressure, heart

rate, and SPO2 with the

same FiO2 as INO is

withdrawn.

Aly H, Sahni R, Wung JT

Arch Dis Child 1997;76:

Discontinuation

of INO (2)

Acute deterioration of mean

blood pressure, heart rate,

and SPO2 with the same

FiO2 followed the initial

attempt at weaning. FiO2

was increased and the

weaning was successful.

Note how quickly FiO2 was

reduced following

successful weaning.

Aly H, Sahni R, Wung JT

Arch Dis Child 1997;76:

Changes in PaO2 30 minutes after

discontinuing INO treatment gases

PPHN Case #8 (1)• 4250g B/M 40 wk. gestation

• 35y.o. G5 P4 gestational D.M. on Insulin Variable deceleration, vaginal delivery, cord around neck x 2

• In nursery - tachypnea & acrocyanosis

• 2hrs - oxyhood FiO2 90% VBG 7.31/54/55

• Endotracheal intubation

• 28.5 hrs - arrived CHONY

• 29.1hrs - INO 25 PPM started

• 56hrs - INO discontinued

• 3d - extubated, 7d - off CPAP

PPHN Case #8 (2)Hrs IMV P Ti FiO2 pH PCO2 PO2

8 40 25/5 0.35 100 7.44 31 150

9 7.50 27 127

12 7.48 21 150

17 7.32 39 57

19 60 35/5 0.48 100 7.45 25 81

19.1 7.44 28 58

21 86 22/3 0.25 7.49 26 81

24 80 24/4 0.35 7.37 37 52

28.5 Arrived at CHONY

29 100 25/0 0.3 100 7.21 56 16

29.1 INO 25 ppm started

30 100 22/0 0.3 65 7.45 33 99

PPHN 4250g IMV 100 P25/0 Ti 0.3

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80

Time

FiO2

Pre-SO2

INO 25 INO 20

PPHN 4250g IMV 100 P25/0 Ti 0.3

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80

Time

FiO2

Pre-SO2

Post-SO2

INO 25 INO 20

PPHN 4250g IMV 100 P25/0 Ti 0.3

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80

Time

FiO2

Pre-SO2

Post-SO2

SBP

INO 25 INO 20

PPHN 4250g IMV 100 P25/0 Ti 0.3

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80

Time

FiO2

Pre-SO2

Post-SO2

SBP

DBP

INO 25 INO 20

Fig. 8. BP and O2 saturation change after INO for a PPHN infant 4250g IMV 100 P25/0 Ti 0.3.

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80

Time

FiO2

Pre-SO2

Post-SO2

SBP

DBP

HR

INO 25 INO 20

Case #8 –(3), on IMV 100, P 25/0, Ti 0.3

O2 saturation and BP response to INO,

•Understand the nature of the disease

•Watch for trending

•Be patience

• 735 gm, 26 wks,PROM x7 days, oligohydramions

• Stat c-section for preterm labor, variable deceleration,

breech presentation, cord prolapse,

• Apgar score 7/1’, 8/5’

• CPAP FiO240%, Deteriorated during transport from

TN to NICU, FiO260%,→ NTT → FiO2100%,IMV

rate 40, P 20/5, O2 sat. 50’s→Curosurf → O2 sat.

transiently ↑to 90’s for 5 min. and then ↓to <20’s

• ECHO revealed PPHN

• INO 20ppm started with slowly ↑ O2 sat.

• INO x 3days, IMV x 4days, CPAP x 85 days,

Discharged at DOL#100

30% of PPHN fail to respond to iNO

It is not the single magic bullet for the

complex pathophysiology of PPHN

Nitic Oxide Pathway

GTP cGMP Relaxation

guanylyl cyclase

NO or NO donor

X Sildenafil(Type 5 phosphodiesterase inhibitor)

Ca++

Sildenafil (PDE 5 Inhibitor) inhibits cGMP-specific

phosphodiesterase type 5 (PDE 5, an enzyme that promotes

degradation of cGMP.)

• Oral sildenafil (dose range 1-2 mg/kg every 6 h) improves

oxygenation and reduces mortality

• Intravenous sildenafil is administered as a load of 0.42 mg/kg

over 3 hours (0.14 mg/kg/h) followed by 1.6 mg/kg/day as a

continuous maintenance infusion (0.07mg/kg/h). Steinhorn et

al, J Pediatr, 2009

• It should be restricted to refractory cases at a center with ECMO

back-up, due the potential risk of systemic hypotension and

pulmonary hemorrhage, presumably due to sudden reversal of

ductal shunt

• Systemic hypotension is a major side effect and can increase

morbidity in PPHN by worsening right-to-left shunt.

• Long-term therapy with sildenafil in children (1-17 years) has

been associated with increased mortality.

Prostacycline Pathway

cAMP Relaxation

PGI2

X milrinone(Type 3 phosphodiesterase inhibitor, PDE)

Adenylyl cyclase



sildenafil

Prostacycline:

ventavis ( iloprost) inhalation

treprostinil (remodulin) I.V. or S.C.

(tyvaso) oral inhalation (>18 yr. old)

epoprostenol (flolan) I.V.2ng/kg/min, ↑2 ng q8h


milrinone


bosentan, Ambrisentan

Inhaled prostacyclin for term infants

with PPHN refractory to iNO

Four infants with severe PPHN unresponsive to iNO show improvement with inhaled PGI2. The intravenous form of PGI2 was aerosolized in an alkaline solution through the respiratory circuit. Age at initiation of PGI2 ranged from 1 day to 16 days old and was preceded with iNO for at least 3 hours (range 3hr to 14 days). Within 1 hour of initiation of PGI2, mean PaO2 increased from 57 to 100 (p = 0.06) and within 2 hours, mean OI decreased from 29 to 19 (p<0.05). 3 MAS survived, 1 ACD with transient response and died 6 days later.

The journal of Pediatrics 2002;141:830-2, Kelly LK et. al.

Prostaglandin E1 (PGE1)

Dose: PGE1 solution for aerosolization is prepared

from Alprostadil® (Prostin VR 500, Pfizer, New

York NY) and administered as a continuous

nebulization through a MiniHeart low flow jet

nebulizer (WestMed Inc, Tuczon, AZ) at 150-300

ng/kg/min diluted in saline to provide 4 ml/hr67.

Intravenous PGE1 has also been used in patients

with CDH in combination with iNO to promote

pulmonary vasodilation and to maintain ductal

patency and reduce right ventricular afterload69

Inhaled Prostacyclin (PGI2)

Dose: Inhaled PGI2 has been used in PPHN resistant to

iNO at a dose of 50 ng/kg/min68. The intravenous

formulation Flolan° (Glaxo-Wellcome, Middlesex,

UK) is dissolved in 20 ml of manufacturer’s diluent (a

glycine buffer, pH -10). Fresh solution is added to the

nebulization chamber every 4 hours.

Iloprost is an analog of prostacyclin and has

anecdotally shown to be effective in neonates and

children with pulmonary hypertension.

iloprost (Ventavis) inhaled

•2.5 - 5mcg (10 mcg/ml) diluted with Glycine

solution or normal saline to make total volume 2 ml

to be inhaled over 15 min.

•Nebulization using Aeroneb (electronic

micropump) q3hr. 6 - 9 times/day

•(Half-life 20 – 30 min.)

•For severe acute PPHN, q 45 - 60 min

•Continuously nebulization: 10 mcg diluted in 9 ml

N/S to run 2-3 ml/hr, after 2.5 - 5 mcg in 2 ml N/S to

show improvement.

•Monitor vital signs and O2 saturations

Ilopost inhaled continuously

SIMV HFO

flolan I.V. infusion

→inhaled ilopost continuously

1

32 44

1.HFO

2.A/C

3. Iloprost 5 ug

(in 2 ml saline)

nebulization

followed

by continous

nebulization 1.67ug

(in 2 ml saline)/hr

4. Et tube suction

Ilopost 5ug

then 1.67ug/hr

Et tube suctionEt tube suction

Ilopost 2.5ug

in 2 ml N/S

bolus

Ilopost 2.5ug in 2 ml N/S bolus

then Ilopost 10ug in 11 ml N/S

to run 2ml/hr

Increased deadspace

Prosacycline Pathway

cAMP Relaxation

PGI2

X milrinone(Type 3 phosphodiesterase inhibitor, PDE)

Adenylyl cyclase



sildenafil

Prostacycline:


treprostinil (Remodulin) I.V. or S.C.



milrinone (0.3 ug/kg/min → 0.5ug/kg/min)


bosentan ,Ambrisentan

Milrinone (PDE 3 Inhibitor)

Milrinone inhibits PDE3 and increases concentration of cAMP

in pulmonary and systemic arterial smooth muscle and in cardiac

muscle.

IV milrinone: loading dose (50 mcg/kg over 30-60 min) followed

by a maintenance dose (0.33 mcg/kg/min and escalated to 0.66

and then to 1 mcg/kg/min based on response)

Milrinone may be the pulmonary vasodilator of choice in the

presence of PPHN with left ventricular dysfunction

Hypotension is a clinical concern and blood pressure needs to be

closely monitored.

one case series described an increased incidence of intracranial

hemorrhage with the use of milrinone in PPHN



sildenafil

Prostacycline:


treprostinil (Remodulin) I.V. or S.C.



milrinone


bosentan (ETA & ETB antagonist, 1.5mg/kg/d

q12h → 3mg/kg/d q12h, P.O. )

ambrisentan (selective ETA antagonist)

Bosentan (Endothelin-1 receptor blocker):Endothelin receptor antagonists are beneficial and well

tolerated in adult patients with pulmonary arterial

hypertension

The results of a multi-center, randomized, double-blind,

placebo-controlled exploratory trial of bosentan in PPHN

was recently reported. Bosentan (2mg/kg/dose BID) did

not show any additive effect on the top of iNO in term

neonates with PPHN.

However, endothelin receptor antagonists may have a

role in the management of chronic pulmonary

hypertension associated with BPD or CDH.

Endothelin receptor antagonists

• bosentan and sitaxsentan

have been reported to be effective in

treating pulmonary hypertension. It

remains to be seen if they are safer,

more effective or even complementary

to sildenafil.

Which is the gold standard in diagnosis of PPHN?

1. Pre- / Post- Oxygen Saturation discrepancy

2. Echocardiography

3. Cardiac Catheterization

4. Biochemical Marker: BNP and NT-proBNP

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