Volume-targeted ventilation: The long road to acceptance

Martin Keszler, MD, FAAP Professor of Pediatrics

Brown University Women and Infants Hospital

Providence, RI

Disclosure - Research Support:

• NIH (COBRE) • NICHD Neonatal Research Network • Draeger Medical (HFOV study) • Mallinckrodt, Inc. (iNO study)

- Speakers Honoraria: • Draeger Medical

- Other: • DSMB for Medipost America stem cell study • DSMB for Chiesi clinical trial

Alphabet Soup of Respiratory Support: State-of-the-Art 2018

BiPAP

? ??? PSV

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Unique Challenges in NB Ventilation Children ≠ Small Adults!

Newborns ≠ Small Children! Transitional circulation Compliant chest wall, stiff lungs Unfavorable chest wall mechanics Limited muscle strength and endurance Immature respiratory control Rapid RR, short time constants Small trachea, high ETT resistance Uncuffed ETT Tidal volume measurement Awake, breathing patient

Need to understand the pathophysiology

A Act P

fl II

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II ~ II

htl

l I f

htl Matthay MA and Zimmerman GA. 2005 Am J Respir Cell Mol Biol 33:319–327

Lung Injury: Strategies for Prevention

Optimal DR stabilization Avoidance of mechanical ventilation Surfactant replacement therapy Avoid excessive VT

Volume-targeted ventilation Optimize lung volume / avoid atelectasis Permissive hypercapnia/lower SPO2

High-frequency ventilation

The Pathogenesis of BPD

Fetal Lung Development

Postnatal Lung Growth and Development

Antenatal

Steroids

Postnatal

Steroids

Chorioamnionitis

Preterm Labor

Initiation

of air-

breathing

Mechanical

Ventilation Oxygen Infection

Cannalicular Stage

Saccular Stage Alveolar Stage

PDA

Pulmonary

outcome

Preterm

Delivery

Nutrition,

Fluid

intake

!!!

antioxidants,

Compliant chest wall Limited muscle strength

C-section/ absence of labor

Fluid filled lungs Respiratory depression

Limited ability to establish FRC

0::: LL

C 0

:.:; ~ ·5. (/) C ••

"'O C w

OPEEP

Effect of PEEP on

Rabbit Lung Aeration:

Phase contrast radiographs after

20 inflations. Siew, et al, JAP

2009

Volume or Pressure Ventilation?

Bourns LS 104 -150 BP 200

Pressure Ventilation- Controls the set pressure- Cycles when set time or flow is

reached- Volume depends on compliance

Volume vs. Pressure Ventilation Volume Ventilation

- Controls the set flow rate - Cycles when set volume is

delivered - Pressure rises passively

Volume Ventilation- Controls the set flow rate- Cycles when set volume is

delivered- Pressure rises passively

Volume vs. Pressure Ventilation Pressure Ventilation

- Controls the set pressure - Cycles when set time or flow is

reached - Volume depends on compliance

Pressure vs. Volume as Primary Control variable: VCV, VTV

Volume is the Independent Variable V When compliance , PIP , VT

VT

P FRC

PEEP PIP 2 PIP 1 P

Pressure vs. Volume as Primary Control variable: PCV, PLV

Pressure is the Independent Variable V When compliance , VT , PIP

VT2

P

VT1

FRC

PEEP PIP P

Why Volume-Targeted Ventilation?

Volutrauma not Barotrauma

Inadvertent hyperventilation is common

Hypocapnia is bad for the brain and the lungs

Adult-type volume controlled ventilation poses challenges in NB

Effect of Pressure v. Volume on Lung Injury Hernandez, et al, J Appl Physiol 1989

Capillary filtration coefficient: measure of acute lung injury

PIP is Excessive Relative to Compliance!

P

VT

FRC

E

I

!!

!

Ventilator-Induced Lung Injury: Volutrauma, not Barotrauma

Rodents ventilated Qwl/BW (mL/kg) * *

DLW/BW (g/kg) *

with 3 modes: 10 1.2 100 - High pressure

80(45 cm H2O), 8 0.9

high volume 606 - Low (negative) 0.6

pressure, high 404 volume

0.3 20- High pressure 2 (45 cm H2O), low

0 0volume (strapped 0

chest & abdomen)

Albumin space (%)

*P<0.01.

Dreyfuss D et al. Am Rev Respir Dis. 1988;137:1159-1164.

Both High and Low PCO2 Increase Risk of IVH Fabres, et al, Pediatrics 2007

Odds Ratio 95% CI P Gestational age 0.82 0.74-0.91 <0.001 PIH 0.51 0.31-0.83 <0.01

Antenatal steroids 0.51 0,34-0.76 <0.01 Apg 5 min 0.87 0.78-0.96 <0.01 Mech. ventilation 2.04 1.07-3.89 <0.05 Max PaCO2 >60 mmHg 1.97 1.23-3.15 <0.01 Min PaCO2 <39 mmHg 2.51 1.53-4.12 <0.001

V.

CRS

Limitations of Volume - Controlled Ventilation in Newborns

Tubing System and Humidifier

Respiratory System

1

Actual tidal volume is influenced by: 1) Ratio of circuit compliance to respiratory system compliance

Flow Sensor

C T Vent

V .

Humid

C RS

Leak

=VTLung VT set * CT1 + CRS

2) compressible volume of the circuit, including humidifier

Pressure-limited IMV

Continuous flow Continuous flow

Patient Patient

Spont. breath

Pressure limit Leak

PEEP valve

Expiratory phase Inflation

Relationship between lung volume and lung compliance

TLC

Normal FRC with optimal lung expansion, good

lung compliance

Low FRC due to atelectasis

Poor lung compliance, hypoxemia

A

B

V

O

L

U

M

E

DANGER!!!

P R E S S U R E

Volume “Guarantee” Principles of operation

The PIP (“working pressure”) is servo-regulated within preset limits (“pressure limit”) to achieve VT that is set by the user. Regulation of PIP is in response to exhaled VT to minimize artifact due to ETT leak. Breath terminates if 130% of TVT reached. Separate algorithm for spontaneous and machine breaths.

Pressure limit Working Pressure

VT = VT set by user

••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••

- - - - - ~..,,,~-----,-

Pressure Limit

Working Pressure

PRESSURE

Target tidal volume

VOLUME

-

....

-0 I E (.) 0 -~ :c ro E 0.. ~

PSV+VG

q

Ii

0

I~ LO

5s

NAVA · capsule

~--apnoea apnoea apnoea

5s saturation - -- 30s -

VG vs. NAVA and Extreme Periodic Breathing

Owen, et al, ADC 2010

200 NAVA .

::, C'G ._, 100

<( w

0 40 ..--

0 ::t 5 20 .._.,

0 .-----------

Variability of support with NAVA

Sinderby et al, 2007

The benefits of VTV can not be realized without ensuring that the tidal volume is evenly distributed throughout an “open lung”!!!

Atelectrauma in RDS

Recruitment/de- Surfactant inactivation Volutrauma recruitment injury

Expiration

Ventilated Ventilated Unventilated Inspiration Stable Unstable Shear forces

Adequate PIP, Adequate PEEP

Good oxygenation, low FiO2, minimal lung injury V

FRC

VT

P

CCP COP P CCP = critical closing pressure; COP = critical opening pressure

Lung volume recruitment

Alveolar Recruitment maneuver

Ventilation on the expiratory limb of the P-V loop, once recruitment occurs.

The high-tech, --~ high-risk drama of ~~ keeping the tiniest "';",..-babies alive ~, ·:.·

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Benefits of VG Maintenance of (relatively) constant tidal

volumes Prevention of hypocapnia, overdistention and

volutrauma due to • Surfactant administration • Lung volume recruitment • Clearance of lung fluid

Automatic lowering of pressure support level during weaning

Compensation for variable respiratory drive • stabilization of tidal volume and minute ventilation due to changes of respiratory drive (periodic breathing)

PLV vs. VTV Meta-analysis Peng, et al, ADC-FNN 2014

Outcome No. of Studies

No. of Subjects

RR (95% CI) or Mean diff (95%CI)

Mortality 11 767 0.73 (0.51-1.05)

Any IVH 11 759 0.65 (0.42-0.99) * Grade 3-4 IVH 11 707 0.55 (0.39-0.79) * BPD @ 36 wks 9 596 0.61 (0.46-0.82) * Cystic PVL 7 531 0.33 (0.15-0.72) * Pneumothorax 8 595 0.46 (0.25-0.86) *

Failure of assigned mode 4 405 0.64 (0.43-0.94) *

Any hypocapnia 2 58 0.56 (0.33-0.96) *

Duration of suppl. O2 (d) 2 133 -1.68 (-2.5to-0.88)*

Cochrane Meta-analysis Klingenberg, et al 2017

Relative risk or Mean difference 95% CI NNTB

(95% CI)

Death or BPD@ 36 wk 0.75 0.53 - 1.07 NA

BPD @ 36 weeks PMA 0.73 0.59 - 0.89 8 (5-20)

Grade 3-4 IVH 0.53 0.37 - 0.77 11 (7-25)

PVL +/- severe IVH 0.47 0.27 - 0.80 11 (7-33)

Pneumothorax 0.52 0.31 - 0.87 20 (11-100)

Hypocapnia 0.49 0.33 - 0.72 3 (2-5)

Days of MV -1.35 -1.83 to -0.86

Sixteen parallel studies with 977 infants + four crossover studies

Barriers to acceptance

Inertia / fear of the unknown Rationalization: need more evidence Lack of understanding of

- Rationale - Functionality - Appropriate settings - Limitations - Leak tolerance

Q15: North East ...

Q15: Mid Atlantic ...

Q15: Great Lakes ...

Q15: t~orth Central ...

Q15: North west ...

Q15: South central ...

Q15: South East ...

Q15: South West ...

Q15:West( CA,AK,HI)

Q15:Canada

0%

Q3 How often you use volume-targeted ventilation ?

Answered: 347 Skipped: 3

10% 20% 30% 40% 50% 60% 70%

- Neve r - rare ly ( <1 5 % ) - Occas ionally ( 1 5-30 % of th e time )

- Oft en (3 1 -50% of th e tim e ) - Most of th e tim e (>50% )

80% 90% 100%

Gupta, et al, AJ Perinat 2018

14

12

- 10 E

~ 8 :J -0

> 6

4

2

0

-6- M a ur d msp1ratory Volum ~ - M asur d xpiratory Volum _.___ lnsp1ratory Leak Volume _,. _ Expiratory Lea Vo lume ~ Corre ed I me

20 40 0 80

Effect of Leak on VT measurement

Herber-Jonat, Ped Crit Care Med 2008

Leak Compensation

V . 6 ml

2 ml V . 3 ml

1 ml

Expiration Inspiration

Leak Compensated VT = VT in the lung

4 ml4 ml

VG-Clinical Caveats VG should be implemented immediately upon

initiation of mechanical ventilation. The initial target VT is 4 - 5 mL/kg during the acute

phase of the illness. Larger VT is needed in ELBW infants, those with

MAS and older infants with chronic lung disease! PIP limit should be set 25% above the PIP currently

needed to deliver the target VT and adjusted as needed.

pH, not PaCO2 drives respiration, look at pH! If the low VT alarm sounds repeatedly, increase the

pressure limit AND INVESTIGATE THE CAUSE

Question #1

Which of the following two infants needs a larger VT/kg for eucapnia?

1. 2400 g term infant with MAS, 1d old

2. 2400 g LPT infant with RDS, 1d old

MAS (n=28) Control (n=40) p value

VT (ml/kg) 6.11 + 1.05 4.86 + 0. 77 <0.0001 - -

MV (ml/kg/min) 371 ± 110 262 + 53 <0.0001 -

PaCO2(mmHg) 41.0 ± 3.9 41.5 + 3.12 0.55 -

VT in infants with MAS Sharma, et al, Am J Perinatol. 2015

e1gl t 3500 gra s eco 1 11111 ro e

VTV Survey Results

Question #2

Which of the following two infants needs a larger VT/kg for eucapnia?

1. 540 g preemie with RDS, 2 days old

2. 980 g preemie with RDS, 2 days old

da . o ld prete rm bab y . e igh ing 500 grams

LOO

VTV Survey Results

Relationship of Birth Weight and VT Montazami,et al, Ped Pulmonol 2009

3

3.5

4

4.5

5

5.5

6

6.5

0.3 0.4 0.5 0.6 0.7 0.8 0.9

Weight (kg)

VT

(m

l/k

g)

ELBW RLBW *

*RLBW = Ridiculously LBW

R= -0.563 p<0.001

Conventional Physiology Anatomical dead-space = 2mL/kg. Instrumental dead-space is fixed.

Anatomical + Instrumental dead-space = 3mL in a typical 1 kg infant

Anatomical + Instrumental dead-space = 2.5mL in a typical 0.5 kg infant

Alveolar ventilation = tidal volume – dead-space volume) x RR

VT = 5mL , DS=3mL VT = 4mL , DS=3mL VT = 3mL , DS=3mL

Alveolar ventilation = X Alveolar ventilation = 0.5 X

Alveolar ventilation = 0

(mmHg) ET CO2 Waveform

160 -.----------------11 120

1~ : =,-- --120

100

80

60

40

20

0

60 - --20- -· __ _ ._ __ _ ---------- - o.___..._ ...... ___ .___.. _ __.

I • CO2 (mmHg) I

1 3292 6583 9874 13165 16456 19747 23038 26329

050

100150200250300350400450500

DS + 2 DS+ 1 DS DS -0.5 DS - 1 DS -1.5

500 □

D 2.5 ETT O 3.0ETT D. 3.SETT

400

300

200

100

0 - ...................... - ........... --.--..................... - ........... --.--..................... --.--........... --.--...................... --.--........... --.--...................... -.....-........... --.--...................... --2 -1.5 -1 -0.5 0 0.5 1 1.5 2

Added Dead Space (mls) Tidal Volume (ml)

Seconds

Time to Eliminate CO2 from Test Lung 2.5 mm ETT, DS = 3.5 ml

Keszler, et al. ADC FN in print

Gas Flow Through Narrow ETT Fresh gas inflow spikes through DS gas

Mixing when flow abruptly stops

Exhaled gas spikes through mixed DS gas

Flow pattern matters!

VCV or VG with a slow rise time do not form a spike as effectively

Approximately 10-20% larger VT is needed to maintain same PCO2

Hurley, et al, ADC-FN 2016

Question #3

Which of the following two infants needs a larger VT/kg for eucapnia?

1. 650 g 24 week preemie on day 2 of life

2. 650 g 24 week preemie on day 21 of life

Relationship of Post-Natal Age and VT (mL/Kg)

Day 1-2 n = 251

Day 5-7 n = 185

Day 14-17 n = 216

Day 18-21 n = 176

VT (mL/kg) 5.15 + 0.6 5.24 + 0.7 5.63 + 1.0 6.07 + 1.4

PCO2 (torr) 44.0 + 5.4 46.3 + 5.2 53.9 + 7.3 53.9 + 6.2

Keszler et al, Arch Dis Child ‘09

VG Clinical Caveats: Weaning

Weaning occurs automatically (“self-weaning”) Set VT at low end of normal If VT is set too high the baby will not have a

respiratory drive and will not “self-wean”. If the VT is set too low, there will be excessive WOB ! Most infants can be extubated when:

VT is at or above the target value with working PIP is < 10-12 cm H2O

< 12-15 cm H2O in infants > 1 kg with FiO2 < 0.35 and good sustained respiratory effort.

TABLE 2 PTPdi Results According to VT Level

PTPdi, Mean+ SD, cm H2O .. s/min

Baseline 4 ml /kga 5 ml / kga

Overall 158 + 70b 174 + 5gc,d

TABLE 3 VTE, Inflation Time,, Peak lns,piratory Pre,ssure,, and

Minute Volume According to VT Le,vel

v·rE, mean + SD, ml/kg Inflation time, mean + SD, s Peak inspiratory pressure,

mean + SD, cm H20

4 ml/kga

5.1 + 1.3

0.24 + 0.09 10.8 + 3.6

Sml/k ·a

55.-+ QS' .. .. - !1!1 . ·.

+ Q,7-_-- !I! ' ·

12.0 + 3.3

65 + o- , __ . !I! ·· - -· !I •

0.29 + 0.07 13.4 + 3.7

Infant respiratory rate, C ........... __ 6~o~-, +.....:1~6 __ __:.5.:_5_+_r ~9 ___ 4~9 ____ +_7 __ - __ > mean + SD, breaths per

I

min

Work of Breathing @ Different VT target Patel, et al Pediatrics 2009

Take home message It’s time to embrace VTV

One size does NOT fit all !!

Optimize lung volume / avoid atelectasis

Start early

Verify appropriateness of settings

Re-evaluate strategy often

Use all available information (waveforms)

When all else fails, examine the patient!

mkeszler@WIHRI.org

Thank You

When NIH funding runs out….