Time (h)

-1 0 1 2 3 4

VD

/ V

T

0.6

0.7

0.8

0.9

Time (h)

-1 0 1 2 3 4

Qs/

Qt

-0.2

0.0

0.2

0.4

0.6

0.8

Time (h)

-1 0 1 2 3 4

VD (

mL)

400

500

600

700

• In a sheep model of RDS, we applied VV based on a theoretical PV curve.

• After saline-lavage, sheep were randomized into one of two groups and ventilated for 4hrs:

• CV (n=6)• VT = 10ml/kg• f = 16 breaths/min• VE= 160 ml/kg/min• I:E = 1:3• PEEP = 7.5 cmH20• FIO2 = 1

• VV (n=7)• VT = 10ml/kg• f and I:E chosen to match CV VE

• PEEP = 7.5 cmH20• FIO2 = 1

1 2 3 4

Num

ber

of C

ells

(K

/UL

)

0.00

0.02

0.04

0.06

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0.12

0.14

0.16

1 2 3 4

Pe

rce

nta

ge

of T

ota

l Ce

lls

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CV-baselineVV-baselinePost 4hr CV and RDSPost 4hr VV and RDS

• It has recently been shown, in a variety of lung injury animals models, the application of variable ventilation (VV) when compared to conventional ventilation CV during respiratory distress syndrome (RDS) results in significantly better blood oxygen levels and lung mechanics [1,2,3].

• Recently, Suki et al. described the apparent improvements in gas exchange during VV through a mathematical model. They hypothesized that oxygenation may be improved during VV by exploiting the non-linear nature of the pressure-volume (PV) curve. Figure 1 shows a model of the PV curve of a lung region in the case of severe, acute lung injury. By placing the mean PIP near the lower inflection point (P2) in the PV curve, a small increase in PIP will result in a dramatic increase in lung volume while comparable decreases in PIP will result in a relatively insignificant loss of lung volume. The net effect of VV will be an increase in lung volume, a resulting increase in surface area available for gas exchange without the need to increase mean airway pressures. Additionally, it was predicted that the amount of noise place about the PIP can be fine tuned to provide an optimal level of oxygenation in a manner analogous to stochastic resonance [4].

•Arold et al. tested the hypothesis that gas exchange can be optimized by the addition of noise to mechanical ventilation in a rodent model of RDS. They applied Vt distributions ranging from 0% to 60% variation. It was found that as the level of noise in VT is increased PaO2 improves stepwise until 40-50% variability is reached. Addition of further noise results in a decline in oxygenation, in apparent agreement with the stochastic resonance hypothesis [2].

ethernet cable

A/Dcable

NPB840

laptop

DAQconnectorblock

10 Hz Low-Pass Filter

Box

Q Ptp Pao

transducers

EVW Delivery System

3-WayValve

ethernet cable

A/Dcable

NPB840

laptop

DAQconnectorblock

10 Hz Low-Pass Filter

Box

Q Ptp Pao

transducers

EVW Delivery System

3-WayValve

Variable Versus Conventional Ventilation After Saline Lavage Induced Respiratory Distress Syndrome

C. Bellardine1, A. Hoffman3, L. Tsai2, E.P. Ingenito2, F. Lopez4, W. Sanborn4, and K.R. Lutchen1

1Biomedical Engineering, Boston University, Boston, MA, 2Pulmonary Division, Brigham and Women's Hospital, Boston, MA, 3Tufts Veterinary School of Medicine, N. Grafton, MA, 4Puritan Bennett/Tyco Healthcare, Pleasanton, CA

INTRODUCTION

OBJECTIVE AND STUDY DESIGN

REFERENCES1. Lefevre, GR, SE Kowalski, LG Girling, DB Thiessen, WA Mutch. Improved Arterial Oxygenation after Oleic Acid Lung Injury in the Pig Using a Computer-controlled Mechanical Ventilator. Am J Respir Crit Care Med. 1996; 154: 1567-1572.2. Arold, SP, R Mora, KR Lutchen, EP Ingenito, B Suki. Variable Tidal Volume Ventilation Improves Lung Mechanics and Gas Exchange in a Rodent Model of Acute Lung Injury. Am J Respir Crit Care Med. 2002; 165: 366-371.3. Boker, A, MR Graham, K.R. Walley, BM McManus, LG Girling, E. Walker, GR Lefevre, and WC Mutch. Improved Arterial Oxygenation with Biologically Variable or Fractal Ventilation Using Low Tidal Volumes in a Porcine Model of Acute Respiratory Distress Syndrome. Am J Respir

Crit Care Med. 2002; 165: 456-462.4. Suki, B, AM Alencar, MK Sujeer, KR Lutchen, JJ Collins, JS Andrade, EP Ingenito, S Zapperi, HE Stanley. Life-Support System Benefits from Noise. Nature. 1998; 393: 127-128.5. Lewis, J, L McCaig, D. hafner, R. Spragg, R. Veldhuizen, C. Kerr. Dosing and Delivery of a Recombinant Surfactant in Lung-Injured Adult Sheep. Am J Respir Crit Care Med. 1999; 159: 741-747.

RESULTS I: GAS EXCHANGE

• In a large animal model of saline lavage induced RDS, our goal was to evaluate the effect of applying VV (40-50% variability in VT) vs. CV in two separate groups of sheep by comparing arterial blood gases, lung mechanics, and peak and mean pressures over a 4 hour period and broncho-alveolar lavage cell counts at the conclusion of the experiment.

• In conjunction with Puritan Bennett/Tyco Healthcare, a LabView program (Figure 2) was designed to communicate (via remote ethernet/laptop control) directly with an NPB840 and control the VT and f of each breath delivered based on a predetermined probability function

• A VT probability distribution with approximately 40-50% variation (Figure 3C) was designed based on a sample PV curve obtained from a sheep during saline-lavage induced RDS (Figure 3B) and a uniform pressure distribution with 7.5% variation centered at the lower inflection point (Figure 3A). This was based on the modeling and experimental work of Suki and Arold, respectively [2,4].

Sample Sheep Saline Lavage Pressure-Volume Curve

Pressure (cmH20)

0 10 20 30 40

Vol

ume

(L)

0

1

2

3

4

Pressure (cmH20)

24 26 28 30 32

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un

t

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600

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1000

Volume (mL)

400 500 600 700 800 900 1000

Cou

nt

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1200

Sample Variable Ventilation Pressure Pattern

Time (s)

100 120 140 160 180 200 220 240

Pre

ssur

e (c

mH

20)

5

15

25

35

45

55

Figure 1. Solid line is a model of the normalized PV curve of a collapsed lung region. Ventilation is applied between end-expiratory pressure (P1) and peak inspiratory pressure (P2). V2 corresponds to recruited volume. When noise with standard deviation (SD=0.075) is added to P2 (guassian under PV curve), recruited volume increases from V2=0.15 to V3=0.363. The difference V is the difference.

Time (h)

0 1 2 3 4

PaO

2 (

mm

Hg

)

50

100

150

200

250

300

350 VVCVVV Sheep ExcludedCV Sheep Excluded

Time (h)

0 1 2 3 4

PaC

O2

(m

mH

g)

20

40

60

80

100

120

140

160

Time (h)

0 1 2 3 4

PIP

(cm

H20)

30

40

50

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70

Time (h)

0 1 2 3 4

E a

t 0.2

Hz

(cm

H2O

)

0

20

40

60

80

100

Time (h)

0 1 2 3 4

Pm

ea

n (

cmH

20

)

8

10

12

14

Time (h)

0 1 2 3 4

E 4

Hz

- E

0.2

Hz

(cm

H2O

)in

dex

of h

eter

ogen

eity

of l

ung

dise

ase

0

20

40

60

80

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120

METHODS AND EXPERIMENTAL SETUP

RESULTS IV: BAL CELL COUNTS AND DIFFERENTIALS

• The distribution of VTs are scaled to the appropriate mean VT needed for a given subject. Depending upon that subject’s individual PV curve, the resulting pressure profile including mean PIP and percent variation can vary. An example VV pressure pattern is shown in Figure 3D.

A

BC

D

Figure 3. A) PIP probability distribution with 7.5% variation, B) Sample PV curve used to get VT distribution from PIP distribution, C) VT distibution with 40-50% variation, D) Sample VV pressure profile obtained when applying the VT distribution shown in Fig3C.

RESULTS II: LUNG MECHANICS

RESULTS III: HEMODYNAMICS DERIVED PARAMETERS

SUMMARY AND FUTURE WORK• On average, over the 4hr ventilation period during RDS, the VV sheep showed continuous improvement in blood gas levels while the CV sheep did not improve.

• The CV sheep exhibited elevated levels of elastance measured at 2Hz and increased frequency dependence of elastance. In the VV sheep, the elastance levels and frequency dependence were significantly improved when compared to the CV sheep at 4hrs.

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• At 30m intervals, arterial and mixed venous blood gas (ABG and MV) and hemodynamic measurements were taken.

• Every 1hr, the Enhanced Ventilator Waveform (EVW) was used to ventilate the sheep for 1-2m in order to obtain dynamic (0.2 to 8Hz) lung and respiratory system resistance (R) and elastance (E).

• Three CV and six VV sheep satisfied the starting saline-lavage induced RDS criteria of 60mmHg<PaO2<120mmHg [5].

• Additionally, broncho-alveolar lavage (BAL) samples were taken at baseline and after the 4hr ventilation period.

Time (h)

0 1 2 3 4

E a

t 8H

z (c

mH

2O

)

-50

0

50

100

150

†*

*** ††††

****

*

††††

*

†

* * ** * *

*

† † † † † † †

* *

† † †

†

†

*

†† † † † † † † †

* * * *

* * * *

† † † †

† p<0.05 compared to CV at time point* p<0.05 compared to 0hr within group