stm.sciencemag.org/cgi/content/full/12/549/eabb9401/DC1

Supplementary Materials for

A rapidly deployable individualized system for augmenting ventilator capacity

Shriya S. Srinivasan, Khalil B. Ramadi, Francesco Vicario, Declan Gwynne, Alison Hayward, David Lagier, Robert Langer,

Joseph J. Frassica, Rebecca M. Baron, Giovanni Traverso*

*Corresponding author. Email: cgt20@mit.edu, ctraverso@bwh.harvard.edu

Published 24 June 2020, Sci. Transl. Med. 12, eabb9401 (2020)

DOI: 10.1126/scitranslmed.abb9401

This PDF file includes:

Fig. S1. Photographs of the iSAVE setup. Fig. S2. Differential tidal volume and PEEP delivery on the iSAVE using an open-circuit ventilator and test lungs. Fig. S3. Accommodation to changes in compliance of one test lung using the iSAVE and an open-circuit ventilator. Fig. S4. Ventilation at high lung resistances. Fig. S5. Ventilator alarm response to occlusion. Fig. S6. Adding a test lung to the circuit. Fig. S7. Cross-contamination validation using artificial lungs on a closed-circuit ventilator. Fig. S8. Individualized management of ventilation using the iSAVE on a pig lung and a test lung. Fig. S9. Modification of sensing circuit for a Hamilton G5 ventilator. Fig. S10. Whistle ring designs for two types of common pressure release (PEEP) valves. Table S1. List of components required for the assembly of the iSAVE. Table S2. Mechanical components used in the iSAVE and their readily available medical industry equivalents. Table S3. Measurement of respiratory mechanics for iSAVE system using test lungs. Table S4. Blood electrolytes and chemistry during ventilation in pigs. Table S5. Stratification for patient matching.

Fig. S1. Photographs of the iSAVE setup. Left: Hamilton G5; middle: Puritan Bennett 840;

right: Philips VX850 ventilators.

Hamilton G5 Puritan Bennett 840 Philips VX850

Fig. S2. Differential tidal volume and PEEP delivery on the iSAVE using an open-circuit

ventilator and test lungs. Pressure, flow, and volume traces for two test lungs (capacity 1L),

one denoted in blue and the other in black. By adjusting the flow valve, various ratios of the

ventilator’s tidal volume of 400 mL were delivered to the two lungs. The range of ratios tested

(50:50, 65:35, 80:20) demonstrate that the iSAVE can split the ventilator's tidal volume to lungs

with markedly different needs without creating unreasonable pressure of flow conditions. The

waveform denoted in blue represents the lower proportion in the ratio.

Fig. S3. Accommodation to changes in compliance of one test lung using the iSAVE and an

open-circuit ventilator. Initially, both lungs (C = 60 cmH2O, R = Rp20) were supplied with VT

= 200 mL. (A) The compliance of one lung (blue) was decreased (C = 30 cmH2O) as indicated

by the red dotted line, causing a shift in volume delivery to the other lung (black). Titration of

the flow valve, indicated by the purple lines, restored flow to the baseline values. (B) The

compliance of one lung (blue) was increased (C = 120 cmH2O) as indicated by the red dotted

line, causing a decrease in volume delivery to the other lung (black). Titration of the flow valve,

indicated by the purple lines, restored flow to the baseline values.

5 10 15 20 25 30 35

20

40

Pre

ssu

re (

cmH

20

)

5 10 15 20 25 30 35

-0.2

0

0.2

Flo

w (

L/s

)

5 10 15 20 25 30 35

Time (s)

0

200

400

Vo

lum

e (m

L)

Vo

lum

e(m

L)

Flo

w(L

/m)

Pre

ssu

re(c

mH

2O

)

Time (s)Time (s)

A Decrease in compliance of blue lung B Increase in compliance of blue lung

Fig. S4. Ventilation at high lung resistances. The iSAVE was implemented using an open-

circuit ventilator to support two artificial lungs with high resistances (R = Rp50, C = 60 cmH2O).

The valves were serially adjusted (as indicated by vertical dotted lines) to titrate flow. At the

medium setting, 200 mL was able to be delivered at a pressure of 22 cmH2O. The resistances

simulated here are much higher resistance than what is expected in patients with ARDS, even

when comorbid with restrictive pathology. This test demonstrated the ability for the ventilator to

supply multiple patients with sufficient volume, even when resistances are high.

Fig. S5. Ventilator alarm response to occlusion. During the ventilation of two test lungs, (blue

and black) using a closed-circuit ventilator, tubing of one test lung (black) was occluded to

simulate the case of a sudden event causing a high resistance or complete shunt in one limb

(orange dotted line). The ventilator’s alarm immediately activated (photograph on lower right;

boxed orange region). This was resolved by removing the occlusion (green dotted line).

50 100

5

10

15

50 100

-50

0

50

50 100

Time (s)

-400-200

0200400600

Occlusion Alarm

Baseline

Vo

lum

e(m

L)

Flo

w(L

/m)

Pre

ssu

re(c

mH

2O

)

Time (s)

Tubing occluded Tubing unoccluded

Fig. S6. Adding a test lung to the circuit. During the ventilation of one test lung (denoted in

blue) using a closed-circuit ventilator, the second breathing circuit was isolated by closing its

flow control valve. 1) Prior to the addition of the second test lung (denoted in black), volume

was decreased to 75% of VT. 2) The second lung was attached to the second breathing circuit and

the valve was fully opened. 3) Both flow valves were titrated until the desired volumes and

pressures were achieved. Each step is denoted by a dotted vertical line.

Vo

lum

e(m

L)

Flo

w(L

/m)

Pre

ssu

re(c

mH

2O

)

Time (s)

5 15 25

1 2 3

Fig. S7. Cross-contamination validation using artificial lungs on a closed-circuit ventilator.

(A) Schematic of circuit used for cross-contamination testing. Trypan blue was nebulized in the

inspiratory circuit. Wipe/elution tests were performed in each segment of the circuit, indicated by

a numbered yellow hexagon. (B) Photographs of filters from the inspiratory and expiratory tract

of each channel. The expiratory filter (6) for subject A is purple, having trapped the nebulized

particles. (C) Absorption spectrum of samples from each segment of the test circuit.

Contaminants were contained by the filter at location 6. A sample of deionized water was used

for the negative control. A sample consisting of 0.1 mL Trypan blue in 1 mL water was used as

the positive control. Homoscedastic, two-tailed t-tests were performed to assess significance on

the data from the contamination testing with a threshold of P < 0.05.

Fig. S8. Individualized management of ventilation using the iSAVE on a pig lung and a test

lung. (A) Schematic of the setup for in vivo testing of iSAVE on a closed-circuit ventilator

supporting a 70 kg pig and an artificial test lung (1L capacity). (B) Pressure, flow, and volume

when differential tidal volumes were delivered to the pig and artificial lungs as indicated by the

ratio headings. Simulation of (C) decreased compliance in the artificial lung (black, orange

dotted line) and (D) increased compliance in the artificial lung (black, orange dotted line).

Simulation of (E) decreased compliance of the animal lung following 100 mL of saline infusion

(black, green dotted line) and (F) decreased resistance of the artificial lung (black, orange dotted

line). In all cases, titration of the valves restored ventilation (green dotted lines) to desired

baseline parameters.

A

B Differential Tidal Volume Delivery

Pre

ssure

(cm

H2O

)V

olu

me

(mL

)F

low

(L/m

)

25 50 75 1000

50

25 50 75 1000

0.5

25 50 75 100

Time (s)

0

500

Time (s) 2.5s

C Decreased compliance of artificial (black) lung D Increased compliance of artificial (blue) lung

250

20

40

60

Pre

ssu

re (

cmH

20

)

250

0.2

0.3

0.4

Flo

w (

L/s

)

250

Time (s)

0

200

400

Vo

lum

e (m

L)

0 10 20 30

20

40

Pre

ssu

re (

cmH

20)

0 10 20 300

0.5

Flo

w (

L/s

)

0 10 20 30

Time (s)

0

500

Vo

lum

e (m

L)

Pre

ssure

(cm

H2O

)

E Decreased compliance of animal (black) lung F Increased resistance of artificial (black) lung

Vo

lum

e

(mL

)F

low

(L/m

)

Time (s) Time (s)

Time (s) Time (s)50

Fig. S9. Modification of sensing circuit for a Hamilton G5 ventilator. For ventilators using

closed-loop flow control (such as Hamilton G5), the ventilator requires that the flow sensing

remain unaltered in order to complete calibration and self-test procedures. Here, the following

steps can be used to reconfigure the flow sensing from both breathing circuits. (A) Using a

standard stopcock, connect the blue and clear tubes from either patient's flow sensor to either

side of the stopcock. (B) Attach the stopcock housing the blue tubes to the blue connector port on

the ventilator. Attach the stopcock housing the clear tubes to the silver connector port on the

ventilator, pictured in the boxed area (C) Connect flow sensors to Y-piece in their normal

configuration to both patients.

A B C

Fig. S10. Whistle ring designs for two types of common pressure release (PEEP) valves. These enable an auditory alarm when the PEEP valve actuates. Whistle rings can be 3D printed

and assembled onto standard PEEP valves with a 22-mm inner diameter.

Table S1. List of components required for the assembly of the iSAVE.

Required components for closed-circuit (dual limb) ventilator

Per patient:

[ ] 2 one-way valves

[ ] 1 pressure release valve

[ ] 1 flow regulator

[ ] bacterial/viral filters

[ ] set of pressure/volume sensors

[ ] capnostat (CO2 sensor)

[ ] respiratory profile monitor

Required components for open-circuit (single limb) ventilator

Per patient:

[ ] 1 flow regulator

[ ] 1 bacterial/viral filter

[ ] 1 set of pressure/volume sensors (optional)

[ ] 1 capnostat (optional)

[ ] 1 monitor (optional)

Table S2. Mechanical components used in the iSAVE and their readily available medical

industry equivalents.

Mechanical

component Medical equivalent

One-way

valve

Positive expiratory pressure (PEP) threshold device

Unidirectional resistance/one-way valve

Duckbill valve

Pressure

release valve

Positive end-expiratory pressure (PEEP) valve

Ventilator pressure relief valve

Flow

regulator

Proportional flow control valve

Bacterial/viral

filters

HEPA filter

Pressure/volume

sensors

Mechanical

component Medical equivalent

CO2 sensor Capnostat for volumetric capnography (including EtCO2 monitoring) or

LoFlo for EtCO2 monitoring

Respiratory

profile monitor

Table S3. Measurement of respiratory mechanics for iSAVE system using test lungs. A

closed-circuit ventilator was used. Pplat, plateau pressure; PEEP, positive end-expiratory pressure.

Parameters Units Trial 1: Equal

Compliance

Trial 2: Mismatched Compliance

Trial 3: Mismatched Compliance

Lung A

Lung B

Lung A

Lung B

Lung A

Lung B

Tidal volume mL 347 262 418 257 433 89

Pplat - PEEP cmH2O 6.45 4.6 7.3 9 7 8

Computed compliance mL/cmH2O 53 56.9 53 28 61 11

Actual compliance mL/cmH2O 60 60 60 30 60 10

Error 11% 5% 11% 6% 2% 10%

Table S4. Blood electrolytes and chemistry during ventilation in pigs. BUN, blood urea

nitrogen; HCt, hematocrit; PCV, packed cell volume; HB, hemoglobin.

Parameter Units Pig A (70 kg) Pig A on iSAVE Pig B (88 kg) PigB on iSAVE

Na mmol/L 143 142 141 141

K mmol/L 2.9 3.8 3.4 3.6

Cl mmol/L 97 97 97 98

Anion Gap mmol/L 14 12 13 10

Glu mg/dL 138 127 118 125

BUN mg/dL 7 8 5 7

HCt % PCV 28 26 26 27

HB g/dL 9.5 8.8 8.8 9.2

Table S5. Stratification for patient matching.

FiO2

Patients requiring FiO2 > 60% should be grouped separately from patients

requiring FiO2 < 60% given common FiO2 settings and a desired threshold to

lower FiO2 < 60% to avoid theoretical O2 toxicity

Compliance (C) Patients with a C < 30 mLcmH20 should be grouped separately from patients with

C > 30 cmH2O

PEEP within the range of 5-18 cmH2O and the difference between patients should be

minimized to < 5 cmH2O

Driving

pressure

within the range of 5-15 cmH2O and the difference between patients should be

minimized to < 6 cmH2O

Difference in

height minimized to 3-6 inches to ensure relatively similar tidal volume needs

Comorbidities

Patients presenting with comorbid diseases (asthma, emphysema/chronic

obstructive pulmonary disease, bronchiectasis) should be grouped similarly to

make circuit dynamics more uniform