The Effect of Positive End-Expiratory Pressure on Pulmonary Vascular Resistance Depends on

Lung Recruitability in Patients with Acute Respiratory Distress Syndrome

Simone CAPPIO BORLINO, Julien HAGRY, Christopher LAI, Eduardo ROCCA, Gaëlle FOUQUÉ,

Daniela ROSALBA, Marta FASAN, Rui SHI, Agnese RECANATINI, Irene CISTERNA, Mattia BAROTTI,

Tài PHAM, Jean-Louis TEBOUL, Xavier MONNET

Online Data Supplement

E1
Patients and methods

Pressure measurements

All pressures were measured at end-expiration. Central venous pressure (CVP) was measured at

the “z” point at end-expiration (E1). Invasive blood pressure was obtained from a radial catheter.

The pressure transducers for pulmonary artery pressure, CVP and blood pressure were attached to

the patient's arm at the level of the mid-axillary line and 5 cm below the sternal angle level (E1).

Intra-abdominal pressure was estimated through the bladder pressure, after clamping bladder

catheter and injecting 25 mL of sterile saline solution. The pressure transducer was zeroed at the

level where the mid-axillary line crosses the iliac crest (E2).

All pressure waveforms were continuously recorded through HEM3.5 software (Notocord, Croissy-

sur-Seine, France).

Positioning of the pulmonary artery catheter

The positioning of the tip of the pulmonary artery catheter in a non-3 West zone was checked

according to the method proposed by Teboul and colleagues (E3). In brief, the respiratory

variation of the pulmonary artery pressure (∆PAP) and of the pulmonary artery occlusion pressure

(∆PAOP) during a respiratory cycle were measured. The ratio of ∆PAOP/∆PAP was calculated. The

right position of the tip of the pulmonary artery catheter was checked by a value of the

∆PAOP/∆PAP ratio <1.5 (E3).

Measurement of esophageal pressure

The esophageal balloon (FluxMed, MBMED, Buenos-Aires, Argentina) was first positioned in the

stomach to observe a positive deflection during an external manual compression. The catheter

was then retracted into the esophagus and its position was checked by the visualization of a

E2
positive and concordant deflection on the airway and the esophageal pressure curves during

external manual compressions on the ribs during an expiratory occlusion (E4–E6).

Estimation of alveolar recruitment and distension

The balance between pulmonary recruitment and distension induced by PEEP was assessed by

calculating the R/I ratio (E8). This method estimates the recruitability potential associated with

PEEP by measuring the volume derecruited by a sudden drop in PEEP level during expiration. The

presence of an airway opening pressure (AOP) was carefully checked to correctly estimate the R/I

ratio.

Results

Number of measurements performed per patient

We performed 57 measurements in 23 patients (i.e., a median of 2 (2-3) measurements per

patients): in 4 patients we conducted one measurement, in 10 patients two measurements, in 5

patients three measurements, in 2 patients 4 measurements and in 2 patients five measurements.

E3
 Supplementary Table E1. Respiratory and hemodynamic variables according to PEEP level and
lung recruitment potential.

Low PEEP High PEEP

Tidal volume, median (IQR), ml/kg PBW
High recruiters 6.1 (6.0-6.4) 6.1 (6.0-6.4)
Low recruiters 6.3 (6.0-7.0) 6.3 (6.0-7.0)
Respiratory rate, median (IQR), breaths/min
High recruiters 30 (28-30) 30 (28-30)
Low recruiters 26 (25-28)* 26 (25-28)*
PEEP, median (IQR), cmH2O
High recruiters 5 (2-5) 15 (12-15)†
Low recruiters 4 (2-5) 14 (12-15)†
PaO2, median (IQR), mmHg
High recruiters 82 (72-116) 125 (109-166)†
Low recruiters 111 (82-141) 111 (90-131)
FiO2, median (IQR), %
High recruiters 70 (60-80) 70 (60-80)
Low recruiters 60 (50-60) 60 (50-60)
PaO2/FiO2, median (IQR), mmHg
High recruiters 127 (103-151) 179 (152-268)†
Low recruiters 175 (144-258) 179 (138-262)
PaCO2, median (IQR), mmHg
High recruiters 44 (36-50) 42 (38-50)
Low recruiters 40 (38-41) 40 (39-42)
Ventilatory ratio, median (IQR)
High recruiters 2.12 (1.63-2.44) 2.23 (1.66-2.35)
Low recruiters 1.75 (1.67-1.79) 1.75 (1.62-1.89)
Plateau pressure, median (IQR), cmH2O
High recruiters 15 (13-17) 26 (25-29)†
Low recruiters 12 (11-14) 27 (24-29)†
Driving pressure, median (IQR), cmH2O
High recruiters 10 (7-13) 10 (9-14)†
Low recruiters 9 (6-9) 12 (8-16)†
Inspiratory esophageal pressure, median (IQR), cmH2O
High recruiters 10 (7-12) 13 (11-14)†
Low recruiters 8 (7-12) 11 (9-16)†
Expiratory esophageal pressure, median (IQR), cmH2O
High recruiters 7 (5-9) 10 (9-11)†
Low recruiters 7 (5-8) 8 (8-10)†
CRS, median (IQR), mL/cmH2O
High recruiters 47 (27-50) 36 (26-49)†
Low recruiters 38 (31-66) 30 (20-49)†
CL, median (IQR), mL/cmH2O
High recruiters 60 (42-78) 47 (30-66)
Low recruiters 56 (38-85) 49 (23-51)†
Inspiratory PL (elastance ratio method), median (IQR), cmH2O
High recruiters 10 (10-14) 20 (18-24)†
Low recruiters 10 (8-10) 21 (18-25)†

E4
R/I ratio, median (IQR)
High recruiters 0.72 (0.68-0.77)
Low recruiters 0.35 (0.29-0.42)*
Lung volume recruited by PEEP, median (IQR), mL
High recruiters 256 (181-421)
Low recruiters 124 (90-202)*
Heart rate, median (IQR), bpm
High recruiters 76 (70-95) 74 (70-93)
Low recruiters 77 (65-100) 74 (60-108)
Systolic arterial pressure, median (IQR), mmHg
High recruiters 140 (127-155) 136 (126-152)
Low recruiters 142 (134-151) 142 (134-153)
Diastolic arterial pressure, median (IQR), mmHg
High recruiters 59 (52-67) 61 (52-68)
Low recruiters 63 (58-74) 66 (60-71)
Mean arterial pressure, median (IQR), mmHg
High recruiters 84 (72-90) 84 (69-90)
Low recruiters 89 (85-94) 89 (85-94)
CVP, median (IQR), mmHg
High recruiters 7 (7-9) 10 (9-11)†
Low recruiters 8 (5-12) 11 (9-13)†
Intra-abdominal pressure, median (IQR), mmHg
High recruiters 10 (8-12) 11 (8-12)
Low recruiters 14 (8-18) 14 (9-18)
Cardiac index, median (IQR), L/min/m2
High recruiters 3.4 (2.9-4.0) 3.1 (2.6-3.5)
Low recruiters 2.9 (2.4-4.2) 2.8 (2.3-4.1)
SPAP, median (IQR), mmHg
High recruiters 44 (43-45) 42 (39-45)
Low recruiters 36 (33-45) 40 (36-43)
DPAP, median (IQR), mmHg
High recruiters 23 (20-27) 26 (23-29)†
Low recruiters 21 (19-22) 25 (21-27)
MPAP, median (IQR), mmHg
High recruiters 31 (29-34) 31 (28-33)
Low recruiters 26 (22-30)* 31 (26-32)†
PAOP, median (IQR), mmHg
High recruiters 14 (11-15) 14 (13-17)
Low recruiters 12 (10-15) 13 (10-15)
PVR, median (IQR), dyn.s /cm5
High recruiters 224 (185-289) 235 (168-300)
Low recruiters 160 (120-297) 243 (166-380)†
MPAP-PAOP, median (IQR), mmHg
High recruiters 18 (16-22) 18 (14-20)†
Low recruiters 15 (12-16)* 17 (14-19)†
RV/LV end-diastolic areas ratio, median (IQR)
High recruiters 0.70 (0.65-0.79) 0.68 (0.58-0.80)
Low recruiters 0.54 (0.50-0.59)* 0.64 (0.56-0.70)†

E5
TAPSE, median (IQR), mm
High recruiters 22 (20-24) 21 (20-25)
Low recruiters 25 (22-26) 21 (19-23)†
TAPSE/SPAP, median (IQR), mm/mmHg
High recruiters 0.50 (0.43-0.55) 0.54 (0.47-0.56)
Low recruiters 0.66 (0.53-0.76)* 0.50 (0.40-0.64)†
LVOT velocity time integral, median (IQR), cm
High recruiters 22 (20-27) 22 (18-26)
Low recruiters 24 (22-27) 20 (18-24)
Arterial lactate, median (IQR), mmol/L
High recruiters 1.2 (1.0-1.6) 1.2 (0.8-1.6)
Low recruiters 1.5 (1.3-2.3) 1.4 (1.3-2.3)
SvO2, median (IQR), %
High recruiters 68 (63-71) 68 (64-71)
Low recruiters 72 (67-79) 66 (61-74)
Oxygen consumption, median (IQR), mL/min
High recruiters 261 (175-308) 243 (196-365)
Low recruiters 210 (148-235) 235 (189-271)
Noradrenaline dose, median (IQR), mcg/kg/min
High recruiters 0.49 (0.27-0.76) 0.49 (0.27-0.76)
Low recruiters 0.19 (0.09-0.57) 0.19 (0.09-0.57)

High recruiters (n=13) and low recruiters (n=10). Results are expressed as median (IQR).
* p less than 0.025 high vs low recruiters at the same PEEP level.
† p less than 0.025 high PEEP vs low PEEP in the same group of recruitment potential.
CL = lung compliance; CRS = compliance of the respiratory system; CVP = central venous pressure;
DPAP = diastolic pulmonary artery pressure; FiO2 = inspired fraction of oxygen; LVOT = left
ventricular outflow tract; MPAP = mean pulmonary artery pressure; PaCO2 = arterial partial
pressure of carbon dioxide; PaO2 = arterial partial pressure of oxygen; PAOP = pulmonary artery
occlusion pressure; PBW = predicted body weight; PEEP = positive end-expiratory pressure; PL =
transpulmonary pressure; PVR = pulmonary vascular resistance; R/I ratio = recruitment-to-inflation
ratio; RV/LV end-diastolic areas ratio = right-to-left ventricular end-diastolic areas ratio; SPAP =
systolic pulmonary artery pressure; SvO2 = mixed venous oxygen saturation; TAPSE = tricuspid
annulus plane systolic excursion.

E6
 Supplementary Table E2. Respiratory and hemodynamic variables according to PEEP level and
preload responsiveness.
Low PEEP High PEEP
Tidal volume, median (IQR), mL/kg PBW
Preload responders 6.3 (6.0-6.6) 6.3 (6.0-6.6)
Preload non-responders 6.1 (6.0-6.7) 6.1 (6.0-6.7)
Respiratory rate, median (IQR), breaths/min
Preload responders 28 (25-30) 28 (25-30)
Preload non-responders 28 (26-30) 28 (26-30)
PEEP, median (IQR), cmH2O
Preload responders 5 (2-5) 15 (12-15)†
Preload non-responders 5 (2-5) 14 (12-15)†
PaO2, median (IQR), mmHg
Preload responders 114 (69-141) 129 (107-190)
Preload non-responders 89 (77-115) 114 (97-131)
FiO2, median (IQR), %
Preload responders 60 (50-70) 60 (50-70)
Preload non-responders 70 (60-90) 70 (60-90)
PaO2/FiO2, median (IQR), mmHg
Preload responders 173 (145-213) 251 (179-317)
Preload non-responders 127 (103-154) 152 (127-208)
PaCO2, median (IQR), mmHg
Preload responders 39 (38-44) 40 (38-42)
Preload non-responders 40 (38-49) 42 (38-46)
Ventilatory ratio, median (IQR)
Preload responders 1.73 (1.62-1.97) 1.74 (1.62-1.89)
Preload non-responders 1.75 (1.72-2.31) 1.96 (1.72-2.26)
Plateau pressure, median (IQR), cmH2O
Preload responders 14 (12-19) 27 (24-29)†
Preload non-responders 14 (12-16) 26 (24-29)†
Driving pressure, median (IQR), cmH2O
Preload responders 8 (6-13) 11 (9-14)†
Preload non-responders 9 (8-12) 11 (9-16)†
Inspiratory esophageal pressure, median (IQR), cmH2O
Preload responders 8 (7-10) 11 (9-12)†
Preload non-responders 11 (6-13) 13 (12-18)†
Expiratory esophageal pressure, median (IQR), cmH2O
Preload responders 7 (6-7) 9 (8-10)†
Preload non-responders 5 (5-10) 10 (9-11)†
CRS, median (IQR), mL/cmH2O
Preload responders 39 (26-66) 31 (21-45)†
Preload non-responders 43 (31-56) 35 (24-49)†
CL, median (IQR), mL/cmH2O
Preload responders 46 (32-79) 30 (24-48)†
Preload non-responders 62 (44-86) 49 (37-67)
Inspiratory PL (elastance ratio method), median (IQR), cmH2O
Preload responders 10 (9-17) 24 (19-26)†
Preload non-responders 10 (9-11) 19 (15-21)†

E7
R/I ratio, median (IQR)
Preload responders 0.68 (0.37-0.72)
Preload non-responders 0.53 (0.34-0.70)
Lung volume recruited by PEEP, median (IQR), mL
Preload responders 204 (177-248)
Preload non-responders 150 (95-421)
Heart rate, median (IQR), bpm
Preload responders 70 (57-78) 66 (60-72)
Preload non-responders 84 (72-99) 86 (74-96)
Systolic arterial pressure, median (IQR), mmHg
Preload responders 144 (133-155) 139 (126-153)
Preload non-responders 138 (129-151) 143 (127-150)
Diastolic arterial pressure, median (IQR), mmHg
Preload responders 57 (50-64) 59 (52-63)
Preload non-responders 65 (59-69) 68 (60-70)
Mean arterial pressure, median (IQR), mmHg
Preload responders 85 (72-89) 82 (70-94)
Preload non-responders 89 (83-94) 89 (84-90)
CVP, median (IQR), mmHg
Preload responders 8 (7-9) 11 (10-11)†
Preload non-responders 7 (7-12) 10 (9-13)†
Intra-abdominal pressure, median (IQR), mmHg
Preload responders 12 (8-13) 12 (9-13)
Preload non-responders 10 (7-18) 11 (7-18)
Cardiac index, median (IQR), L/min/m2
Preload responders 3.1 (2.5-3.5) 2.6 (2.0-2.9)†
Preload non-responders 3.4 (2.7-4.4) 3.1 (2.7-4.4)
SPAP, median (IQR), mmHg
Preload responders 42 (36-47) 43 (39-46)
Preload non-responders 43 (38-44) 40 (36-43)
DPAP, median (IQR), mmHg
Preload responders 21 (19-26) 24 (21-25)†
Preload non-responders 22 (21-27) 27 (23-29)
MPAP, median (IQR), mmHg
Preload responders 28 (25-32) 30 (27-32)
Preload non-responders 30 (26-34) 31 (29-33)
PAOP, median (IQR), mmHg
Preload responders 14 (11-15) 15 (13-17)
Preload non-responders 12 (9-15) 13 (11-15)
PVR, median (IQR), dyn.s/cm5
Preload responders 232 (136-289) 236 (233-357)†
Preload non-responders 196 (175-297) 193 (155-317)
MPAP-PAOP, median (IQR), mmHg
Preload responders 14 (13-17) 15 (13-19)
Preload non-responders 16 (15-21) 18 (17-20)
RV/LV end-diastolic areas ratio, median (IQR)
Preload responders 0.70 (0.59-0.79) 0.68 (0.56-0.70)
Preload non-responders 0.60 (0.50-0.67) 0.62 (0.58-0.70)

E8
TAPSE, median (IQR), mm
Preload responders 22 (20-25) 21 (19-23)
Preload non-responders 24 (21-26) 21 (19-23)
TAPSE/SPAP, median (IQR), mm/mmHg
Preload responders 0.51 (0.47-0.58) 0.54 (0.40-0.57)
Preload non-responders 0.55 (0.53-0.61) 0.53 (0.47-0.61)
LVOT velocity time integral, median (IQR), cm
Preload responders 27 (20-28) 26 (17-27)†
Preload non-responders 22 (20-23) 21 (18-22)
Arterial lactate, median (IQR), mmol/L
Preload responders 1.2 (0.8-1.3) 1.3 (0.8-1.5)
Preload non-responders 1.6 (1.3-1.9) 1.6 (1.3-1.8)
SvO2, median (IQR), %
Preload responders 68 (63-73) 67 (64-68)
Preload non-responders 69 (65-77) 71 (61-74)
Oxygen consumption, median (IQR), mL/min
Preload responders 192 (165-281) 211 (181-235)
Preload non-responders 235 (161-288) 264 (210-335)
Noradrenaline dose, median (IQR), mcg/kg/min
Preload responders 0.28 (0.11-0.57) 0.28 (0.11-0.57)
Preload non-responders 0.49 (0.09-0.83) 0.49 (0.09-0.83)

Preload responders (n=10) and preload non-responders (n=13). Results are expressed as median
(IQR).
* p less than 0.025 preload responders vs preload non responders at the same PEEP level.
† p less than 0.025 high PEEP vs low PEEP in the same group of preload responsiveness.
CL = lung compliance; CRS = compliance of the respiratory system; CVP = central venous pressure;
DPAP = diastolic pulmonary artery pressure; FiO2 = inspired fraction of oxygen; LVOT = left
ventricular outflow tract; MPAP = mean pulmonary artery pressure; PaCO2 = arterial partial
pressure of carbon dioxide; PaO2 = arterial partial pressure of oxygen; PAOP = pulmonary artery
occlusion pressure; PBW = predicted body weight; PEEP = positive end-expiratory pressure; PL =
transpulmonary pressure; PVR = pulmonary vascular resistance; R/I ratio = recruitment-to-inflation
ratio; RV/LV end-diastolic areas ratio = right-to-left ventricular end-diastolic areas ratio; SPAP =
systolic pulmonary artery pressure; SvO2 = mixed venous oxygen saturation; TAPSE = tricuspid
annulus plane systolic excursion.

E9
Supplementary Figure E1

A. Potential mechanisms explaining the hemodynamic effects of positive end-expiratory pressure

(PEEP).

B. Theoretical relationship between pulmonary vascular resistance (PVR) and lung volume. As lung
volume increases from residual volume (RV) to the functional residual capacity (FRC), the lung
tissue unfolds, the diameter of the extra-alveolar vessels increases, and PVR decreases. From the
FRC to the total lung capacity (TLC), while the transpulmonary pressure increases, the alveolar
vessels are compressed by the alveoli, their diameter decreases and PVR increases. The resulting
relationship between PVR and lung volume describes a U shape.

E10
Supplementary Figure E2. Change in cardiac index (median and IQR) induced by increasing
positive end-expiratory pressure (PEEP), according to lung recruitment potential.

E11
Supplementary Figure E3. Change in transpulmonary gradient [mean pulmonary artery pressure
(MPAP) – pulmonary artery occlusion pressure (PAOP)] (median and IQR) induced by increasing
positive end-expiratory pressure (PEEP), according to lung recruitment potential. * p less than
0.025.

E12
Supplementary Figure E4. Change in the ratio of tricuspid annulus plane systolic excursion (TAPSE)
over systolic pulmonary artery pressure (SPAP) (median and IQR) induced by increasing positive
end-expiratory pressure (PEEP), according to lung recruitment potential. * p less than 0.025.

E13
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