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Supplementary Table 1

Title: Cardiopulmonary physiology at baseline and after acute pulmonary embolism (group 1)

Variable BASELINE PULMONARY

EMBOLISM

p-value

Hemodynamics

CVP, mmHg 3.91.7 4.41.8 0.3506

SVR, dynes 1499492 1551576 0.8141

PVR/SVR 0.0890.058 0.3350.103 0.0018

Ventilation

Arterial pH 7.480.03 7.400.03 0.0007

PaCO2, kPa 5.290.26 6.690.48 0.0005

PaO2/PaCO2 2.110.50 0.920.23 0.0004

PaO2/FiO2, kPa/% 0.530.11 0.290.06 0.0004

Arterial saturation, % 97.0 [90.0-97.8] 68.6 16.7 0.0078

Arterial O2 content, mL/dL 13.30.7 10.22.3 0.0064

Oxygen delivered, mL/dL 5.61.4 5.41.1 0.8242

PvCO2, kPa 6.530.26 7.460.46 0.0002

PvO2, kPa 4.670.56 3.630.76 0.0034

Mixed venous O2 content, mL/dL 7.61.8 4.71.6 0.0023

Alveolar O2 partial pressure, mmHg 92.53.2 79.45.1 0.0005

Shunt fraction, % 4.8 [3.8-17.4] 43.915.2 0.0078

EtCO2, kPa 5.30.2 4.90.5 0.0189

Right ventricular function

RV ESP, mmHg 286 529 <0.000

1

RV EDP, mmHg 42 51 0.5451

RV ESV, mL 319 4319 0.0958

RV Ea, mmHg/mL 0.4290.140 1.1640.539 0.0028

RV SW, mmHg*mL 2003663 20931037 0.7487

RV dP/dtmax, mmHg/s 31342 441 [399-499] 0.0078

RV dP/dtmin, mmHg/s -34462 -53772 <0.000

1

RV tau, ms 4611 415 0.2741

RV Ees, mmHg/mL 0.580.25 0.850.40 0.0399

RV Eed, mmHg/mL 0.0660.035 0.057 [0.039-0.082] 0.5469

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RV PRSW, mmHg 17.033.41 15.7212.20 0.7284

RV PVA/EDV 20.355.56 28.6113.47 0.1405

Left ventricular function

LV ESP, mmHg 9416 9619 0.7844

LV EDP, mmHg 91 91 0.0715

LV ESV, mL 6119 5218 0.0393

LV EF, % AUTO RESP 63 [60-66] 6110 0.7422

LV Ea, mmHg/mL 0.9660.193 1.2210.355 0.0193

LV SW, mmHg*mL 82192022 70871617 0.3093

LV dP/dtmax, mmHg/s 1551246 1605 [1395-2043] 0.3828

LV dP/dtmin, mmHg/s -1911418 -1912520 0.9948

LV tau, ms 373 385 0.9462

LV Ees, mmHg/mL 0.820.55 0.67 [0.56-1.55] 0.1484

LV Eed, mmHg/mL 0.08 [0.07-0.13] 0.090.02 0.3828

LV PRSW, mmHg 53.4913.56 64.0327.25 0.2930

LV PVA/EDV 84.4315.17 94.3227.19 0.4454

LV Ees/Ea 0.840.49 0.850.44 0.9740

Caption: Hemodynamics at baseline and after acute pulmonary embolism induction for group 1, n=8 for all. Data are presented as meanSD or median [interquartile range] where appropriate.

Groups are compared with paired t-test or Wilcoxon signed rank test where appropriate.

Abbreviations: CVP, central venous pressure; SVR, systemic vascular resistance; RV, right ventricular; ESP, end-systolic pressure; EDP, end-diastolic pressure; ESV, end-systolic volume;; EF, ejection fraction; Ea, arterial elastance; SW, stroke work; Ees, end-systolic elastance; Eed, end- diastolic elastance; PRSW, preload recruitable stroke work; PVA, pressure-volume area.

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Title: Effects of increasing fractions of inspired oxygen in acute pulmonary embolism (group 1)

Variable FiO2=21

% (PE)

FiO2=40% FiO2=21

%

FiO2=60% FiO2=21

%

FiO2=100% FiO2=21

%

iNO

Hemodyna mics Heart rate, min^-1

719 545* 685 515**** 667 485*** 666 587*

MAP, mmHg

7921 7613 7813 7614 8113 7612 7911 7711

RV CO, mL/min

436720 96

30271225

*

447020 66

28501362

**

443023 11

27241396

*

384322 86

3264148 6

RV SV, mL ^# 48 [45- 72]

5724 6627 5625 6732 5625 6033 5625

Pulse oximetry,

%

886 100 [99- 100]**

8611 100 [99- 100]***

878 100 [100- 100]**

886 897

mPAP, mmHg

32.96.2 22.05.1**

*

31.86.0 19.54.0**

**

30.56.8 18.13.1** 28.67.2 18.84.1*

**

CVP, mmHg ^#

4.41.8 4.51.5 5.11.6 4.91.6 3.91.9 4.61.4 3.82.1 3.31.8

PVR, dynes 500188 369185* 464188 337246 487322 315232** 537386 277192 SVR, dynes 155157

6

2128820*

*

148753 6

23791179

*

174297 5

26031337

*

198891 8

2156943

PVR/SVR 0.3350.

103

0.1700.05 4**

0.3150.

079

0.1310.04 3***

0.2790.

081

0.1120.03 4**

0.2540.

083

0.1220.0 49**

Ventilation Arterial pH

#

7.400.0 3

7.390.03 7.410.0 2

7.400.03 7.410.0 2

7.410.02 7.420.0 2

7.410.02

PaCO2, kPa

#

6.690.4 8

6.590.38 6.710.4 7

6.650.43 6.580.5 1

6.500.36 6.580.3 0

6.630.42

PaO2, kPa 6.11

1.32

15.133.34

****

6.731.1 6

27.436.97

***

7.031.3 3

54.7914.4 3***

7.091.1 4

7.470.98

PaO2/PaCO

2

0.920.2 3

2.300.51*

***

1.010.2 1

4.131.05*

**

1.080.2 5

8.422.14*

***

1.080.1 8

1.130.17

PaO2/FiO2, kPa/%

0.290.0 6

0.380.08* 0.320.0 6

0.450.11* 0.340.0 6

0.560.15*

*

0.300.1 0

0.360.05

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Arterial saturation,

%

68.6

16.7

97.51.9**

*

74.710.

9

100 [99.9- 100]****

77.312.

0

100 [100- 100]**

78.67.8 81.56.4

Arterial O2

content, mL/dL

10.22.3 14.50.7** 11.21.7 15.20.9**

*

11.31.8 15.70.7**

*

11.51.1 11.81.1

Oxygen delivered, mL/dL

5.41.1 7.01.2 6.10.7 6.70.4* 5.50.8 6.80.6** 5.60.6 5.20.9

Mixed venous PvCO2,kPa^#

7.460.4 6

7.660.64 7.580.4 6

7.940.53 7.540.3 4

7.870.49 7.630.4 1

7.670.36

Mixed venous PvO2, kPa

3.630.7 6

5.150.29*

*

3.870.6 3

5.350.21*

*

4.130.5 4

5.710.29*

***

4.230.6 6

4.490.50

Mixed venous saturation,

%

32.712.

4

52.49.8**

*

35.010.

7

57.72.6** 40.010.

2

61.84.0**

*

41.311.

1

45.59.0

Mixed venous O2

content, mL/dL

4.71.6 7.61.3*** 5.11.6 8.40.9** 5.81.5 8.90.9*** 5.91.5 6.61.5

Alveolar O2

partial pressure, mmHg

79.45.1 210.66.3*

***

79.25.2 348.98.9*

***

80.55.5 604.110.7

****

80.43.0 79.94.0

Shunt fraction, %

43.915.

2

7.64.2*** 36.610.

7

5.83.1*** 35.613.

6

7.23.5** 36.28.2 33.29.5

EtCO2, kPa 4.90.5 4.80.3 5.30.4 4,70.2** 5.40.3 4.60.3*** 5.40.3 5.20.2*

Right ventricular function RV ESP, mmHg

529 366*** 529 325*** 5011 314** 469 324**

RV EDP, mmHg

51 51 52 42 52 52 42 42

RV ESV, mL 4319 3511 4517 3310* 4215 329* 3812 289**

RV EDV, mL 15554 11940* 16452 11140** 15051 10642* 12446 9639*

RV EF, % ^# 5610 5910 567 6111 5812 6211 5713 649

RV Ea, 1.160.5 0.850.43* 1.080.5 0.800.51* 1.130.7 0.56 [0.42- 1.190.8 0.790.44

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mmHg/mL 4 * 2 5 1.89] 0 RV SW,

mmHg*mL

209310 37

1617752 226910 41

1513700* 226312 57

1454689 (p0.08)

198712 44

1531695

RV dP/dtmax, mmHg/s

441 [399- 499]

35257* 459102 32755** 455129 31554*** 43580 37771

RV dP/dtmin, mmHg/s

-53772 -41448

***

-52964 -39346

****

-51684 -38141** -49471 -42586*

RV tau, ms 415 434 414 427 416 477 427 4011

RV Ees, mmHg/mL

0.850.4 0

0.690.18 0.820.3 2

0.610.25 0.820.3 5

0.630.23 0.880.4 0

0.800.34

RV Eed, mmHg/mL

0.06 [0.04- 0.08]

0.120.06* 0.080.0 4

0.120.04 (p0.055)

0.100.0 5

0.120.06 0.120.0 5

0.150.07

RV PRSW, mmHg

15.721 2.20

15.464.74 14.916.

05

15.394.33 15.777.

43

15.823.45 18.078.

68

18.704.5 2

RV PVA/EDV

28.611 3.47

23.793.87 28.116.

16

22.814.22 30.968.

81

23.064.65

*

34.216.

38

27.357.4 1*

RV Ees/Ea 1.130.5 5

1.350.50 1.180.5 7

1.420.56*

*

1.010.5 6

1.350.40 1.300.4 7

1.450.36

Left ventricular function LV ESP, mmHg

9619 9310 9311 9511 9610 9610 9611 9511

LV EDP, mmHg

91 102** 91 101** 91 101* 91 91

LV ESV, mL 5218 6512* 5514 7114**** 5811 7711** 679 7312 LV EDV, mL 14725 17026* 15627 18329** 16828 19229* 18523 20230*

LV EF, % 6010 577 617 567 605 566 595 607

LV Ea,

mmHg/mL

1.220.3 6

1.040.20 0.090.2 5

1.020.21 1.050.2 2

0.960.16 0.950.1 7

0.830.17 (p0.053) LV SW,

mmHg*mL

#

708716 17

7386867 740799 1

79011445 813112 13

85141787 897915 42

1000522 53

LV dP/dtmax, mmHg/s

1605 [1395- 2043]

1465257 174242 5

1426283*

*

178949 2

1378212*

*

167627 8

1658276

LV dP/dtmin, mmHg/s

- 191352 0

-1950368 -1877

329

-1971335 -1989

418

-2091352 -2087

468

-2124489

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LV tau, ms 385 384 383 392 382 403 383 373 LV Ees,

mmHg/mL 0.67 [0.56- 1.55]

0.550.12 0.680.1 7

0.440.13* 0.640.2 1

0.400.11 (p0.07)

0.630.2 1

0.580.25

LV Eed, mmHg/mL

0.090.0 2

0.070.03 0.080.0 6

0.080.02 0.070.0 2

0.070.02 0.080.0 2

0.070.03

LV PRSW, mmHg

64.032 7.25

54.5210.6 9

56.781 2.64

52.6013.9 8

61.951 7.92

51.2412.4 4

57.70 [50.40- 67-70]

60.0813.

05

LV PVA/EDV

94.322 7.19

83.5316.7 5

91.742 4.34

87.4314.2 6

94.161 6.34

86.7818.9 4

92.711 8.34

86.4217.

38 LV Ees/Ea 0.850.4

4

0.580.15 0.670.2 5

0.460.14 0.680.3 1

0.440.14 0.720.2 9

0.770.37

Caption: Effects of increasing doses of oxygen and inhaled nitric oxide. Data are presented as meanSD or median [interquartile range] where appropriate, n=8 for all. Effects of the interventions were evaluated by one-way ANOVA for repeated measurements using Sidak’s multiple comparisons test comparing each intervention to the FiO2 21% measurement recorded immediately before. Alternatively, Friedman test with Dunn’s multiple comparisons test. *p<0.05,

**p<0.01, ***p<0.001, ****p<0.0001 vs the FiO2=21% recorded just before each intervention.

#overall ANOVA significant but none in the multiple comparisons test.

Abbreviations: MAP, mean arterial pressure; CO, cardiac output; mPAP, mean pulmonary arterial pressure; CVP, central venous pressure; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; RV, right ventricular; ESP, end-systolic pressure; EDP, end-diastolic pressure; ESV, end- systolic volume; EDV, end-diastolic volume; EF, ejection fraction; Ea, arterial elastance; SW, stroke work; Ees, end-systolic elastance; Eed, end-diastolic elastance; PRSW, preload recruitable stroke work; PVA, pressure-volume area.

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(8)

Title: Cardiopulmonary physiology at baseline and after acute pulmonary embolism (group 2)

Variable BASELINE PULMONARY

EMBOLISM

p-value

Hemodynamics

Heart rate, min^-1 4710 6412 0.0002

MAP, mmHg 717 729 0.9004

RV CO, mL/min 3768 [3410-4112] 44831650 0.5469

RV SV, mL 8529 7122 0.2703

Pulse oximetry, % 982 8012 0.0013

mPAP, mmHg 15.42.5 32.95.3 <0.000

1

CVP, mmHg 4.32.0 5.50.9 0.0719

PVR, dynes 15268 471130 0.0002

SVR, dynes 1377362 1356616 0.9296

PVR/SVR 0.120.05 0.380.11 0.0003

Biochemistry

Troponin-I, ng/L 405 [309-517] 798372 0.0078

8-isoprostane, pg/mL 51.713.8 59.517.4 0.2396

Ventilation

Arterial pH 7.470.03 7.390.02 <0.000

1

PaCO2, kPa 5.440.47 6.840.42 <0.000

1

PaO2, kPa 11.991.32 6.601.24 <0.000

1

PaO2/PaCO2 2.220.31 0.970.16 <0.000

1

PaO2/FiO2, kPa/% 0.570.06 0.310.06 <0.000

1

Arterial saturation, % 96.81.9 73.210.0 0.0003

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Arterial O2 content, mL/dL 12.90.7 10.41.4 0.0030

Oxygen delivered, mL/dL 5.11.0 5.61.2 0.4290

PvCO2, kPa 6.490.67 7.690.39 0.0028

PvO2, kPa 5.050.78 3.800.70 0.0145

Mixed venous saturation, % 59.313.0 33.711.1 0.0052

Mixed venous O2 content, mL/dL 7.81.6 4.81.6 0.0069

Alveolar O2 partial pressure, mmHg 965 835 <0.000 1

Shunt fraction, % 65 3912 0.0001

EtCO2, kPa 5.30.1 4.70.3 0.0007

Right ventricular function

RV ESP, mmHg 284 485 0.0002

RV EDP, mmHg 52 61 0.4382

RV ESV, mL 3111 43 [41-66] 0.0078

RV EDV, mL 14443 15737 0.4605

RV EF, % 728 556 0.0007

RV Ea, mmHg/mL 0.410.17 0.800.21 0.0011

RV SW, mmHg*mL 1911408 2484954 0.1669

RV dP/dtmax, mmHg/s 36968 51086 0.0015

RV dP/dtmin, mmHg/s -31352 -50076 0.0002

RV tau, ms 54 [49-64] 486 0.0781

RV Ees, mmHg/mL 0.630.28 0.620.18 0.9553

RV Eed, mmHg/mL 0.090.05 0.110.06 0.1785

RV PRSW, mmHg 14.973.81 20.115.67 0.1081

RV PVA/EDV 20.02.9 34.612.6 0.0184

RV Ees/Ea 2.30 [1.18-4.19] 0.970.30 0.0156

Left ventricular function

LV ESP, mmHg 8913 8712 0.7308

LV EDP, mmHg 82 82 0.2882

LV ESV, mL 5512 5319 0.7449

LV EDV, mL 17028 15437 0.1036

LV EF, % 59 [58-73] 5813 0.3828

LV Ea, mmHg/mL 0.930.17 1.260.51 0.0417

LV SW, mmHg*mL 79282284 63432593 0.0658

LV dP/dtmax, mmHg/s 1589347 1597385 0.9580

LV dP/dtmin, mmHg/s -1627498 -1440452 0.2626

LV tau, ms 4511 4610 0.6388

LV Ees, mmHg/mL 1.020.78 1.170.59 0.5481

LV Eed, mmHg/mL 0.100.05 0.090.03 0.6180

LV PRSW, mmHg 48.813.8 53.09.6 0.5372

LV PVA/EDV 86.013.5 80.715.5 0.5458

LV Ees/Ea 0.83 [0.50-2.21] 1.020.51 0.7422

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Caption: Hemodynamics at baseline and after acute pulmonary embolism induction for group 2, n=8 for all. Data are presented as meanSD or median [interquartile range] where appropriate.

Groups are compared with paired t-test or Wilcoxon signed rank test where appropriate.

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Title: Extended effects of increased fraction of inspired oxygen 40% in acute pulmonary embolism (group 2)

Variable FiO2=21% (PE) FiO2=40% (early) FiO2=40%

(late)

FiO2=21% iNO

Hemodynamics

Heart rate, min^-1 6412 5110**** 5210 6211^‡‡ 5610*

MAP, mmHg 729 725 766 817^‡‡‡ 776**

RV CO, mL/min 44831650 38831237 44101253 56052367 44591457

RV SV, mL 7122 7618 8821 9330 8121

Pulse oximetry, % 8012 100 [100-100]*** 100 [100-100] 855^‡‡ 856

mPAP, mmHg 335 224**** 204^§§ 304^‡‡‡‡ 194****

CVP, mmHg 61 51 51 41 41

PVR, dynes 471130 279110** 20366^§ 34085^‡ 204107 (p0.07)

SVR, dynes 1356616 1489411 1393467 1256493 1423400

PVR/SVR 0.380.11 0.200.09**** 0.160.08^§§ 0.290.07^‡‡‡‡ 0.150.07****

Ventilation

Arterial pH 7.390.02 7.380.02 7.380.02 7.400.02^‡‡ 7.400.02 PaCO2, kPa 6.840.42 6.950.50 6.960.54 6.730.52

(0.07)

6.840.43

PaO2, kPa 6.601.24 16.393.24**** 18.233.56 (p0.052)

7.430.82^‡‡‡‡ 7.390.87

PaO2/PaCO2 0.970.16 2.360.42**** 2.620.49 (p0.059)

1.110.12^‡‡‡‡ 1.080.13

PaO2/FiO2, kPa/% 0.310.06 0.410.08** 0.460.09 (p0.052)

0.350.04^‡‡ 0.350.04

Arterial saturation, % 73.210.0 98.51.2*** 98.80.9 81.94.6^‡‡‡‡ 81.34.4 Arterial O2 content,

mL/dL

10.41.4 13.80.5*** 13.60.6 11.20.6^‡‡‡‡ 11.10.8

Oxygen delivered, mL/dL

5.61.2 6.30.8 5.71.0 5.61.0 5.51.0

Mixed venous PvCO2, kPa

7.690.39 7.940.41 8.200.35 7.590.69 7.860.45

Mixed venous PvO2, 3.800.70 5.200.48* 5.450.54 4.310.56^‡‡ 4.05 [3.90-4.43

(12)

kPa

Mixed venous

saturation, %

33.711.1 54.96.4*** 58.87.2 42.28.6^‡‡ 41.59.6

Mixed venous O2

content, mL/dL

4.81.6 7.51.0 (p0.055) 7.91.1 5.1 [4.7-6.2]^‡ 5.3 [4.6-5.7]

Alveolar O2 partial pressure, mmHg

835 2157**** 2157 846^‡‡‡‡ 835

Shunt fraction, % 3912 63**** 54 308^‡‡‡‡ 315

EtCO2, kPa 4.70.3 4.60.3 4.80.2^§§ 5.50.3^‡‡‡‡ 5.10.3***

Right ventricular function

RV ESP, mmHg 485 375** 354^§§ 475^‡‡‡ 334****

RV EDP, mmHg 61 61 62 61 52

RV ESV, mL 43 [41-66] 4312* 4114 4918^‡ 3411**

RV EDV, mL 15737 14929 16041 17546 13929

RV EF, % 556 625** 676 (p0.075) 635 705*

RV Ea, mmHg/mL 0.800.21 0.550.16* 0.450.12 0.580.17^‡ 0.470.15 RV SW, mmHg*mL 2484954 2209563 2548695 32671311 2307641*

RV dP/dtmax, mmHg/s 51086 62464 (p0.07) 444114 516 [417- 680]^‡‡

459117*

RV dP/dtmin, mmHg/s -50076 -39749*** -40570 -563140 (p0.06)

-38886 (p0.06)

RV tau, ms 486 529 515 508 518

RV Ees, mmHg/mL 0.620.18 0.540.11 0.500.12 0.620.15 0.580.14 RV Eed, mmHg/mL 0.110.06 0.110.04 0.090.04 0.100.05 0.120.04

RV PRSW, mmHg 20.115.67 17.62.0 18.23.4 22.54.8 19.53.3

RV PVA/EDV 34.612.6 27.97.4 25.54.8 34.07.3^‡ 26.14.1*

RV Ees/Ea 0.970.30 1.400.34 1.570.43 1.460.32 1.640.34

Left ventricular function

LV ESP, mmHg 8712 908 969^§§ 978 948**

LV EDP, mmHg 82 92 91 82 92

LV ESV, mL 5319 6216* 6919 6320^‡ 6521

LV EDV, mL 15437 17330* 18929^§ 18030^‡ 19331*

LV EF, % 5813 5712 5813 5913 6113

LV Ea, mmHg/mL 1.260.51 1.080.36 0.92 [0.79- 1.12]

1.01 [0.85- 1.15]

0.940.30***

LV SW, mmHg*mL 63432593 72692329 85642732^§§ 84512523 91612847**

LV dP/dtmax, mmHg/s 1597385 1502163 1543155 1704229 1677195 LV dP/dtmin, mmHg/s -1440452 -1549479 -1708465^§ -1737389 -1745455

LV tau, ms 4610 4814 4712 4511 4513

LV Ees, mmHg/mL 1.170.59 0.950.55 1.000.76 0.970.49 0.690.35 LV Eed, mmHg/mL 0.090.03 0.100.04 0.070.03^§ 0.080.04 0.070.02 LV PRSW, mmHg 53.09.6 56.718.5 58.011.5 61.910.0 55.010.7

(13)

LV PVA/EDV 80.715.5 92.725.3 88.514.3 98.916.8 88.58.1

LV Ees/Ea 1.020.51 1.000.60 0.62 [0.48-

1.68]

0.68 [0.53- 1.53]

0.870.54

Caption: Extended effects of oxygen and inhaled nitric oxide. Data are presented as meanSD or median [interquartile range] where appropriate, n=8 for all. Groups are compared with paired t- test or Wilcoxon signed rank test where appropriate. *p<0.05, **p<0.01, ***p<0.001,

****p<0.0001 vs the FiO2=21% recorded just before each intervention, ^‡p<0.05, ^‡‡p<0.01,

‡‡‡p<0.001, ^‡‡‡‡p<0.0001 vs FiO2=40% (late), ^§p<0.05 vs FiO2=40% (early).