Laveena Munshi, MD, MSc

November 1, 2016

Critical Care Canada Forum

Interdepartmental Division of Critical Care MedicineMount Sinai Hospital/University Health NetworkUniversity of Toronto

Toronto, Canada

The Association Between Oxygenation

Thresholds and Mortality During

Extracorporeal Life Support

Disclosures:

No Financial Disclosures

Extracorporeal Life Support Organization Research Grant

Is It Possible to

O.D. on O2??

Hyperoxia Not Uncommon During ECLS?

ObjectivesTo evaluate the association between oxygen thresholds and hospital mortality in patients undergoing ECLS in 3 cohorts:

1.Venovenous ECMO

for respiratory failure

2.Venoarterial ECMO

for cardiogenic shock

3. eCPR for cardiac

arrest20

30

40

50

60

70

80

90

100

0 80 160 240 320 400 480

HYPOTHESIS

paO2

Perc

ent

Mo

rtal

ity

Methods

Retrospective Cohort Study

Adult Patients Undergoing ECLS

2010-2015

Methods

COHORT 1: VV ECMO RESP Venous outflow/inflow or bicaval dual lumenRespiratory Indication (eg. ARDS)

COHORT 2: VA ECMO CARDIAC Venous outflow/arterial inflow or venous/arterial inflowCardiac Indication (eg. post MI cardiogenic shock)

COHORT 3: eCPR Veno-arterial cannulation during cardiac arrest

EXPOSURE Oxygenation determined by ABG 24 hours after ECLS initiationHypoxemia: PaO2 <60mmHg

Normoxia: PaO2 60-100mmHg (ref)

Moderate Hyperoxia:PaO2101-300 mmHg

Extreme Hyperoxia: PaO2 >301mmHg

OUTCOME In-hospital Mortality

STATISTICAL ANALYSIS Multivariable logistic regression analysis controlling for all clinically relevant confounders (Patient demographic, pre ECLS clinical data, post-ECLSparameters)

Results

Cohort Creation

VV ECMO VA ECMO VA ECMO

Configuration, Indication and ABG Datan=7,337

VV ECMO RESP VA ECMO CARDIAC VA ECMO eCPR

Cohort Characteristics

Mean (± Standard Deviation)

Median (Interquartile Range)VV RESP VA CARDIAC eCPR

Age 44 ± 16 52 ± 15 53 ± 16

Sex (% Male) 64% 67% 71%

Weight 87 ± 28 82 ± 23 81 ± 22

Duration MV pre ECMO

55 hours (18-144) 15 hours (6-40) 2 hours (0-17)

ABG pre ECMOph/pCO2/O2/HCO3

7.20/64/67/26 7.30/40/124/20 7.20/47/120/18

ECMO Mode VV 61%BCDL 38%

VA 99%VVA 1%

VA 99%VVA 1%

ECMO Flow 4 ± 1 4 ± 1 3.5 ± 1

ABG post ECMOph/pCO2/O2/HCO3

7.23/41/94/26 7.40/36/180/22 7.40/34/195/23

Duration of ECMO (days)

8 (4-15) 5 (3-8) 4 (3-8)

Discharged Alive 59% 41% 39%

0

10

20

30

40

50

60

70

80

90

100

VV ECMO RESP VA ECMOCARDIAC

eCPR

Hypoxemia <60 mmHg

Normoxia 61-100 mmHg

Mod Hyperoxia 101-300 mmHg

Severe Hyperoxia >300 mmHg

Distribution of Oxygenation

21%

52%

25%

2%8%

19%

58%

15%

23%

8%

46%

22%

Perc

ent Extreme Hyperoxia >301 mmHg

Crude Association Between O2 and

Mortality

paO2

Perc

ent

---- VV ECMO RESP---- VA ECMO CARDIO---- eCPR

VV ECMO Respiratory Failure:

Moderate Hyperoxia and Hypoxemia

Associated with Increased Mortality

OR 95% CI

Hypoxemia

paO2<60 mm Hg

(161 patients, 21%)

1.68 (1.09-2.57)

Normoxia

paO2 60-100 mm Hg

(394 patients, 52%)

1 reference

Moderate Hyperoxia

paO2 101-300 mm Hg

(194 patients, 25%)

1.66 (1.11-2.50)

Extreme Hyperoxia

paO2 >301 mm Hg

(15 patients, 2%*)

0.75 (0.21-2.64)

*Older age, liver failure, higher peak inspiratory pressure at 24 hours, higher HCO3,

lower pH at 24 hours also statistically significantly associated with increased mortality

101-120 mmHg

121-140 mmHg

141-160 mmHg

161-180 mmHg

181-200 mmHg

201-220 mmHg

221-240 mmHg

241-260 mmHg

VA ECMO Cardiogenic Shock:

No Association with Mortality

OR 95% CI

Hypoxemia

paO2<60 mm Hg

(62 patients, 8%)

1.67 (0.74-3.75)

Normoxia

paO2 60-100 mm Hg

(145 patients, 19%)

1 reference

Moderate Hyperoxia

paO2 101-300 mm Hg

(450 patients, 58%)

0.89 (0.59-1.34)

Extreme Hyperoxia

paO2 >301 mm Hg

(117 patients, 15%)

1.43 (0.80-1.00)

*Older age, lower mean arterial pressure, post ECMO MV FiO2, lower pH & pCO2,

statistically significantly associated with a higher mortality

VA ECMO eCPR:

Moderate Hyperoxia Associated with

Increased Mortality

OR 95% CI

Hypoxemia

paO2<60 mm Hg

(96 patients, 23%)

1.33 (0.48-3.69)

Normoxia

paO2 60-100 mm Hg

(34 patients, 8%)

1 reference

Moderate Hyperoxia

paO2 101-300 mm Hg

(191 patients, 46%)

1.77 (1.03-3.03)

Extreme Hyperoxia

paO2 >301 mm Hg

(91 patients, 22%)

1.92 (0.9-3.69)

*post ECMO MV FiO2 & lower pH statistically significantly associated with a higher

mortality

MECHANISM of HARM ASSOCIATED with HYPEROXIA:

• Direct Lung Toxicity

• Interstitial fibrosis, atelectasis, tracheobronchitis, ocular toxicity

• Systemic Hyperoxia Effect

• pro-inflammatory response, increased reactive O2 species

• vasoconstriction leading to end organ dysfunction

ECLS Types VV ECMO

RESPIRATORY

FAILURE

VA ECMO

CARDIOGENIC

SHOCK

VA ECMO

eCPR

Association

w/ Mortality

Moderate Hyperoxia

Hypoxemia

No Association Moderate Hyperoxia

Mechanism for Harm – VV ECMO

• Oxygen free radicals exacerbated on ECMO

• Vasoconstriction induced by hyperoxia leading to MSOF

• Mechanisms to achieve higher arterial paO2 may be harmful

• Higher ECMO flow

• Higher ventilation intensity

• Higher FiO2

No Harm Seen - VA ECMO

• Predominant mechanism of death may be due to underlying disease

• Death due to underlying disease may precede harm potentially attributable to hyperoxia

• VA ECMO deaths occurred earlier than VV ECMO

Death on VA ECMO Occurred

Earlier than VV ECMO

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

24 HOURS 48 HOURS 72 HOURS 96 HOURS 120 HOURS 230 HOURS

VA ECMO

VV ECMO

VA – 90% deaths occurred by day 12

VV – 90% 0f deaths occurred by day 30

Mechanism for Harm – eCPR

• Consistent with reports of increased harm in literature with for anoxic brain injury population

• Neurologic injury and brain edema following cardiac arrest particularly susceptible to O2 free radicals and vasocontriction

Limitations:

• Exploratory analysis

• Adequate capture of exposure? (24 hour time point ABG)

• Bias towards the null

• Clustering at hospital level

• Would impact standard errors but not point estimates

• Selection Bias

• Sufficient Control for Confounding

O2: Too Much of a Good Thing??

• Recent growing body of literature over the past 6 years suggesting harm associated with hyperoxia

• Recent growing body of literature surrounding lower O2

thresholds at which potential harm may be seen

RCT, 434 Patients, MSICU

MSICU, anticipated admission >72 hours

CONSERVATIVE CONVENTIONAL

paO2 70-100 mmHg paO2 up to 150 mmHg

Saturation 94-98% Saturation 97-100%

Exclude ARDS with PaO2/FiO2 <150mmHgChronically hypercapnic COPD

Potential Overestimation

of Treatment Effect

• Stopped Early

• Baseline imbalances

• Small number of Outcomes

• Underpowered

Conclusions and Future Directions• Moderate hyperoxia (paO2 101-300 mmHg) associated with

increased mortality in select cohorts of ECLS (VV ECMO Respiratory Failure and VA ECMO for eCPR)

• Possible mechanisms: vasoconstriction and oxygen free radicals or harm associated with increased ECLS or MV intensity to achieve higher O2

• Lack of association between hyperoxia and mortality in VA ECMO may be attributable to death due to underlying disease process

• Future research needed to further confirm results, explore thresholds, understand duration and dose-response as well as mechanisms for harm

A word of caution for the visitors to Toronto regarding your Tuesday night plans…..

Oxygen bars are places people can go to inhale

high purity Oxygen for recreation and relaxation. It is a fun and profitable business that succeeds in many different settings.

The first "Oxygen Bar" in North America was the "Oxygen Spa Bar" opened by <name omitted> in Toronto Canada in 1995.

$5.00/3 minutes

Acknowledgements

Dr. Eddy Fan

Dr. Alex Kiss

Dr. Niall Ferguson

Dr. Shaf Keshavgee

Dr. Marcelo Cypel

ELSO Research Grant

VV ECMO RESP

MORTALITY RespAcidosis<7.35, >45

RespAlkalosis>7.45, <35

Full VV RespCohort

Hypoxemia 48% (56) 39% (77) 36%

Normoxia 43% (86) 41% (34) 39%

Hyperoxia 27% (11) 42% (52) 45%

Hyperoxia 100% (3) 33% (6) 46%

Interaction (exploratory)VA ECMO CARDIAC

MORTALITY RespAcidosis<7.35, >45

RespAlkalosis>7.45, <35

Full VA Cardiac Cohort

Hypoxemia <60

92% 61% 64%

Normoxia 61-100

76% 53% 57%

Hyperoxia101-300

56% 52% 56%

Hyperoxia>301

79% 60% 67%

VV ECMO RESP VA ECMO CARDIAC eCPR

Sex

Race

Age

Weight

Year

Pre ECMO ABG data

Pre ECMO Duration of MV

Pre ECMO Vent (FiO2, PIP,

PEEP)

Pre ECMO MAP

Pre ECMO Vasopressors

Pre ECMO CVVHD

Pre ECMO Narcotics

Pre ECMO NMBA

Pre ECMO iNO

Pre ECMO Steroids

Acute Comorbid Conditions Pre

ECMO (cardiac, AKI, acute liver

failure)

Post ECMO flow

Post ECMO vent parameters

Post ECMO ABG data

Sex

Race

Age

Weight

Year

Pre ECMO ABG data

Pre ECMO Duration of MV

Pre ECMO Vent (FiO2, PIP, PEEP)

Pre ECMO MAP

Pre ECMO Vasopressors

Pre ECMO CVVHD

Pre ECMO Narcotics

Pre ECMO CPB, iNO

Pre ECMO paced

Pre ECMO Steroids

Acute Comorbid Conditions Pre

ECMO (resp failure, AKI, acute

liver failure)

Post ECMO flow

Post ECMO vent parameters

Post ECMO ABG data

Sex

Race

Age

Weight

Year

Post ECMO flow

Post ECMO vent parameters

Post ECMO ABG data

MAP

*did not include pre-ECMO ABG

and MV data as the majority are

not intubated pre-arrest

Appendix Table 1: Variables Incorporated Into Each Model (*determined by clinical relevance)

ECMO paO2 mmHg OR 95% CI

100-120 1.97 (0.84-4.65)

120-140 1.17 (0.29 – 4.66)

141-160 0.717 (0.10-5.34)

161-180 3.56 (0.26-49.38)

181-200 3.16 (0.14-71.34)

201-220 3.99 (0.10-153.99)

221-240 3.62 (0.04-361.24)

241-260 1.49 (0.01-201.86)

280-300 0.96 (0.002-415.50)

VV ECMO paO2 Detailed Overview

Moderate Hyperoxia

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00%

24 HOURS 48 HOURS 72 HOURS 96 HOURS 120 HOURS 230 HOURS

VA ECMO

VV ECMO

(VA) 90% of deaths occurred by day 12

(VV) 90% of deaths occurred by day 30

Timing of Death Across those who Died on ECMO

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12

VV ECMO

VA ECMO

eCPR

Days

0

10

20

30

40

50

60

70

80

90

100

Hypoxia Normoxia ModerateHyperoxia

SevereHyperoxia

VV ECMO RESP

VA ECMO CARDIAC

eCPR

Distribution of Oxygenation

<60mmHg 61-100mmHg 101-300mmHg >300mmHg

Perc

ent