The Association Between Oxygenation Thresholds and Mortality During Extracorporeal Life Support Laveena Munshi, MD, MSc November 1, 2016 Critical Care Canada Forum Interdepartmental Division of Critical Care Medicine Mount Sinai Hospital/University Health Network University of Toronto Toronto, Canada
Disclosures: No Financial Disclosures Extracorporeal Life Support Organization Research Grant
Is It Possible to O.D. on O 2??
Hyperoxia Not Uncommon During ECLS?
Percent Mortality Objectives To 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 arrest 100 90 80 70 60 50 40 30 20 HYPOTHESIS 0 80 160 240 320 400 480 pao 2
Methods Retrospective Cohort Study Adult Patients Undergoing ECLS 2010-2015
Methods COHORT 1: VV ECMO RESP COHORT 2: VA ECMO CARDIAC COHORT 3: ecpr EXPOSURE OUTCOME STATISTICAL ANALYSIS Venous outflow/inflow or bicaval dual lumen Respiratory Indication (eg. ARDS) Venous outflow/arterial inflow or venous/arterial inflow Cardiac Indication (eg. post MI cardiogenic shock) Veno-arterial cannulation during cardiac arrest Oxygenation determined by ABG 24 hours after ECLS initiation Hypoxemia: PaO 2 <60mmHg Normoxia: PaO 2 60-100mmHg (ref) Moderate Hyperoxia:PaO 2 101-300 mmhg Extreme Hyperoxia: PaO 2 >301mmHg In-hospital Mortality Multivariable logistic regression analysis controlling for all clinically relevant confounders (Patient demographic, pre ECLS clinical data, post-ecls parameters)
Results
Cohort Creation Configuration, Indication and ABG Data n=7,337 VV ECMO VA ECMO VA ECMO 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 ECMO 7.20/64/67/26 7.30/40/124/20 7.20/47/120/18 ph/pco 2 /O 2 /HCO 3 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 ECMO 7.23/41/94/26 7.40/36/180/22 7.40/34/195/23 ph/pco 2 /O 2 /HCO 3 Duration of ECMO (days) 8 (4-15) 5 (3-8) 4 (3-8) Discharged Alive 59% 41% 39%
Percent Distribution of Oxygenation 100 Hypoxemia <60 mmhg 90 80 70 60 52% 58% Normoxia 61-100 mmhg Mod Hyperoxia 101-300 mmhg Severe Extreme Hyperoxia Hyperoxia >300 >301 mmhg mmhg 50 46% 40 30 20 10 21% 25% 2% 8% 19% 15% 23% 8% 22% 0 VV ECMO RESP VA ECMO CARDIAC ecpr
Percent Crude Association Between O 2 and Mortality ---- VV ECMO RESP ---- VA ECMO CARDIO ---- ecpr pao 2
VV ECMO Respiratory Failure: Moderate Hyperoxia and Hypoxemia Associated with Increased Mortality Hypoxemia pao 2 <60 mm Hg (161 patients, 21%) Normoxia pao 2 60-100 mm Hg (394 patients, 52%) Moderate Hyperoxia pao 2 101-300 mm Hg (194 patients, 25%) Extreme Hyperoxia pao 2 >301 mm Hg (15 patients, 2%*) OR 95% CI 1.68 (1.09-2.57) 101-120 mmhg 121-140 mmhg 1 reference 141-160 mmhg 161-180 mmhg 1.66 181-200 (1.11-2.50) mmhg 201-220 mmhg 221-240 mmhg 0.75 (0.21-2.64) 241-260 mmhg *Older age, liver failure, higher peak inspiratory pressure at 24 hours, higher HCO 3, lower ph at 24 hours also statistically significantly associated with increased mortality
VA ECMO Cardiogenic Shock: No Association with Mortality Hypoxemia pao 2 <60 mm Hg (62 patients, 8%) Normoxia pao 2 60-100 mm Hg (145 patients, 19%) Moderate Hyperoxia pao 2 101-300 mm Hg (450 patients, 58%) Extreme Hyperoxia pao 2 >301 mm Hg (117 patients, 15%) OR 95% CI 1.67 (0.74-3.75) 1 reference 0.89 (0.59-1.34) 1.43 (0.80-1.00) *Older age, lower mean arterial pressure, post ECMO MV FiO2, lower ph & pco 2, statistically significantly associated with a higher mortality
VA ECMO ecpr: Moderate Hyperoxia Associated with Increased Mortality Hypoxemia pao 2 <60 mm Hg (96 patients, 23%) Normoxia pao 2 60-100 mm Hg (34 patients, 8%) Moderate Hyperoxia pao 2 101-300 mm Hg (191 patients, 46%) Extreme Hyperoxia pao 2 >301 mm Hg (91 patients, 22%) OR 95% CI 1.33 (0.48-3.69) 1 reference 1.77 (1.03-3.03) 1.92 (0.9-3.69) *post ECMO MV FiO2 & lower ph statistically significantly associated with a higher mortality
ECLS Types VV ECMO RESPIRATORY FAILURE VA ECMO CARDIOGENIC SHOCK VA ECMO ecpr Association w/ Mortality Moderate Hyperoxia Hypoxemia No Association Moderate Hyperoxia MECHANISM of HARM ASSOCIATED with HYPEROXIA: Direct Lung Toxicity Interstitial fibrosis, atelectasis, tracheobronchitis, ocular toxicity Systemic Hyperoxia Effect pro-inflammatory response, increased reactive O 2 species vasoconstriction leading to end organ dysfunction
Mechanism for Harm VV ECMO Oxygen free radicals exacerbated on ECMO Vasoconstriction induced by hyperoxia leading to MSOF Mechanisms to achieve higher arterial pao 2 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 90% 80% 70% 60% 50% 40% VA ECMO VV ECMO 30% 20% 10% 0% 24 HOURS 48 HOURS 72 HOURS 96 HOURS 120 HOURS 230 HOURS 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 O 2 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
O 2 : 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 O 2 thresholds at which potential harm may be seen
RCT, 434 Patients, MSICU MSICU, anticipated admission >72 hours CONSERVATIVE pao 2 70-100 mmhg Potential Overestimation of Treatment Effect CONVENTIONAL paostopped 2 up 150 Early mmhg Saturation 94-98% Saturation Baseline 97-100% imbalances Exclude ARDS with PaO2/FiO2 Small <150mmHg number of Outcomes Chronically hypercapnic COPD Underpowered
Conclusions and Future Directions Moderate hyperoxia (pao 2 101-300 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 O 2 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
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Acknowledgements Dr. Eddy Fan Dr. Alex Kiss Dr. Niall Ferguson Dr. Shaf Keshavgee Dr. Marcelo Cypel ELSO Research Grant
Interaction (exploratory) VV ECMO RESP VA ECMO CARDIAC MORTALITY Resp Acidosis <7.35, >45 Resp Alkalosis >7.45, <35 Full VV Resp Cohort MORTALITY Resp Acidosis <7.35, >45 Resp Alkalosis >7.45, <35 Full VA Cardiac Cohort Hypoxemia 48% (56) 39% (77) 36% Hypoxemia <60 92% 61% 64% Normoxia 43% (86) 41% (34) 39% Normoxia 61-100 76% 53% 57% Hyperoxia 27% (11) 42% (52) 45% Hyperoxia 101-300 56% 52% 56% Hyperoxia 100% (3) 33% (6) 46% Hyperoxia >301 79% 60% 67%
Appendix Table 1: Variables Incorporated Into Each Model (*determined by clinical relevance) VV ECMO RESP VA ECMO CARDIAC ecpr Sex Race Age Weight Year Sex Race Age Weight Year 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 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 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
VV ECMO pao 2 Detailed Overview Moderate Hyperoxia 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) 90% of deaths occurred by day 30 Timing of Death Across those who Died on ECMO 90.00% 80.00% 70.00% 60.00% 50.00% 40.00% VA ECMO VV ECMO 30.00% 20.00% 10.00% 0.00% 24 HOURS 48 HOURS 72 HOURS 96 HOURS 120 HOURS 230 HOURS (VA) 90% of deaths occurred by day 12
100 90 80 70 60 50 40 VV ECMO VA ECMO ecpr 30 20 10 0 0 2 4 6 8 10 12 Days
Percent Distribution of Oxygenation 100 90 80 70 VV ECMO RESP VA ECMO CARDIAC ecpr 60 50 40 30 20 10 0 Hypoxia Normoxia Moderate Hyperoxia Severe Hyperoxia <60mmHg 61-100mmHg 101-300mmHg >300mmHg