Oxygen:..Nothing is without poison.. the poison is in the dose..

Transcription

1 Interdepartmental Division of Critical Care Medicine Mount Sinai Hospital/University Health Network University of Toronto Toronto, Canada Oxygen:..Nothing is without poison.. the poison is in the dose.. Laveena Munshi, MD, MSc Critical Care Canada Forum - Paracelsus; 1526

2 Disclosures: No Relevant Financial Disclosures

3 Evolution of Oxygen and Monitoring Billion Years Ago

4 Despite supplemental O 2 being cornerstone of CCM, emerging evidence suggests harm associated with excessive O 2 uh- O

5 OBJECTIVES: 1. Pathophysiology of oxygen toxicity 2. Evidence to date across critical care 3. How much is too much? 4. Future research considerations

6 Local effects of excessive oxygen Mucociliary clearance O 2 O 2 O O 2 O 2 2 O 2 N 2 surfactant Tracheobronchitis Absorptive atelectasis by displacement of alveolar nitrogen Rapid diffusion of oxygen into venous blood Reduction in alveolar volume leading to ventilation/perfusion mismatch Can be overcome by PEEP (Aboab et al ICM 2006) Obstructive and adhesive atelectasis Poor mucociliary clearance and surfactant impairment Tracheo/Bronchial irritation Prolonged exposure: Alterations in microbial flora in upper airways Lung injury and edema

7 Exogenous Stimuli Microbes Toxins Chemotherapy Radiation Other pathologic processes When considering systemic ROS effects ROS of excess O 2, typically not ROS described until thresholds above 100 mm Hg ROS Dissolved Oxidative O 2 readily Stress increases at pao 2 >100mm Hg when oxyghemoglobin saturation is nearly complete Breakdown product of ATP synthesis Necrosis Apoptosis ROS ROS with oxygen tension Cell Damage ROS Cell Death Inflammation ROS

8 Neurology: Nausea, Dizziness, Confusion, Seizures Edema Ocular: Retinopathy Pulmonary: Decreased Compliance: Alveolar/Interstitial Edema Leukocyte Sequestration Absorption Atelectasis Organ Specific Considerations Cardiac: Impaired Cardiac Output/ Stroke Volume Vital players in host defence systems and signalling molecules Systemic: Systemic: ROS superoxide Inflammation Inflammation Systemic: Vasoconstriction anion inactivates NO Organ Damage Cerebral/Coronary Shock Reversal CNS HSC Systemic hypoperfusion at thresholds >150 mm Hg

9 Evidence to Date

10 Early experimental studies demonstrated pulmonary injury, shock & inflammation Journal of Applied Physiology 1985 No change Histopathologic Changes in Lungs by Time Exposed CO SV Endothelial SVRCell Destruction PVR Endothelial Injury Neutrophil Accumulation Interstitial Edema Substantial Destruction of Endothelial and Type 1 Epithelial Cells Type 1 Cell Injury Congestion of Capillaries Substantial Interstitial Edema 40 h-exposed 66 h-exposed 80 h-exposed 110 h-exposed

11 What about critically ill mechanically ventilated patients Post mortem evaluation of 6 patients MV patients exposed to hyperoxia (FiO ) Range of exposure 14 hours 30 days Endothelial injury noted in subset exposed to hyperoxia for >3 days

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13 Objectives: To assess whether a conservative protocol for O 2 could improve outcomes in ICU patients Potential Overestimation of Treatment Effect 434 patients, MSICU, anticipated admission >72 hours CONSERVATIVE Stopped Early pao mmhg Baseline imbalances CONVENTIONAL pao 2 up to 150 mmhg Saturation 94-98% Saturation % Exclude: ARDS with PaO2/FiO2 <150mmHg; Chronically hypercapnic COPD Small number of Outcomes PaO 2 87 mm Hg (IQR 79-97) vs PaO mm Hg (IQR ) p <0.001 Underpowered 88-92% vs >96% PaO 2 (70 [68 73] mm Hg vs. 92 [89 96] mm Hg) Only 20% in liberal arm Sa02 >98%

14 ARDS?

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16 Percent Mortality Objectives To evaluate the association between oxygen thresholds and hospital mortality in patients undergoing ECLS in 3 cohorts (~2000 patients): 1.Venovenous ECMO for respiratory failure HYPOTHESIS 2.Venoarterial ECMO for cardiogenic shock 3. ecpr for cardiac arrest pao 2

17 Moderate hyperoxia associated with an increased mortality for VV and ecpr

18 Mechanisms of harm likely related to ROS :Oxygen Free Radicals Ventilation Intensity :Death Due to Alternative Causes Possibly Occurring At Earlier Time Point :Oxygen Free Radicals Exacerbating Brain Injury LIMITATIONS Exploratory Analysis Selection Bias Adequate Capture of Exposure Clustering at Hospital Level Confounding (time frame/location)

19 Hyperoxia/ excessive oxygen administration is not infrequent in general ICU population Study Definition Frequency De Graaffe 5,500 MV pts Eastwood, 150,000 MV pts Rachmale 210 MV pts pao 2 >120 mmhg 22% in first 24 hours pao 2 >120 mmhg 50% in first 24 hours FiO2 >50% despite saturation >92% 120 mm Hg 75% exposed for a median of 17 hours

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21 Acute Myocardial Infarction 441 patients STEMI without hypoxia Empiric 8L/min vs. No supplemental O 2 Increased early myocardial injury Increased myocardial infarct size at 6 months, recurrent MI s and frequency of cardiac arrhythmias

22 Brain Injury Theoretic benefit of vasoconstriction in reducing ICP Data in TBI is conflicting HOWEVER, CONCERN for HARM in ISCHEMIC BRAIN INJURY Delayed cerebral ischemia Cerebral excitotoxicity after CVA

23 Cardiac Arrest Myocardial Injury Ischemia Reperfusion Injury CNS Injury Creates a perfect storm of injury that are especially susceptible to the presence of ROS Subset of studies have demonstrated hyperoxia associated (dose-dependently) to worse outcome However, this association not consistent across the literature

24 What is the Optimal Target to Avoid Harms of Excessive Oxygen in the ICU?..we don t know yet

25 Expert statements establish min. thresholds but O 2 creep likely occurs due to lack of attentive titration SpO 2 of at least 90% Slutsky S et al. Consensus conference on mechanical ventilation Part ESICM ACCP SCCM, 1993 SpO %; pao mmhg ARDS Network Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. NEJM, 2000 SpO % European Resuscitation Council Guidelines SpO % ; pao mmhg British Thoracic Society Guideline for Emergency Oxygen Use in Adults, Thorax 2008 pao 2 >60 mmhg Tobin M et al. Mechanical ventilation. N Engl J Med 1994

26 What is the Optimal pao 2 for ICU? Nadir in mortality at pao mm Hg Increase in mortality at pao 2 <67 mm Hg Increase in mortality at pao 2 >225 mm Hg

27 Rigid thresholds where harm > benefits are not known and a static measurement across all conditions may not exist? pao 2 Munshi >100 Girardis >107 De Jong >225 Helmerhorst M/A >300

28 Permissive hypoexmia slide

29 Considerations for future research Concomitant Inflammatory Processes Outcomes Short and long term Prospective Randomized Trials Exposure PaO 2, Sat, FiO2 Dose Range of interest Confounders Acid base status Homogeneous Population Duration of Exposure Source Excess FiO2 vs. Oxygen util

30 Conclusions Evolving and increasing body of evidence demonstrating possible harm in acute care and critical care setting related to hyperoxia/excessive, unnecessary oxygen administration However, there remains some conflict surrounding potential harm and thresholds for harm; attributable to heterogeneity likely related to dose/exposure/population Need to better understand appropriate thresholds needed to facilitate adequate tissue O 2 while preventing hyperoxic harm and hypoxemia harm Until future high quality research, we know that conservative oxygen is safe and should avoid unnecessary excessive oxygen administration or hyperoxia; Safety data on lower limit thresholds needed

31 Thank you

32 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. ROS ROS The first "Oxygen Bar" in North America was the "Oxygen Spa Bar" opened by <name omitted> in Toronto Canada in $5.00/3 minutes ROS ROS ROS ROS ROS ROS ROS ROS ROS

33 My trial Inclusion: Mild ARDS Moderate ARDS Severe ARDS Exposure: Conservative mm Hg, saturation 88-96% Liberal >101 mm Hg, >98% Outcomes: Stratify 28 d mortality Secondary: shock, new sepsis, delirium LTO: neurocognitive 6 months Severity type

34 Hyperoxia is not always bad.

35 VV ECMO Respiratory Failure: Moderate Hyperoxia and Hypoxemia Associated with Increased Mortality Hypoxemia pao 2 <60 mm Hg (161 patients, 21%) Normoxia pao mm Hg (394 patients, 52%) Moderate Hyperoxia pao mm Hg (194 patients, 25%) Extreme Hyperoxia pao 2 >301 mm Hg (15 patients, 2%*) OR 95% CI 1.68 ( ) mmhg 1 reference mmhg mmhg mmhg ( ) mmhg mmhg mmhg ( ) 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

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