How much oxygen do you need? ◦ “natural experiments” ◦ “critical care research” Is...
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How much oxygen do you need?◦“natural experiments”◦“critical care research”
Is oxygen toxic?
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Origins of mitochondria – ancient invasions > 1.5 billion years ago
Eukaryote
-proteobacterium
proto-mitochondria
genetransfer
• genetic similarity to bacteria• What drove the union• protect anarobic host from oxygen tension
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Energy production in Mitochondria
glucose pyruvate
2 ATP
mitochondria
pyruvate + O2H2O & CO2
glycolysis
30 ATP
Oxidative phosphorylation
Inefficient process Very efficient process
Pyruvate +O2O2
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Energy production in Mitochondria
H+ H+
e H+
O2
2H2O
ADP
ATP
Outer membrane
matrix
Inner membrane
H+
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Ascent without oxygen
All 8000+ m peaks have been climbed without O2
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Location Height (m)
Aircraft cabin 1800 – 2500
Mont Blanc 4800
Everest base camp 5500
Everest summit 8900
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Location Atmosphericpressure (kPa)
Inspired PO2 (kPa)
Sea level 100 0.21X(100-6.3) = 19.6
Everestbasecamp
50 0.21X(50-6.3) = 9.2
Everestsummit
30 0.21X(30-6.3) = 5.0
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Alveolar PO2 PIO2 -PaCO2
Everest summit PAO2 = 5.0 -5.0 = 0!!
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PACO2 CO2 output/alveolar ventilation
Normal alveolarventilation
6 L/min
Everest summit > 40 L/min
Everest summitPaCO2
1 kPa
Everest summitPAO2
5-1 = 4 kPa
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Gas transfer at altitude
Diffusion limited
PaO2 3.5 kPa
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Sea Level Hb = 14.5 96/100X14.5X1.39 = 20ml 100ml-1
5300 Hb = 18.9 75/100X18.9X1.39 = 20ml 100ml-1
Everest summit
Hb = 18.9 60/100X18.9X1.39 = 16ml 100ml-1
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VO2 = cardiac output X arterial O2 content
VO2 at sea level at rest
5000 X 20 = 1000 ml/min
VO2 at Everest summit
Critical oxygen
delivery
5000 X 15.8 = 790 ml/min
= 300 ml/min
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Supplemental oxygen and montaineer death rates on Everest and K2 - JAMA 2000
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Two theories of the “vertical limit”
◦Oxygen delivery limit
◦Oxygen diffusion limit from capillary to mitochondria
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Cardiac output Respiratory rate and MV Haemoglobin Skeletal muscle ? Capillary/endothelial ? Mitochondrial/OXPHOS
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Hypoxaemia & Metabolism
Hypoxia Inducible factorTransduction factor> 100 genesErythropoietinMetabolismAngiogenesisCell differentiation
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Climbers Success
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Oxygen is bad for you! Oxidative phosphorylation vs. ROS Ubiquitous cellular defences against ROS Marked depletion of these in critically ill Many trials of “anti-oxidants” No RCTs of limiting oxygen
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(Crit CareMed 2004; 32:2496 –2501)
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Additive effects of high TV and high oxygen
permeability
Inflammatory cells
cytokines
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FIO2 75 – 100%◦ Tracheobronchitis◦ Loss of VC◦ Time & dose dependent
Single volunteer FIO2 100% for 100 hrs◦ Deteriorating respiratory function◦ Acute respiratory failure
Winter PA Anaesthesiology 1972;37:210
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Number of volunteers
FIO2 (%) Duration (hrs)
Outcome
1 100 100 Respiratory failure !
9 100 6-12 No change
4 100 6-60 Fall VC fall Kco
6 100 17 No change
14 95 18 BAL + albumin + transferrin
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“Irreversible coma”◦ 100% O2 for a few days◦ Patchy pulmonary infiltrates & reduced gas
exchange Barber New Engl J Med 1970; 283:1478-84
Five patients with neuromuscular disease◦ 85-100 % FIO2 for a few days◦ Patch chest radiology changes◦ Fever◦ Raised wbc◦ No infection
Hyde Ann Intern Med 1969;71;517-31
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Experimental evidence for O2 toxicity in the lung
Evidence for additive effect of hyperoxia on VILI No evidence that survival is determined by
oxygenation alone
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Ventilation at a reduced FIO2 (accepting lower SaO2) will improve outcome in patients receiving prolonged (4+ day mechanical ventilation) in General ITUs
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We do not know how low we can allow oxygen delivery to fall
Our patients are not Mountaineers!◦ Increase CO◦ Increase RR◦ Increase Hb◦ Adapt by complex changes in gene expression◦ Good genes
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Oxygen toxicity occurs in small animals and neonates
Some but controversial evidence in healthy man
Little or no evidence in the critically ill Shouldn't assume that oxygen is
harmless (= a drug at FIO2 > 21%) Need for more research