ICS State of the Art Meeting 2015

1. zmfu www.biomechanics.de
Crit Care Med 2008;36(2):637
Can you have too much oxygen?
P. Asfar, X. Leverve, P. Radermacher

2. zmfu www.biomechanics.de
Weil MH & Shubin H: The "VIP" approach to the
bedside management of shock.
JAMA 1969;207:337-40
“…ventilate (oxygen administration), infuse
(fluid resuscitation), pump (vasoactive drugs)..”
Vincent JL & De Backer D: Circulatory Shock.
NEJM 2013;369:1726-34
“. “…administration of oxygen should be started
immediately to increase oxygen delivery and
prevent pulmonary hypertension...”

3. zmfu www.biomechanics.de
FiO21.0
Hb-SO2 
 DO2 
-vascular PO2 
peri-capillary O2-diffusion 
ROS   host
defense 
NO   SVR 
 MAP 
Inhibition of HPV / resorption
atelectasis  right-to-left shunt  
pulmonary gas exchange 
NO   -vascular
perfusion 
ROS   NO  
oxidative /
nitrosative stress 
Mitochondrial O2 consumption  /
carbohydrate oxidation   efficiency
of mitochondrial respiration 
ROS   Uncoupling of
mitochondrial respiration
Inflammation 
 HIF-1 
Inflammation 
 NF-B 
Mitochondrial O2
consumption 
 ATP synthesis 

4. zmfu www.biomechanics.de
„For as a candle burns much faster
indephlogisticated (oxygen-enriched) than
incommon air, so we might live out too fast,
and the animal powers be too soon exhausted
in this pure kind of air. A moralist, at least,
may say, that the air which nature has
provided for us is as good as we deserve.“
In:THE DISCOVERY OF OXYGEN, section 3:
„Experiments and Observations on Different Kinds of Airs“
Joseph Priestley 1733- 1804

5. zmfu www.biomechanics.de
Mitochondrial cytochrome oxidases
2
-
O2
O2
2
H O
H2O2
+ e-
+ e-
+ 2 e
-
(OH)
.
+ 4 e-+ 2 ATP + 6 ATP
Xanthine-
oxidase
Superoxide-
dismutase
Catalase
Why is O2 a poison? The radicals

6. zmfu www.biomechanics.de
Why is O2 a poison? The radicals
Target Mechanism Effect
Membrane Lipid peroxidation Membran damage
Proteins Protein oxidation Enzyme inhibition
Nucleic acids DNA strand breaks Mutagenesis
Enzymes SH-depletion Enzyme inhibition
Carraway & Piantadosi: Oxygen toxicity. Respir Care Clin N Am 1999;5:265

7. zmfu www.biomechanics.de
Warum ist O2 ein Gift? Die RadikaleWhy is O2 a poison? The radicals
O2-Radicals
H2O ATP
ADP
Respiration
Cell
Work
O2

8. zmfu www.biomechanics.de
75 150 225 300 375 75 150 225 300 37
mmHg mmHg
PO2   radicals ?
Khaw et al: Effects of high inspired oxygen fraction during elective
Caesarean section under spinal anaesthesia on maternal and fetal
oxygenation and lipid peroxidation. BJA 2002;88:18
24 patients, FiO2 0.21 % vs. 0.6 (Venturi-mask)

9. zmfu www.biomechanics.de
FiO21.0
Hb-SO2 
 DO2 
-vascular PO2 
peri-capillary O2-diffusion 
ROS   host
defense 
NO   SVR 
 MAP 
Inhibition of HPV / resorption
atelectasis  right-to-left shunt  
pulmonary gas exchange 
NO   -vascular
perfusion 
ROS   NO  
oxidative /
nitrosative stress 
Mitochondrial O2 consumption  /
carbohydrate oxidation   efficiency
of mitochondrial respiration 
ROS   Uncoupling of
mitochondrial respiration
Inflammation 
 HIF-1 
Inflammation 
 NF-B 
Mitochondrial O2
consumption 
 ATP synthesis 

10. zmfu www.biomechanics.de
Hyperoxia prolongs the „window of
opportunity“ during hypoxia or ischemia

11. zmfu www.biomechanics.de
Hyperoxia and the lung

12. zmfu www.biomechanics.de
Calzia et al:
Hyperoxia may be beneficial.
CCM 2010;38:S559-68
Hyperoxia and the lung

13. zmfu www.biomechanics.de
Hyperoxia prolongs the „window of
opportunity“ during hypoxia or ischemia

14. zmfu www.biomechanics.de
FiO21.0
Hb-SO2 
 DO2 
-vascular PO2 
peri-capillary O2-diffusion 
ROS   host
defense 
NO   SVR 
 MAP 
Inhibition of HPV / resorption
atelectasis  right-to-left shunt  
pulmonary gas exchange 
NO   -vascular
perfusion 
ROS   NO  
oxidative /
nitrosative stress 
Mitochondrial O2 consumption  /
carbohydrate oxidation   efficiency
of mitochondrial respiration 
ROS   Uncoupling of
mitochondrial respiration
Inflammation 
 HIF-1 
Inflammation 
 NF-B 
Mitochondrial O2
consumption 
 ATP synthesis 

15. zmfu www.biomechanics.de
„…Taken together, these
clincial studies indicate
that hypoxia promotes
inflammation…“
„…We stress that in the
case of inflamed tissue,
hypoxia is not a
bystander but instead
can influence the
environment of the
itssue by regulating
oxygen-dependent gene
epxression…“
(Eltzschig & Carmeliet:
Hypoxia and inflammation.
NEJM 2011;364:656)
Hyperoxia and inflammation

16. zmfu www.biomechanics.de
„Oxygène“
Guinea pigs exposed to oxygen ► death from
hemorrhagic pulmonary edema!
Antoine Lavoisier 1743-1794

17. zmfu www.biomechanics.de

18. zmfu www.biomechanics.de
• 100% O2 over 25 h: modest reduction of vital capacity,
symptoms of tracheitis at 6 h
Comroe et al. JAMA 1945
• 100% O2 over 6-12 h, A-aDO2, Compliance, extravascular
lung water unchanged
De Water et al. N Eng J Med 1970
• 100% O2 over 6 h, symptoms of tracheitis
Sackner et al. Ann Intern Med 1975
• 95% O2 over 17 h, increased albumin levels in BAL fluid
Davis et al. N Eng J Med 1983
• 100 vs. 30% O2 over 8 h, normal bronchoscopy
Kotani et al. Anesthesiology 2000
Hyperoxia and the lung

19. zmfu www.biomechanics.de
Interstitium
15 mechanically ventilated patients
FiO2 60 – 100 %, 14 hours – 30 days
Kapanci et al: Oxygen pneumonitis in man. Chest 1972;62:162
Gould et al: Oxygen pneumonitis in man. Lab Invest 1972;26:499
Hyperoxia and the lung

20. zmfu www.biomechanics.de
Interstitium
14 hrs
3 days
6 days
13 days
15 mechanically ventilated patients
FiO2 60 – 100 %, 14 hours – 30 days
Kapanci et al: Oxygen pneumonitis in man. Chest 1972;62:162
Gould et al: Oxygen pneumonitis in man. Lab Invest 1972;26:499
Hyperoxia and the lung

21. zmfu www.biomechanics.de
FiO21.0
Hb-SO2 
 DO2 
-vascular PO2 
peri-capillary O2-diffusion 
ROS   host
defense 
NO   SVR 
 MAP 
Inhibition of HPV / resorption
atelectasis  right-to-left shunt  
pulmonary gas exchange 
NO   -vascular
perfusion 
ROS   NO  
oxidative /
nitrosative stress 
Mitochondrial O2 consumption  /
carbohydrate oxidation   efficiency
of mitochondrial respiration 
ROS   Uncoupling of
mitochondrial respiration
Inflammation 
 HIF-1 
Inflammation 
 NF-B 
Mitochondrial O2
consumption 
 ATP synthesis 

22. zmfu www.biomechanics.de

23. zmfu www.biomechanics.de
Hopf HW et al: Wound Tissue Oxygen Tension Predicts the Risk of
Wound Infection in Surgical Patients. Arch Surg 1997; 32: 997-1005

24. zmfu www.biomechanics.de
O2 as an „antibiotic“
• Antibiotics
• Normothermia
• Adequate fluid resuscitation
• Adequate hematocrite
• Normoglycemia
• Hyperoxia
Mauermann WJ:
The Anesthesiologist`s Role in the
Prevention of Surgical Site Infections
Anesthesiology 2006;105:413-21

25. zmfu www.biomechanics.de
Hovaguimian et al, Anesthesiology 2013;119:303
Meta-Analysis of 5103 patients!
All 5103 patients Colo-rectal-OP 1977 patients

26. zmfu www.biomechanics.de
Cancer
Non-Cancer
Meyhoff et al, Anesth Analg 2012;115:849
1400 patients, emergency- and elective-laparotomy, 30% / 80 % O2
until 2 h post OP; Follow-up 2 years!

27. zmfu www.biomechanics.de
Conger & Fairchild:
Breakage of chromosomes
by oxygen.
PNAS 1952;38:289-99
O2 induces DNA damage…

28. zmfu www.biomechanics.de
The more O2, the more damage…
O2 induces DNA damage…

29. zmfu www.biomechanics.de
FiO21.0
Hb-SO2 
 DO2 
-vascular PO2 
peri-capillary O2-diffusion 
ROS   host
defense 
NO   SVR 
 MAP 
Inhibition of HPV / resorption
atelectasis  right-to-left shunt  
pulmonary gas exchange 
NO   -vascular
perfusion 
ROS   NO  
oxidative /
nitrosative stress 
Mitochondrial O2 consumption  /
carbohydrate oxidation   efficiency
of mitochondrial respiration 
ROS   Uncoupling of
mitochondrial respiration
Inflammation 
 HIF-1 
Inflammation 
 NF-B 
Mitochondrial O2
consumption 
 ATP synthesis 

30. zmfu www.biomechanics.de
FiO2<0,5 50‘ FiO2=1,0 FiO2<0,5
HR [1/min] 94 ± 20 93 ± 22 96 ± 22
MAP [mmHg] 86 ± 15 90 ± 16 85 ± 14
CI [L/minxm2] 4,3 ± 1,7 4,0 ± 1,5 # 4,3 ± 1,5
DO2 [L/minxm2] 617 ± 275 609 ± 258 582 ± 240
EO2 [%] 23 ± 9 14 ± 5 # 23 ± 7
VO2 [L/minxm2] 125 ± 33 81 ± 31 # 122 ± 28
Reinhart et al, AJRCCM 1995;151:773
Hyperoxia and blood flow

31. zmfu www.biomechanics.de
Mak et al,
AJP 2002;282:H2414
Hyperoxia and blood flow

32. zmfu www.biomechanics.de
Cortés et al: Normobaric hyperoxia alters the microcirculation in healthy volunteers.
Microvasc Res 2015;98:23
Hyperoxia and blood flow

33. zmfu www.biomechanics.de
n=6
n=9
Hyperoxia and blood flow

34. zmfu www.biomechanics.de
FiO21.0
Hb-SO2 
 DO2 
-vascular PO2 
peri-capillary O2-diffusion 
ROS   host
defense 
NO   SVR 
 MAP 
Inhibition of HPV / resorption
atelectasis  right-to-left shunt  
pulmonary gas exchange 
NO   -vascular
perfusion 
ROS   NO  
oxidative /
nitrosative stress 
Mitochondrial O2 consumption  /
carbohydrate oxidation   efficiency
of mitochondrial respiration 
ROS   Uncoupling of
mitochondrial respiration
Inflammation 
 HIF-1 
Inflammation 
 NF-B 
Mitochondrial O2
consumption 
 ATP synthesis 

35. zmfu www.biomechanics.de
FiO2<0,5 50‘ FiO2=1,0 FiO2<0,5
HR [1/min] 94 ± 20 93 ± 22 96 ± 22
MAP [mmHg] 86 ± 15 90 ± 16 85 ± 14
CI [L/minxm2] 4,3 ± 1,7 4,0 ± 1,5 # 4,3 ± 1,5
DO2 [L/minxm2] 617 ± 275 609 ± 258 582 ± 240
EO2 [%] 23 ± 9 14 ± 5 # 23 ± 7
VO2 [L/minxm2] 125 ± 33 81 ± 31 # 122 ± 28
Reinhart et al, AJRCCM 1995;151:773
Hyperoxia and metabolism

36. zmfu www.biomechanics.de
Hyperoxia and metabolism

37. zmfu www.biomechanics.de
FiO21.0
Hb-SO2 
 DO2 
-vascular PO2 
peri-capillary O2-diffusion 
ROS   host
defense 
NO   SVR 
 MAP 
Inhibition of HPV / resorption
atelectasis  right-to-left shunt  
pulmonary gas exchange 
NO   -vascular
perfusion 
ROS   NO  
oxidative /
nitrosative stress 
Mitochondrial O2 consumption  /
carbohydrate oxidation   efficiency
of mitochondrial respiration 
ROS   Uncoupling of
mitochondrial respiration
Inflammation 
 HIF-1 
Inflammation 
 NF-B 
Mitochondrial O2
consumption 
 ATP synthesis 

38. zmfu www.biomechanics.de
Hyperoxia Normoxia P-value
Mean peak CKMB [U/L]
1948 (1721-2205) 1543 (1348-1776) 0.01
Peak troponin [g/L]
57 (48-69) 48 (40-58) 0.18
Arrhythmia [%]
40 31 0.05
Recurrent MI (at
hospital discharge) [%]
5.5 0.9 < 0.01
Infarct size @ 6 mo [g]
20 (10-30) 13 (5-24) 0.04
Mortality [%]
1.8 4.5 0.11
Hyperoxia and ACS
Stub D, et al: Air versus oxygen in ST-segment-elevation myocardial infarction.
Circulation 2015;131:2143-50

39. zmfu www.biomechanics.de
Hyperoxia Normoxia P-value
Mean peak CKMB [U/L]
1948 (1721-2205) 1543 (1348-1776) 0.01
Peak troponin [g/L]
57 (48-69) 48 (40-58) 0.18
Arrhythmia [%]
40 31 0.05
Recurrent MI (at
hospital discharge) [%]
5.5 0.9 < 0.01
Infarct size @ 6 mo [g]
20 (10-30) 13 (5-24) 0.04
Mortality [%]
1.8 4.5 0.11
Hyperoxia and ACS
Stub D, et al: Air versus oxygen in ST-segment-elevation myocardial infarction.
Circulation 2015;131:2143-50

40. zmfu www.biomechanics.de
Asher et al: Survival advantage and
PaO2 threshold in severe traumatic
brain injury. J Neurosurg Anesthesiol
2013:25:168
n=193; GCS < 8
PaO2 > 250 mmHg
60 mmHg < PaO2 < 250 mmHg
Hyperoxia and the brain

41. zmfu www.biomechanics.de
Ray et al: Hyperoxemia and long-term outcome after traumatic
brain injury. Crit Care 2013;17:R177
n=1016; 2003-12; 6 months post SHT
< 75 75-100 > 100 mHg
< 75 75-100 > 100 mHg
Hyperoxia and the brain

42. zmfu www.biomechanics.de
Ray et al: Hyperoxemia and long-term outcome after traumatic
brain injury. Crit Care 2013;17:R177
n=1016; 2003-12; 6 months post SHT
< 75 75-100 > 100 mHg
< 75 75-100 > 100 mHg
The emerging clinical experience
demonstrates that hyperoxia is safe and
beneficial to the brain, and does not
injure the lung as previously feared.
Narotam, Crit Care 2013:17:197
Hyperoxia and the brain

43. zmfu www.biomechanics.de
J Neurol Neurosurg Psychiatry 2014
Hyperoxia and the brain

44. zmfu www.biomechanics.de
Rincon et al: Hyperoxemia and long-term outcome after traumatic
brain injury. Crit Care Med 2014;42:387
n=2894 (AIS 19%; SAH 32%; ICH 49%)
Hyperoxia and the brain

45. zmfu www.biomechanics.de
Rincon et al: Hyperoxemia and long-term outcome after traumatic
brain injury. Crit Care Med 2014;42:387
n=2894 (AIS 19%; SAH 32%; ICH 49%)
Hyperoxia (n = 1084) 
PaO2 > 300 mmHg  60 %
Hypoxia (n = 450) 
PaO2 < 60 mmHg  53 %
SAH, ICB, AIS 
Hyperoxia and the brain

46. zmfu www.biomechanics.de
FiO21.0
Hb-SO2 
 DO2 
-vascular PO2 
peri-capillary O2-diffusion 
ROS   host
defense 
NO   SVR 
 MAP 
Inhibition of HPV / resorption
atelectasis  right-to-left shunt  
pulmonary gas exchange 
NO   -vascular
perfusion 
ROS   NO  
oxidative /
nitrosative stress 
Mitochondrial O2 consumption  /
carbohydrate oxidation   efficiency
of mitochondrial respiration 
ROS   Uncoupling of
mitochondrial respiration
Inflammation 
 HIF-1 
Inflammation 
 NF-B 
Mitochondrial O2
consumption 
 ATP synthesis 

47. zmfu www.biomechanics.de
FiO21.0
Hb-SO2 
 DO2 
-vascular PO2 
peri-capillary O2-diffusion 
ROS   host
defense 
NO   SVR 
 MAP 
Inhibition of HPV / resorption
atelectasis  right-to-left shunt  
pulmonary gas exchange 
NO   -vascular
perfusion 
ROS   NO  
oxidative /
nitrosative stress 
Mitochondrial O2 consumption  /
carbohydrate oxidation   efficiency
of mitochondrial respiration 
ROS   Uncoupling of
mitochondrial respiration
Inflammation 
 HIF-1 
Inflammation 
 NF-B 
Mitochondrial O2
consumption 
 ATP synthesis 

48. zmfu www.biomechanics.de
Air
Kilgannon JAMA 2010
6326 patients
Bellomo Crit Care 2011
12108 patients
Intra-hospital
mortality (%)
3561 (56) 6968 (58)
Discharge
home (%)
1203 (19) 3341 (28)
Highest T °C
(mean ± SD)
38 ± 3 37.1 ± 1.5
Lowest T °C
(mean ± SD)
36 ± 3 34.9 ± 1.7
Hyperoxie and CPR

49. zmfu www.biomechanics.de
Air
Kilgannon JAMA 2010
6326 patients
Bellomo Crit Care 2011
12108 patients
Intra-hospital
mortality (%)
3561 (56) 6968 (58)
Discharge
home (%)
1203 (19) 3341 (28)
Highest T °C
(mean ± SD)
38 ± 3 37.1 ± 1.5
Lowest T °C
(mean ± SD)
36 ± 3 34.9 ± 1.7
Hyperoxie and CPR

50. zmfu www.biomechanics.de
Air
Hyperoxie and CPR
Kilgannon JAMA 2010
6326 patients
Bellomo Crit Care 2011
12108 patients
Intra-hospital
mortality (%)
3561 (56) 6968 (58)
Discharge
home (%)
1203 (19) 3341 (28)
Highest T °C
(mean ± SD)
38 ± 3 37.1 ± 1.5
Lowest T °C
(mean ± SD)
36 ± 3 34.9 ± 1.7

51. zmfu www.biomechanics.de
Air
Hyperoxie and CPR
Helmerhorst et al: Associations of arterial carbon dioixde and
arterial oxygen concentrations with hospital mortaltiy after
resuscitation from cardiac arrest. Crit Care 2015;19:348
6496 patients!
Lowest mortality art. PO2  150-200 mmHg!!

52. zmfu www.biomechanics.de
Air
Lowest mortality art. PO2  150 mmHg!!
Hyperoxie and outcome
de Jonge et al: Association between administered oxygen, arterial
partial oxygen pressure and mortality in mechanically ventilated
intensive care patients. Crit Care 2008;12:R156

53. zmfu www.biomechanics.de
Air
Helmerhorst et al: Association between
arterial hyperoxia and outcome in
subsets of critical illness: a systematic
review, meataanalysis, and meta-
regression of cohort studies. Crit Care
Med 2015 in press
“..Considering the substantial
heterogeneity..more evidence is
needed..“
Damiani et al: Arterial hyperoxia and
mortality in critically ill patients: a
systematic review and meta-analysis.
Crit Care 2014;18:711
“..However,..results are limited
by the high heterogeneity..“
Hyperoxie and outcome

54. zmfu www.biomechanics.de
Air
Helmerhorst et al: Association between
arterial hyperoxia and outcome in
subsets of critical illness: a systematic
review, meataanalysis, and meta-
regression of cohort studies. Crit Care
Med 2015 in press
“..Considering the substantial
heterogeneity..more evidence is
needed..“
Damiani et al: Arterial hyperoxia and
mortality in critically ill patients: a
systematic review and meta-analysis.
Crit Care 2014;18:711
“..However,..results are limited
by the high heterogeneity..“
Hyperoxie and outcome

55. zmfu www.biomechanics.de
“…Consequently,… “conservative” O2
therapy, i.e. targeting an arterial hemoglobin
O2 saturation of 88 – 95 % as suggested by the
guidelines of the ARDS Network and the
Surviving Sepsis Campaign, represents the
treatment of choice to avoid exposure to both
hypoxemia and excess hyperoxemia.”…
Can you have too much oxygen?
Hafner S, Beloncle F, Koch A, Radermacher P, Asfar P.
Hyperoxia in intensive care, emergency, and peri-operative medicine: Dr. Jekyll or
Mr. Hyde? A 2015 update.
Ann Intensive Care 2015;5:42

56. zmfu www.biomechanics.de
Any…
…questions?
Can you have too much oxygen?