1. Refractory Hypoxemia in the ICU
Gordon D. Rubenfeld, MD MSc
Associate Professor of Medicine
University of Washington
Harborview Medical Center

2. Disclosures
NIH grant funding to study implementation strategies for lung protective ventilation in the community
Speaking fees from KCI – usually speak on the con side of prone ventilation
No funding from the ARDS Network – but some of my best friends do
I think that medicine should be evidence based – most of the time

3. What is Refractory Hypoxemia?
No official definition
PaO2 < 50 on an FIO2 = 1.0
Persistent for > 1 hour
Despite PEEP trial of up to cm H2O
Despite ruling out readily reversible causes
Mucus plugging/lobar or greater collapse
Pneumothorax
Systemic vasodilators enhancing shunt
Pulmonary embolism
Intra-cardiac R > L shunt
Circulatory collapse (low SvO2)

4. But first, a note from our sponsor
ALI
Common
Frequently missed
Lethal
Easily treatable with evidence based life saving interventions
Refractory hypoxemia in ALI
Extremely rare
Never missed
Not that much more lethal than regular ALI
All treatments are experimental (but very cool and sexy)

5. ALI is common and 3-5x more lethal than a heart attack
383,000 and 190,000 cases of sepsis and acute lung injury respectively in US
Mortality rates of 30-60%
540,000 people die following ICU admission each year
58% of hospital deaths in or following ICU admission

6. ALI cases are frequently missed
Mahoney AM, et al, American Thoracic Society Abstract. 2002
ALI not documented even in patients with significant risk factors for ALI

7. Easily treatable with evidence based life saving intervention – that isnt used!
Tidal Volume ml/kg
Not PBW
Scandinavia
Scandinavia
International
Scandinavia
International
Australia
ARF
ALI
ARDS
COPD
Luhr OR, et al. Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. AJRCCM. 1999;159(6):
Bersten AD, et al. Incidence and Mortality of Acute Lung Injury and the Acute Respiratory Distress Syndrome in Three Australian States. AJRCCM. 2002;165(4):
Esteban A,, et al. How is mechanical ventilation employed in the intensive care unit? An international utilization review. AJRCCM. 2000;161(5):

8. Community physicians [a little] more likely to use injurious tidal volumes
Academic
Community
Biased toward underestimating ml/kg PBW as BW used if height not recorded
and height generally less recorded in community hospitals

9. Patients with Ppl<30 on 12/kg
No obvious “safe” Pplat Tidal volume reduction lowers mortality at every Pplat
Patients with Ppl<30 on 12/kg
Quartile of Pplat
Hager, etal AJRCCM 2005

10. Hypoxemia associated with increased mortality but is a rare cause of death
< 10% of ALI deaths
Montgomery AB, et al. ARRD 1985; 146:486-9
Estenssorro E, et al. CCM 2002; 30:
Stapleton RD, et al. Chest 2005; 128:525-32

11. How harmful is hypoxemia?
Your pO2 here is ??
Unclear
Rare cause of death in ALI
Associated with some cognitive abnormalities in 1 study

12. How harmful is hypoxemia?
Your pO2 here is 47
Unclear
Rare cause of death in ALI
Associated with some cognitive abnormalities in 1 study

13. Refractory hypoxemia therapy Conclusions
Refractory hypoxemia is never missed
None of the treatments that improve oxygenation have been shown to affect mortality
Deaths from hypoxemia are very rare – and side effects of hypoxemia unclear
While cool - some have harmful side effects
There is no evidence that one is better than others – have several in your bag of tricks

14. Routine Approaches to Severe Hypoxemia
Rule out readily reversible causes
Mucus plugging/lobar or greater collapse
Pneumothorax
Systemic vasodilators enhancing shunt
Pulmonary embolism
Intra-cardiac R > L shunt
Circulatory collapse (low SvO2)
Positive end-expiratory pressure (PEEP)
Diuresis
Permissive hypoxemia

15. Routine Approaches to Severe Hypoxemia
What about transfusion?
DO2 directly proportional to Hgb
Unfortunately, transfused blood is not ‘normal’
Transfusion from Hgb 7-9 to > 10 does not clearly improve (and may actually worsen) DO2
Serum free hemoglobin may worsen VQ
Do not ‘routinely’ transfuse patients above Hgb 7 just because they have severe hypoxemia
Crit Care Med Feb;32(2):364-71
JAMA Jun 16;269(23):3024-9

16. Experimental Approaches to Refractory Hypoxemia
HFO
Inhaled vasodilators (iNO and prostacyclin)
ECMO
Prone ventilation

17. How much of an improvement in oxygenation is significant?
Variation in ABG and SaO2 in respiratory cycle
Noise
Tendency to over-interpret 5-10 mm Hg transient differences
I look for mm Hg differences
Be prepared to be flexible

18. Mode of Ventilation
When VT, PEEP, I:E ratio are held constant, PCV does not improve oxygenation or lower plateau pressure (does ‘lower’ peak pressure - but who cares …)
Lessard MR et al. Anesthesiology 1994;80:983-1
Mang H, et al. AJRCCM 1995; 151:731-6
Zavala E, et al. Anesthesiology 1998;88:35-42
When VT and PEEPTOT are held constant, PC-IRV at 2:1 does not improve oxygenation
Mercat A et al. AJRCCM 1997;155:

19. PEEP improves oxygenation but no effect on mortality
ARDSNet ALVEOLI study
Assessment of Low tidal Volume and elevated End-expiratory volume to Obviate Lung Injury
6 ml/kg PBW tidal volumes
Plateau pressure limit of 30 cm H2O
High PEEP/low FiO2 protocol vs. Low PEEP/high FiO2
N = 549 patients with ALI/ARDS
Similar findings in LOVES and EXPRESS

20. Adverse Effects of PEEP
Overdistends recruited lung
Decreased cardiac output
Increased physiologic dead space
Increased shunt fraction and worsen oxygenation
Redirects pulmonary blood flow to atelectatic regions of lung
Increases RAP which can lead to intra-cardiac, right-to-left shunting across a PFO

21. Paralysis improves oxygenation
Crit Care Med Jan;32(1):113-9

22. But … The reason why is unclear The effect is highly variable
Anti-inflammatory -  compliance  recruitment
 SvO2 by  VO2
The effect is highly variable
Paralytics increase risk for delayed neuromuscular complications
Save for rescue - Avoid steroidal (-uronium)
Therapeutic trial - Look for big effect
Monitor train-of-4 titrate to effect
Anaesth Intensive Care Apr;30(2):192-7.

23. Clearance of Alveolar Edema
ß - agonists
Inhaled
Intravenous
Lasix plus albumin
Atrial natriuretic peptide

24. Beta-agonists Clearance of alveolar edema
Stimulates Na+-K+-ATPase activity
Increases secretion of surfactant from Type II pneumocytes
Anti-inflammatory?
Appealing
No serious side effects
Easy to use
inexpensive

25. Furosemide Plus Albumin
Martin GS, et al. Crit Care Med 2002;30:2175
Randomized controlled trial
N = 37 adults with acute lung injury and total protein < 5 g/dL
Treatment (N = 19)
25 g human serum albumin q8h
Continuous IVI furosemide
Placebo (N = 18)
Placebo + placebo

26. Furosemide Plus Albumin Improvement in Gas Exchange
Reversal of ARDS
Change in PaO2/FiO2 Ratio
p = 0.01
p = 0.03
Martin GS, et al. Crit Care Med 2002;30:2175

27. Recruitment Maneuvers
Designed to open collapsed alveoli and shift the volume-pressure curve up and to the right
Most common methodology
40 cm H2O CPAP
40 seconds
Often possible to reverse hypoxemia and completely recruit the lung in early ARDS
24/26 patients; transient  BP and  PaCO2
Borges JB, et al. AJRCCM 2006;174:268-78

28. Recruitment Maneuvers
A decremental PEEP trial can then identify the PEEP level needed to maintain oxygenation after a recruitment maneuver
Girgis K, et al. Respir Care 2006;51:
But, RMs are generally not associated with sustained effects in early ARDS
Brower RG, et al. CCM 2003;31:
SPO2 was higher 10 minutes after the RM
Highly variable response; not sustained
Oczenski W, et al. Anesthesiology 2004;101:620-5

29. Prone ventilation – Takes the heart off the lungs
Supine
Ppl - - -
+ + +
Prone
Ppl -
Gattinoni L. et al.
Intens Care Med
1986; 92:137 +

30. Prone Positioning Implications of observations Speculation
Less overinflation of non-dependent lung
Less airspace opening/closing of dependent lung
Speculation
Less ventilator-induced lung injury

31. Effect of prone ventilation can be transient
SupineProne
 Improving Oxygenation
Gattinoni L, et al. N Engl J Med. 2001;345(8):

32. Four Clinical Trials Disappointing
Gattinoni L, et al. NEJM 2001
N = 304
6 hours per day x 10 days
Oxygenation (PaO2/FIO2) improved
No difference in survival
Mancebo J, et al.
N = 133

33. Four Clinical Trials Disappointing
Guerin C, et al. JAMA 2004
N = 791 (AHRF)
8 hours per day
Oxygenation (PaO2/FIO2) improved
No difference in survival
More complications in prone group
Curley MAQ, et al. ATS (A294)
N = 102 (pediatric ALI)
20 hours per day x 7d
No difference in VFD or survival (stopped for futility)

34. Rationale for HFV-Based Lung Protective Strategies
HFV uses very small tidal volumes
Avoids excessive end-inspiratory lung volumes
Allows for higher end-expiratory lung volumes to achieve better recruitment
HFV uses much higher respiratory rates
Allows for maintenance of normal PaCO2 even with very small tidal volumes

36. HFV gas transport mechanisms

37. HFV vs CV: Adults
Author Device Patients Design Main outcomes (HFV vs CV)
Carlon HFJV 300 ARF RCT Lower PeakP, same survival
MacIntyre HFJV 58 ARF X-over Lower PeakP, same PO2
Gluck HFJV 90 ARDS X-over Lower PeakP, better PO2
Forte HFO 18 ARDS X-over Same gas exchange
Mehta HFO 24 ARDS X-over Better PO2, higher mean Paw

38. HFO in Adults with Severe ARDS
Appeared to be feasible
Appeared to be the most promising form of HFV
Prospective, controlled trials needed to test efficacy compared to low-stretch conventional ventilation with adequate recruitment

39. MOAT Survival Curves
P = 0.08
Derdak S, et al. AJRCCM 2002;166:

40. Extra-corporeal Life Support (ECLS)
Extra-corporeal membrane oxygenation (ECMO)
Veno-arterial ECMO (VA-ECMO)
Veno-venous ECMO (VV-ECMO)
Extra-corporeal CO2 Removal (ECCO2R)
IVOX (intra-venous oxygenator)

41. ECMO - Problems VA-ECMO has adverse cardiopulmonary effects
Bleeding is excessive
L/day of blood loss

42. Extracorporeal Life Support The University of Michigan Experience
N = 1000 patients as of 1998
Techniques have evolved from 1979 & 1994
VV-ECMO is now the standard
Bleeding complications have decreased
UK Multicenter RCT of ECMO completed enrollment at 180 ECMO compared to lung protective ventilation
Inclusion LIS > 3

43. One Approach to Refractory Hypoxemia
Safety first
Use things in order of
Local experience, cost, and availability
Likelihood of worsening other organ failure or complications
Experimental trials with fixed endpoints
Finally, and most importantly,
If you are routinely using lung protective ventilation targeting tidal volumes of < 6 ml/kg PBW and Pplat<30 and diuresis
Do not feel like your patients are missing state-of-the-art care if you cannot provide (ECMO, iNO, HFO, prone, etc)

44. Package 1 – ALWAYS
Reassess goals of care
Reassure self of outcomes of refractory hypoxemia
Eliminate reversible causes of hypoxemia
PEEP trial (UP? DOWN?)
Consider diuresis
Massive resusc – consider chest tubes and abdomen

45. Therapeutic trial of paralysis Prone Violate Pplat criteria for LPV
Package 1 – ALWAYS
Reassess goals of care
Reassure self of outcomes of refractory hypoxemia
Eliminate reversible causes of hypoxemia
PEEP trial (UP? DOWN?)
Consider diuresis
Massive resusc – consider chest tubes and abdomen
Package 2 – Usually
Recruitment maneuver
Therapeutic trial of paralysis
Prone
Violate Pplat criteria for LPV

46. iNO or inhaled prostacyclin HFOV
Package 1 – ALWAYS
Reassess goals of care
Reassure self of outcomes of refractory hypoxemia
Eliminate reversible causes of hypoxemia
PEEP trial (UP? DOWN?)
Consider diuresis
Massive resusc – consider chest tubes and abdomen
Package 2 – Usually
Recruitment maneuver
Therapeutic trial of paralysis
Prone
Violate Pplat criteria for LPV
Package 3 – Rarely
iNO or inhaled prostacyclin
HFOV

47. Refractory hypoxemia therapy Conclusions
All patients with ALI should be on lung protective ventilation
Refractory hypoxemia is never missed
None of the treatments that improve oxygenation have been shown to affect mortality
Deaths from hypoxemia are very rare – and side effects of hypoxemia unclear (repeat)

48. Refractory hypoxemia therapy Conclusions
While cool – some of the treatments for refractory hypoxemia can be harmful particularly if you use them rarely
Paralysis
Recruitment
Inhaled prostacyclin
Prone
There is no evidence that one is better than others – have several in your bag of tricks

49. The P’s of refractory hypoxemia
PEEP
Pee (diuresis)
Prone
Paralysis
Pleural evacuation
Prostacyclin (or iNO)
More Peep