Refractory Hypoxemia in the ICU

Gordon D. Rubenfeld, MD MScAssociate Professor of Medicine

University of WashingtonHarborview Medical Center

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

What is Refractory Hypoxemia?

• No official definition• PaO2 < 50 on an FIO2 = 1.0• Persistent for > 1 hour• Despite PEEP trial of up to 20 - 25 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)

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)

• 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

ALI is common and 3-5x more lethal than a heart attack

Mahoney AM, et al, American Thoracic Society Abstract. 2002

ALI not documented even in patients with significant risk factors for ALI

N=76 N=32 N=28

ALI cases are frequently missed

Easily treatable with evidence based life saving intervention –

that isnt used!

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lLuhr OR, et al. Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. AJRCCM. 1999;159(6):1849-1861.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):443-448.Esteban A,, et al. How is mechanical ventilation employed in the intensive care unit? An international utilization review. AJRCCM. 2000;161(5):1450-1458.

Community physicians [a little] more likely to use injurious tidal volumes

23%20%

12%

41%

36%

29%

> 11 ml/kg PBW > 11.5 ml/kg PBW > 12 ml/kg PBW

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Biased toward underestimating ml/kg PBW as BW used if height not recorded and height generally less recorded in community hospitals

AcademicCommunity

Hager, etal AJRCCM 2005

No obvious “safe” PplatTidal volume reduction lowers mortality at every Pplat

Patients with Ppl<30 on 12/kg

Quartile of Pplat

Hypoxemia associated with increased mortality but is a rare cause of death

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P:F ratio at ALI onsetMontgomery AB, et al. ARRD 1985; 146:486-9Estenssorro E, et al. CCM 2002; 30:2450-56Stapleton RD, et al. Chest 2005; 128:525-32

< 10% of ALI deaths

How harmful is hypoxemia?

• Unclear• Rare cause of death in ALI• Associated with some

cognitive abnormalities in 1 study

Your pO2 here is ??

How harmful is hypoxemia?

• Unclear• Rare cause of death in ALI• Associated with some

cognitive abnormalities in 1 study

Your pO2 here is 47

Refractory hypoxemia therapyConclusions

• 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

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

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 hypoxemiaCrit Care Med. 2004 Feb;32(2):364-71JAMA. 1993 Jun 16;269(23):3024-9

Experimental Approaches to Refractory Hypoxemia

• HFO• Inhaled vasodilators (iNO and prostacyclin)• ECMO• Prone ventilation

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 20-30 mm Hg differences• Be prepared to be flexible

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;155:1637-42

PEEPimproves 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

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

Paralysis improves oxygenation

Crit Care Med. 2004 Jan;32(1):113-9

But …

• The reason why is unclear– 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. 2002 Apr;30(2):192-7.

Clearance of Alveolar Edema

• ß - agonists– Inhaled– Intravenous

• Lasix plus albumin• Atrial natriuretic peptide

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

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

Furosemide Plus AlbuminImprovement in Gas Exchange

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Martin GS, et al. Crit Care Med 2002;30:2175

Reversal of ARDS Change in PaO2/FiO2 Ratio

p = 0.01 p = 0.03

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

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;51:1132-39

• But, RMs are generally not associated with sustained effects in early ARDS– Brower RG, et al. CCM 2003;31:2592-97

• SPO2 was higher 10 minutes after the RM– Highly variable response; not sustained

– Oczenski W, et al. Anesthesiology 2004;101:620-5

Supine

Prone

Ppl - - -

+ + +

Ppl -

+Gattinoni L. et al. Intens Care Med

1986; 92:137

Prone ventilation –Takes the heart off the lungs

Prone Positioning

• Implications of observations– Less overinflation of non-dependent lung– Less airspace opening/closing of dependent lung

• Speculation– Less ventilator-induced lung injury

Effect of prone ventilation can be transient

SupineProne

Gattinoni L, et al. N Engl J Med. 2001;345(8):568-73.

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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– No difference in survival

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 2005 (A294)– N = 102 (pediatric ALI)– 20 hours per day x 7d– No difference in VFD or survival (stopped for futility)

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

HFV gas transport mechanisms

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

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

MOAT Survival Curves

P = 0.08

Derdak S, et al. AJRCCM 2002;166:801-808

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)

ECMO - Problems

• VA-ECMO has adverse cardiopulmonary effects• Bleeding is excessive

– 1.76 - 2 L/day of blood loss

Extracorporeal Life SupportThe 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

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)

Package 1 – ALWAYSReassess goals of careReassure self of outcomes of refractory hypoxemiaEliminate reversible causes of hypoxemiaPEEP trial (UP? DOWN?)Consider diuresisMassive resusc – consider chest tubes and abdomen

Package 2 – UsuallyRecruitment maneuverTherapeutic trial of paralysisProneViolate Pplat criteria for LPV

Package 1 – ALWAYSReassess goals of careReassure self of outcomes of refractory hypoxemiaEliminate reversible causes of hypoxemiaPEEP trial (UP? DOWN?)Consider diuresisMassive resusc – consider chest tubes and abdomen

Package 2 – UsuallyRecruitment maneuverTherapeutic trial of paralysisProneViolate Pplat criteria for LPV

Package 1 – ALWAYSReassess goals of careReassure self of outcomes of refractory hypoxemiaEliminate reversible causes of hypoxemiaPEEP trial (UP? DOWN?)Consider diuresisMassive resusc – consider chest tubes and abdomen

Package 3 – RarelyiNO or inhaled prostacyclinHFOV

Refractory hypoxemia therapyConclusions

• 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)

Refractory hypoxemia therapyConclusions

• 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

The P’s of refractory hypoxemia

• PEEP

• Pee (diuresis)

• Prone

• Paralysis

• Pleural evacuation

• Prostacyclin (or iNO)• More Peep