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

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

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

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

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

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; 30:2450-56 Stapleton RD, et al. Chest 2005; 128:525-32

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

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

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

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 hypoxemia Crit Care Med. 2004 Feb;32(2):364-71 JAMA. 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

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

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 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. 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 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

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

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

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

Effect of prone ventilation can be transient SupineProne  Improving Oxygenation Gattinoni L, et al. N Engl J Med. 2001;345(8):568-73.

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

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 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

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 – 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

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

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

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)

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

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