ARDS TRIALS UPDATE 2015 Jeffrey L. Garland, MD, FCCP

Departments of Medicine, Critical Care Medicine, and Pulmonary Medicine

Mayo Clinic Florida

Jacksonville, Florida

DISCLOSURES

• None

PRIMARY TOPICS

• Low Tidal Volume Ventilation (LTVV)

• High PEEP

• Recruitment maneuvers

• Prone Ventilation

• Conservative Fluid Management

• Neuromuscular Blockade

• Corticosteroids

SECONDARY TOPICS

• NIPPV

• HFOV

• ECMO

• Macrolides

• Nitric Oxide and Epoprostenol

• Beta Agonists

• Surfactant

• Statins

• Anti-oxidants

• Red Cell Transfusions

• Nutrition

• GI Prophylaxis

LOW TIDAL VOLUME VENTILATION (LTVV)

• ARDS Network Trial. NEJM 2000; 342:1301.

• Patients with ARDS randomized to LTVV (6 cc/kgm IBW) vs Conventional ventilation (12 cc/kgm IBW).

• Study stopped after 861 patients enrolled due to lower mortality to hospital discharge (31% vs 39.8%, p = 0.007).

• LTVV with more ventilator free days by day 28 (12 vs 10).

Mean (+SE) Mortality Rate among 257 Patients with Acute Lung Injury and the Acute Respiratory Distress Syndrome Who Were Assigned to Receive Traditional Tidal Volumes and 260 Such

Patients Who Were Assigned to Receive Lower Tidal Volumes, According to the Quartile of Static Compliance of the Respiratory System before Randomization.

The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301-1308.

LOW TIDAL VOLUME VENTILATION • Metanalysis of six randomized trials. Ann Intern

Med 2009; 151:566.

• 1297 patients. LTVV vs conventional

• Improved 28 day mortality (27% vs 37%) and hospital mortality (35% vs 43%).

• Metanalysis of four randomized trials. Cochrane 2013.

• 1149 patients. LTVV vs conventional.

• Reduced hospital mortality (34% vs 41%).

LOW TIDAL VOLUME VENTILATION SUMMARY OF TRIALS

• LTVV is overall very well tolerated. Main complication of permissive hypercarbia is generally well tolerated.

• Overall evidence supporting LTVV is very strong and LTVV has become the standard of care.

HIGH PEEP STRATEGY

• The second part of the Open Ventilation model.

• Mechanisms of Action:

• Opens collapsed alveoli, which decreases alveolar overdistention of open alveoli.

• Reduces atelectrauma.

• Both should reduce lung injury.

HIGH PEEP STRATEGY

• Multiple ways to do High PEEP:

• Set PEEP at 2 cm above the lower inflection point of the PV curve.

• Do recruitment maneuver and then slowly decrease PEEP until static lung compliance decreases 2% and go 2 cm H2O above this.

• Use PEEP/FiO2 high PEEP arm from the ARDS Network trial .

• Apply highest PEEP to keep plateau pressure under 30 cm H2O.

HIGH PEEP STRATEGY

• JAMA 2010; 305:865. Metanalysis of 2299 patients.

• High PEEP improved oxygenation and increased vent free days.

• Lower ICU mortality (29% vs 33%), but no lower hospital mortality overall.

• In subgroup with P/F <= 200 hospital mortality was lower (34% vs 39%). Mild ARDS patients had trend toward increased mortality.

HIGH PEEP STRATEGY

• Cochrane Metanalysis 2013: 2565 patients.

• Improved oxygenation.

• No improved hospital mortality.

• Only decreased ICU mortality in patients with P/F <=200.

HIGH PEEP STRATEGY

• Potential Harm:

• Barotrauma and potentiation of lung injury due to increasing plateau pressure and causing alveolar overdistention.

• Hypotension due to decreased venous return.

• Overall assessmentof High Peep strategy:

• Consider in patients with P/F <= 200.

RECRUITMENT MANEUVERS

• Application: Apply high level of CPAP for a brief time, such as 40 cm H2O CPAP for 40 sec.

• Proposed Mechanism: open alveoli that have collapsed.

• 2009 Cochrane Metanalysis:

• Improved oxygenation, particularly when the recruitment maneuver is followed by application of High PEEP.

• No increased risk of barotrauma

• No effect on mortality or length of stay

RECRUITMENT MANEUVER

• Overall Assessement:

• No good evidence that it helps patient outcomes.

• Consider in specific circumstances such as for salvage therapy; or when patient is disconnected from the vent transiently, moves, or for another reason is without PEEP for a period of time.

PRONE POSITIONING

• Proposed Mechanisms:

• In the supine position there is overinflation of ventral alveoli and atelectasis of dorsal alveoli. Prone position makes ventilation more homogenous with decrease in ventral overinflation and reduction of dorsal atelectasis.

• Compression: in the supine position the heart and diaphragm both compress the lungs thus worsening dependent lung collapse. This is relieved in the prone position.

PRONE POSITIONING PROPOSED MECHANISMS • Perfusion: in ARDS in the supine position blood

flow and alveolar collapse are both greatest in the dorsal dependent portions of the lungs. When turned prone blood flow modestly decreases dorsally, still remaining greater in the dorsal than ventral lung, which also gets improved ventilation due to decreased atelectasis. VQ matching and oxygenation thus improve.

CLINICAL TRIALS OF PRONE POSITIONING AND OXYGENATION

• Consistent improvement in oxygenation found. • Improved oxygenation may last for hours after

patient’s return to the supine position. • Many patients improve each time prone

ventilation is repeated. • Those most likely to benefit seem to be patients

with diffuse pulmonary edema, dependent alveolar collapse, patients with increased intraabdominal pressure.

• Less likely to benefit are patients with predominantly anterior abnormalities, severe consolidation, and fibrosis.

CLINICAL TRIALS OF PRONE POSITIONING AND MORTALITY • PROSEVA TRIAL: NEJM 2013; 368:2159.

• 466 patients on LTVV with P/F < 150 on FiO2 >=60% and PEEP >=5.

• Randomized to supine position full-time vs 17 hours of prone ventilation started between 12 and 33 hours of intubation. (average of four prone sessions of 17 hours per patient). The latter group had an average percent of time prone of 73%.

• Patients received 17 hrs/day prone positioning daily until P/F >= 150, on FiO2 <= 60% and PEEP <=10.

• Prone vs supine group had decreased 28 day mortality (16 vs 33%) and 90 day mortality (24 vs 41%). Also more ventilator free days at day 28 (14 vs 10).

PROSEVA TRIAL SURVIVAL

CLINICAL TRIALS OF PRONE POSTIONING AND MORTALITY • PROSEVA Exclusion Criteria: • Elevated ICP • Spinal and other fracture instability. • Massive hemoptysis • MAP < 65 mmHG • Anterior Chest Tubes • Chronic oxygen dependence • Use of NIPPV, NO or ECMO before inclusion.

• PROSEVA Complications in prone position: • Including unplanned extubation, ET tube obstruction,

hemoptysis, desaturations, bradycardia, and hypotension no difference between supine and prone groups.

• There was a lower rate of cardiac arrest in the prone position (31 vs 16). P=0.02.

CLINICAL TRIALS OF PRONE POSITIONING AND MORTALITY

• PROSEVA Limitations: • supine patients had higher sequential organ failure

assessment scores (SOFA) and received more pressors and NM blockers.

• The 25 study centers had at least five years of experience with prone ventilation, which other centers may not have. This may effect success rate and complication rate.

• Multiple metanalyses excluding the PROSEVA trial

confirm the improved survival with prone positioning found in the PROSEVA trial. They found this again in the sickest patients with ARDS, who were also ventilated with LTVV.

CLINICAL TRIALS OF PRONE POSITIONING AND MORTALITY JAMA 2009; 302:1977 trial with 342 randomized patients showed no survival difference and the following increase in adverse events with prone ventilation:

• Increased sedation/paralysis (80 vs 56%)

• Hypotension or arrhythmias (72 vs 55%)

• Transient desaturations (64 vs 51%)

• Airway obstruction (51 vs 34%)

• Vomiting (29 vs 13 %)

• Loss of venous access (16 vs 4 %)

• ET tube displacement (11 vs 5%)

Date of download: 10/8/2014 Copyright © 2014 American Medical

Association. All rights reserved.

From: Prone Positioning in Patients With Moderate and Severe Acute Respiratory Distress Syndrome: A

Randomized Controlled Trial

JAMA. 2009;302(18):1977-1984. doi:10.1001/jama.2009.1614

Figure Legend:

Overall Assessment of Prone Positioning • Efficacy with improved survival clearly demonstrated.

• Concerns with complications remain.

• How would it fair in the “real-world” setting in centers not nearly as experienced as those in the studies.

• Overall, it would be worthwhile for centers to train up to a level where prone positioning can be safely administered to patients with ARDS and P/F < 150.

CONSERVATIVE FLUID MANAGMENT • Mechanism of Pulmonary Edema in ARDS:

• Primary cause is increased vascular permeability.

• Quantity of fluid, however, depends upon the hydrostatic pressure. Thus even if not volume overloaded, conservative fluid management may help reduce edema formation.

CONSERVATIVE FLUID MANAGEMENT • NEJM 2006; 354:2564. ARDS Clinical Trials Network

Study.

• 1000 patients with ARDS randomized to conservative or liberal fluid strategy for seven days.

• Goal of conservative group: CVP < 4 or PCWP < 8

• Goal of liberal group: CVP=10-14 or PCWP = 14-18

• Conservative group did not reach its goals

• Mean cumulative fluid balance was -136 cc in the conservative group and +6992 cc in the liberal group.

CONSERVATIVE FLUID MANAGEMENT • Results:

• Increase in vent free days: 15 vs 12 days.

• Increase in ICU free days: 13 vs 11 days.

• Improved oxygenation.

• Improved lung injury scores.

• No change in 60 day mortality.

CONSERVATIVE FLUID MANAGEMENT • Summary: appropriate to do as long as

hypotension and organ perfusion can be avoided.

• Albumin in combination with lasix may further improve fluid balance, oxygenation, and hemodynamics.

NEUROMUSCULAR BLOCKADE

• NEJM 2010; 363:1107.

• Multicenter trial randomized 340 patient with ARDS and P/F ratios < 150 within 48 hours of presentation, to cisatracurium or placebo by continuous infusion for 48 hours.

• Both groups were deeply sedated.

• Primary endpoint: ICU, 28 day, and 90 day mortality were lower, but did not reach statistical significance (90 day mortality placebo 40.7% vs cisatracurium 31.6%, p = 0.08).

NEUROMUSCULAR BLOCKADE

• When adjusted for pre-specified differences in baseline P/F ratio, SAPS II severity score, and plateau pressure, there was a significant decrease in ventilator free days, in barotrauma and in mortality.

• The mortality difference was limited to patients who presented with a P/F ratio < 120 (placebo mortality 44.6%, atracurium 30.8%, p = 0.04).

• No difference in neuromuscular weakness.

NEUROMUSCULAR BLOCKADE (survival when PF < 120)

NEUROMUSCULAR BLOCKADE

• Overall, consider NM blockade early in ARDS in patients with P/F ratios < 120-150.

GLUCOCORTICOID THERAPY IN LATE ARDS ARDS network trial. NEJM 2006; 354: 1671.

Late ARDS = Fibroproliferative phase of ARDS

• Double blind randomized trial of 180 patients with persistent ARDS of 7-28 day duration.

• Patients received solumedrol or placebo. Solumedrol dose was 2 mg/kgm IBW X 1, then 0.5 mg/kgm IBW q 6hr X 14 days, then 0.5 mg/kgm IBW q 12 hrs X 7 days, then taper.

GLUCOCORTICOID THERAPY IN LATE ARDS • Primary endpoint: no change in 60 or 180 day

mortality in the group as a whole.

• Secondary endpoints in Glucocorticoid group:

• Increased ventilator free days

• Increased shock free days

• Improved oxygenation

• Improved lung compliance

• More neuromuscular weakness.

Probability of Survival and the Proportion of Patients with Persistent ARDS Who Became Able to Breathe without Assistance during the First 180 Days after Randomization.

The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. N Engl J Med 2006;354:1671-1684.

GLUCORTICOID THERAPY IN LATE ARDS • Subgroup randomized at days 7-13 of onset of

ARDS: non-statistically significant reduction in 60 day mortality (27 vs 36%) and 180 day mortality (27 vs 39%).

• Subgroup randomized at days 14-28 significant increase of 60 day mortality (35 vs 8%) and 180 day mortality (44 vs 12%).

• Overall, would only consider glucocorticoid therapy in patients when it is initiated on days 7-13.

GLUCORTICOID THERAPY IN EARLY ARDS • Meduri CHEST 2007; 131:954.

• Double blind trial of patients with early ARDS (<72 hours onset) randomized to solumedrol 1 mg/kgm (n=63) or placebo (n=28) for up to 28 days.

• Results: decreased days on the vent, length of ICU stay, and ICU mortality (21 vs 43%).

• However: small trial size and uneven treatment arm numbers, and more patient with pressor-dependent shock in the placebo group.

SUMMARY THUS FAR

• LTVV: Standard of Care.

• High PEEP: Consider for P/F < 200.

• Recruitment: Consider only for salvage therapy.

• Prone: Strongly consider for P/F < 150.

• Conservative Fluid Management: Generally do once hemodynamics allow.

• Neuromuscular Blockade: Consider for P/F < 120-150.

• Glucocorticoids: ?Consider days 7-13 (second week).

NON-INVASIVE POSITIVE PRESSURE VENTILATION • Critical Care Medicine 2012; 40:455.

• 40 patient with ARDS randomized to NIPPV or high concentration oxygen.

• NIPPV group with improved P/F ratio and less likely to need intubation (5 vs 37%).

• Limitations: small study; possible selection bias; not blinded, which may have effected decision to intubate; excluded patients over age 70, MSOF and P/F under 200.

• Overall, not enough data to recommend this.

HIGH FREQUENCY OSCILLATORY VENTILATION • Multiple smaller studies showed improved oxygenation

vs conventional ventilation.

• OSCAR Trial: NEJM 2013.

• Randomized study in the UK that showed no mortality benefit, or possibly harm, with HFOV compared to ARDSNET ventilaton.

• OSCILLATE Trial: NEJM 2013.

• Patients with mod to severe ARDS randomized to HFOV vs ARDSnet ventilation with planned enrollment of 1200 patients.

• Terminated early after 548 patients were enrolled due to harm. In-hospital mortality 47% in the HFOV group and 35% in the ARDSnet group.

Overall HFOV

• No proven benefit in ARDS.

• Potential for Harm.

EXTRACORPOREAL MEMBRANE OXYGENATION • H1N1 Influenza Study (JAMA 2011): 150 patients

with half of the patients transferred to an ECMO center. The ECMO center patients (85% of whom received ECMO) had a 23.7% hospital mortality vs a 52.5% hospital mortality in the non-transferred patients.

ECMO

• CESAR trial (Lancet 2009): 180 patients in the UK randomized to transfer to a single ECMO center (75% of the patients received ECMO), or to stay at their initial hospital. Survival at 6 months was 63% in the ECMO center group vs 47% in the non-ECMO center group.

• Overall, question remains as to how much of improved survival was due to ECMO and how much was due to being transferred to a referral center with strict protocols.

MACROLIDE ANTIBIOTICS

• CHEST 2012; 141:1153.

• Macrolide antibiotics have antimicrobial and anti-inflammatory activity.

• Observational study of 47 patients with ARDS who received a macrolide antibiotic within the first 24 hours compared to 188 patient who did not.

• Result: trend toward a lower 180 day mortality in macrolide group (23 vs 36%).

• After adjusting for potential confounders the 180 day mortality decrease was statistically significant.

• Overall, intriguing, but need larger/better studies.

INHALED VASODILATORS

• Nitric Oxide and Prostacyclin selectively dilate the pulmonary artery.

• Nitric Oxide: improves oxygenation and reduces pulmonary artery pressures, but multiple studies show no effect on mortality. Extremely expensive. Rare complication of methemoglobinemia.

• Prostacyclin: improves oxygenation and reduces pulmonary artery pressure with effects comparable to NO. Much less expensive than NO.

• Overall, consider these meds for salvage therapy.

BETA AGONISTS

• Several studies have shown an improvement in physiologic endpoints.

• AJRCCM 2006; 173:281. 40 patients randomized to IV albuterol or placebo for seven days. The albuterol group had less lung water and a lower plateau pressure (24 vs 30 cm H2O).

• However, studies looking at patient outcomes showed futility. Specifically, there were no differences found in ventilator free days found in any study, and hospital mortality was unchanged in most studies, and actually worse in one study.

• Overall, the use of these drugs in ARDS is limited to patients with the standard indication of bronchospasm.

SURFACTANT

• Theoretical reasons to suspect benefits of surfactant administration in ARDS: prevention of atelectasis, multiple surfactant abnormalities are found in ARDS, insufficient surfactant production in ARDS.

• Overall, there is a large amount of conflicting data on the use of surfactant in ARDS, and no clear recommendation can be made.

STATIN THERAPY

• NEJM June 2014; 370:2191-2200

• Rosuvastatin for Sepsis-Associated ARDS

• Study stopped for futility after 745 of planned 1000 patients enrolled

• Primary endpoint: no change in 60 day in-hospital mortality

• No change in ventilator free days

• More days with renal failure and with liver failure in statin group

ANTIOXIDANTS

• Potential Mechanism: reactive oxygen species release, and partial depletion of antioxidant defense, are likely important in the ARDS cascade.

• Overall, while theoretically plausible, to date there has not been a study showing benefit of antioxidant supplementation, be it with NAC or other compounds.

RED BLOOD CELL TRANSFUSIONS • TRICC Trial. NEJM 1999; 340: 409.

• 838 critically ill patients randomized to a restrictive transfusion strategy with goal Hgb 7-9 vs a liberal strategy to keep Hgb 10-12. Restrictive group had a lower in hospital mortality (22% vs 28%, p = 0.05), but no difference in 30 day mortality.

• Critical Care Medicine 2005; 33: 1191.

• RBC transfusions may increase the risk of a critically ill patient developing ARDS, and of dying once ARDS is present.

Overall, a transfusion threshold Hgb of 7.0 is appropriate in ARDS, as it is in most ICU patients.

Kaplan–Meier Estimates of Survival in the 30 Days after Admission to the Intensive Care Unit in the Restrictive-Strategy and Liberal-Strategy Groups.

Hébert PC et al. N Engl J Med 1999;340:409-417.

TRISS TRIAL

NEJM October 2014;371:1381-1391

• Multicentered, randomized, non-blinded study of 998 patients with sepsis given blood for Hgb < 7.0 (low threshold) vs < 9.0 (high threshold).

• Results: No difference in mortality at 90 days (43% low, 45% high), in coronary ischemia, or in severe transfusion reactions. 50% less blood given.

• Note that patients with life threatening bleeding or coronary ischemia could be given blood based on clinical judgement.

Time to Death and Relative Risk of Death at 90 Days.

Holst LB et al. N Engl J Med 2014;371:1381-1391.

NUTRITIONAL SUPPORT

• Patients with ARDS have a severely catabolic state, which may be offset with adequate nutritional support.

• Enteral Route advantages:

• Fewer vascular infections

• Less GI bleeding due to gastric buffering

• Preserves the intestinal mucosal barrier, which may reduce the risk of bacterial translocation.

• Trophic low volume feeing may have less side effects.

GI PROPHYLAXIS

• Prolonged mechanical ventilation is associated with a significantly increased risk of GI bleeding, and prophylaxis is recommended.

SUMMARY: Greatest level of evidence • LTVV: Standard of Care.

• High PEEP: Consider for P/F < 200.

• Prone: Strongly consider for P/F < 150 (or 120).

• Conservative Fluid Management: Generally do once hemodynamics allow.

• Neuromuscular Blockade: Consider early on for P/F < 120-150.

• Glucocorticoids: ?Consider days 7-13 (second week).

SUMMARY: Salvage Therapies

• Recruitment Maneuvers

• ECMO (possibly greater role)

• Inhaled Nitric Oxide and Epoprostenol

SUMMARY: Experimental Therapies

• Macrolides

• Surfactant

• Anti-Oxidants

SUMMARY: Do not work or potential for harm

• HFOV

• Beta Agonists

SUMMARY

• Supportive Therapy

• Limit Red Blood Cell Transfusions

• GI Prophylaxis

• DVT Prophylaxis

• Enteral Nutrition

THANK YOU