Clinical Management of ARDS: Concepts and Controversies

Clinical Management ofARDS: Concepts andControversiesKristin Miller, MDAssistant ProfessorDepartment of Internal MedicineDivision of Pulmonary & Critical CareMedicineNovember 5, 2011

Objectives•Review the definition of ARDS•Discuss etiology, pathophysiology of ARDS• Review ARDSnet protocol and Landmark trials:evidence for low tidal volume ventilation•Discuss controversial treatment modalites inARDS

Case42 yo male who presented to the ED with 5 day hx ofcough, fevers, myalgias. No pmh, nonsmoker. VS inthe ED: BP 159/89 P 128 R 18 T 100.7 98% on 3L,90% on RA.Labs: wbc 4.3 hemog 14.4 plt 145 na 139 bun/cr10/1.3 glc 189. Pt was admitted to internal medicineservice with diagnosis of CAP.

CaseHD #2: Pt required intubation secondary to increasedwork of breathing and worsening hypoxemia. ABGjust prior to intubation (on NRB): 7.16/62/63

CaseBronchoscopy performed, only positive culture wasInfluenza. He remained on antiviral medications aswell as broad spectrum antimicrobials. There wasno evidence of cardiac dysfunction. Dx: ARDS due toinfluenza (H1N1) pneumonia.

ARDS: Historical Perspectives• First described by David Asbaugh and colleaguesin 1967 (The Lancet)• Initially termed adult respiratory distresssyndrome• Description of 12 pts with acute onset oftachypnea, hypoxemia and poor lung compliance“not responding to usual and ordinary methodsof respiratory therapy”• Speculated about the role of PEEP andsurfactantAsbaugh et al. AcuteRespiratory Distress inAdults. The Lancet,Saturday 12 August 1967.

ARDS: Historical Perspectives• Noted that these pts exhibited similar featurescompared to the infantile respiratory distesssyndrome (hyaline membrane disease)• Etiologies discussed: infection (pneumonia),pancreatitis , trauma, shock• CXR: patchy, bilateral infiltrates, frequentlyconfused with pulmonary edema• 7 of the 12 patients died, autopsy revealedhyaline membranes• Peep seemed to helpAsbaugh et al. AcuteRespiratory Distress inAdults. The Lancet,Saturday 12 August 1967.

ARDS: Definition (1994)• Acute onset• Bilateral pulmonary infiltrates on CXR• PA wedge pressure < 18 mmHg or theabsence of clinical evidence of left atrialhypertension• Acute lung injury considered to bepresent if PaO2/FiO2 is < 300• ARDS considered to be present ifPaO2/FiO2

ARDS: Epidemiology•Incidence: 200,000 pts annually in the US•Affects children and adults•Overall mortality: 40%•Some studies suggest increased mortality inAfrican American and Hispanic population•May manifest as single or multi-organ failure•Direct and indirect causes

ARDS: Direct and Indirect Injury

Clinical Disorders Associated with the Development of the Acute Respiratory DistressSyndrome.Ware LB, Matthay MA. N Engl J Med 2000;342:1334-1349.

ARDS: Clinical, Pathological,Radiographic FeaturesSyndrome, can be progressive.Stages:Acute (exudative): rapid onset of respiratory failurein pt with risk factor(s), refractory hypoxemia,radiographic looks like pulmonary edemaProgress to fibrosing alveolitisRecovery phase. Ware and Matthay. NEJM2000. 342:1334

Acute (exudative phase) Fibrosing alveolitisResolutionRapid onset of respiratory failurePersistent hypoxemia, increasedalveolar dead space, furtherdecrease in complianceGradual resolution of hypoxemia,improved lung complianceIdentifiable risk factor for ARDSRefractory hypoxemiaPulmonary hypertension due toobliteration of pulmonary capillarybed, may be severe and lead to RVfailurePneumothorax may occurCXR: bilateral patchy airspaceopacitiesCXR: linear opacities (fibroticpattern)Typically, the radiographicabnormalities resolve completelyCT: alveolar consolidation,atelectasis predominantly independent lung zonesCT: diffuse interstitial opacities,bullaePath: DAD, neutrophils,macrophages, hyaline membranesProtein rich edema in alveolarspaces, capillary, endothelial andepithelial injuryPath: fibrosis, acute and chronicinflammatory cells, partialresolution of pulmonary edemaNot well characterized

Radiographic and Computed Tomographic (CT) Findings in the Acute, or Exudative, Phase(Panels A and C) and the Fibrosing-Alveolitis Phase (Panels B and D) of Acute Lung Injuryand the Acute Respiratory Distress Syndrome.Ware LB, Matthay MA. N Engl J Med 2000;342:1334-1349.

ARDS: Pathophysiology• Exudation of protein-rich fluid from microvasculatureinto interstitial space andalveoli• Disruption of surfactant, reducing lungcompliance and promoting atelectasis• Persistent inflammation, fibrotic repair• Failure of hypoxic vasoconstrictionresulting in shunt and severe hypoxemiaSlide:Sessler 2011

The Normal Alveolus (Left-Hand Side) and the Injured Alveolus in the Acute Phase of AcuteLung Injury and the Acute Respiratory Distress Syndrome (Right-Hand Side).Ware LB, Matthay MA. N Engl J Med 2000;342:1334-1349.

Management of ARDS‣ Treat underlying condition‣ Support oxygenation and ventilation– Mechanical ventilation; avoid / minimize barotrauma– Use lung protective ventilation‣ Supportive (non-ventilatory) therapy‣ Conservative fluid management‣ Corticosteroids?‣ Rescue for severe hypoxemiaparalytics, iNO, prone positioningSlide: Sessler 2011

Concept: what ventilatorsettings do we institute in ptswith ARDS?

Lung Protective MechanicalVentilation for ARDS‣ Lung injury isheterogeneous, but withfunctional“compartments”:– Normal lung (B) – potentialfor overdistention– Atelectatic, but recruitablelung (C) – potential for cyclicrecruitment / collapse– Densely consolidatedSlide: Sessler lung 2011 (A) – poorly recruitableMoloney & Griffiths Br J Anaesth 2004; 92:261-70

ARDSNET: Landmark PublicationsVentilation with Lower Tidal Volumes as Compared toTraditional Tidal Volumes For Acute Lung Injury and theAcute Respiratory Distress SyndromeRandomized trial of conventional TV (11.8 ml/kg) vs lowTV (6.2 ml/kg) ventilation in 861 patients with ALIExclusion Criteria: >36 hrs since eligible, pregnancy,Increased ICP, sickle cell disease, vasculitis with alveolarhemorrhage, severe chronic liver disease, severe NMdisease, HSCT, lung transplant.NEJM 2000; 342: 1301-8

Lower Tidal VolumeVentilation for ALI and ARDSARDS Network. N Engl J Med 2000; 342:1301Low TV Conventional*p < .01Randomized trial ofconventional TV (11.8ml/kg) vs low TV (6.2ml/kg) ventilation in861 patients with ALIMortalityVent-freedaysOrgan failurefreedays***Barotrauma0 10 20 30 40Percent of cases

Probability of Survival and of Being Discharged Home and Breathing without Assistanceduring the First 180 Days after Randomization in Patients with Acute Lung Injury and theAcute Respiratory Distress Syndrome.The Acute Respiratory Distress Syndrome Network. N EnglJ Med 2000;342:1301-1308.

ARDSNet Recommendations forMechanical Ventilation in ARDSN Engl J Med 2000; 342:1301• Volume - Assist Control Mode• Tidal volume (Vt) = 8 ml/kg PBW*• Reduce Vt by 1 ml/kg until Vt = 6 ml/kg• Set inspiratory flow > pt demand (usually >80L/min)• Adjust RR and Vt to achieve Pplat & pH goals• Aim for Pplat < 30 cm H 2 O• Aim for pH = 7.3-7.45 by increasing RR (to 35if necessary) and adding bicarbonate* PBW = predicted body weight: M = 50 + 2.3[height (inches) - 60],Slide: Sessler, 2011 F = 45.5 + 2.3[height (inches) - 60]

Utilize Strategies to Improve LungProtective Ventilation: ProtocolsSessler, C. Hypoxemic Respiratory Failure, in ACCPPulmonary Board Review 2009

ARDSNET: Landmark PublicationsHigher versus Lower Positive End-ExpiratoryPressures in Patients with the AcuteRespiratory Distress Syndrome549 pts with ALI/ARDS received MV witheither lower or higher peep levels (up to 24cm water). Traditional low volume TV (6cc/kg IBW) and plateau pressure

Higher versus Lower Positive End-Expiratory Pressuresin Patients with the Acute Respiratory DistressSyndrome.NEJM 2004; 351:327-36

ARDSNET: Landmark PublicationsHigher versus Lower Positive End-Expiratory Pressures in Patients with theAcute Respiratory Distress Syndrome549 pts with ALI/ARDS received MV witheither lower or higher peep levels (up to24 cm water). Traditional low volume TV(6 cc/kg IBW) and plateau pressure

Controversies amongNonventilatory TreatmentStrategies: Steroids forFibroproliferative ARDS?The National Heart, Lung, and Blood InstituteAcute Respiratory Distress Syndrome (ARDS)Clinical Trials Network. N Engl J Med2006;354:1671-1684.

Nonventilatory Strategies:Steroids forFibroproliferative ARDS?180 pts with ARDS of at least 7 days duration,randomly assigned to placebo orMethylprednisolonePrimary end point: mortality at 60 daysSecondary end point: VFD, organ failure free days,infection, biomarkers of inflammation

Nonventilatory Strategies:Steroids forFibroproliferative ARDS?•No decrease in mortality•Increase in mortality in pts who received steroidsafter 14 days after the onset of ARDS•Methylprednisolone increased the number ofVentilator Free Days and shock free days duringthe first 28 days as well as improvement inoxygenation, compliance•No increase risk of infection, but increase in NMweakness in steroid group

Corticosteroids in ARDS:Discussion• Use of low dose, longer duration corticosteroidsis associated with more rapid recovery and maybe associated with reduced mortality risk– Consistent in randomized & non-randomized studies– But, small studies, methodological quality issues– No increase in adverse events• If use corticosteroids in ARDS– Avoid starting after day 14– Methylprednisolone 2 g/kg/d, taper over 4 weeks– Infection surveillance, avoid NMBASessler & Gay. Respir Care 2010; 55:175-83

Nonventilatory Strategies:Fluid Management-the FacttTrialThe National Heart, Lung , and Blood InstituteAcute Respiratory Distress Syndrome (ARDS)Clinical Trials Network. N Engl J Med2006;354:2564-2575.

Relationship between pulmonary hydrostatic pressure and lung edema formation undernormal conditions and increased permeability.Calfee C S , Matthay M A Chest 2007;131:913-920©2007 by American College of Chest Physicians

Fluid Management Strategies in ALI:OutcomesRCT comparing conservative and liberal strategies for fluidmanagement using explicit protocols applied for 7 days in1000 patients with ALIParameter Conservative Liberal P valueMortality 25.5% 28.4% 0.30Ventilator-free d 14.6 12.1 .001ICU-free d 13.4 11.2 .001Electrolyte abnl 42 19 .001RRT 10% 14% .06Slide:Sessler: 2011al. N Engl J Med 2006; 354:2564-75

Overview of the Protocol for Conservative and Liberal Fluid Management in the GroupAssigned to a Pulmonary-Artery Catheter (PAC) and the Group Assigned to a Central VenousCatheter (CVC).The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome(ARDS) Clinical Trials Network. N Engl J Med 2006;354:2564-2575.

Slide: Sessler 2011

“Rescue” Therapy for LifethreateningHypoxemia in ARDS• Ventilatory– Higher PEEP– Recruitmentmaneuvers– Higher meanairway pressure• Longer Tinsp• APRV– HFOV• Non-ventilatory– Neuromuscularblockade– Prone positioning– Inhaled pulmonaryvasodilator (iNO)– ECMOEsan et al. Chest 2010;137:1203Raoof et al. Chest 2010;137:1437

Prone Positioningin ARDS• Improves oxygenation in 70% pts• Proposed mechanisms– increased end-expiratory lung volume– improved ventilation-perfusionmatching– regional changes in ventilation• Requires personnel (4-5) andplanning to safely turn patient• Potential for complications:unintended tube/line removalSlide: Sessler 2011

Mean (±SE) Ratios of the Partial Pressure of Arterial Oxygen (PaO 2) to the Fraction ofInspired Oxygen (FiO 2) Immediately before Prone Positioning (Circles), after One Hour(Squares), at the End of the Period of Pronation (Triangles), and on the Morning of theFollowing Day (Diamonds) during the 10-Day Study Period.Gattinoni L et al. N Engl J Med 2001;345:568-573.

Inhaled Nitric Oxide• Endogenous vasodilator• Inhalation of 2 - 40 ppmproduces selective dilation ofpulmonary vessels• RVEF and RVEDV• Rapidly inactivated by combiningwith hemoglobin and byoxidation

• Routine use of inhaled NO is not supported• Oxygenation benefit for up to 4 days (5-20ppm)• No methemoglobin or hNO 2 unless 40ppm• Improves oxygenation but not mortality• CostlyWhat is the Role forNitric Oxide in ARDS?• Potential role for inhaled NO as rescue therapyfor severe refractory hypoxemia– Demonstrate clinically significant benefit to continue

ACURASYS• French multicenter RCT comparing cisatracurium (CIS) orplacebo x 48h in severe ARDS (PaO2:FiO2 < 150 mmHg)• CIS group deeply sedated (Ramsay 6), paralyzed• CIS group…– Lower 90d mortality rate (31.6% vs 40.7%, p = 0.08)– Lower 28d mortality (23.7% vs 33.3%, p = 0.05)– More ventilator-free days (10.6 vs 8.5, p = 0.04)– Fewer pneumothoraces (4% vs 11.7%, p = 0.01)– No difference in rate of ICU-acquired paresisPapazian et al. N Engl J Med 2010; 363: 1107-16

Probability of Survival through Day 90, According to Study Group.Papazian L et al. N Engl J Med 2010;363:1107-1116.

ARDS: Summary• Recognize ARDS in the appropriate setting usingclinical/radiographic data• Use “lung protective approach” – 6 ml/kg IBW ineligible pts• Aim for plateau pressure

ARDS: Summary• Conservative fluid management: KEEP THELUNGS DRY• Consider low-dose, long duration methylpred if

Acknowledgements:Curtis Sessler, MD