Management of Acute Respiratory Distress Syndrome

Ronald Pearl, MD, PhD Professor and Chair Department of Anesthesiology Stanford University Rpearl@stanford.edu

2015 Winter Anesthesia Conference

• No financial disclosures

Disclosures

• At the conclusion of the activity participants should be able to: – Discuss mechanisms of ventilator-associated

lung injury and how appropriate ventilator management of the patient with ARDS can prevent such injury

– Discuss fluid management of the patient with ARDS in the context of issues of systemic perfusion

– Recognize complications associated with the use of high tidal volume, low PEEP ventilation in the operating room and the ICU

Learning Objectives

Intraoperative Ventilation in ARDS • Blum, Anesthesiology 2011; 115:75

U. Michigan database 2005-2009 8.7 ml/kg TV 5 cm PEEP FIO2 0.9 PIP ≈ 30 cm

Acute Respiratory Distress Syndrome

• 23 year old woman involved in MVA – Bilateral chest contusions – Ruptured spleen – 15 units PRBC – Over next 2 days develops diffuse fever,

tachycardia, bilateral infiltrates, hypoxemia on mechanical ventilation with 100% oxygen, increased bilirubin

– What is the management and prognosis?

Acute Respiratory Distress Syndrome

• 23 year old man involved in MVA – Bilateral chest contusions – Ruptured spleen – Massive transfusion in the ED – Over next 2 days develops diffuse fever,

tachycardia, bilateral infiltrates, and hypoxemia

– What is the management and prognosis?

ARDS • Which of the following interventions have

been demonstrated to improve outcome in the patient with ARDS: – Tidal volume of 6 mL/kg – Fluid restriction – Pulmonary artery catheter monitoring – Inhaled nitric oxide – High dose steroids

ARDS

• Ashbaugh, Lancet 1967;12;319 – 12 patients with tachypnea, hypoxemia,

and decreased compliance following trauma, aspiration, or pulmonary infection

– Improved oxygenation with PEEP – 60% mortality – Hyaline membrane formation on autopsy – “Adult respiratory distress syndrome”

American-European Consensus Conference (1994)

• Acute lung injury – a syndrome of inflammation and increased

permeability – cannot be explained by left atrial or

pulmonary capillary hypertension – acute in onset and persistent

Acute Lung Injury and ARDS

Timing Chest X-ray Oxygenation PAWP

ALI Acute Bilateral infiltrates

PaO2/FIO2 < 300 mm Hg <18 mm Hg

ARDS Acute Bilateral infiltrates

PaO2/FIO2 < 200 mm Hg <18 mm Hg

Berlin Definition of ARDS

Timing Within 1 week of clinical insult

Chest imaging

Bilateral opacities not fully explained by effusions, lobar

collapse, or nodules Origin of edema

Not fully explained by cardiac failure or fluid overload

Oxygenation Mild

Moderate Severe

Measured on ≥ 5 cm PEEP PaO2/FIO2 200 - 300 mm Hg PaO2/FIO2 100 - 200 mm Hg

PaO2/FIO2 < 100 mm Hg

JAMA 2012; 307:2526

Incidence of ARDS

• 200,000 patients/year • Probability depends upon number of

risk factors and the specific risk factors • Mortality 40%

Was This Patient At Risk of ARDS?

Causes of ARDS

• Direct lung injury – Pneumonia – Aspiration – Pulmonary contusion – Near-drowning – Fat embolism – Reperfusion injury

• Indirect lung injury – Sepsis – Shock – Multiple transfusions – Acute pancreatitis – Burns – Cardiopulmonary

bypass

Stages of ARDS

• Acute exudative phase – Hypoxemia – Bilateral infiltrates – Pulmonary edema – Neutrophils

Stages of ARDS • Established injury phase

– Severe tachypnea, tachycardia – Refractory hypoxemia – Hypermetabolic state – Diffuse alveolar infiltrates – Protein-rich alveolar edema – Neutrophil and mononuclear cells – Early fibroblast proliferation

• Progresses to recovery, death, or fibrosing alveolitis stage

Stages of ARDS

• Fibrosing alveolitis phase – Bilateral infiltrates – Pulmonary edema – Persistent hypoxemia – Increased dead space – Decreased compliance

Therapy in ARDS

• Supportive care –Infection therapy, nutrition, GI

prophylaxis, DVT prophylaxis • Ventilatory therapy • Adjunctive therapy

Goals Of Mechanical Ventilation • Oxygenation • Alveolar ventilation (CO2 exchange) • Prevent lung injury

Ventilator-Associated Lung Injury

Dreyfuss, AJRCCM 1998; 157:294

45 cm H2O x 5 min 45 cm H2O x 20 min Normal

Ventilator-Associated Lung Injury

Dreyfuss, AJRCCM 1998; 157:294

What Ventilatory Factors Cause Lung Injury?

Ventilator-Associated Lung Injury

• Mechanisms –Volutrauma –Barotrauma –Oxygen toxicity –Atelectrauma –Biotrauma

Matthay, Annu Rev Pathol 2011;6:147.

Lung-Protective Strategy

• ARDS Network, NEJM 2000;342:1301 –Mortality with 12 ml/kg PBW: 40% –Mortality with 6 ml/kg PBW: 30%

Lung-Protective Strategy

How Should We Choose PEEP?

Allowable FIO2/PEEP Combinations

FIO2 PEEP 0.3 5 0.4 5 or 8 0.5 8 or 10 0.6 10 0.7 10, 12, or 14 0.8 14 0.9 14, 16, or 18 1.0 18, 20, 22, or 24

Efficacy of Lung-Protective Ventilation

• Needham D, BMJ 2012; 344:e212 • Survival related to adherence to LPV

– TV ≤ 6.5 ml/kg; Pplat ≤ 30 – 8% absolute risk reduction if both variables

What TV Do We Use?

• 23 year old woman • Height 5’5” • Weight 80 kg

Predicted Body Weight

• Males: 50 + 2.3 (Height inches – 60) – 5’9”: PBW 71 kg; TV 424 ml

• Females: 45.5 + 2.3 (Height inches – 60) – 5’5”: PBW 57 kg; TV 342 ml

• 9

Lellouche, Anesthesiology 2012; 116:985

9.2 11.5

Is Lung Protective Ventilation Relevant to Patients without ARDS?

Two-Hit Hypothesis of ARDS

• Ventilatory impact only in patients already primed for ARDS

• Heterogeneity among patients – Degree of atelectasis – Underlying lung disease – Inflammation

Tidal Volume Without ARDS

• Gajic, Intens Care Med 2005; 31:922 – ICU patients requiring mechanical

ventilation who initially did not have ARDS

– Tidal volume > 700 ml increased risk of ARDS by 2.6-fold

Tidal Volume Without ARDS

• Determann, Crit Care 2010; 14:R1 – 150 critically ill patients without ALI – Randomized to 6 vs. 10 ml/kg PBW

Tidal Volume Without ALI

• Serpa Neto, JAMA 2012; 308: 1651 – Meta-analysis of 20 articles (n = 2,822) – Decreased ALI (RR 0.33; NNT 11) – Decreased mortality (RR 0.64; NNT 23) – Decreased pulmonary infection (RR 0.45) – Decreased hospital LOS (7 vs. 9 days) – Minor increase PaCO2 (3 mm Hg) – Minor decrease pH (0.03) – No difference in oxygenation

OR Applications

• Patients undergoing major surgery may benefit from decreased tidal volumes and moderate levels of PEEP

• Tidal volumes during one lung ventilation should not exceed 6 ml/kg, plus should also use PEEP

Tidal Volume During Pneumonectomy

• Fernandez-Perez, Anesthesiology 2006; 105:14 – Patients undergoing pneumonectomy who

developed postoperative respiratory failure had higher tidal volume (8.3 vs. 6.7 ml/kg PBW)

– Odds ratio of 1.56 for each ml/kg increase in tidal volume

Tidal Volume During Pneumonectomy

• Jeon, Anaesth Intensive Care 2009; 37:14 – Development of ALI/ARDS following

pneumonectomy – OR 3.37 per ml/kg increase in tidal

volume during OLV – OR 2.32 per cm H2O increase in airway

pressure during OLV

Tidal Volume During Lobectomy

• Yang, Chest 2011; 139:530 – 100 patients undergoing lobectomy – Randomized during OLV to: – VCV with TV 10 ml/kg, no PEEP, FIO2 1.0 – PCV with 6 ml/kg, 5 cm PEEP, FIO2 0.5 – Pulmonary dysfunction (PaO2/FIO2 < 300,

infiltrates, or atelectasis) decreased from 22% to 4%

Tidal Volume During Cardiac Surgery

• Sundar, Anesthesiology 2011; 114:1102 – Patients undergoing cardiac surgery

randomized to 6 vs. 10 ml/kg TV after induction of anesthesia until extubation

– Median ventilation time 450 vs. 643 min (P = 0.10)

– Higher proportion extubated at 6 h (37% vs. 20%; P = 0.02)

– Decreased reintubation (1.3 vs. 9.5%; P = 0.03)

Lung Protective Ventilation for Donors

• Mascia, JAMA 2010; 304:2620 – Potential donors (n = 118) randomized to:

• TV 10-12 ml/kg with 3-5 cm PEEP • TV 6-9 ml/kg, 5-8 cm PEEP, and CPAP

during apnea test and airway suction – 46% vs. 5% no longer met donor eligibility

(P/F > 300) at 6 hours (NNT = 3) – 27% vs. 54% transplanted

Effects of PEEP • Improved oxygenation

– Decreased intrapulmonary shunting • Decreased cardiac output

– Decreased venous return – Increased PVR

• Variable effect on VALI – Decreased VALI due to prevention of cyclic

collapse of alveoli – Increased VALI due to end-inspiratory

overdistention of alveoli

How Should We Choose PEEP?

• Patient develops severe ARDS – FiO2 0.80 – PEEP 14

• Will higher PEEP be of benefit?

Alveoli Study

• Brower RG, N Engl J Med 2004;351:327 • Compared combinations of low PEEP/high

FIO2 and high PEEP/low FIO2(n = 550) • PEEP: 9 ± 3.5 vs. 14.6 ± 3.6 • No difference in outcome

Briel, JAMA 2010;303:865

Meta-analysis of 3 trials

Intraoperative PEEP

• Imberger, Cochrane Database Syst Rev 2010; CD007922. – 8 RCTs, 330 patients – Higher PaO2/FIO2 on POD 1 (+23) – Decreased postop atelectasis by CT scan – No significant effect on mortality (relative

risk 0.95, 95% CI 0.14 to 6.39) – Mortality study would require 21,200

patients

Postoperative CPAP

• Ferreyra, Ann Surg 2008; 247:617 – Meta-analysis of 9 RCT of postop CPAP – 34% decrease in postoperative pulmonary

complications

How Do We Optimize Fluid

Management? • FiO2 0.80 • PEEP 14 MAP 68 mm Hg • CVP 8 mm Hg • Urine output 15 ml/h • Warm extremities with good capillary refill • Should we place a PA catheter? • Should we give fluid or dobutamine to

optimize urine output?

Fluid Therapy and ALI

• ARDSnet, NEJM 2006;354:2213 – 1000 patients with ALI – Randomized to CVP vs. PAC – Randomized to fluid restriction vs. liberal

fluid strategy

Fluid Management Decisions

• ARDSnet, NEJM 2006;354:2564 – First priority was management of hypotension – Fluid management then dependent upon two

factors • Adequate urine output (≥ 0.5 ml/kg/h) • Presence of ineffective circulation

–PAC group: CI < 2.5 L/min/m2

–CVP group: Cold, mottled extremities with slow capillary refill (> 2 seconds)

Target CVP Range

Effective circulation with UOP ≥ 0.5 ml/kg/h

Effective circulation with UOP < 0.5 ml/kg/h

Ineffective circulation

Liberal 10-14 14-15 15-18

Conservative <4 8-9 9-13

• Conservative group received more furosemide and less fluid, resulting in a less positive fluid balance but no increase in renal insufficiency

• Average fluid balance prior to enrollment was positive by 2700 ml

Daily Fluid Balance

-500

0

500

1000

1500

2000

2500

3000

1 2 3 4 5 6 7

LiberalConservative

Case Example

• MAP 68 mm Hg • Urine output 15 ml/h • Warm extremities with good capillary refill • CVP 8 mm Hg

Target CVP Range

Effective circulation with UOP ≥ 0.5 ml/kg/h

Effective circulation with UOP < 0.5 ml/kg/h

Ineffective circulation

Conservative <4 8-9 9-13

Adjunctive Therapies in ARDS • Continued severe ARDS

– FiO2 1.0 – PEEP 22 – PaO2 55 – Optimal diuresis

• Are there additional therapies which will improve oxygenation and outcome?

New Therapies in ARDS • Liquid ventilation • Surfactant replacement therapy • Beta-agonists • Immunonutrition • Anti-mediator therapies • Prone position • Steroids • Inhaled nitric oxide • ECMO

Prone Position and ARDS

Gattinoni, N Engl J Med 2001; 345:56

Prone Position and ARDS

Sud, CMAJ 2014; 186: E38

But more pressure ulcers, ETT complications and unintended extubations

Steroids and ARDS

• ARDSnet, N Engl J Med 2005; 354:1671 • RCT, n = 180 at 7-28 days • Methylprednisolone 0.5 mg/kg q 6h x 14

days, then q 12 h x 7 days, then tapered • Increased mortality in patients enrolled

after 14 days

Steroids and ARDS

ARDSnet, N Engl J Med 2005; 354:1671

Inhaled Nitric Oxide

Inhaled Nitric Oxide and Neonatal Respiratory Failure

• Neonatal inhaled nitric oxide study (NINOS) group – New Engl J Med 1997; 338:597 – Randomized to 100% oxygen or to NO – 20 ppm NO followed by 80 ppm NO if

needed

NINOS Results

CONTROL INO Change in PaO2 10 58 Response to gas 25% 66% Death or ECMO 64% 46%

Inhaled NO and ARDS

Control NO (18 ppm) Prostacyclin PaO2/FIO2 152 ± 15 199 ± 23* 114 ± 11* Normal V/Q (%) 55 ± 6 60 ± 5* 44 ± 4* QS/QT (%) 36 ± 5 31 ± 5* 45 ± 4*

Rossaint NEJM 1993; 328:399

Vasodilators and ARDS

PGI2 PGI2

Intravenous PGI2

Inhaled NO and ARDS

• No improvement in oxygenation in 1/3 of patients

• No sustained improvement in oxygenation • Rebound with discontinuation • No improvement in survival in multiple

RCTs

ELSO Registry

• ECMO for respiratory failure – Newborn: 75% survival (n = 24,017) – Pediatrics: 56% survival (n - 4,635) – Adults: 53% survival (n = 2,121)

UK Experience with H1N1

• Noah, JAMA 2011; 306:1659 – Patients referred to 4 ECMO centers in the UK – P/F 55, age 36, 80% on FIO2 1.0, half received

adjunctive treatments (prone position, INO, HFO)

– Lung protective ventilation during ECMO – Mortality of 24% vs. 52% in patients not

referred (RR 0.45, CI 0.26 – 0.79)

CESAR Trial

• Peek, Lancet 2009; 374:135 – Randomized 180 patients to conventional

therapy vs. transfer to central ECMO center – Age 18-65 – Severe but potentially reversible respiratory

failure – Murray LIS ≥ 3 or pH < 7.20 – Mechanical ventilation < 7 days – During ECMO, FIO2 = 0.3, rate 10, PIP ≤ 20,

PEEP 10

CESAR Results • Survival at 6 months without severe

disability increased from 47% to 63% • $31,000 per QALY • But results may have been due to better

treatment at ECMO center (1/4 patients did not receive ECMO)

Defining the Role of ECMO • EOLIA Trial: ECMO to Rescue Lung Injury in

Severe ARDS • French REVA group • 3 entry pathways

– PaO2/ FIO2 < 50 on FIO2 ≥ 0.8 for at least 3 hours – PaO2/ FIO2 < 80 on FIO2 ≥ 0.8 for at least 6 hours – pH < 7.25 for at least 6 hours with respiratory rate

of 35 breaths per minute

EOLIA • Up to 331 patients with early respiratory failure

(MV ≤ 6 days) • Protocolized treatment in both groups

– EXPRESS trial protocol in CMV group – FIO2 < 0.6 and Ppl < 25 in ECMO group

• Veno-venous ECMO with centrifugal pump and heparinized circuit

• Endpoint of mortality at day 60 – 80% power based on 60% mortality with CMV and

absolute mortality reduction of 20% with ECMO • Will complete enrollment this year (2013)

What Is Her Prognosis?

• Likelihood of survival? • Functional recovery?

Prognosis of ARDS

• Initial prognostic variables – Chronic liver disease – Nonpulmonary organ dysfunction – Sepsis – Advanced age – Not related to oxygenation indices or lung

injury score • Failure to improve during the first week is a

major negative prognostic factor

Prognosis of ARDS

– One organ failure for 3 days • 30% mortality

– Two organ failure for 3 days • 60% mortality

– Three or more organ failure for 5 or more days • >90% mortality

Outcome in ARDS

• Continuous improvement in survival over time –34-36% in two major studies from

mid-1990’s

Survival in ARDS

Milberg, JAMA 1995; 273:306

Survival in ARDS

Phua, Am J Respir Crit Care Med 2009; 179:220

Outcome in ARDS

• Relatively normal pulmonary function – FVC, FEV1, TLC, RV, DLCO

• Decreased quality of life (Herridge, NEJM 2003; 348:683 – Less than half return to work within first

year – 6 minute walk, physical measures on SF-

36

Herridge NEJM 2011; 364:1293

ARDS • Which of the following interventions have

been demonstrated to improve outcome in the patient with ARDS: – Tidal volume of 6 mL/kg – Fluid restriction – Pulmonary artery catheter monitoring – Inhaled nitric oxide – High dose steroids

Prevention of Lung Injury in the OR • Tidal volume 6-8 ml/kg • Limit plateau pressures to 20-25 cm • Moderate levels of PEEP

– During induction, anesthesia, and postoperatively • Prevent atelectasis by using PSV during spontaneous

ventilation; reverse atelectasis with recruitment maneuvers

• Avoid 100% oxygen • Volatile anesthetics and propofol may protect during

inflammation and ischemia-reperfusion injury • Limit fluid administration • Avoid blood transfusion

THANK YOU!