ARDS 2012 Summer Lecture Series Urvashi Vaid MD, MS.

ARDS

2012

Summer Lecture Series

Urvashi Vaid MD, MS

OUTLINE

Overview Ventilation Strategies

Tidal volume Plateau pressures PEEP VC vs PCV (APRV) Recruitment maneuvers Prone positioning ECMO

Pharmacologic interventions Fluid Management

DEFINITION1967-The Lancet

“severe dyspnea, tachypnea, cyanosis that is refractory to oxygen therapy,loss of lung compliance, and diffuse alveolar infiltration seen on chest x-ray.”

AECC DEFINITION-1994

ALI Acute onset Bilateral chest infiltrates PCWP ≤ 18mm Hg or absence of clinical e/o LA

hypertension PaO2 : FiO2 ratio ≤ 300

ARDS PaO2 : FiO2 ratio ≤ 200 And all the above

Independent of PEEP

Bernard et al, Am J Respir CCM; 1994;149:818-24

MURRAY LUNG INJURY SCORE (LIS)

Radiography Oxygenation Compliance PEEP But doesn’t exclude left heart failure

BERLIN DEFINITION

Mild Moderate Severe

Compared with the AECC definition, the final Berlin Definition had better predictive validity for mortality, with an area under the ROC of 0.577 (95% CI, 0.561-0.593) vs 0.536 (95% CI, 0.520-0.553;P<.001)

Gordon D. Rubenfeld, MD,JAMA. 2012;307(23):doi:10.1001/jama.2012.5669

EPIDEMIOLOGY

8-year retrospective cohort study of ICU patients in the Mayo Clinic, which provides all ICU-level care to the population of Olmsted County, Minnesota

Total of 795 episodes (787 new, 8 recurrent) of ARDS/ALI identified

Age- and sex-adjusted incidence rates dropped from 81 to 38 cases per 100,000 person-years

MORTALITY: Observational studies indicate 40%, but RCTs indicate 20-25%

OBSERVED 60-DAY MORTALITY-2944 PATIENTS

Spragg RG, Bernard GR, CheckleyW, et al. Beyond mortality: future clinicalresearch in acute lung injury. Am J Respir Crit Care Med 2010;181(10):1121–7

ETIOLOGY

Direct pulmonary causes pneumonia (bacterial or viral) aspiration pneumonitis inhalation injury/ Near drowning lung contusion

Indirect extrapulmonary causes extrapulmonary sepsis trauma with shock burn injury blood transfusion drug overdoses pancreatitis

PROGRESSION FROM ALI TO ARDS The Acute Lung Injury Verification of Epidemiology (ALIVE) study COHORT STUDY performed in 78 ICUs of 10 European countries All patients admitted for > 4 hours were screened for ALI and followed

for 2 months ALI occurred in 463 (7.1%) of 6522 admissions and 16.1% of all

mechanically ventilated patients 65.4% of cases present on ICU admission Among 136 patients initially presenting with ALI, 74 patients (55%)

evolved to ARDS within 3 days The ICU and hospital mortality rates were 22.6% and 32.7% (P <.001)

and 49.4% and 57.9% (p=.0005), respectively, for ALI and ARDS Importantly, this study confirmed that more than half of patients

admitted with ALI rapidly evolved to ARDS, and that mortality rates associated with ALI are significantly lower than those of patients with ARDSBrun-Buisson C, Minelli C, Bertolini G, et al. Epidemiology and outcome of acute lung injury in European intensive care units. Results from the ALIVE study. Intensive Care Med 2004;30(1):51–61.

RISK FACTORS PREDICTING MORTALITY Patient variables

Etiology of ALI (aspiration, pulmonary-sepsis vs trauma) Severity of illness and immunosuppression Age Alcohol abuse Active and passive cigarette smoking ↑BMI- ↑incidence but decrease/unchanged mortality African Americans (higher risk of death)

Treatment variables VILI- TV>6ml/kg Sepsis + fluid balance Plasma transfusion

RISK FACTORS

Genetics (Fas pathway modulation of apoptosis)

PATHOPHYSIOLOGY

The acute phase of acute lung injury and ARDS is characterized by the influx of protein-rich edema fluid into the air spaces as a consequence of increased permeability of the alveolar–capillary barrier

PATHOLOGY

Apex

Hilum

Base

“BABY LUNG” to “SPONGE LUNG” CT scans: amount of normally aerated tissue, measured

at end-expiration, was in the order of 200–500 g in severe ARDS

Respiratory compliance (ΔV/ΔP) was well correlated only with the amount of normally aerated tissue and not with the amount of non-aerated lung

The ARDS lung is not “stiff” at all, but small, i.e. the elasticity of the residual inflated lung is nearly normal

Sponge lung: edema evenly distributed, dependant changes are due to atelectasis from increased hydrostatic pressures

Luciano Gattinoni Antonio Pesenti The concept of “baby lung” Intensive Care Med (2005) 31:776–784

OUTCOMES

Pulmonary Function Heterogeneous, but most young patients without documented

preexisting lung disease regain normal or near-normal function with a persistent mild reduction in diffusion capacity and seem to maintain stable pulmonary function up to 5 years after the initial episode of severe lung injury

Herridge MS, Tansey CM, Matte´ A, et al. Canadian Critical Care Trials Group. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011;364(14):1293–304.

Functional Disability CINMA

Herridge MS, Tansey CM, Matte´ A, et al.Functional disability 5 years after acuterespiratory distress syndrome. N Engl J Med 2011;364(14):1299

ARDS and Brain injury

OUTLINE




DICTUM:

LUNG PROTECTIVE VENTILATION

VILI

Oxidant injury- keep FiO2 <60 Barotrauma- keep alveolar inflation pressures <35 cm

H2O Volutrauma- Baby lung concept or stretch injury Atelectrauma- repeated opening and closing Biotrauma- release of inflammatory mediators and

bacterial translocation

VILI

Oxidant injury- keep FiO2 <60 Barotrauma- keep alveolar inflation pressures <35 cm

H2O Volutrauma- Baby lung concept or stretch injury Atelectrauma- repeated opening and closing Biotrauma- release of inflammatory mediators and

bacterial translocation

OPEN GENTLY AND KEEP THEM OPEN

Pressure-volume curve derived from a patient with ARDS. FRC, functional residualcapacity; LIP, lower inflection point; UIP, upper inflection point. (Adapted from Whitehead T,Slutsky AS. The pulmonary physician in critical care: ventilator induced lung injury. Thorax2002;57:636

TIDAL VOLUMEARDSNET: NEJM May 2000

6cc/kg PBW N= 432 Death before discharge=

31% Breathing w/o assistance

day 28 = 65.7% Plateau Pressure (cm of

H2O) 25±7 Lower IL-6 levels

12cc/kg PBW N= 429 39.8%

55%

33±9

PLATEAU PRESSURES

Hager DN et al. Tidal Volume Reduction in Patients with Acute Lung Injury When Plateau Pressures Are Not High. AJRCCM 2005. Vol 172 1241-1245

787 patients from ARDS Network study

PEEP

EXPRESS LOVS ALVEOLI Meta-analysis of these trials revealed no difference in

hospital mortality, although higher PEEP was associated with reduced ICU mortality, total rescue therapies, and death after rescue therapy

Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome. JAMA 2010;303(9):865–73.

VC vs PCV

PCV: variable flow so more comfortable if dyssynchrony, prolong i time for oxygenation, control peak pressures

VC vs PCV

RCT multicenter, 79 patients with ARDS PCV (n-37) versus VCV (n=42). P plat ≤ 35 cm H2O No difference in mortality, trend to more renal failure in

VCV group BUT patients in VCV group had a higher in-house

mortality related to higher number of extra-pulmonary organ failures (78% vs 51%)

Also TV 8cc/kg of weight

RECRUITMENT

A recent systematic review analyzed 40 studies that evaluated RMs; 4 were RCTs, 32 prospective studies, and 4 retrospective cohort studies

The sustained inflation method (ie, continuous positive airway pressure [CPAP] of 35–50 cm H2O for 20–40 seconds) was used most often (45%), followed by high pressure control (23%), incremental PEEP (20%), and a high VT/sigh (10%)

Current evidence suggests that that RMs should not be routinely used on all ARDS patients unless severe hypoxemia persists or as a rescue maneuver to overcome severe hypoxemia, to open the lung when setting PEEP, or following evidence of acute lung derecruitment such as a ventilator circuit disconnect

Fan E, Wilcox ME, Brower RG, et al. Recruitment maneuvers for acute lung injury.Am J Respir Crit Care Med 2008;178(11):1156–63.

PRONE POSITIONING

Computed tomography scan of the lungs showing ARDS when the patient is lyingsupine (left) and prone (right).Gattinoni L, Protti A. Ventilation in the prone position:for some but not for all? CMAJ 2008;178(9):1174–6)

Evidence for Proning

The Prone-Supine II Study is the largest clinical trial (N 5342) in adult ARDS patients, conducted in 23 centers in Italy and 2 in Spain

20 hours/day Similar 28-day mortality- 31.0% vs 32.8%; RR 0.97; (95%

CI 0.84–1.13; p=.72) Mortality in severe hypoxemia was decreased in the

prone group-37.8% in the prone group and 46.1% in the supine group (RR, 0.87; 95% CI, 0.66–1.14 p=.31)

Taccone P, Pesenti A, Latini R, et al. Prone positioning in patients with moderate and severe acute respiratory distress syndrome: a randomized controlled trial. JAMA 2009;302:1977–84.

Evidence for Proning/Mortality

Effect of mechanical ventilation in the prone position on clinical outcomes in patientswith acute hypoxemic respiratory failure: a systematic review and meta-analysis. CMAJ2008;178(8):1153–61

Evidence for Proning/Oxygenation

Sud S, Sud M,Friedrich JO, et al. Effect of mechanical ventilation in the prone position on clinicaloutcomes in patients with acute hypoxemic respiratory failure: a systematic review andmeta-analysis. CMAJ 2008;178(8):1153–61

PRONING-COMPLICATIONS

ECMO

ECMO is supportive care and is not intended as a primary ARDS treatment

CESAR trial- Patients were randomized to either conventional

care at 1 of 68 tertiary care centers or to a single center using a treatment protocol that included ECMO

The trial was stopped for efficacy after 180 patients Survival without severe disability at 6 months was

47% vs 63% at 6 months Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment

of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 2009;374(9698):1351–63.

A French prospective, randomized multicenter trial (EOLIA) (ExtracorporealMembrane Oxygenation to Rescue Lung Injury in ARDS) has opened and will enrollpatients to test the efficacy of early VV ECMO in ARDS.

BEYOND THE SCOPE…

APRV HFOV SURFACTANT BIOMARKERS GENE THERAPY STEM CELLS

OUTLINE




STEROIDS

At the cellular level, patients with unresolving ARDS have inadequate glucocorticoid-glucocorticoid receptor (GC-GR)–mediated down-regulation of inflammatory transcription factor nuclear factor-kB (NF-kB) despite elevated levels of circulating cortisol, a condition recently defined as critical illness–related corticosteroid insufficiency (CIRCI)

Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 2008;36:1937–49

STEROIDS

LATE STEROID RESCUE STUDY: LASRS

Objective To determine if the administration of methyl-

prednisolone (MP), in severe persistent ARDS after 7 days, will reduce mortality and morbidity

Study Design Multicenter, prospective, randomized, controlled

clinical trial. MP and placebo administered in a double-blind fashion

MP patients came off ventilator sooner 14 days vs. 23 days, P=0.0002

Associated with improved physiology in MP patients PaO2/FIO2; static compliance

More MP patients went back on ventilator 20 vs. 6, P = 0.008

60 day mortality

60 day mortality Mean % 95% CI

Placebo 28.6 % 19.8-38.4

Methylprednisone 29.2 % 20.2-39.3

METHYLPREDNISOLONE INFUSION IMPROVES LUNG FUNCTION IN PATIENTS WITH EARLY ARDS: RESULTS OF A RCT

63 in MP and 28 in placebo

GU Meduri, E Golden, AX Freire, E Taylor, M Zaman, S Carson, M Gibson, R Umberger Memphis Lung Research Program University of Tennessee HSC Memphis, TN, USA Chest 2007

SteroidsN=63

PlaceboN=28

P value

Extubated or 1 pt reduction in LIS

44(70%) 10(35%) 0.002

Extubated >48hrs

34(53%) 7(25%) 0.01

LIS 2.14 2.67 0.004

P/F ratio 256 178 0.006

CRP 2.9 13.1 0.001

Mortality 20.6 42.9 0.03

CONSENSUS ON STEROIDS

Recent consensus statement from the American College of Critical Care Medicine quotes the results of one randomized trial in patients with early severe ARDS and recommend 1 mg/kg/d of methylprednisolone given as an infusion and tapered over 4 weeks

For patients with unresolving ARDS, beneficial effects were shown for treatment (methylprednisolone, 2 mg/kg/d) initiated before day 14 of ARDS and continued for at least 2 weeks after extubation

If treatment is initiated after day 14, no evidence has shown either benefit or harm

Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 2008;36:1937–49

VASODILATORS-iNO

NO activates cGMP in turn activates a protein kinase that leads to SM relaxation and vascular dilatation

iNO flows only into well ventilated areas-improves shunt Shown to improve PaO2/FiO2 ratio but not mortality It remains a safe option for salvage therapy in ARDS

patients with refractory hypoxemia Ashfari A, Brok J, Moller AM, et al. Inhaled nitric oxide for acute respiratory

distress syndrome [ARDS] and acute lung injury in children and adults.Cochrane Database Syst Rev 2010;7:CD002787

VASODILATORS-PC

PGI2 derived from arachidonic acid from vascular endothelium Stimulates adenylate cyclase to create cAMP leads to increased

intracellular calcium and thus smooth muscle relaxation A Cochrane Database review in 2010 of IP in ARDS

determined that none of the trials of IP in adults was appropriate for consideration for meta-analysis due to methodologic limitations

A randomized, double-blind placebo controlled safety and efficacy study started in 2006 that tested IP in ARDS and pulmonary hypertension is finished and has been submitted for publication

NEUROMUSCULAR BLOCKADE 340 patients with an onset of severe ARDS within

previous 48 hours randomly assigned to receive, for 48 hours, either

cisatracurium besylate (178 patients) or placebo (162 patients)

Severe ARDS was defined as a P/F ratio of less than 150, with a PEEP of 5 cm or more of water and a tidal volume of 6 to 8 ml per kilogram of PBW

HR 0.68 (95% CI 0.48 to 0.98; P=0.04)

Beta-agonist infusions were found to be harmful to ARDS patients in the BALTI trials (2011)

EDEN trial- trophic feeds equivalent to full feeds in first 7 days

OUTLINE




“KEEP THEM DRY”

FACTT

497 in liberal and 503 in conservative During the study, the seven-day

cumulative fluid balance was –136±491 ml in the conservative-strategy group, as compared with 6992±502 ml in the liberal-strategy group (P<0.001)

SUMMARY

TV 6 cc/kg PBW Plateau < 30 cm H2O Use PEEP AC- VC or PC Keep them dry iPC? Steroids?

THANKS!

ARDS 2012 Summer Lecture Series Urvashi Vaid MD, MS.

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