ARDS: Evidence Based Practice and Beyond Benjamin D. Medoff, MD Massachusetts General Hospital and Harvard Medical School
Outline • Definition and Epidemiology • Pathophysiology • Management – Ventilator – Therapy – Ancillary Management – Just the FACTTs
ALI/ARDS in the United States in 2000 Estimates • 190,600 ALI/ARDS cases per year • 74,500 deaths • 3.6 million hospital days • Pneumonia and septic shock (eg severe sepsis) as the ALI risk factor in ~80% Rubenfeld et al NEJM 2005
THE CONCEPTUAL MODEL OF ARDS 1. ARDS is a type of acute diffuse lung injury associated with recognized risk factors, characterized by inflammation leading to increased pulmonary vascular permeability and loss of aerated lung tissue. 2. The hallmarks of the clinical syndrome are hypoxemia and bilateral radiographic opacities (standard chest x-ray or CT scan). 3. Physiological derangements include increased pulmonary right-to-left venous admixture, increased physiological deadspace, decreased respiratory system compliance. 4. morphological hallmarks are lung edema, inflammation, hyaline membrane, and alveolar hemorrhage (i.e., diffuse alveolar damage)
ARDS Mild (22%) 27% Mortality Timing
Hypoxemia
Origin of Edema
Radiological Abnormalities
Moderate (50%) 32% Mortality
Severe (28%) 45% Mortality
Acute onset within 1 week of a known clinical insult or new/worsening respiratory symptoms PaO2/FiO2 201-300 with PEEP/CPAP ≥ 5
PaO2/FiO2 ≤ 200 with PEEP ≥ 5
PaO2/FiO2 ≤ 100 with PEEP ≥ 5
Respiratory failure associated to known risk factors and not fully explained by cardiac failure or fluid overload. Need objective assessment of cardiac failure or fluid overload if no risk factor are present
Bilateral opacities*
Bilateral opacities*
Bilateral opacities*
Common Risk Factors for ARDS • Treatment of the underlying cause is the highest priority • Direct Pneumonia Aspiration of gastric contents Inhalation injury Pulmonary contusion Near drowning
• Indirect Non-pulmonary sepsis Major trauma
Multiple transfusions Severe burns Pancreatitis Non-cardiogenic shock Drug overdose
* Radiographic and physiological abnormalities following direct or indirect injury overlap to such a degree that this classification does aid in individual supportive treatment decisions (eg PEEP, RMs)
ARDS - Pretenders • • • • • • • •
CHF – out COP/BOOP - out Extrinsic allergic alveolitis - out Acute Eosinophilic pneumonia - out Pulmonary vasculitis – In Bland alveolar hemorrhage - out Lymphangitic carcinomatosis - out Bronchiolo-alveolar carcinoma – out
Risk of Developing ALI by Tidal Volume for Non-ALI ARF: OR for ALI = 1.3 per mL/kg above 6 Percent Developing ALI
Gajic et al CCM 2004
The Role of Potentially Preventable Hospital Exposures in the Development of Acute Respiratory Distress Syndrome: A Population-Based Study*. Ahmed, Adil; Litell, John; Malinchoc, Michael; Kashyap, Rahul; Schiller, Henry; Pannu, Sonal; Singh, Balwinder; Li, Guangxi; Gajic, Ognjen; MD, MSc 2 2014. Critical Care Medicine. 42(1):31-39, January DOI: 10.1097/CCM.0b013e318298a6db
Ventilation with low tidal volumes prevents lung injury in patients without ALI
Determann, Critical Care 2010
ARDS Pathology: Diffuse Alveolar Damage (DAD) • Early exudative phase (hours to days) – Intra-alveolar and interstitial edema/clotting – necrosis of type I alveolar lining cells – hyaline membranes
• Late fibroproliferative phase (days to weeks) – Inflammation -> alveolar and peri-bronchial fibrosis – vascular thrombosis and remodeling
Early DAD
Ware, NEJM 2000
Proliferative Phase of DAD
Acute Phase
Late Phase
Ware and Matthay NEJM 2000
ARDS - Physiology • Acute – High permeability pulmonary edema – Hypoxia (R->L shunt) improves with PEEP – Decreased compliance (edema, surfactant)
• Late – – – –
increased vascular resistance hypoxia (V/Q mismatch, ? diffusion) refractory to PEEP decreased compliance (tissue) Increased dead space – capillary drop out
Ventilator Induced Lung Injury: Conceptual Framework • Lung Injury from: – Overdistension-> physical injury – mechanotransduction -> “biotrauma”
“volutrauma”
– repetitive opening/closing – shear at open/collapsed lung interface
“atelectrauma”
• Systemic inflammation and death from: – systemic release of cytokines, endotoxin, bacteria, elastase
Ventilator-Induced Lung Injury
Volutrauma: overdistention of Aerated Lung
Atelectrauma: Tidal opening and closing, shear
Constant Tidal Volume Zero Zero Peep Peep 15cm H20 Peep
A. S. Slutsky
AJRCCM 2014, 189:149
Vt ~ 6 ml/kg PEEP ~13-16
Amato et al NEJM 1998; 338: 347-354
Vt ~12 ml/kg PEEP ~9 Days After Randomization Amato et al N Engl J Med 1998
ARDS Network 01: Lower Vt •
RCT of 6 vs 12 ml/kg PBW Tidal Volume • PBW based on height/gender; 20% less than measured wt • Therefore, Vt was ~5 vs ~10 ml/kg MBW
•
Patients with ALI/ARDS of < 36 hours
•
Stopped early after the fourth interim analysis (n=861 for efficacy; p45 cm H20) 1. PaO2/FiO2 at PEEP = 5 < 150 mmHg? Raise PEEP from 5 to 15 2. Decrease in dead space? 3. Increase in compliance? If 2/3 Criteria + Sens Spec PPV NPV 79% 81% 81% 79% Gattinoni et al NEJM 2006
Modified ARDS Net Protocol-Basics 1. Get out tape measure -> calculate PBW and target Vt 2. Reduce Vt by 1mg/kg q2h -> 6 ml/kg PBW 3. Pplat q4; decrease Vt if Pplat > 28 4. Rate up to 35 for pH 7.3-7.45 5. Consider Higher PEEP/FI02 scale if recruitable 6. Pressure Support when PEEP/FI02 = 8/.4 or 5/.5 < www.ardsnet.org>
Relative Risk of Death in the Hospital versus ΔP in the Combined Cohort after Multivariate Adjustment.
Amato MB et al. N Engl J Med 2015;372:747-755.
• N = 340 subjects with P/F < 150 • Vt 6-8 ml/kg • Deep sedation • Randomized 1:1 to the addition of cisatricurium x 48 hrs
28 d (p = 0.05) and 90 d mortality (p=0.08) favors cisatricurium
Young D et al. N Engl J Med 2013;368:806-813.
HFOV
Ferguson ND et al. N Engl J Med 2013;368:795-805.
Kaplan–Meier Plot of the Probability of Survival from Randomization to Day 90.
Guérin C et al. N Engl J Med 2013;368:2159-2168.
Probability of Survival and of Being Discharged Home during the First 90 Days after Randomization.
The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. N Engl J Med 2014;370:2191-2200.
Probabilities of Survival and Breathing without Assistance from Randomization to Day 28, According to Whether Patients Received Simvastatin or Placebo.
McAuley DF et al. N Engl J Med 2014;371:1695-1703.
Results of the Fluid And Catheter Treatment Trial (FACTT) Factorial Design: • PAC vs CVC guided therapy (n=1000) • Liberal Versus Conservative Fluid Management (n=1000)
ARDS Network, NEJM 2006: v304, p2213; v304, p2564
FACTT Fluid: Rx Background • High pulmonary vascular pressures – cause to stress failure of capillaries – augment VILI
• Reduction in PAOP a/w improved survival • EVLW targeted therapy a/w less fluid balance and improved survival West J Appl Physiol 2000; Hotchkiss et al AJRCCM 2000; Humphrey et al. Chest 1990; Mitchell et al. Am Rev Respir Dis 1992
After Resolution of Shock “Conservative” fluid Rx – Diuretics and fluid restriction – Prioritizes ↓ lung water > perfusion
• “Liberal” fluid Rx – Targets ↑ CVP, accepts positive fluid balance – Prioritizes systemic perfusion > lung water
ARDS Net Study 06: FACTT 12 hours after vasopresors stopped: • For Oliguria – If “wet” -> Diuresis – If “dry” -> Fluids, no lasix for 12 hours • Non-Oliguria, no acute renal failure – Diuresis to CVP < 4, PAOP < 8
ARDS Net NEJM 2006
Cumulative fluid balance Liberal Conservative ARMA 6 ml (1996-1999) ALVEOLI all (1999-2002)
ml of fluid
8000 6000 4000 2000 0 0
1
2
3
4
5
-2000 Study Day
6
7
ml of fluid
Cumulative fluid balance at day 7: Baseline shock vs. no shock 12000 10000 8000 6000 4000 2000 0 -2000 -4000 -6000
Liberal Conservative
7234 ml
6863 ml
Shock free
Shock
Baseline
CVP separation 13 12 11 10 9 8
Liberal Conservative Prerand
Prefluid
1
2
3
Study Day
4
5
6
7
FACTT Fluid: Safety • Conservative – More AEs of hypokalemia and metabolic alkalosis
• No difference – new shock (~15%) or shock duration – renal failure free days – Renal Replacement Therapy • 10% in conservative vs 14% in liberal (p=0.06)
60 Day mortality P = 0.30 30
25 Mortality (%)
28.4
25.5
20
15 Liberal
Conservative
Ventilator and ICU free days (day 28) Vent Free Days
ICUFree Days
Conservative
14.55
Conservative
Liberal
12.09
Liberal
0
2
4
6
8
10
P=0.0002
12
14
16
13.4
11.13
0
2
4
6
8
10
P