ALI/ARDS

Dr. Ashraf ELMasry M.D.

aaaelmasry@yahoo.com

Objectives

• Introduction.• Discovery of ARDS.• Definition.• Etiology / Risk Factors.• Pathology & Pathogenesis.• Functional disorders and lung mechanics.• Management of ALI/ARDS.• ARDS network and its trials up-to-date.• Open Lung Concept.• Summary & Wrap up.

Introduction

• ALI/ARDS is a clinical devastating syndrome that affects both medical and surgical patients.

• Despite great advances in understanding the pathogenesis of disease mortality rate is still high.

• Mortality rates ranges between 40-60%, although some trials had demonstrated lower mortality rates.

Introduction

• Even survivors of ARDS usually experience long ICU stay, hospital stay and several co-morbidities.

• Moreover survivors require prolonged rehabilitation time till full recovery.

• Restoration of normal activities ranges between 6 months to 12 months.

• ALI/ARDS not only represent great impact on ICU but on nation's economics as well.

Discovery of the disease

• an old 1954 model of the Engstrom anesthesia/ventilator had lead to discovery of the disease.

“In the cards was ARDS “Ashbaugh, D. G., D. B. Bigelow, T. L.

Petty, and B. E. Levine. 1967. Acute respiratory distress in adults. Lancet 2(7511):319-23.

Definition

Basic Definition: No criteria, just description of the

disease, course and outcome. Drawbacks: Physicians faced many problems in

selecting cases and no definite research can be focused.

• In 1988 Murray and colleagues proposed an expanded definition intended to describe the syndrome in three parts.

DefinitionThree part expanded definition of ALI/ARDS proposed by

Murray and colleagues

Part One.

Part Two.

Part Three.

Acute or chronic depending on course.

Severity of lung injury depending on LIS.

Cause or associated risk factor.

Murray, J. F., M. A. Matthay, J. M. Luce, and M. R. Flick. 1988. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 138(3):720-3.

DefinitionThe 1994 AECC definition for ALI/ARDS

Onset Acute and persistent.

PaO2/FIO2 ≤ 300.

PaO2/FIO2 ≤ 200.

ALI.ARDS.

Exclusion criteria. PAOP > 18 mm Hg, or clinical evidence of left atrial

hypertension.

Radiographic criteria. Bilateral chest infiltrates consistent with pulmonary

edema.Bernard, G. R., A. Artigas, K. L. Brigham, J. Carlet, K. Falke, L. Hudson, M. Lamy, J. R. Legall, A. Morris, and R. Spragg. 1994. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149(3 Pt 1):818-24.

Definitioncomparison between various definitions of ARDS

Reference Year Criteria Advantages Disadvantages

Petty & Ashbaugh

1971 No criteria First description and

describesClinical

manifestations well.

No specific criteria to identify

patients.

Murray et al 1988 3 part definition.LIS.

Identify clinical spectrum.Identifies etiology.

LIS not predictive of outcome.

Does not include exclusion

criteria

Bernard et al 1994 Acute onset.ALI or ARDS.Bilateral chest

infiltrates.PAOP < 18 mm

Hg.

Simple and easy to use.

Recognizes clinical

spectrum

Does not specify the cause.

Radiographic data are not specific.

Etiology / Risk Factors•Sepsis.•Aspiration.•Pneumonia•Trauma and Burns.•Massive blood transfusion.•Following relief of upper airway obstruction.•Lung and bone marrow transplant.•Drugs. (Aspirin, opioids, radiological contrast

media)•Leukoagglutinin reactions.•Others. (Drowning, cardiopulmonary by pass)

Etiology / Risk factors

• Now it had been established that ALI/ARDS is divided into pulmonary and extrapulmonary ARDS according to the cause.

• This classification had been made as Pathophysiology, course, treatment and outcome are not the same.

• Thus risk factors are now classified as ARDSp or ARDSexp.

Pulmonary or extra-pulmonaryClinical disorders associated with the development of ALI/ARDS.

Direct (Pulmonary) Indirect (Extra Pulmonary)

Common Common

Aspiration pneumonia.Pneumonia.

Sepsis.Severe trauma with prolonged

hypotension Multiple fractures.

Less common Less common

Inhalation injury.Pulmonary contusion.Fat embolism.Near drowning.Reperfusion injury.

Acute pancreatitis.Cardiopulmonary bypass.

Drug overdose.DIC.

Burns.Head injury.

Pathology

• Like interstitial nephritis and acute hepatitis, the term ARDS encompasses many distinct disorders that share common clinical and pathophysiologic features.

• The pathological features of ARDS are typically described as passing through three overlapping phases: exudative, proliferative and finally fibrotic phase.

Pathology

Myointimal thickening.

Tortuous vessels.

Loss of capillaries.Pulmonary

Hypertension.

Local Thrombus.

Vasculature

Fibrosis.Macrophages.Lymphocytes.Matrix formation.Deranged

architecture.emphysematous

changes.

Barrier disruption.Edema.

Type II cell proliferation.

↑ Myofibroblasts. ↑ Neutrophils.

Alveolar collapse.Alveoli filled with

cells.Epithelial apoptosis.

Fibroproliferation.

Hyaline memb.Edema.

Neutrophils.Epithelial damage>

endothelial damage

Microscopic

Cobblestone appearance.

Heavy and gray.Heavy, rigid and dark.

Macroscopic

Fibrotic PhaseProliferative PhaseExudative Phase

Pathology

Pathogenesis

• Lung injury is primarily initiated by a specific insult (sepsis, trauma, VILI); with the initiation of inflammation there is rapid and increased recruitment of leucocytes, together with inflammatory mediators to the site of injury, several mechanisms had been involved in the pathogenesis of ARDS.

Pathogenesis

Lung Insult

Inflammatory Cells Inflammatory Mediators

Cell Adhesion Molecules VILI

Surfactant Depletion Fibrosing Alveolitis

ALI/ARDS

Easy!!Last Chance??

concentrate

Pathogenesis

Pathogenesis

• Primary lung insult is associated with cascade of events.

• The corner stone of such cascade is inflammatory cells mainly neutrophils.

• Recruitment of neutrophils and activation of macrophages leads to release of both pro-inflammatory and anti-inflammatory cytokines.

Pathogenesis

• Balance between Pro-anti inflammatory cytokines is crucial in determining outcome.

Pathogenesis

Surfactant depletion:

• In the past the disease was named as Adult respiratory distress syndrome, due to the resemblance between ARDS and respiratory distress syndrome in infants, which is mainly due to surfactant deficiency.

Pathogenesis

The degree to which surfactant dysfunction contributes to the pathogenesis of ARDS is currently unknown, however the function of lung surfactant can be altered in ARDS by:

• Damage of type II alveolar cells leads to decreased surfactant synthesis and recirculation of surfactant.

• Accumulation of protein-rich edema contaminates surfactant and reduces its functional capacity.

Pathogenesis

VILI:1. Barotrauma.

2. Volutrauma.

3. Atelectotrauma.

4. Biotrauma.

5. Oxygen toxicity.

N.B: VILI can predispose to ALI/ARDS, while ALI/ARDS patients are more prone to effects of VILI.

Functional disorders & Lung mechanics

• ALI/ARDS is a syndrome of low lung compliance.

• Pulmonary edema initially, repair and fibrosis later.

• Impaired V/Q matching in the lung, causing hypoxemia and hypercarbia.

• Endotracheal intubation and mechanical ventilation are almost always necessary.

Management of ALI/ARDS

• Since it was discovered in 1967 numerous trials had been conducted in an attempt to improve outcome in ALI/ARDS patients.

• All measures used did not effectively show improvement in outcome.

• It is accepted that management of ALI/ARDS is a supportive measure until natural healing process occurs / or treatment (sepsis, pneumonia) takes effect.

General Supportive measures

• Antibiotics: Why??

• Anticoagulants: Why??

• Antacids: H2, proton pump or sucralfates.

• Fluids? Restrictive or liberal.

• Feeding?? Enteral or parentral.

• Measures to improve oxygenation.DO2= (1.34 X Hb x Sao2) + (0.003x PaO2) X C.O (dl)

Ventilatory management of ALI/ARDS

• It should be noted that ventilatory management of ALI/ARDS is a supportive measure that prevents secondary organ insult.

• Ventilatory strategy applied should provide adequate oxygenation, respect underlying lung pathology and more importantly does not harm the diseased lung.

• Protective ventilatory strategy means a strategy that protects against VILI.

ARDS network and its trials

• ARDS Network??

• In order to hasten the development of effective therapy for ARDS, the National Heart, Lung, and Blood Institute, National Institutes of Health, initiated a clinical network to carry out multi center clinical trials of ARDS treatments.

ARDS network and its trials

• The goal of the Network is to efficiently test promising agents, devices, or management strategies to improve the care of patients with ARDS.

• In this section we will discuss the findings of the ARDS network conducted trials.

ARDS network and its trialsKetoconazole for ALI/ARDS:• The first clinical trial completed by the Network was a

randomized, controlled trial of Ketoconazole versus placebo in patients with acute lung injury and ARDS.

• Ketoconazole was chosen because of its anti-inflammatory actions noted in the laboratory suggested benefit in patients with or at risk for ARDS.

• This trial was stopped early in January 1997 after finding Ketoconazole to be ineffective.

Ketoconazole for early treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome. A randomized controlled trial. JAMA, 2000;283:1995-2002).

ARDS network trials

Lisofylline for ALI/ARDS:• A second randomized placebo controlled trial

compared Lisofylline, an antiinflammatory and antioxidant drug that also showed promising results in phase II trials of immunosuppressed patients.

• Lisofylline also proved to be ineffective.

Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome. Crit Care Med Vol 30:1-6).

ARDS network trialsLower tidal volume trial:• A third trial examined lower tidal volume ventilation

versus a traditionally recommended higher tidal volume approach in patients with acute lung injury.

• This landmark randomized controlled trial, which enrolled 861 subjects, clearly demonstrated that lower tidal volumes result in improved survival.

The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; Vol 342: 1301-1308).

ARDS network trialsALVEOLI study:• A fourth trial examined the role of higher

positive end-expiratory pressure (PEEP) to keep the lung open between breaths and to further improve lung healing and repair during acute lung injury.

• The ALVEOLI study tested lower tidal volumes with higher PEEP and, after enrolling 449 patients, found no further improvement in survival with the addition of higher PEEP.

Higher vs. lower positive end-expiration pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004 Jul 22;351(4):327-36).

ARDS network trials Late steroid rescue study (LaSRS trial)• The use of corticosteroids in the later phases of

ARDS showed promise in a small randomized controlled trial.

• The ARDS Network enrolled 200 patients over 6 years in a placebo controlled trial of methylprednisolone versus placebo for patients with presistend ARDS after 7 to 28 days.

• Methyplrednisolone improved lung function resulting in earlier liberation from mechanical ventilation however no difference in mortality rates.

Unfortunately, these promising findings did not result in improved survival. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006;354:1671-168)

ARDS network trialsThe FACCT trial:• This study examined two different strategies for

managing intravenous fluids and fluid balance in patients with acute lung injury.

• A second goal of this trial was to determine if a Pulmonary Artery Catheter (PAC) was superior to a smaller, and less invasive central venous catheter in the management of patients with ARDS.

• No benefit was seen with the PAC guided therapy.• restrictive or conservative fluid administration was

superior to the traditional approach by shortening the duration of mechanical ventilation.

Wheeler AP, Bernard GR, Thompson BT, Schoenfeld D, Wiedemann HP, deBoisblanc B, Connors AF, Jr., Hite RD, Harabin AL: Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006; 354: 2213-24

ARDS network trialsEDEN – Omega Trial (Pending) : • Prospective, Randomized Trial of initial

trophic enteral feeding followed by advancement to full-calorie enteral feeding vs. early advancement to full-calorie enteral feeding.

• This trial will be run simultaneously with a trial of omega-3 fatty acid, gamma-linolenic acid, and anti-oxidant supplementation vs. a control.

• These trials will test the safety and efficacy of these treatments in the management of patients with ALI or ARDS.

ARDS network trials

Albuterol for the Treatment of ALI (ALTA):

• A prospective, randomized trial of Aerosolized Albuterol vs. Placebo to test the safety and efficacy of aerosolized beta-2 adrenergic agonist therapy for improving clinical outcomes in patients with acute lung injury.

Open Lung concept

• Open the lung and keep the lung open.

• How to open lung?

• How to keep lung open?

• Who is against?

• Why?

• Do you believe that low tidal volumes can protect against VILI?

Open Lung Concept

Why use High PEEP despite the evidence that High PEEP did not improve outcome? (The ALVEOLI Study).

With all due respect to

ALVEOLI trial, I will recruit the

ALVEOLI

The ALVEOLI Trial• Most patients requiring mechanical

ventilation for acute lung injury and the acute respiratory distress syndrome (ARDS) receive positive end-expiratory pressure (PEEP) of 5 to 12 cm of water. (!!!5-12)

• Higher PEEP levels may improve oxygenation and reduce ventilator- induced lung injury but may also cause circulatory depression and lung injury from overdistention. (1ry outcome should be VILI or cardiac depression)

• We conducted this trial to compare the effects of higher and lower PEEP levels on clinical outcomes in these patients.

The ALVEOLI Trial

•549 patients with acute lung injury and

ARDS to receive mechanical ventilation

with either lower or higher PEEP levels,

were randomly enrolled.•PEEP was set according to different

tables of predetermined combinations of

PEEP and fraction of inspired oxygen.

(Why, and what is the rationale behind

such technique).

The ALVEOLI Trial

The ALVEOLI Trial

The ALVEOLI Trial

The ALVEOLI Trial

Why alveolar recruitment

• Low tidal volumes and pressures do not protect against all components of VILI.

• Do low tidal volumes and pressures guard against atelectotrauma, oxygen toxicity and biotrauma?

• Why mortality had decreased with the use of low tidal volumes?

• What had happened that prevents more reduction in mortality when using open lung?

Critique of the ALVEOLI

• Did the ALVEOLI trial worsened outcome when high PEEP was used?

• Did any drawbacks had appeared when using high PEEP levels?

• The trial demonstrated that the use of low PEEP compared to moderate PEEP 13.4 cmH2O did not significantly affect mortality but significantly affected most of respiratory parameters.

Why Alveolar recruitment

• Moreover, recruitment maneuvers was not used.

• Finally why they stopped the trial despite no worse outcome had occurred, similar to low tidal volumes.

Summary & Wrap UP

• ALI/ARDS is a clinical devastating syndrome.

• ALI/ARDS is defined according to the AECC criteria.

• Characterized by very low lung compliance, early pulmonary edema and late fibrosis.

• Such changes leads to V/Q mismatch with subsequent hypoxemia and hypercarbia.

Summary & Wrap UP

• Mechanical ventilation is almost always required to improve V/Q mismatch.

• Pathogenesis is complex and involves both cell mediated response together with inflammatory mediators following an initial lung insult.

• VILI can lead to ALI/ARDS in healthy population, Moreover patients with ALI/ARDS are prone to VILI.

Summary & Wrap Up

• Lower tidal volumes (4-8 ml/kg) was the first intervention to show any beneficial effect in patients with ARDS.

• Late steroid use aids in earlier ventilator free days but no added effect on mortality.

• PAC is not required to aid fluid management and a CVC can be used.

• Restrictive fluid therapy aids in earlier disconnection from mechanical ventilators.