ACUTE RESPIRATORY DISTRESS SYNDROME

Jerome R. Barrera, M.D. Third Year IM Resident

MANSUETA SABELLINA, M.D., FPCP, FPCCP MARGARITA ABALON, M.D., FPCP, FPSN BINNASRI ABUBAKAR, M.D., FPCP, DPCCP Consultants

Objectives
Present a case ARDS
Define ARDS and describe the pathological

process Know causes of ARDS, and differential diagnosis Understand specific challenges in mechanical ventilation of patients with ARDS Understand treatment strategies and evidence behind them

General Data
25 M

Manicahan, Zamboanga City

Islam Date of admission April 27, 2009 Date of Expiration - April 29, 2009

History of Present Illness

High grade fever Calf pain Tea-colored urine Difficulty of breathing

LBM Vomiting Body malaise Headache Calf pain

Day of Admission

3 days PTA

Review of System
No weight loss

No jaundice
No edema No orthopnea and PND No cough

Past Medical History

No previous consult and admissions

No bronchial asthma, cardiac disease

History of waiding No history of food and drug allergy

Personal and Social History

High school graduate

Previously worked as laborer

Non- smoker, non-alcoholic drinker

Physical Examinations
At the emergency room conscious, coherent and not in respiratory distress BP - 70/50mmHg HR - 115 bpm T36.8C RR - 24 cpm Sunken eyeball, anicteric sclerae JVP was 2-3 cm, no neck vein engorgement Symmetrical chest expansion,clear breath sounds Adynamic precordium, tachycardic with loud S1 at apex and base, soft pulses Hyperactive bowel sounds

Physical Examinations
At the ward
Awake, conscious, coherent, in respiratory distress BP 60/20 mmHg HR 110 bpm RR 28 32 cpm O2 sat 92 95% Sunken eyeball, icteric sclerae, conjunctival suffusion JVP at 4 cm, no neck vein engorgement Supraclavicular and intercostals muscle contractions,

T - 38.5 C

symmetrical chest expansion, crackles all over his lung fields Adynamic precordium, tachycardic, S1 was louder at both apex and base Soft abdomen, non-tender, normoactive bowel sounds, liver Span - 9 10 cm at right midclavicular line, tymphanitic traubes space Calf tenderness

Diagnosis
Consider Acute Respiratory Distress

Syndrome probably secondary Weils WHO leptospirosis Syndrome secondary to Leptospirosis

criteria 21 -suggestive

1994 Consensus Definition Acute onset (<2 weeks) Bilateral infiltrates on chest xray PCWP 18mmHg or lack of evidence of left atrial hypertension Acute lung injury if PaO2/FiO2 300 ARDS if PaO2/FiO2 200

Differentials
Community Acquired Pneumonia

Gram negative septicemia secondary Acute

Gastroenteritis Acute Pulmonary Edema secondary to LV Failure

Management
Initially managed as AGE with severe dehydration

Diagnostics Complete blood count Stool examination, stool culture and sensitivity Serum electrolytes Na, K Creatinine, BUN Long lead II Chest radiograph

Management - therapeutics
Hydrated with normal saline at 90 ml /kg

Fluid replacement volume per volume loss

Supportive therapy
Metoclopromide Anti-secretory agent racecadotril

Hourly monitoring of urine output

4 hours after the admission...

Initial laboratory results CBC Hgb 79 Hct 0.23 BP - 60/20 mm Hg RBC 3.02 HR 110 bpm Additional diagnostics WBC 16.80 T 38.5C N 0.93 oMAT for leptospires RR 28 32 cpm L 0.04 oBlood culture and Platelet 64 Oxygen saturation 92 95%

sensitivity Conjunctival suffusion, icteric Creatinine 711.9 umol/L oABG sclerae Sodium 140 JVP at 4 cm,Crackles ALF Potassium 3.1 oStarted on inotropics dopamine at 10 Calf tenderness ug/kg/hr No urine output o(ideally norepinephrine) Respiratory to oTarget MAP of Failure 65 mmsecondary Hg Acute drip Respiratory Distress oFurosemide once SBP is at least 100 Syndrome probably secondary to mm Hg Weils Syndrome to oAntibiotic coverage forsecondary leptospirosis Leptospirosis oStarted on mechanical ventilation

Mechanical ventilation set up

Assist control mode

FIO2 100%
PEEP 12 cm H20 BUR 20 22 cpm TV 8ml/kg BW for the first

2 hour (440 ml) Target 6 ml/kg BW

According to ARDS network

oLow tidal volumes 6-8mL/kg PBW omale = 50 + 0.91(centimeters of height 152.4) = 494.64 ml ofemale = 45.5 + 0.91(centimeters of height 152.4) oPlateau (end-inspiratory) pressures <30cm H20 not done oPEEP allowable combinations

Other therapeutic measures

Control blood sugar to less than 150 mg/dl

Frequent suction secretion

BP stabilize, still with fever and tachycardia Still with inadequate urine output Noted frothy secretion per ETT

Failures.....
To start broad spectrum antibiotics to cover other

possible causes of sepsis AGE Inavailability of Norepinephrine NO ABG To follow ARDS network guidelines on mechanical ventilation

At 20 - 24 hours after admission,

Intubated with no spontaneous breathing on MV BP 90/70 mm Hg, HR 110 140 bpm, o2 sat 99% T 37.9 C Inadequate urine output 0.40 ml/kg/24 hr Icteric sclerae, conjunctival suffusion JVP at 4 cm, crackles ALF Soft abdomen, liver edge not palpable Rounds with Pulmonologist oSuggested to continue hydration with NSS, inotrophics and diuresis oIncrease PEEP to 15 cm H20 oCorrect anemia with blood transfusion

ABG
PH 7.2 HCO3 12.2 PCO2 31.9 PaO2 - 107.7 SaO2 96.9% PaO2/ FIO2 = 107.7 Metabolic acidosis, partially compensated

Referred to Nephrologist Suggested to correct HCO3 deficit Suggested to do emergency renal replacement therapy refused

At 40 hours of admission
oHypotensive even with maximal dose of dopamine, tachycardic, desaturation at 80-90%, T 38.5 C oEdema with crepital sounds at anterior neck and trunk oCrackles all lung field o1 ml/kg/24 hr urine output

Rounds with Pulmonologist Adjusted TV to 6 ml/kg PBW Decrease PEEP to 8cm H2O Suggested to start broad spectrum antibiotics to cover for sepsis

Patient expired....

Multiple Organ Failure secondary Severe Leptospirosis

ARDS
First described 1967 by Ashbaugh and colleagues Severe lung injury characterized by non-cardiogenic pulmonary edema, decreased lung compliance, refractory hypoxemia 1994 Consensus Definition
Acute onset (<2 weeks) Bilateral infiltrates on chest xray PCWP 18mmHg or lack of evidence of left atrial

hypertension Acute lung injury if PaO2/FiO2 300 ARDS if PaO2/FiO2 200

Epidemiology
Incidence of acute lung injury (ALI): 17.9-78.9

cases per 100,000 person-years Incidence of acute respiratory distress syndrome (ARDS): 13.5-58.7 cases per 100,000 personyears Approx 9% of ICU beds in US

N Engl J Med. 2005;353:1685-93. Am J Respir Crit Care Med. 1999;159:1849-61.

Most common causes ARDS

Pneumonia (34%), (~4050% - in harrisons)

Sepsis (27%)
Aspiration (15%) Trauma (11%)
Pulmonary contusion Multiple fractures

ARDSnet NEJM 2000:342:1301-8.

Causes of ARDS

NEJM 2000;342,18:1334-1349

Risk factors for ARDS

Preexisting lung disease

Chronic alcohol use

Low serum pH Sepsis
40% of patients with sepsis develop ARDS

Differential diagnosis
Pulmonary edema from left BOOP or COP Hypersensitivity

heart failure Diffuse alveolar hemorrhage Acute eosinophilic pneumonia Lupus pneumonitis Acute interstitial pneumonia Pulmonary alveolar proteinosis

pneumonitis Leukemic infiltrate Drug-induced pulmonary edema and pneumonitis Acute major pulmonary embolus Sarcoidosis Interstitial pulmonary fibrosis

 Tomiyama and coworkers reported that,

patients with AIP tended to have more honeycombing and a more symmetrical and lower zone distribution of abnormalities than patients with ARDS

Harrisons Principle of Internal Medicine, 17 th

Acute (Exudative) Phase Pathophysiology

Increased leukocytes and hyaline membrane whorls

Cell injury Loss of barrier to fluid and macromolecules

Edema

Increased cytokines and lipid mediators Proteins aggregate

Vascular obliteration by microthrombi fibrocellular proliferation

Pulmonary vascular injury

Harrisons Principle of Internal Medicine, 17 th

Harrisons Principle of Internal Medicine, 17 th

Acute (Exudative) Phase Pathophysiology

Alveolar edema Diminished aeration and atelectasis Decrease lung compliance

Hypercapne a
Microvascular occlusion Reductions in pulmonary arterial blood dead space and pulmonary hypertension

Intrapulmonary shunting and hypoxemia

Harrisons Principle of Internal Medicine, 17 th

Acute (Exudative) Phase Clinical course

Rapid onset respiratory failure in patient at risk

for ARDS - first 7 days of illness Symptoms usually present during 12 36 hr

Delayed by 5 -7 days Rapid shallow breathing and inability to get

enough air
Hypoxemia refractory to oxygen

Laboratory results indicates underlying primary

disorders

Harrisons Principle of Internal Medicine, 17 th

Acute Phase - Radiographs

Resembles

cardiogenic pulmonary edema Alveolar and interstitial opacities involving at least three-quarters of the lung fields Bilateral infiltrates worse in dependent lung zone Infiltrates may be

Harrisons Principle of Internal Medicine, 17 th

Acute Phase - Radiographs

Unlike in cardiogenic pulmonary edema....ARDS

rarely shows
Cardiomegaly Pleural effusions Pulmonary vascular redistribution

Harrisons Principle of Internal Medicine, 17 th

Acute Phase - Radiographs

Chest computed

tomography (CT) scanning

extensive

heterogeneity of lung involvement

NEJM 2000;342,18:1334-1349

Pathology findings
Diffuse alveolar damage
Neutrophils, macrophages, erythrocytes Hyaline membranes Protein-rich edema in alveolar spaces

Acute Phase Histology

Alveolar Filling

Expansion of interstitium with macrophages and inflammation

Hyaline Membranes

Proliferative Phase Pathophysiology

Reparative process
Proliferation of type II pneumocytes New pulmonary surfactant Differentiate into type I pneumocytes

Progressive lung injury

Decreased pulmonary compliance

Persistent hypoxemia

Increased alveolar dead space Early changes of pulmonary fibrosis

Pulmonary hypertension

Alveolar type III procollagen

Harrisons Principle of Internal Medicine, 17 th

Proliferative phase Clinical course

Last from day 7 to 21
Recover rapidly and are liberated from mechanical

ventilation
May still present with dyspnea, tachypnea and

hypoxemia
Not present in every patient with ARDS, but does

portend poorer prognosis

Harrisons Principle of Internal Medicine, 17 th

Fibroproliferative - Radiograph
Linear opacities

consistent with evolving fibrosis Pneumothorax in 10-13% of patients

Fibroproliferative - Radiograph
CT Scan
diffuse interstitial

opacities and bullae

Proliferative - Histology
First signs of lung repair
Organization of alveolar exudates Neutrophilic to lymphocytic infiltrates

Harrisons Principle of Internal Medicine, 17 th

Fibrosing alveolitis

fibrosis, mesenchymal cells, vascular proliferation, collagen and fibronectin accumulation

NEJM 2000;342,18:1334-1349.

Recovery phase
Usually on the 3rd to 4th week
Gradual resolution of hypoxemia
Hypoxemia improves as edema resolves via active

transport Na/Cl, aquaporins Protein removal via endocytosis Re-epithelialization of denuded alveolar space with type II pneumocytes that differentiate into type I cells
Improved lung compliance

Chest xray and CT findings resolve

PFTs improve, often normalize

Fibrotic Phase Pathophysiology

Intimal fibroproliferation in microcirculation

Progressive vascular occlusion Pulmonary hypertension

Pneumothorax Reductions in lung compliance Pulmonary dead space

Harrisons Principle of Internal Medicine, 17 th

Fibrotic Phase Clinical Course

Require long-term mechanical ventilation and

supplemental oxygen Associated with increase mortality

Harrisons Principle of Internal Medicine, 17 th

Fibrotic Phase Histology

Extensive alveolar duct and interstitial fibrosis

Emphysema-like changes

Harrisons Principle of Internal Medicine, 17 th

Management of ARDS
Recent reductions in ARDS/ALI mortality
(1) Recognition and treatment of the underlying

medical and surgical disorders (e.g., sepsis, aspiration, trauma) (2) Minimizing procedures and their complications (3) Prophylaxis against venous thromboembolism, gastrointestinal bleeding, and central venous catheter infections (4) Prompt recognition of nosocomial infections; (5) Provision of adequate nutrition

Harrisons Principle of Internal Medicine, 17 th

Keys to management
Treat underlying illness Supportive care
Low tidal volume ventilation Nutrition Prevent ICU complications Stress ulcers DVT Nosocomial infections Pneumothorax No routine use of PA catheter Diuresis/avoidance of volume overload

Give lungs time to recover

Harrisons Principle of Internal Medicine, 17 th

ARDS Network
NIH-funded consortium of 10 centers, 24

hospitals, 75 intensive care units Goal to design large RCTs to determine effective treatments Key ARDSnet studies:

Ventilator volumes PEEP Steroids Volume management/PA catheter

Mechanical Ventilation Tidal Volume

861 patients randomized to Vt 10-12 mg/kg ideal

body weight and plateau pressure 50cmH2O vs Vt 6-8 mg/kg IBW and plateau pressure 30cm H2O KEYS
Low tidal volumes 6-8mL/kg ideal body weight Maintain plateau (end-inspiratory) pressures <30cm

H20 Permissive hypercapnia and acidosis

Decreased mortality by 22%
NEJM 2000;342:1301-8.

Mechanisms of Low-Tidal Volume

Lung injury on dependent area ( sparing other regions)

Low Attempt to Tidal Overdistention inflate the of normal lung affected lung volum e
Harrisons Principle of Internal Medicine, 17 th

ARDSnet Tidal Volume Study

NEJM 2000;342:1301-8.

Permissive Hypercapnea
Allowing increased CO2 retention

Decreasing the tidal volume on the ventilator

(usually 8-12 mL/kg) to 4-6 mL/kg Decrease barotrauma by decreasing ventilatory peak airway pressures Leads to improved respiratory recovery respiratory acidosis Hypoxemia is a major life threatening condition and hypercapnia is not, one might choose to accept the latter.
Irwin and Rippe's Intensive Care Medicine (Fifth

Positive End-Expiratory Pressure (PEEP)

Titrate PEEP to decrease FiO2
Goal sat 88% with FiO2 <60% Minimize oxygen toxicity PEEP can improve lung recruitment and decrease

end-expiratory alveolar collapse (and therefore rightto-left shunt) Can also decrease venous return, cause hemodynamic compromise, worsen pulmonary edema
ARDSnet PEEP trial of 549 patients show no

difference in mortality or days on ventilator with high vs low PEEP

NEJM 2004:351(4):327-336

Mechanism of PEEP
Positive endexpiratory pressure
Presence of alveolar and interstitial edema and Loss of surfactant

Marked reduction of lung compliance

Alveolar opening--improving oxygenation

Alveolar collapse

Harrisons Principle of Internal Medicine, 17 th

Mechanism of PEEP
Static pressure-volume curve Lower inflection of the curve alveolar opening Inverse ratio ventilation Inspiratory time > expiratory time Dynamic hyperinflation

Harrisons Principle of Internal Medicine, 17 th

Other Ideas in Ventilator Management

Prone positioning
May be beneficial in certain subgroup, but

complications including pressure sores

RCT of 304 patients showed no mortality benefit

High-frequency oscillatory ventilation

In RCT, improved oxygenation initially, but results not

sustained after 24 hours, no mortality benefit

ECMO
RCT of 40 adults showed no benefit

JAMA 1979;242:2193-6. Am J Respir Crit Care Med. 2002;166:801-8

Complications in Managing ARDS patients

Mechanical ventilation causes:
Overdistention of lungs (volutrauma) usually high

tidal volume
Further damaging epithelium Increased fluid leak, indistinguishable from ARDS damage

Barotrauma Rupture alveolar membranes Pneuomothorax, pneumomediastinum Sheer stress Opening/closing alveoli Inflammatory reaction, cytokine release

Oxygen toxicity
Free radical formation

Oxygen toxicity
Damage the pulmonary epithelium and inactivate the surfactant Intra-alveloar edema and interstitial thickening Fibrosis and pulmonary atelectasis

o100% oxygen - tolerated for about 24 - 48 hours without any serious tissue damage oLonger exposures produce definite tissue injury.

Pulmonary artery catheters

Often used to help evaluate for cardiogenic

pulmonary edema SUPPORT trial (retrospective study) first raised doubts about utility Two multicenter RCTs confirmed lack of mortality benefit of PA catheters in ARDS (ARDSnet FACTT) Monitoring CVP equally effective, so PAC not recommended in routine management

JAMA. 1996;276:889-97. N Engl J Med. 2006:354:2213-24

Drug therapy
Agents studied:
Corticosteroids Ketoconazole Inhaled nitric oxide Surfactant

No benefit demonstrated

Steroids in ARDS
Earlier studies showed no benefit to early use steroids,

but small study in 1990s showed improved oxygenation and possible mortality benefit in late stage ARDSnet trial (Late Steroid Rescue Study LaSRS lazarus) of steroids 7+ days out from onset of ARDS
80 patients enrolled, RCT methylprednisolone vs placebo Overall, no mortality benefit Steroids increased mortality in those with sx >14 days

Currently conducting large-scale study of

glucocorticoids in the late phases of ARDS

JAMA 1998;280:159-65, N Engl J Med 2006;354:1671-84

Steroids in ARDS

N Engl J Med 2006;354:1671-84

Other drugs in ARDS

Ketoconazole ( thromboxane synthase inhibitor)
ARDSnet study of 234 patients, ketoconazole did NOT

decrease mortality, duration of mechanical ventilation or improve lung function

Surfactant
Multicenter trial, 725 patients with sepsis-induced ARDS,

surfactant had no effect on 30-day survival, ICU LOS, duration of mechanical ventilation or physiologic function
Inhaled Nitric oxide
177 patients RCT, improved oxygenation, but no effect on

mortality of duration of mechanical ventilation

N Engl J Med. 1996;334:1417-21. Crit Care Med. 1998;26:15-23.

Fluid Management
Dry lungs are happy lungs
ARDSnet RCT of 1000 patients (FACTT),

Conservative vs liberal fluid strategy using CVP or PAOP monitoring to guide, primary outcome: death. Conservative fluids
Improved oxygenation More ventilator-free days More days outside ICU No increase in shock or dialysis No mortality effects

According to Harrisons...
Normal or low left atrial filling pressure Minimizes pulmonary edema and prevents further decrements in arterial oxygenation and lung compliance Improves pulmonary mechanics Shortens ICU stay and the duration of mechanical ventilation Associated with a lower mortality

ARDSnet Fluid Management

NEJM 2006;354:2564-75.

Harrisons Principle of Internal Medicine, 17 th

Survival and Long Term Sequelae

Traditionally mortality 40-60%
May be improving, as mortality in more recent

studies in range 30-40% Nonetheless survivors report decreased functional status and perceived health 79% of patients remember adverse events in ICU
29.5% with evidence of PTSD

Survival and Long Term Sequelae

Mortality is largely attributable with nonpulmonary

causes Risk factors of mortality

Age > 75 Chronic medical illness Chronic liver disease Liver cirrhosis Chronic renal disease Nonpulmonary organ failure Chronic immunosuppression Sepsis Increased APACHE II score Chronic alcohol abuse
Harrisons Principle of Internal Medicine, 17 th

Survival and Long Term Sequelae

Extent of hypoxemia and other measures of

severity can not predict mortality

Level of PEEP Respiratory compliance Extent of alveolar infiltrates

Lung injury score

Early elevation of dead space ( 24 hour)

predict increase mortality

Harrisons Principle of Internal Medicine, 17 th

1 year after ARDS survival

Lung Function: FEV1 and FVC were normal; DLCO minimally reduced Only 20% had mild abnormalities on CXR Functionally: Survivors perception of health was <70% of normals in:
Physical Role: Extent to which health limits physical activity Physical Functioning: Extent to which health limits work Vitality: Degree of energy patients have

6 minutes walk remained low Only 49% had returned to work

NEJM 2003: 348: 683-693

Future research on ARDS

Improved understanding of disease heterogeneity

through use of evolving biologic, genomic, and genetic approaches should provide major new insights into pathogenesis of ALI. Cellular and molecular methods combined with animal and clinical studies should lead to further progress in the detection and treatment of this complex disease.