ACUTE RESPIRATORY ACUTE RESPIRATORY DISTRESS SYNDROMEDISTRESS SYNDROME

FANER, Ned DenebeFANER, Ned DenebeLACANILAO, SunshineLACANILAO, Sunshine

PAGADUAN, MaribecPAGADUAN, MaribecPUA, MonalisaPUA, Monalisa

NUCUM, Billie KimNUCUM, Billie Kim

B.V., 63 Years oldB.V., 63 Years old

Chief Complaint: Difficulty of breathingChief Complaint: Difficulty of breathingDiagnosis: ARDS 2° to Pneumonia, Septic Diagnosis: ARDS 2° to Pneumonia, Septic

ShockShock

HistoryHistory

- Known Hypertensive for 28 years and is - Known Hypertensive for 28 years and is maintained on Metoprolol 50mg.maintained on Metoprolol 50mg.

- In 2004, patient has been hospitalized - In 2004, patient has been hospitalized due to PTB. due to PTB. 2 weeks PTA: 2 weeks PTA:

mild episodes of dizzinessmild episodes of dizziness BP was elevated to 150/100BP was elevated to 150/100

2 days PTA:2 days PTA: Productive cough with whitish Productive cough with whitish

sputumsputum Carbocisteine provided minimal reliefCarbocisteine provided minimal relief Weakness after walking 2 blocksWeakness after walking 2 blocks

Few hours PTA: Symptoms persistedFew hours PTA: Symptoms persistedUpon Admission: conscious, coherent but Upon Admission: conscious, coherent but

in respiratory distress.in respiratory distress.

Physical Assessment: Physical Assessment: (+) subcostal retractions, (+) crackles (+) subcostal retractions, (+) crackles

at both lung fieldsat both lung fields VS: BP – 140/80 mmHg, HR – 140 VS: BP – 140/80 mmHg, HR – 140

bpm, RR: 42, Temp: 36.6 °Cbpm, RR: 42, Temp: 36.6 °C

Hooked to mechanical Hooked to mechanical ventilator, cardiac monitor ventilator, cardiac monitor and pulse oximeter. and pulse oximeter.

CXR showed confluence of CXR showed confluence of densities, R lower and densities, R lower and upper lung fields, L middle upper lung fields, L middle and upper lungsand upper lungs

Furosemide dripFurosemide dripMetabolic Acidosis - Metabolic Acidosis -

NaHCO3NaHCO3

Tachycardia at 150s – Tachycardia at 150s – 160s – Digoxin 0.5mg/IV 160s – Digoxin 0.5mg/IV

Runs of AfibRuns of AfibHooked to Amiodarone Hooked to Amiodarone

dripdripABG revealed hypoxemiaABG revealed hypoxemiaHypotensive episodes Hypotensive episodes

70/40, Urine output – 70/40, Urine output – inadequateinadequate

Dopamine and Dopamine and dobutamine drip starteddobutamine drip started

A clinical syndrome of severe dyspnea of rapid onset, hypoxemia, and diffuse pulmonary infiltrates leading to respiratory failure.

Acute Respiratory Distress Syndrome (ARDS) is also known as shock lung, wet lung, post perfusion lung and a variety of other names related to specific causes.

According to the American Lung Association, the incidence of ARDS ranges from 2 to 71 per 100,000 persons in the United States.

Clinical Disorders Commonly Associated with Clinical Disorders Commonly Associated with ARDS according to HARRISONARDS according to HARRISON

Direct Lung InjuryDirect Lung Injury Indirect Lung InjuryIndirect Lung InjuryPneumoniaPneumonia Sepsis Sepsis

Aspiration of gastric Aspiration of gastric contentscontents

Severe traumaSevere trauma

Pulmonary contusionPulmonary contusion   Multiple bone fracturesMultiple bone fracturesNear-drowningNear-drowning   Flail chestFlail chest

Toxic inhalation injuryToxic inhalation injury   Head traumaHead trauma     BurnsBurns   Multiple transfusionsMultiple transfusions   Drug overdoseDrug overdose   Pancreatitis Pancreatitis    Post-cardiopulmonary Post-cardiopulmonary

bypass bypass

• Type II pneumocyte– proliferate– differentiate into Type I cells– reline alveolar walls

• Characterized by:– local fibrosis– resolution

ANATOMY and PHYSIOLOGY

The Alveoli

Found at the end of the terminal bronchioles, the smallest subdivisions of the bronchial tree, these are clusters of tiny air sacs in which most gas exchange takes place.

The wall of each alveolus is made of a single-cell layer of squamous (flat) epithelium.

This thin wall provides easy passage for the gases entering and leaving the blood as the blood circulates through the millions of tiny capillaries covering the alveoli.

bronchiole

alveoli

The Alveolar Epithelium

Type I alveolar cells (pneumocytes) - extremely thin squamous cells that line about 95% of the alveolar surface area.

responsible for the gas (oxygen and carbon dioxide) exchange that takes place in the alveoli. It is a very large thin cell stretched over a very large area

Type II alveolar cells (pneumocytes) or septal cells - cuboidal cells cover about

5% of the alveolar air surface

-responsible for the production and secretion of surfactant

-can replicate in the alveoli and will replicate to replace damaged type 1 pneumocytes.

Surfactant-Produced by Alveolar Type II cells

Functions1.Lowers surface tension & provide alveolar stability2.Prevents alveolar flooding3.Maintains patency & stabilization of small airways4.Plays an important role in host defense

Critical components :1.Dipalmitoylphosphatidylcholine2.Surfactant Proteins

a. SP-Ab. SP-Bc. SP-Cd. SP-D

Metabolic trafficking of surfactant phospholipids

Surfactant secretingcell

Respiratory Membrane (Air-Blood Barrier)

Thin squamous epithelial layer lining alveolar walls

Pulmonary capillaries cover external surfaces of alveoli

Respiratory Membrane (Air-Blood Barrier)

Figure 13.6

4 layers:a layer of type 1 and 2

alveolr cells and associated alveolar macrophage= alveolar wall

Epithelial basement membrane underlying the alveolar wall

Capillary basement membrane

Endothelial cells of the capillary

Respiratory membrane thickness

Increasing the thickness of the respiratory membrane decreases the rate of diffusion.

In healthy lungs, the respiratory membrane (alveolar membrane + endothelial membrane + fused basement membranes) is 0.5-1.0um thick, but the thickness can be increased by respiratory diseases.

Surface Area

The total surface area of the respiratory membrane is approximately 70 m2

(approximately the area of one half of a tennis court) in the normal adult.

When the total surface area of the respiratory membrane is decreased to one third or one fourth of normal, the exchange of gases is significantly restricted even under resting conditions.

Partial Pressure Differencedifference between the partial pressure of the gas in the

alveoli and the partial pressure of the gas in the blood of the alveolar capillaries.

When the partial pressure of a gas is greater on one side of the respiratory membrane than on the other side, net diffusion occurs from the higher to the lower pressure.

Normally the partial pressure of oxygen (P02) is greater in the alveoli than in the blood of the alveolar capillaries, and the partial pres sure of carbon dioxide (Pco2) is greater in the blood than in the alveolar air.

Partial Pressure Difference

The partial pressure difference for oxygen and carbon dioxide can be increased by increasing the alveolar ventilation rate. The greater volume of atmospheric air exchanged with the residual volume raises alveolar Po2, lowers alveolar Pco2, and thus promotes gas exchange.

Conversely, inadequate ven tilation causes a lower-than-normal partial pressure difference for oxygen and carbon dioxide, resulting in inadequate gas exchange.

Events of Respiration

Pulmonary ventilation – moving air in and out of the lungs

External respiration – gas exchange between pulmonary blood and alveoli

Events of Respiration

Respiratory gas transport – transport of oxygen and carbon dioxide via the bloodstream

Internal respiration – gas exchange between blood and tissue cells in systemic capillaries

Mechanics of Breathing (Pulmonary Ventilation)

Completely mechanical processDepends on volume changes in the

thoracic cavityVolume changes lead to pressure

changes, which lead to the flow of gases to equalize pressure

Inspiration

Figure 13.7a

Expiration

Figure 13.7b

Pressure Differences in the Thoracic Cavity

Normal pressure within the pleural space is always negative (intrapleural pressure)

Differences in lung and pleural space pressures keep lungs from collapsing

Boyle’s Law

Pressure Changes in Pulmonary Ventilation

Other Factors affecting Pulmonary Ventilation:Surface tension of alveolar fluid

Compliance of lungs

Airway resistance

Transport of Oxygen

2 FORMS of TRANSPORT

1.Small amount dissolves in plasma

2.Binds to hemoglobin

capillaries

Alveolus (air sac)

Capillary bedin tissue

O2 CO2

Capillary

Capillary Wall

Alveolar Wall

Alveolus

O2 Concentration high

O2 Concentration high

CO2 Concentration high

CO2 Concentration high

Capillary

Capillary Wall

Interstitial Fluid

Body Cellscells

A

B

Erythrocyte

Diffusion across ALVEOLOCAPILLARY MEMBRANE

Diffusion occurs:

• Large surface area and very thin membrane

• partial pressure of O2 is greater in alveolar gas than in capillary blood

↑P area → ↓ P area

Determinants of arterial oxygenation

Partial Pressure of O2

- pressure exerts by O2 dissolved in plasma

- as PaO2 increases oxygen moves from plasma to bind with hemoglobin

- continues to bind until hemoglobin binding sites are saturated

Oxygen saturation - percentage of available hemoglobin

that is bound to oxygen

Hemoglobin concentration- amount of hemoglobin available for

binding- as amount of hemoglobin decreases,

O2 content also decreases

Oxyhemoglobin association and dissociation

hemoglobin binds with O2 (lungs) –

OXYHEMOGLOBIN hemoglobin released O2 (tissues) –

HEMOGLOBIN DESATURATION

BOHR Effect – shift in the oxyhemoglobin dissociation curve caused by changes in CO2 and H ion concentrations in the blood.

↑CO2 → ↓O2 affinity

↓CO2→ ↑O2 affinity

4 steps transport of oxygen

1. Ventilation of the lungs

2. Diffusion of O2 from the alveoli into the capillary blood

3. Perfusion of systemic capillaries into the cells

4. Diffusion of CO2 form the cells into systemic capillaries

Transport of carbon dioxide

3 forms of transport:

1.Dissolves in plasma

2.Bicarbonate

3.Carbamino compound

CO2 + H2O carbonic acid H + (RBC)

(Hgb)

HCO3

(plasma)

carbonic anhydrase

↓ O2 in hgb = ↑ CO2 binds in hgb

↑O2 in hgb = ↓ CO2 binds in hgb

HALDANE EFFECTS

4 steps in transport of carbon dioxide

1. Diffusion of carbon dioxide from the cells into the systemic capillaries

2. Perfusion of the pulmonary capillary bed by venous blood

3. Diffusion of carbon dioxide into alveoli

4. Removal of carbon dioxide from lung by ventilation

LABORATORY AND LABORATORY AND DIAGNOSTIC EXAMSDIAGNOSTIC EXAMS

BY: FANER, NED DENEBE V. RNBY: FANER, NED DENEBE V. RN

Complete Blood CountComplete Blood Count

11/ 14/ 08 11/ 16/ 08 11/ 19/ 08Hgb 143 119 ↓ 107 ↓Hct 0.43 ↓ 0.36 ↓ 0.32 ↓Rbc 6.12 5.20 4.65Platelet 298 282 244Wbc 35.20 ↑ 20.40 ↑ 24.00 ↑Segmenters 0.83 0.93 0.93Lymph 6.09 0.07 0.04

↓ ↓ Hct level and Hgb - ↓O2 in bloodHct level and Hgb - ↓O2 in blood ↑↑RBC – compensate ↓O2 in bloodRBC – compensate ↓O2 in blood ↑ ↑ WBC – cause by infection , inflammatory responseWBC – cause by infection , inflammatory response

Chest X-rayChest X-ray

Normal Chest X-ray Patient with ARDSPatchy infiltrates

Chest X-rayChest X-ray11/ 14/ 08 11/ 14/ 08 11/ 16/ 08 11/ 19/ 08Haziness on both lung fields, confluence of densities mostly on right lower and upper lung fields, left middle and part of upper lung fields

Confluent densities appreaciated on both perihilar and basal regions. Heart is enlarged. Cvp line is in place.

Clearing of previously noted bilateral densities. Heart remains enlarged.Aorta is atheromatous.

There is progression of alveolar infiltrates.Cardiomegaly is present.

Arterial Blood GasesArterial Blood Gases11/14 11/15 11/15 11/16 11/17 11/18 11/19 11/20 11/21

pH 7.16 ↓ 7.145 ↓ 7.27 ↓ 7.358 7.373 7.421 7.390 7.420 7.51

pCO2 38.1 39 36.7 26.4 ↓ 35.7 39.6 44.5 48.6 ↑ 42.5

pO2 74.0↓ 38.4↓ 56.8↓ 152.7 108.0 261.0 116.9 192.4 123.5

HCO3 13.7↓ 13.2↓ 16.5↓ 14.5↓ 20.4↓ 25.3 26.3 31.1↑ 33.8↑

O2 sat 90.8% 61.5%↓ 85.8%↓ 98.9% 97.9% 99.6% 98.2% 99.3% 98.8%

dFiO2 104.8 186.82 146 51 73.7 22.9 51 29.69 41.19

Arterial Blood GasArterial Blood Gas

11/14 Uncompensated Metabolic Acidosis

11/15 Uncompensated Metabolic Acidosis

11/15 Uncompensated Metabolic Acidosis

11/16 Compensated Respiratory AlkalosisCompensated Metabolic Acidosis

11/17 Compensated Metabolic Acidosis

11/18 -

11/19 -

11/20 Compensated Respiratory AcidosisCompensated Metabolic Alkalosis

11/21 Compensated Metabolic Alkalosis

METABOLIC ACIDOSIS RESPIRATORY ALKALOSIS

SIGNS AND SYMPTOMS Headache Lethargy Coma Kussmaul’s breathing Nausea and vomiting Diarrhea Abdominal discomfort

SIGN AND SYMPTOMSDizzinessConfusionTingling sensationConvulsions

Oxygen toxicity

Pure oxygen is being breathe in and no nitrogen gas is present – maintainance of alveolar expansion is loss leading to alveolar collapse.

Oxygen has toxic effects on Type II pneumocytes cells that produce surfactant. Inadequate production of surfactant leads to alveolar collapse and further fluid shifts from capillaries to alveolar sacs, aggravating the patient condition.

Arterial Blood GasArterial Blood Gas

↓↓O2 → hyperventilation → ↓CO2 = O2 → hyperventilation → ↓CO2 =

RESPIRATORY ALKALOSISRESPIRATORY ALKALOSIS

↓↓BP and ↓O2 → lactic acid production BP and ↓O2 → lactic acid production → bicarbonate binds to acids → ↑ loss → bicarbonate binds to acids → ↑ loss of bicarbonate =of bicarbonate =

METABOLIC ACIDOSISMETABOLIC ACIDOSIS

ACUTE ACUTE RESPIRATORYRESPIRATORY

DISTRESS DISTRESS SYNDROMESYNDROME

Sepsis

Alveolar damage

Damage to type II pneumocytes

↓ surfactant production

atelectasis

Regeneration of the alveolar membrane with

thick epithelial cells

Eventual scarring and loss of functional lung

tissue

Endothelial damage

Platelet aggregation

Severe organ dysfunction

Fluid and protein move into the

alveoli

↓ SVR

Pulmonary edema↓ blood volume

V/Q mismatchR-L shunting

↓ venous return

ischemia

↓ CO

Diffuse alveolar infiltrates, crackles, cough

↓ tissue perfusion

Severe dyspnea,Hypoxemia unresponsive to O2

↓ BP

Release of mediators

Attract / activate neutrophils

Inc permeabilityInc alveolar

permeability

Inc vascular permeability

Cellular hypoxia

Metabolic acidosis

TachypneaDOBretractions

Compensatory mechanismsTachycardiaAF

ACUTE RESPIRATORY FAILURE

Unmet myocardial demands

Clinical lung injury

Myocardial depression

↓ renal perfusion

↓ UOInc creatinine

↓ cerebral tissue perfusion

↓ LOC

Impaired lung compliance

MV w/ PEEP

antibiotics

pressors

diuretics

Digoxin, amiodarone

death

Nursing ProblemsNursing Problems

A.A. Ineffective Breathing PatternIneffective Breathing Pattern

1. Dyspnea1. Dyspnea

2. Crackles2. Crackles

3. Cough3. Cough

Nursing ProblemsNursing Problems

B. Impaired Gas ExchangeB. Impaired Gas Exchange

1. Hypoxemia1. Hypoxemia

2. Dizziness2. Dizziness

Nursing ProblemsNursing Problems

c. Decreased Tissue Perfusionc. Decreased Tissue Perfusion

1. Decreased urinary output1. Decreased urinary output

2. Hypotension2. Hypotension

Roger G. Spragg, M.D., James F. Lewis, M.D., Hans-Dieter Walmrath, M.D.,Jay Johannigman, M.D., Geoff Bellingan, M.D., Pierre-Francois Laterre, M.D.,

Michael C. Witte, M.D., Guy A. Richards, M.D., Gerd Rippin, Ph.D.,Frank Rathgeb, M.D., Dietrich Häfner, M.D., Friedemann J.H. Taut, M.D.,

and Werner Seeger, M.D.

N Engl J Med 2004;351:884-92.Copyright © 2004 Massachusetts Medical Society.

Optimal Ventilator Settings in Acute Lung Injury and Acute

Respiratory Distress Syndrome

M. Yilmaz, O. GajicMayo Clinic College of Medicine, Division of Pulmonary and

Critical Care Medicine, Rochester MN, USAAkdeniz University, Medical Faculty, Development of Anesthesiology and Intensive Care, Antalya, Turkey

November 16, 2007

Overdistention injury induced by High Vt ventilation has been identified as the single most important determinant of VILI

Ventilation at low lung volumes in the absence of PEEP may lead to lung injury caused by repetitive collapse and reopening of the alveolar units

Better understanding of the pathophysiology of ALI/ARDS and the role of VILI prompted the use of smaller Vt with lower inspiratory pressures and a moderate amount of PEEP to prevent respiratory collapse=Lung protective ventilation strategy

Strategy: Low Vt mechanical ventilation in patients with ARDS

1990 RTC: Conventional vs Lung protective approach

Villar, et al

Result: The incidece of barotrauma, mortality has decreased significantly in the lung protective group

The threshold of Vt of <7.7 ml Kg PBW and Ppl < 30 mmHg to be associated with improved outocmes.

USE OF PEEPUSE OF PEEP

help achieve adequate oxygenation and decrease the requirement for high fractions of inspired oxygen.

Three mechanisms have been proposed to explain the improvement in gas exchange with PEEP:

(1) Alveolar recruitment with increased functional residual capacity(2) Redistribution of extravascular lung water(3) Improved ventilation-perfusion matching.

Computed tomography studies demonstrated PEEP induced recruitment of previously collapsed alveoli and that lung regions recruited with PEEP may not completely collapse at end-expiration . This in turn leads to more even distribution of airway pressures within the lung parenchyma.

USE OF PEEPUSE OF PEEP

In conclusion, in patients with ALI/ARDS lung protectiveventilation strategies yield better clinical outcomes compared to traditional approaches in which more generous tidal volumes are used. Limiting Vt to ^6-8 mLkg ' PBW, with further reductions of Vt if the Ppl is high (>30cmH2O) has been shown to improve outcomes and should be considered as a standard of care for the majority of patients with ALI/ARDS.

Recent Developments in the Management of Acute

Respiratory Distress Syndrome in Adults

Heather R. Bream-Rouwenhorst, Elizabeth A. Beltz, Mary B. Ross, and Kevin G. Moores

Corticosteroids*ameliorate the cytokine- and toxic-mediator release associated with ARDS*benefit would be greatest in the initial exudative phase of ARDS when neutrophils begin to invade the pulmonary epithelium* have not demonstrated clear benefit in patients with ARDS. Some trials have found increased complications and mortality related to corticosteroid use

High-dosage, short-course regimens.*Two meta-analyses (1990s)=no benefit with high-dosage, short-course administration of corticosteroids in patients who had various stages of ARDS*Therefore, the current standard of practice is to avoid these regimens.

Research: Methylprednisolone versus placebo at day 7 of ARDS*Intravenous methylprednisolone was dosed as 2 mg/kg once, 2 mg/kg/day on days1–14, 1 mg/kg/day on days 15–21, 0.5 mg/kg/day on days 22–28, 0.25 mg/kg/day on days 29 and 30, and 0.125 mg/kg/day on days 31 and 32.

Result: at day 10, 7 patients receiving methylprednisolone were extubated,compared with 0 patients in the placebo group. Inhospital mortalityrates were 12% in patients treated with methylprednisolone and 62% in those receiving placebo

Moderate-dosage, tapering regimens.

Late administration of corticosteroids.

*mortality rates were higher with methylprednisolone at day 60 (35% versus 8%, p =0.02) and at day 180 (44% versus 12%, p = 0.01)*Mortality was not significantly higher in the group receiving methylprednisolone whose ARDS was present for 7–13 days at the time of study enrollment. *Hence, initiating corticosteroids more than two weeks after the onset of ARDS may actually increase mortality

*Patients who survived 14 days of ARDS may have had less active fibroproliferation and hence a lesser response to corticosteroids.

SUMMARYCorticosteroids should be started early in the course of ARDS (before day14), at moderate dosages (i.v. methylprednisolone <2 mg/kg/day), and tapered over three to four weeks. Initiation of corticosteroid therapy on day 14 or later in patients with ARDS should be discouraged due to the increased mortality rates found

Pharmacological Therapy for Acute Respiratory

Distress Syndrome

Raksha Jain, MD and Anthony DalNogare, MDMayo Clinic ProcFebruary 2006

Vasodilators1.Inhaled Nitric Oxide

relaxes pulmonary vascular smooth muscle and thus has important regulatory effects on regional lung ventilation and perfusion ratios

Although endogenous nitric oxide, produced from nitric oxide synthase,impairs gas exchange during ARDS, exogenous inhaled nitric oxide relaxes vascular smooth muscle that supplies ventilated alveoli and thus may improve ventilation-to-perfusion relationships.

In 1993, Rossaint et al: inhaled nitric oxide reduced pulmonary artery pressuresand increased arterial oxygenation without producing systemic vasodilation.

Other studies showed: adverse effects of methohemoglobinemia, production of toxic compounds such as nitrogen dioxide and peroxynitrate ion, increased pulmonary edema, and rebound pulmonary hypertension. Other studies showed increased mortality with infants treated with NO. Other studies showed no oerall survival benefit

Fig. 1. A. Schematic of vasoconstriction of pulmonary bed with normal and atelectatic alveoli. B. Nitroprusside (NTP) causes non-selective vasodilation of all pulmonary arteries, which may worsen ventilation-perfusion (V/Q) matching. C. Inhaled nitric oxide (NO) dilates only ventilated alveoli, an outcome that improves V/Q matching. (From Lunn R: Subspecialty clinics: Anesthesiology; Inhaled nitric oxide therapy. (Mayo Clin Proc 1995; 70:247-255; with permission.)

Decreased Alveolar Surface Tension1.Surfactant

Lowers surface tension and prevents alveolar collase

1 study showed: a decrease in Fio2 requirement

RTC on 448 adult ARDS patients who received recombinant protein C-based surfactant showed improved gas exchange and oxygenation, but no difference occurred in the number of ventilator-free days or 28-day mortality

References:Books1.McCance. Pathohysiology: The Biologic Basis for Disease in Adults & Children, 5th ed., 2006. Mosby2.Fauci et. Al.. Harrison’s Principles of Internal Medicine, 17th ed., 2008. McGraw Hill.3.Bullock. Pathophysiology: Adaptations & Alterations in Function, 4th ed., 1996. Lippincott.4.Apostalakos & Papadalos. The Intensive Care Manual, 2001. McGraw Hill5.Rumrakhd & Moore. Oxford Handbook of Acute Medicine, 2nd ed. 2004. Oxford University Press.6. Murray & Nadel's Textbook of Respiratory Medicine, 4th ed., 2005 Saunders, An Imprint of Elsevier7. Mayo Clinic Internal Medicine: Concise Textbook, edited by Thomas M. Habermann, Amit K. Ghosh., 2008©

For Bibliography:1. “Recent developments in the management of acute respiratory distress syndrome in adults”, by Heather R. Bream-Rouwenhorst et. al, American Journal of Health System Pharmacy Vol. 65 Jan 1, 2008

2. “Optimal ventilator setting in acute lung injury and acute respiratory distress syndrome”, by M. Ylmaz and O. Gajic, European Journal of Anesthesiology 2008: 25: 89-96, 2007 ©

3. “Prone position in Acute Respiratory Distress Syndrome”, P. Pelosi, L. Brazzi and L. Gattinoni, European Respiratory Journal, 2002: 20: 1017 – 1028, 2002 ©

4. “Effect of Recombinant surfactant protein c-Based Surfactant on the Acute Respiratory Distress Syndrome”, Roger G. Spragg et. al The New England Journal of Medicine, 2004: 351:884- 92, 2004 ©

5. “Surfactant alteration and replacement in acute respiratory distress syndrome”, Andreas Gunther et. al., Respiratory Research Vol.2 No.6, Oct 2001