Adult Respiratory Distress Syndrome

Mazen Kherallah, MD, FCCP

The Inexact Definition for ARDS

• Contributes to difficulty in management• ARDS and ALI consensus statement definitions

– Acute onset (not specified)

– Po2/FiO2 ratio <200 (300 for ALI)

– Bilateral infiltrates on chest radiograph (highly variable)

– PAWP<18 mm Hg or absence of clinical evidence of volume overload

Bernard GR et al, Am J Resp Crit Care Med. 1994;149:818-824

The Nature of Acute Lung Injury

Pulmonary eventsInfectionBleeding

Aspiration

Extrapulmonary eventsSepsis

PancreatitisTrauma

Intestinal ischemia and reperfusion

Acute Inflammatory Response in the Lung

Physiologic cascades may be different and responses to different therapies

Mediators of the Acute Inflammatory Process

• Bacterial products

• Reactive oxygen intermediates

• Proinflammatory cytokines (high mobility group protein 1)

• Activated neutrophils, macrophages, epithelium, endothelium, and platelets.

• Complements

Mechanisms of the Acute Inflammatory Process

• Activation of transcriptional factors

• Initiation of proinflammatory cytokine cascades

• Activation of coagulation cascades

• Activation of pulmonary cell population

Decline in ARDS Fatality Rate

0

10

20

30

40

50

60

70

80

83 84 85 86 87 88 89 90 91 92 93 94 95 96

Years

Mor

talit

y 9%

)

Causes of Mortality in ARDS

1990

36%

22%

15%

6%

4%

6%

11%

Sepsis/MOFCNSRespiratoryCardiovascularHepaticGIOthers

Arterial Oxygenation and Outcome in ARDS

Oxygenation Outcome

Arterial |Oxygenation and Outcome in ARDS

Oxygenation Outcome

Management of ARDS

• Does it really make a difference whether the arterial PO2 is 50 or 100

Management ARDS: Traditional Goals for Gas Exchange

• Normal PaO2 (maximize PaO2/FiO2)

• Normal PaCO2 and pH

Changes in ARDS Management in the 1990’s

• Lower tidal volumes

• Lower alveolar pressures

• Acceptance of hypercapnia

• Acceptance of acidosis

Multicenter study of effectiveness of two Tidal Volumes for Ventilation

ARDS network study• Prospective, randomized, multicenter study to compare

the effectiveness of 2 tidal volumes in patients with ALI and ARDS- 12 ml/kg and 6 ml/kg– 429 subjects randomized to 12 ml/kg of ideal body weight– Airway plateau pressure < 50 cm H2O

– 432 subjects randomized to 6 ml/kg of ideal body weight– Airway plateau pressure < 30 cm H2O

NIH ARDS Network TrialMechanical Ventilation in ARDS

20

30

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50

60

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90

100

110

0 10 20 30 40 50 60 70 80 90 100

Time after onset of ARDS

Sur

viva

ls

( % )

Vt=6 Vt=12

31% mortality40% mortality

NIH ARDS Network TrialMechanical Ventilation in ARDS

0

5

10

15

20

25

30

35

40

45

6 ml/kg 12 ml/kg

Mor

tali

ty

( % )P = 0.0054

Median # Ventilator-Free Days

0

2

4

6

8

10

12

14

6 ml/kg 12 ml/kg

ARDSnet

PaO2/FiO2

120

130

140

150

160

170

180

190

200

0 1 2 3 4

12 ml/lg6 ml/kg

INITIAL VENTILATOR TIDAL VOLUME AND RATE ADJUSTMENTS

A.Calculate predicted body weight (PBW) •Male= 50 + 2.3 [height (inches) - 60] or 50 + 0.91 [height (cm) - 152.4] •Female= 45.5 + 2.3 [height (inches) - 60] or 45.5 + 0.91 [height (cm) - 152.4]

B.Mode: Volume Assist-Control 1.Set initial tidal volume to 8 ml/kg PBW 2.Reduce tidal volume to 7 ml/kg after 1-2 hours and then to 6 ml/kg PBW after 1-2 hours 3.Set initial ventilator rate to maintain baseline minute ventilation (not > 35 bpm)

 

SUBSEQUENT TIDAL VOLUME ADJUSTMENTS

Plateau Pressure Goal: 30 cmH2O

Check inspiratory plateau pressure (Pplat) with 0.5 second inspiratory pause at least every four hours and after each change in PEEP or tidal volume.

•If Pplat > 30 cmH2O, decrease tidal volume by 1 ml/kg PBW

steps to 5 or if necessary to 4 ml/kg PBW. •If Pplat < 25 cmH2O and tidal volume < 6 ml/kg, increase tidal

volume by 1 ml/kg PBW until Pplat > 25 cmH2O or tidal

volume = 6 ml/kg. •If breath stacking or severe dyspnea occurs, tidal volume may be increased (not required) to 7 or 8 ml/kg PBW if Pplat remains 30 cmH2O.

 

ARTERIAL OXYGENATION

FiO2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1.0

PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 20-24

GOAL: PaO2 55-80 mm Hg or SpO2 88-95%

Use these FiO2/PEEP combinations to achieve oxygenation goal.

RESPIRATORY RATE (RR) AND ARTERIAL pHARTERIAL pH GOAL: 7.30-7.45

A.Acidosis Management: •If pH 7.15-7.30:

•Increase set RR until pH > 7.30 or PaCO2 < 25

(Maximum Set RR =35) •If set RR = 35 and pH < 7.30, NaHCO3 may be given (not

required) •If pH < 7.15:

•Increase set RR to 35. •If set RR = 35 and pH < 7.15 and NaHCO3 has been

considered, tidal volume may be increased in 1 ml/kg PBW steps until pH > 7.15 (Pplat target may be exceeded).

B.Alkalosis Management: (pH > 7.45): •Decrease set RR until patient RR > set RR.

•Minimum set RR = 6/min.

I:E RATIO

GOAL: 1:1.0 - 1:3.0•Adjust flow rate and inspiratory flow wave-form to achieve goal.

WEANING

1.Conduct A CPAP trial daily when: a.1. FiO2 0.40 and PEEP 8, and

b.PEEP and FiO2 values of previous day, and

c.Patient has spontaneous breathing efforts (may decrease vent set rate by 50% for 5 minutes to detect effort), and d.Systolic BP 90 mm Hg without vasopressor support.

Conducting the CPAP Trial:Set: CPAP = 5 cmH2O, FiO2 = 0.50.

If patient RR 35 for 5 min., advance to Pressure Support Weaning (Section VI.B) If patient RR > 35, return to previous A/C settings and reassess for weaning next morning.

Pressure Support (PS) Weaning Procedure a.Set PEEP = 5 and FiO2 = 0.50

b.Set initial PS based on RR during CPAP trial: i.If CPAP RR < 25: set PS = 5 cmH2O and go to steps 3c-d.

ii.If CPAP RR = 25-35: set PS = 20 cmH2O, then reduce by 5 cmH2O at

5 min. intervals until patient RR = 26-35, then go to step c-i. iii.If initial PS not tolerated: return to previous A/C settings.

c.REDUCING PS: (No reductions made after 1700 hrs) i.Reduce PS by 5 cmH2O q 1-3 hr.

ii.If PS 10 cmH2O not tolerated, return to previous A/C settings (If

VI.A Criteria O.K., resume last tolerated PS level next morning and go to step c-i). iii.If PS = 5 cmH2O not tolerated, go to PS = 10 cmH2O. If tolerated, PS

of 5 or 10 cmH2O may be used overnight with further attempts at

weaning the next morning. iv.If PS = 5 cmH2O tolerated for 2 hours, assess for ability to sustain

unassisted breathing.

UNASSISTED BREATHING TRIAL

a.Place on T-piece, trach collar, or CPAP < 5 cmH2O

b.Assess for tolerance as below for two hours. c.If tolerated, consider extubation. d.If not tolerated, resume PS 5 cmH2O

Definition of Weaning Intolerance

1.RR > 35 (may exceed 35 5 minutes), and 2.SpO2 < 88% (< 5 minutes at < 88% may be tolerated), and

3.Respiratory distress ( 2 of the following): •Pulse > 120% of rate at 6 A.M. > 5 minutes •Marked use of accessory muscles •Abdominal paradox •Diaphoresis •Marked complaint of dyspnea

Definition of Unassisted Breathing Intolerance

1.RR > 35 2.SpO2 < 90 % and/or PaO2 < 60 mm Hg, and

3.Spontaneous tidal volume < 4 ml/kg PBW, and 4.Respiratory distress (any two of the following):

•Pulse > 120% of usual rate for > 5 minutes •Marked use of accessory muscles •Abdominal paradox •Diaphoresis •Marked complaints of dyspnea

High-Frequency Ventilation:

• Very small tidal volume and very high respiratory rate

• Achieves lung protective objectives• Results of large randomized controlled trial

of HFV in adults with ARDS were disappointing ( was not designed to avoid atelectasis and end-expiration)¤

• More studies are needed

¤Carlon GC et al. Chest. 1983;84:551-559

Tracheal Gas Insufflation:

• Physiological dead space is elevated in ARDS patients, and small tidal volume ventilation frequently causes hypercapnia and acute acidosis

• Without TGI, the bronchi and trachea are filled with CO2-laden gas which is forced back into the alveoli during the next inspiration

• TGI provides a stream of fresh gas which is insufflated into the trachea and thus reduces dead space

• It may cause desiccation of secretion and increased auto-PEEP

Inverse-Ratio Ventilation

• IRV causes shunt reduction and improved arterial oxygenation

• Short exhalation time may cause increased auto-PEEP which may account for the improved oxygenation

• Many patients require heavy sedation and paralysis

Prone Positioning

• Improves ventilation to previously dependent regions of the lung

• Leads to substantial improvement in oxygenation in 65% of ARDS patients

• Prevents ventilator-associated lung injury by promoting more uniform distribution of tidal volume and by recruiting dorsal lung regions

• Clinical outcome did not improve in ARDS patients randomized to prone positioning for at least 6h/d vs patients randomized to remain supine*

*Gattinoni L et al. Lancet 1997;350:815

Nutrition High-Fat, Low-Carbohydrate Diet

• Reduces the duration of ventilation in patients receiving mechanical ventilation

• Reduces the respiratory quotient and the level of carbon dioxide

• Al-Saady NM, et al. Intensive Care Med. 1989;15:290-295

Nutrition Immunomodulatory Nutrients

• Amino acids such as arginine and glutamine, ribonucleotides, and omega-3 fatty acids.

• Meta Analysis: decrease in infectious complications and duration of hospital stay

• Hays SD. Ann Surg 1999;229:467-477

Nitric Oxide

• Vasodilatory effects are restricted to the blood vessels at the site of generation or administration since it is rapidly inactivated

• NO inhalation dilates pulmonary vessels perfusing aerated lung units, diverting blood flow from poorly ventilated or shunt regions

• Potential treatment for pulmonary hypertension and severe hypoxemia in ARDS

Nitric Oxide

• Prospective, multicenter, randomized, double-blind, placebo-controlled trial on inhaled nitric oxide in ARDS

• 208 patients• Payen D et al. Intensive Care Med 1999;25:s166• No effect on mortality or the duration of

mechanical ventilation• There may be a role for NO in some ALI/ARDS

patients with severe refractory hypoxemia and pulmonary arterial hypertension

Surfactant Replacement Therapy

• Multicenter, randomized, placebo-controlled trial in 725 patients with sepsis-induced ARDS

• Artificial protein-free surfactant given by aerosol did not affect arterial oxygenation, duration of mechanical ventilation, or survival

Anzueto A et al: N Eng J Med 334:1417-1421, 1996

Extracorporeal Gas Exchange • Prospective, multicenter, randomized trial was

conducted to compare ECMO to conventional ventilation alone, mortality in both groups of patients was approximately 90%(1).

• Prospective, randomized trial compared clinical outcomes in 40 patients with severe ARDS who received either conventional mechanical ventilation or LFPPV with ECco2R. No significant difference in mortality between the two treatment groups(2).

(1)Zapol WM et al. JAMA 1979;242:2193-2196(2)Morris AH et al. Am J Respir Crit Care Med 1994; 149:295-305

Fluorocarbon Liquid-Assisted Gas Exchange

• Fluorocarbon liquids can dissolve 17 times more oxygen than water, have low surface tension, and spread quickly over the respiratory epithelium. They are nontoxic, minimally absorbed, and eliminated by evaporation.

• Reduced tension improves alveolar recruitment, arterial oxygenation, and increase lung compliance.

• Partial liquid ventilation: lungs are filled to functional residual capacity and gas ventilation is done through conventional ventilation.

• Trials are needed before adoptation.

Anti-inflammatory Strategies

• Glucocorticoid therapy

• Antioxidant therapy

• Prostaglandin E1

• Lisofylline and pentoxyfilline

• Anti IL-8 therapy

Corticosteroid Therapy in the Proliferative Phase of ARDS

• 24 patients, 16 in the methylprednisolone arm and 8 in the placebo arm, Significant changes were observed for PaO2/FIO2 ratio (262 vs 148, p <0.001), LIS (1.7 vs 3.0, p <0.001), mean pulmonary artery pressure (22.5 vs 30.0 mm Hg, p = 0.01), and multiple-organ dysfunction syndrome score (0.7 vs 1.8, p <0.001) in the corticosteroid-treated group vs the placebo group, respectively. ICU survival was 100% (16 of 16) in the steroid group vs 37% (3 of 8) in the placebo group (p = 0.002), while overall survival was 87% (14 of 16) vs 37% (3 of 8), respectively (p = 0.03).

1)       Meduri GU, Headley S, Golden E, et al. JAMA 1998; 280:159-165

The late phase of ARDS is often characterized by excessive fibroproliferation leading to gas exchange and compliance abnormalities. While corticosteroids are not effective in early ARDS, several case reports and uncontrolled case series and one small randomized, controlled trial suggest that corticosteroids may be useful in the management of late-phase ARDS. To test this hypothesis, a randomized, double-blinded trial comparing corticosteroids to placebo in severe, late-phase ARDS after seven days is proposed.The objective is to determine if the administration of corticosteroids, in the form of methylprednisolone sodium succinate, in severe late-phase ARDS, will reduce mortality and morbidity. In addition, bronchoalveolar lavage and serum will be collected during the first week of the study to search for inflammatory markers of fibroproliferation.The study will accrue a maximum of 180 patients. The trial will be reviewed by an independent Data and Safety Monitoring Board every 60 patients. The Board is preparing for its second review.To date, 125 patients have been enrolled in this trial.

Late Steroid Rescue Study

Antioxidant Therapy

• N-acetylcysteine and procysteine are oxygen free-radical scavengers and precursors for glutathione

• Phase II clinical studies showed encouraging results

• Large, randomized, placebo-controlled trial failed to show beneficial effects of procysteine in patients with ALI/ARDS

Ware Lb et al, N Eng J Med 2000; 342:1334-1349

Prostaglandin E1

Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome: a controlled, randomized, double-blind, multicenter clinical trial. TLC C-53 ARDS Study Group.

Critical Care Medicine, Volume 27 • Number 8 • August 1999

Total 350 patients

Ketoconazole

34 35

01020304050

60708090

100

Placebo Ketoconazole

Mor

talit

yPotent inhibitor of thromboxane and leukotriene synthesis

The ARDS Network. JAMA 2000;283:1995-2002

Total 234 Patient

Lisofylline and Pentoxifylline: Inhibits the release of free-fatty acids from cell

membranes under oxidative stressInhibits the release of TNF, IL-1, and IL-6

The ARDS network. Crit Care Med 2002;30:1-6

119 Placebo116 lisofylline

Anti-IL-8 Therapy

• IL-8 is a chemotactic stimulus for migration of neutrophils from an intravascular to an extravascular location

• Substantial quantities of IL-8 are present in BAL fluid or the pulmonary edema fluid of patients in the early phase of ARDS.

• Monoclonal antibodies that neutralize IL-8 reduces acid-induced lung injury in rabbits

• Clinical trials of ant-IL-8 therapy for prevention in high risk patients or in early ALI/ARDS may soon be warranted

Enhanced Resolution of Alveolar Edema: 2 Agonists

2 Agonists increases alveolar fluid clearance either by acting on epithelial sodium channels or the sodium/potassium adenosine triphosphatase pumps, and inhibits the increased vascular permeability

• Controlled clinical trials are needed to evaluate aerolized beta-adrenergic agonist therapy in patients with ALI/ARDS

ALVEOLI Study

Prospective, Randomized, Multi-Center Trial of Higher End-expiratory Lung Volume/Lower FiO2 versus Lower End-expiratory Lung Volume/Higher FiO2 Ventilation in Acute Lung Injury and Acute Respiratory Distress Syndrome.

This study is a prospective, randomized, controlled multi-center trial. The objective is to compare clinical outcomes of patients with acute lung injury and acute respiratory distress syndrome treated with a higher end-expiratory lung volume/lower FiO2 versus a lower end-expiratory lung volume/higher FiO2 ventilation strategy.The study will test the hypothesis that mortality from ALI and ARDS will be reduced with a mechanical ventilation strategy designed to prevent lung injury from repeated collapse of bronchioles and alveoli at end-expiration.The study will accrue a maximum of 750 patients. The trial will be reviewed by an independent Data and Safety Monitoring Board to determine if the study should stop for futility, lack of safety or proven efficacy.To date, the trial has enrolled 450 patients.

 

PAC Study

A maximum of about 1,000 patients will be enrolled. Patients will be treated with the specific fluid management strategy (to which they were randomized) for 7 days or until unassisted ventilation, whichever occurs first. Patients randomized to PAC will utilize this catheter for at least 3 days and up to 7 days (depending on protocol defined stability criteria) or until unassisted ventilation, whichever occurs first. If the PAC is discontinued according to protocol between day 3 and day 7, the fluid management strategy will continue and will be guided by the CVC. Patients randomized to CVC will utilize this catheter for 7 days or until unassisted ventilation, whichever occurs first.

PAC Study

This is a Prospective, Randomized, Multi-Center Trial of evaluating the use of a Pulmonary Artery Catheter (PAC) versus a less invasive alternative, the Central Venous Catheter (CVC) for Management of patients with Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). The study is combined with a second study evaluating a "Fluid Conservative" vs. "Fluid Liberal" Management strategy in patients with ALI or ARDS. These studies are combined using a 2x2 factorial design.

Therapeutic Modalities in ARDS

Not Useful Uncertain Value Useful

Lisofylline -adrenergic agents PEEP

Inhaled nitric oxide Anticytokine therapy

PAF

Open Lung Strategies

Ketoconazole N-acetylcysteine APC

Prostaglandin E1 Late steroids

Early steroids Surfactant

ECMO/ ECco2E Partial liquid ventilation

Immunonutrition