1. ARDS - Management
By H P Shum
Sept 2005

2. ARDS - Definition Bilateral acute lung infiltration Hypoxemia
No clinical evidence of elevated left atrial pressure or PAWP <=18mmHg
Differentiated from Acute lung injury by PaO2/FiO2 <300mmHg
ARDS was first described in 1967, diagnosis was based on following criteria…

3. ARDS - pathophysiology
Formation of protein-rich alveolar edema after damage to the integrity of the lung’s alveolar-capillary barrier
Can be initiated by physical or chemical injury or by extensive activation of innate inflammatory responses
The development of ARDS started with …

4. ARDS - Causes Sepsis or SIRS Severe traumatic injury
Massive transfusion
Near drowning
Smoke inhalation
Drug overdose (commonly TCA)
The commonest causes of ARDS including ..

5. ARDS – physiological derangement
Ventilation-perfusion mismatch
Intrapulmonary shunt
Surfactant inactivation leading to atelectasis
Decreases lung compliance (stiff lung)
Physiological changes were characterized by …

6. This diagram illustrate cellular …
These events include endothelial activation, recruitment of inflammatory cells, activation of coagulation, and inhibition of fibrinolysis

7. ARDS - imaging CXR showed bilateral diffuse infiltration, normal CTR
CXR can be normal early of the course but become complete whiteout within short time
CT scan showed diffuse ground glass opacification with consolidation at most dependent area of the lung

8. ARDS – ventilator setting
Tidal volume
PEEP
Use of specific ventilation modalities
Almost all the patients with ARDS required some form of mechanical ventilation
I will talk about the ventilator setting first, which will cover tidal volume and PEEP setting …

9. ARDS – ventilator setting
Low tidal volume
Mortality benefit mainly based on two studies
Most authorities will suggested the use of low TV …

10. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome
Amato MB et al. N Engl J Med Feb 5;338(6):347-54
N=53
Conventional ventilation
Lowest possible PEEP
TV 12ml/kg
Aim normal PaCO2
Protective ventilation
PEEP above the lower inflection point on the static pressure–volume curve
TV <6ml/kg
driving pressures < 20 cm of water above the PEEP value
permissive hypercapnia   
Amato published the study in NEJM in 1998 …
Survival curves clearly separate between protected and conventional ventilation gps

11. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network
N Engl J Med 2000 May 4;342(18):1301-8
N=861
Traditional gp
TV 12ml/kg
plateau pressure <=50mmH2O
Low TV gp
TV 6ml/kg
plateau pressure <=30mmH2O   
Another landmark study was from ARDS network published in 2000…
Low TV gp have better survival c/w …
Also with high chance to be d/c and short ventilator days

12. But …. Not all studies using low TV ventilation give rise to good outcome compare with conventional ventilation methods

13. Stewart TE et al. N Engl J Med 1998 Feb 5;338(6):355-61
Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure- and Volume-Limited Ventilation Strategy Group
Stewart TE et al. N Engl J Med 1998 Feb 5;338(6):355-61
N =120
Limited ventilation gp
TV 8ml/min
Plateau pressure <30mmH2O
Conventional gp
TV 10-15ml/kg
Plateau pressure <50mmH2O
This study published in 1998 …
There are not significant different between risk of barotrauma …
However, this study is criticized by other investigators because the TV used is not very low

14. Recommendation
Important to avoid over-distension of alveoli in the relatively normal parts of lung
start at 6-7 ml/kg predicted BW (to maintain plateau pressure <30 cm H2O)
allow PCO2 to rise slowly (i.e. giving kidneys time to compensate for respiratory acidosis), aim to keep pH > 7.25 (instead of aiming for a target PCO2, but advisable not to allow Pco2 to rise above 20 kPa)
Allow upper limit of RR to 35 bpm
Use sedation if needed
So, the recommendation is to avoid…

15. Positive end-expiratory pressure (PEEP)
Insufficient PEEP may result in:
alveolar derecruitment
cyclical atelectasis
progressive lung injury
refractory hypoxemia
What about PEEP setting…
PEEP can improve oxygenation in ARDS because …
Insufficient PEEP can result in…
Optimal PEEP allow stable opening of alveoli but further increasing PEEP resulting into…

16. Excessive PEEP, particularly in combination with hypovolemia, can decrease cardiac output and oxygen delivery, and increase the risk of barotrauma
Am J Respir Crit Care Med 2002 Apr 1;165(7):978-82
Clear delineation of Rt heart border …
Deep sulci sign

17. Continuous diaphragm sign

18. CT scan showed Severe surgical emphysema and pneumomediasteum

19. What PEEP level is good for ARDS? High vs low ….
Amato study using low TV 6ml/kg with high PEEP (average >16mmH2O) showed improved mortality
However …

20. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome
Brower RG et al. N Engl J Med 2004 Jul 22;351(4):327-36
N=549
low PEEP gp
8.3mmH2O
High PEEP gp
13mmH2O   
A study published recently in NEJM provided another view
There are no survival benefit for using high PEEP
The ventilator free days and risk of barotrauma do not have any significant different between gps

21. PEEP setting
Optimal PEEP will change from patient to patient, based in different pathophysiology and depending upon the stage and severity of the disease
no optimal way to assess "best PEEP"
PEEP is added in increments of 2-5 cm until the "best/optimal PEEP" is obtained, choose the level which provides the highest static compliance and the lowest airway plateau pressure
PEEP above lower inflection point on static P-V curve
PEEP > 20 cmH2O is rarely beneficial and usually results in additional pressure-induced lung injury
Level of PEEP used in ARDS still controversial

22. Recruitment maneuvers
utilizing a CPAP of 35 to 40 cmH20 for 40 seconds
can improve oxygenation and alveolar recruitment, but are relatively less effective than a continuous high PEEP level
Intensive Care Med 2000 May;26(5):501-7
Am J Respir Crit Care Med 2002 Jan 15;165(2):165-70
Recruitment maneuvers were commonly used in pt with ARDS …
It seem that appropriate PEEP setting is more important in ARDS tx

23. Ventilator modes
fully supported modes of ventilation are favored over partially-supported modes
There is not mortality benefit for ARDS pt treated with specific ventilator modes

24. Inverse ratio ventilation (IRV)
I:E ratio > 1 may be able to improve oxygenation in patients who remain hypoxic despite PEEP
But …
A lot of negative studies a/v showed that IRV do not had survival benefit
Anesthesiology Nov;95(5):1182-8
Anesthesiology Jan;88(1):35-42
Am J Respir Crit Care Med 1997 May;155(5):
increases the risk of air trapping, barotrauma, hemodynamic instability
require significant sedation and possibly neuromuscular blockade which may increase ICU stay and risk of critical illness neuromyopathy
Inverse ratio ventilation with I:E …

25. Prone ventilation Indications:
routine use of prone positioning in all patients with ALI / ARDS cannot be currently recommended due to a lack of clinical data support
Indications:
as an adjunctive therapy to improve oxygenation in established ALI and ARDS
considered in patients who require PEEP >12 cmH2O and a FiO2 >0.60
should better used early within 36 hours of the onset of ARDS
optimum duration unknown
Prone ventilation was commonly used in pt with ARDS with severe hypoxemia

26. The proposed mechanism for prone ventilation including improved …

27. CT images of ARDS in supine (upper panel ), prone (middle panel ), and return to supine position (lower panel ). The CTs were taken at end expiration and 10 cm H2O PEEP. Note how gravity-dependent densities shift from dorsal to ventral within minutes when the patient is turned prone

28. Most previous studies showed improved oxygenation with between PaO2/ FiO2 ratio

29. Effect of prone positioning on the survival of patients with acute respiratory failure
Gattinoni L et al. N Engl J Med 2001 Aug 23;345(8):568-73
N =304
Multicenter RCT
tx gp
prone >=6h/d 10d
control gp
supine  
What about survival benefit ?…

30. Guerin C et al. JAMA 2004 Nov 17;292(19):2379-87
Effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial
Guerin C et al. JAMA 2004 Nov 17;292(19):
N=791
propective, unblinded, multicenter RCT
prone gp
> = 8hr /d
control gp
supine  

31. Prone ventilation had potential complication for those on sedation…
It is also contraindicated in those with …

32. Airway pressure release ventilation (APRV)
lung volume and hence oxygenation is maintained by continuous positive airway pressure
CO2 clearance is achieved by the transient release of circuit pressure allowing gas to escape and lung volume to fall
CPAP is then re-established to the previous level, allowing the entry of fresh gas into the system

33. Intensive Care Med 2002 Oct;28(10):1426-33
This study was published in 1994… showed the improvement of P/F ratio
Also resulted in significant improvement in the cardiac index, systemic haemodynamic, O2 delivery, and vasopressor requirement and renal perfusion
Crit Care 2001 Aug;5(4):221-6
Intensive Care Med 2002 Oct;28(10):

34. Putensen C et al. Am J Respir Crit Care Med 2001 Jul 1;164(1):43-9
Long-term effects of spontaneous breathing during ventilatory support in patients with acute lung injury
Putensen C et al. Am J Respir Crit Care Med 2001 Jul 1;164(1):43-9
determine whether use of APRV with spontaneous breathing better prevents deterioration of cardiopulmonary function
N = 30, MV trauma pt at risk of ARDS
PCV vs APRV for 72 hr, cross over study
This study published in 2001 try to determine ..
Cardiac index and P/F ratio ..

35.     Sample size is small.
Still an experimental strategies and long term outcome still no clear   

36. High frequency ventilation
               
               
High frequency ventilation
proposed as an alternate form of lung protective ventilation that could theoretically prevent overdistension and cyclical atelectasis
lung inflated and kept open with very low tidal volumes and low airway pressure, aimed to produce minimal shear injury

37. Three modes of HFV a/v with different operation mechanism but tx principle are the same

38. However …
Risks of barotrauma and hemodynamic compromise with high frequency ventilation can approximate those of conventional ventilation
Chest 1993 May;103(5):
In theory, CV give had higher TV but may had suboptimal oxygenation with low PEEP. As PEEP increased, CV carry increased risk of volutrauma which do not occur in HFV
By alternating CV breath with HFV breath, FRC and oxygenation can be improved with lower risk of volutrauma

39. High-frequency ventilation versus conventional ventilation for treatment of acute lung injury and acute respiratory distress syndrome
Wunsch H et al. Cochrane Database Syst Rev 2004;(1):CD004085
only include RCT =2
one recruit children, n =58
other recruit adult, n =148
? Any clinical evidence to support use of HFOV
insufficient evidence to support the broad application of HFV to all patient with ALI / ARDS
insufficient evidence to support the broad application of HFV to all patient with ALI / ARDS

40. Inhaled vasodilator Nitric oxide vs prostacyclin
Act locally and short half life
Minimal systemic effect
Rarely cause hypotension
Now, we go to non-ventilation tx for ARDS

41. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group
Dellinger RP et al. Crit Care Med 1998 Jan;26(1):15-23
Prospective, multicenter, randomized, double-blind, placebo-controlled study
N = 177
placebo vs NO at 1.25, 5, 20, 40, or 80 ppm
responsive if PaO2 >=20%
PaO2 improved on first 4 hrs of tx
Percentage of pt who alive and off MV at D28
In view of potential benefit of NO at 5ppm dosage … another study was conducted and …  

42. Taylor RW et al. JAMA 2004 Apr 7;291(13):1603-9
Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial
Taylor RW et al. JAMA 2004 Apr 7;291(13):1603-9
Multicenter, randomized, placebo-controlled study, triple blinded
n = 385
placebo vs NO 5ppm to 28d

43. nitric oxide produce toxic radicals
NO2 and methemoglobin concentrations may increase
immunosuppressant properties that theoretically could increase the risk of nosocomial infection
cause DNA strand breakage and base alterations that are potentially mutagenic

44. Prostacyclin (PG I2) improve PaO2 and decrease PAP
No study shown improvement of mortality associated with prostacyclin use in ARDS
inhaled vasodilators, if used at all, should be reserved for patients with intractable, life-threatening hypoxemia despite conventional management

45. Function of endogenous surfactant
modulate alveolar surface tension
prevent atelectasis
facilitates mucous clearance
scavenges oxygen radicals
suppresses inflammation
Surfactant dysfx occur in ARDS and in theory exogenous surfactant can offer helps
Surfactant dysfx is one of the characteristic of ARDS…

46. Treatment of acute respiratory distress syndrome with recombinant surfactant protein C surfactant
Spragg RG et al. Am J Respir Crit Care Med 2003 Jun 1;167(11):1562-6
N=40
high dose (1ml 4x in 24 hr)
low dose (0.5ml 4x in 24 hr)
control
No significant improvement of PaO2/FiO2, no different between ventilator free days and pt survival

47. Spragg RG et al. N Engl J Med 2004 Aug 26;351(9):884-92
Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome
Spragg RG et al. N Engl J Med 2004 Aug 26;351(9):884-92
multicenter, randomized, double-blind trials
N = 448
1ml 4x in 24hr for tx gp
Outcome may be affected by mode of delivery of surfactant, duration of use and accompanying ventilator setting and further study required to delineate it use in ARDS
Improvement of PaO2/FiO2 but no survival benefit was detected

48. Partial liquid ventilation
involves filling the lungs with a fluid (perfluorocarbon, also called Liquivent or Perflubron) which has
very low surface tension, similar to surfactant
high density, oxygen readily diffuses through it
may have some anti-inflammatory properties
The lungs are filled with the liquid, the patient is then ventilated with a conventional ventilator using a protective lung ventilation strategy.
Liquid will help the transport of oxygen to parts of the lung that are flooded and filled with debris, help remove this debris and open up more alveoli improving lung function. 

50. All of them are case report, some indicate beneficial outcome in true of improved survival and oxygenation but negative reports present as well
Larger studies are needed to determine what role, if any, PLV will play in the treatment of ARDS

51. Extracorporeal membrane oxygenation (ECMO)
withdrawing arterial or venous blood, passing it through a membrane oxygenator, and returning it to the arterial circulation
Very expensive and survival benefit still in doubt
JAMA 1979 Nov 16;242(20):2193-6
Crit Care Med 1994 Oct;22(10):

52. Steroids
clearly have a role in situations when ARDS has been precipitated by a steroid-responsive process, eg eosinophilic pneumonia
Other cases, efficacy not clear
May be useful in fibroproliferative phase of ARDS, which is characterized by fever, purulent secretions, and new pulmonary infiltrates without evidence of infection
Chest 1991 Oct;100(4):943-52
Chest 1994 May;105(5):
But other even showed increased risk of ARDS and infective complications
Arch Surg 1985 May;120(5):536-40
Preliminary results of a large, randomized, controlled trial, performed by the NIH-sponsored ARDSNET presented in ATS May 2004, suggest no mortality advantage when patients with later phase ARDS are treated with steriod

53. Prostaglandin E1 (PGE1)
enhance oxygen delivery by increasing cardiac output
Chest 1990 Aug;98(2):405-10
Chest 1990 Mar;97(3):684-92
Crit Care Med 1999 Aug;27(8):
significant survival advantage at 30 days
Ann Surg 1986 Apr;203(4):371-8
However, subsequent trials failed to confirm this effect
Chest 1989 Jul;96(1):114-9
the role of PGE1 remains uncertain pending further study

54. Neutrophil elastase inhibitor
Neutrophil elastase produces tissue injury at sites of inflammation
play a role in the endothelial injury and increased vascular permeability associated with acute lung injury
Selevelestat (ONO 5046) is a reversible competitive inhibitor of neutrophil elastase, and early animal and human studies suggested this agent improved outcomes following acute lung injury
Crit Care Med 2002 May;30(5 Suppl):S281-7
Eur J Pharmacol 2004 Mar 19;488(1-3):173-80
Transpl Int 2003 May;16(5):341-6
However, multicenter RCT of 492 MV pts with ALI treated with selevestat or placebo found no difference between groups in 28-day all cause mortality, ventilator requirement, or respiratory mechanics
Crit Care Med 2004 Aug;32(8):

55. Key points Low TV ventilation with appropriate PEEP
Oxygenation can be improved with prone ventilation, increased I:E ratio, recruitment maneuvers and APRV
Potential benefit of HFV, NO, exogenous surfactant, partial liquid ventilation still need further investigations