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ARDS Treatment


									ARDS - Management
  By H P Shum
  Sept 2005
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 - 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
    ARDS - Causes
•   Sepsis or SIRS
•   Severe traumatic injury
•   Massive transfusion
•   Near drowning
•   Smoke inhalation
•   Drug overdose (commonly TCA)
    ARDS – physiological
•   Ventilation-perfusion mismatch
•   Intrapulmonary shunt
•   Surfactant inactivation leading to atelectasis
•   Decreases lung compliance (stiff lung)
ARDS - imaging
 ARDS – ventilator setting
• Tidal volume
• Use of specific ventilation modalities
 ARDS – ventilator setting
• Low tidal volume
  – Mortality benefit mainly based on two studies
        Effect of a protective-ventilation strategy on mortality
        in the acute respiratory distress syndrome
              Amato MB et al. N Engl J Med. 1998 Feb 5;338(6):347-54

•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
      •permissive hypercapnia
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
   •Traditional gp
        •TV 12ml/kg
        •plateau pressure
   •Low TV gp
        •TV 6ml/kg
        •plateau pressure
        <=30mmH2O                
But …. Not all studies using low
TV ventilation give rise to good
outcome compare with conventional
ventilation methods
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
  •Conventional gp
       •TV 10-15ml/kg
       •Plateau pressure
• 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
Positive end-expiratory pressure
                    Insufficient PEEP may
                    result in:
                    • alveolar derecruitment
                    • cyclical atelectasis
                    • progressive lung injury
                    • refractory hypoxemia
Excessive PEEP, particularly in combination with
hypovolemia, can decrease cardiac output and
oxygen delivery, and increase the risk of
              Am J Respir Crit Care Med 2002 Apr 1;165(7):978-82
Continuous diaphragm sign
 What PEEP level is good for
 ARDS? High vs low ….
• Amato study using low TV 6ml/kg with high
  PEEP (average >16mmH2O) showed improved
• However …
 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


 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
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
Ventilator modes
• fully supported modes of
  ventilation are favored over
  partially-supported modes
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. 2001 Nov;95(5):1182-8
                                  Anesthesiology. 1998 Jan;88(1):35-42
                    Am J Respir Crit Care Med 1997 May;155(5):1637-42
  – 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
Prone ventilation
 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
 optimum duration unknown
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
Effects of systematic prone positioning in hypoxemic
acute respiratory failure: a randomized controlled trial
Guerin C et al. JAMA 2004 Nov 17;292(19):2379-87

  • N=791
  • propective, unblinded,         
  multicenter RCT
  • prone gp
        • > = 8hr /d
  • control gp
        • supine

 Airway pressure release
 ventilation (APRV)
• lung volume and hence oxygenation is
  maintained by continuous positive airway
• 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
Also resulted in significant improvement in the cardiac index, systemic
haemodynamic, O2 delivery, and vasopressor requirement and renal
                                               Crit Care 2001 Aug;5(4):221-6
                                Intensive Care Med 2002 Oct;28(10):1426-33
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

High frequency ventilation

• proposed as an alternate
  form of lung protective
  ventilation that could
  theoretically prevent
  overdistension and cyclical
• lung inflated and kept open
  with very low tidal volumes
  and low airway pressure,
  aimed to produce minimal
  shear injury
However …
Risks of barotrauma and hemodynamic compromise with high
frequency ventilation can approximate those of conventional
                               Chest 1993 May;103(5):1413-20
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

  insufficient evidence to support the broad application of HFV to all patient with ALI / ARDS
 Inhaled vasodilator

• Nitric oxide vs
• Act locally and short
  half life
• Minimal systemic
• Rarely cause
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,              PaO2 improved on first 4 hrs of tx
double-blind, placebo-controlled study
• N = 177
• placebo vs NO at 1.25, 5, 20, 40,
or 80 ppm
• responsive if PaO2 >=20%

   Percentage of pt who alive and off MV at D28

                        
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
 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
                                               • Prostacyclin (PG I2)
                                               improve PaO2 and decrease

                                               • 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
 Function of endogenous
• 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
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
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

                                                            Improvement of
                                                            PaO2/FiO2 but no
                                                            survival benefit was
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.
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
Extracorporeal membrane oxygenation (ECMO)
• withdrawing arterial or venous
  blood, passing it through a
  membrane oxygenator, and
  returning it to the arterial
• Very expensive and survival
  benefit still in doubt
           JAMA 1979 Nov 16;242(20):2193-6
      Crit Care Med 1994 Oct;22(10):1659-67
• 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):1516-27
• 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
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):1478-85

• significant survival advantage at 30
                            Ann Surg 1986 Apr;203(4):371-8

• However, subsequent trials failed to
  confirm this effect
                                 Chest 1989 Jul;96(1):114-9

                       Crit Care Med 1999 Aug;27(8):1478-85
Neutrophil elastase inhibitor
• Neutrophil elastase produces tissue injury at sites of
• 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):1695-702
 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

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