ARDS

Diagnosis and exclusion of Differential Diagnoses

Therapeutic Aim - Prevention of VILI
Failure to Respond
Steroids in ARDS
Persistent Hypoxaemia
Persistent Hypercapnia
Spontaneous Breathing
Transpulmonary Pressure Measurement
High Frequency Oscillator Ventilation (HFOV)
ECMO
Brain MRI findings after ARDS
Evidence based recommendations
ARDS Mx mnemonic - iPRONE
Recent Papers

Diagnosis and exclusion of Differential Diagnoses 

 ARDS Criteria:
o Acute onset within 7 days of precipitating condition (eg Sepsis, pneumonia etc.)
o Bilateral Infiltrates on CXR or CT
 o Resp. failure not fully explained by cardiac failure or fluid overload
 Severity defined by PaO2/FiO2 ratio on min PEEP 5cmH2O
o Mild - P/F 200-300 (mortality 27%)
o Moderate - P/F 100-200 (mortality 32%)
o Severe - P/F < 100 (mortality 45%)
 Murray score can help to quantify disease progression
 ARDS Differential Diagnoses:
o Pulmonary vasculitis
o PCP pneumonia
o LV failure
o Lymphangitis
o TRALI
o Interstitial Pneumonitis
o Inhalational injury
o Anaphylaxis

Assess whether 1ry or 2ry ARDS

 There is some evidence that ARDS caused by aetiologies that directly traumatize the lung
( e.g. pneumonia, Aspiration - Primary ARDS) may respond differently to ARDS caused
by aetiologies distant from the lung (e.g. Trauma, non-lung Sepsis, Pancreatitis -
Secondary ARDS)
 As well as different aetiologies, CT scans may also aid differentiation of the 2:
o Primary ARDS = patchy, lobar changes, increased consolidation
o Secondary ARDS = more confluent, homogeneous changes on CT, increased
oedema
 In terms of Mx:
o Primary ARDS - more vulnerable to volutrauma hence limit Pplat
o Less likely to recruit hence limit PEEP
 o Primary ARDS due to CAP may benefit from 7 - 14 day course of low dose
steroids from Day 1
o Secondary ARDS - more likely to recruit with High PEEP and higher Pplat
o However, associated mortality also higher than Primary ARDS, most likely due to
primary aetiology

Therapeutic Aim - Prevention of VILI 

Pathophysiology - The 'Open Lung' Approach

 4 lung areas in ARDS:

o normal lung - may be <10% of total lung volume, but in ARDS provides most of
gas exchange , at risk of damage from inappropriate ventilatory strategies
o small airway collapse - opening pressure required = 10-20 PEEP
o alveolar collapse - opening pressure required = 20-30 PEEP
o consolidation - unable to open
 at least 10% of mortality in ARDS due to Ventilator Induced Lung Injury (VILI)
 Aim is to 'open' lung to minimize VILI
o prevents small airway +/- alveolar collapse => larger surface area for gas
exchange
o thus improves lung compliance, improves oxygenation for given mean airway
pressure
 VILI caused by:
o Atelectrauma - lung collapse - correct with PEEP if recruitable
o Volutrauma - over distension - correct with low TV
o Barotrauma - overpressure - correct with low Pplat
o Biotrauma - VILI => lung damage => cytokine release => systemic cytokine
release and secondary cytokine related damage - correct by treating cause of
ARDS and preventing VILI
 Atelectasis mainly due to weight of lung:
o Causes increased stretch at apex of lung
 o Increased collapse at base of lung partly due to oedema / consolidation
 Lung vs Chest wall Compliance:
o In normal lung, lung compliance and chest wall compliance are roughly equal
o In ARDS with stiff lungs and low TV , 75% is lung, 25% chest wall
o In ARDS with stiff lungs and high TV , 90% is lung, 10% chest wall
 Effects of Spontaneous Breathing:
o In normal lung, diaphragm contraction => equal spread of negative pressure
throughout lung since lung acts as a liquid body
o But when lung has heterogeneous atelectasis / consolidation, then get unequal
pressure distribution => pendeluft since can get very high transpulmonary
pressures near areas of consolidation => differential lung stress
o During SV in later stages of ARDS Ventilation, 6ml/kg IBW TV may hide large
degrees of pendeluft causing localised volutrauma due to large diaphragmatic
shifts
o Careful timing and use of high PEEP to minimise spont diaphragm movt during
SV may help
 Lung recruitability related to degree of lung oedema
 Keeping the lung 'Open'
o Maintain the lung in inspiration for as long as possible using:
o 1) inverse ratio Ventilation
o 2) APRV - airway pressure release Ventilation
o Use PEEP to keep lung open during exhalation
 Other benefits of PEEP :
o By opening lung, prevents atelectrauma assoc. with Ventilation
o If lung recruitable, PEEP => mild decrease PVR (increased West zone 1)
o If lung unrecruitable, PEEP => major increase in intrathoracic pressure and PVR
=> RV distension
o Hence PEEP may improve pulm blood flow and RV function if lungs recruitable
The Stress Index - Pressure Time curve in Volume Control mode may help diagnose VILI

Prevention of VILI while maintaining adequate oxygen delivery

Key Targets to achieve this :

1) Low TV Ventilation
a) strict 6ml/kg IBW or less (consider NaHCO3 infusion if too acidotic)
b) plateau pressure measurement
c) early use of NMBs if severe ARDS

2) Assess recruitability - improves oxygenation, reduces VILI

methods of achieving lung recruitment:
a) High PEEP ( ? Guidance by measuring Transpulmonary pressures)
b) Prone positioning
c) early consideration for extra corporeal lung support if failing to achieve adequate vent
parameters

3) Minimize VILI by minimizing duration of Ventilation

a) reduce duration of Ventilation by running negative fluid balance early
b) reduce duration of Ventilation by careful timing of initiation of spont breathing to prevent
Ventilator Induced Diaphragmatic Dysfunction

1) Set TV, Pplat and consider NMB infusion

 Set TV at 4-6ml/kg Ideal Body Weight.
 Use mode that inhibits spont vent induced high TV's initially eg Volume Guaranteed
modes
 Ideal Body Weight Calculation (height in inches):
o For Males = 50 + 2.3 (Ht - 60)
o For Females = 50 + 1.7 (Ht - 60) *Ensure Pplat < 30 (ideally < 28)
 Plateau pressure:
o For Patients on Pressure Control / Bi-Level modes, Pplat = Ppeak when end-
inspiratory flow = zero
o For Patients on Volume Control modes, use inspiratory hold manoeuvre to
measure Pplat
o For Patients with Primary ARDS ( localized changes on CT) consider Pplat < 26
o For Patients with BMI > 30, consider relaxing Pplat target to < 36 ( since low
chest wall compliance => reduced transpulmonary pressures in these pts, and thus
Pplat target < 30 may => inappropriately low TVs and severe resp. acidosis )

 When to use VCV or PCV

o VCV allows easy assessment of Pplat, resistance , compliance, stress index etc.
since pressure curve is dependent. Can also measure autoPEEP
o AUC for pressure is less with VC than PC, hence overall get reduced mean
airway and mean alveolar pressure
o Peak flow higher in PC than VC, peak flow => shear stress, so may cause more
damage with PC
o VC closer to sinusoidal flow trace than PC, this is closer to normal breathing
o Guaranteed volume ensures low TV
o Also, ? minimizes TV during spont breaths when compared to PC - less
comfortable for pt but lung protective **However, recent evidence shows that in
severe ARDS, lung acts as a solid, and during SV get pendeluft => no clear
evidence of reduced VILI with VC
 o Overall - VC good for controlled vent, PC maybe better when pt starting to
improve and make resp efforts

 Use NMB infusion for first 24-48hrs in severe ARDS (P/F < 120)
o May prevent patient from interbreathing
o Spontaneous breathing may increase transpulmonary pressure by inducing large
swings in pleural pressure
o This may cause both barotrauma and volutrauma but be 'hidden'
o Use of volume guaranteed modes of Ventilation may also help prevent VILI
related to early spont. Breathing
 Paralysis vs diaphragm atrophy
o NMBs not associated with atrophy when used for 48hrs
o After 48hrs, pt weaned to PS
o Studies such as LOVS, ALVEOLI etc used NMBs in 50% of pts! Also in proning
studies
o Only beneficial effect on outcome if p/F < 120
o NMBs also reduced mort in Severe Sepsis
 So, regarding NMB infusions :
o use if P/F < 120
o use early in course of disease
o use for very short time (<48hrs) , followed by conversion to SV
 Use SV in moderate / mild ARDS
 With SV aim TV 6-8ml/kg IBW, if TV more than that, use sedation/analgesia ( ? Increase
PEEP )

Permissive Hypercapnoea to pH > 7.25

 Allow Permissive Hypercapnoea, aiming for pH > 7.25, pCO2 < 10.5kPa
o Evidence of improved microperfusion with pCO2 < 10.5, but reduced
microperfusion when >10.5
o Shifts oxy-Hb dissociation curve to Right (O2 offloads easier)
 o Indirect sympathomimetic
o Animal studies - anti-inflamm effects, reduced pulm. CAP. Permeability
 May be associated with severe resp acidosis
o Consider use of NaHCO3 infusion - by providing hi dose Na in small volume, it
reduces SID and thus combats effect of CO2 on acid-base balance (Stewart
theory)
 Absolute Contra-indication - Traumatic Brain Injury
 Relative Contra-Indication - Pulmonary Hypertension
o Target Oxygen Saturation > 92%
o Consider volume guaranteed Bi-level Ventilation mode to allow spont breathing if
pulm. Hypertension on echo
o Aim for Neutral Fluid Balance once CVS stable
 Consider early use of ECCO2R to allow low TV to be used

Set PEEP initially according to ARDSNET Protocol:

FiO2 30% == PEEP 5

FiO2 40% == PEEP 5-8
FiO2 50% == PEEP 8-10
FiO2 60% == PEEP 10
FiO2 70% == PEEP 10-14
FiO2 80% == PEEP 14
FiO2 90% == PEEP 14-18
FiO2 100% == PEEP 20-24

2) Assess potential for Lung Recruitment

 Lung recruitment = ability to open up partially collapsed lung units by application of

pressure
 However, in up to 50% of pts with ARDS, lung is not recruitable, and application of
additional pressure just causes overdistension of existing lung units and potential for
increased VILI
 High recruitability assoc with inc mortality, prob because they are at higher risk of VILI
and atelectrauma
  Recruitability increased if early ( before fibrosis sets in), severe, extrapulmonary, non
lobar ARDS - 80% of early severe ARDS is recruitable
 Recruitment of partially collapsed lung may improve lung compliance, while
overdistension => reduced lung compliance
 Improved compliance translates to a fall in Pplat and also a reduction in transpulmonary
pressure, both of which are associated with reduced VILI and improved outcomes
 Can be done with RMs or Prone positioning, and maintained using HiPEEP or HFO
 However, may cause volutrauma if pt unrecruitable
 No mortality benefit in mild ARDS, only moderate to severe
 Hi PEEP plus high transpulmonary pressure may be assoc with lower survival - this
group may be the unrecruitable subset of ARDS pts,
 ARDS is heterogeneous hence not surprising that some pts are not recruitable eg trauma
pts with pulmonary contusions
 RMs better tolerated in pts <56yrs with secondary ARDS

Assess likelihood for lung recruitment (Primary vs. Secondary ARDS)

1) At Bedside - Compliance and P/F

 At PEEP 5cmH20 note values for P/F, pCO2, Compliance

 Then - perform Recruitment Manoeuvre (Ensure Pt well sedated, closely observe BP /
CO):
o 40cmH2O CPAP for 40 seconds x 2 or
o Maintain TV 6ml/kg IBW
 Reduce PEEP to 15cmH2O and recheck P/F, pCO2, Compliance
 If 2/3 values have improved by > 10%, Pt may benefit from Higher PEEP

2) Use P-V curves

 P-V curve hysteresis is due to recruitability

  Opening pressure is greater than closing pressure, and the greater the difference, the
greater the recruitability . *This is why we look at exhalation part of PV curve to set
PEEP post recruitment, since aim is to prevent collapse and thus atelectrauma

Pressure-Volume Curve may help assess whether lung recruitable or not

Pressure-Volume Curve may also help set PEEP

3) CT scan / Ultrasound

 CT chest at 5cm H20 and 45cm H2O => compare degree of recruitment
 This is the gold standard for anatomical recruitment
 Lung US has been used as surrogate for CT
 Note poor correlation between functional and anatomical recruitment

4) Echocardiography
  Assess RV and PA pressure using echocardiography - recruitment => fall in pulm. Vasc.
Resistance and increased pulmonary blood flow, whilst overdistension does the opposite

5) Measure End Expiratory Lung Volume

 New technique using Nitrogen washout on ventilator

 EELV = delta vol of tracer gas / delta concentration of tracer gas
 Performed by comparing O2 and CO2 inspired and expired, at 2 levels of FiO2, to
calculate nitrogen delta
 Once EELV known, can calculate degree of recruitment with increased PEEP, for
example, if know compliance, since using compliance, can calculate predicted increase in
lung volume, so any additional lung volume at higher PEEP above this = newly recruited
lung ie it differentiates between true recruitment and overdistension of previously
recruited lung
 Can also assess recruitment responders just by changing positions and keeping vent
settings the same
 Stress = delta Pressure, strain = delta Volume, EELV assessment allows assessment of
stress/strain relationship

Setting High PEEP - 2 methods:

 Titrate PEEP until, at 4-6ml/kg IBW TV, Pplat = 30cmH2O (or Pplat 36cmH2O if BMI >
30)
 After RM, reduce PEEP gradually until point of inflection on deflation slope of P-V
curve reached ( = level of PEEP at max lung compliance) then re-recruit and set PEEP
2cmH2O above this level

Prone positioning

 If recruitable, proning assoc. with significant improvement in outcome

 Prone early, to minimize VILI
 Proning shown to:
o improve oxygenation
 o reduce incidence of VAP
o reduce lung stress esp. in heterogenous ARDS
o reduce RV strain by improving recruitment
 Proning:
o Aids recruitment of collapsed dorsal lung and prevents overinflation of ventral
lung
o Results in more homogeneous distribution of aeration and improved compliance
o Reduces shunt, improves V/Q
o Proning eliminates compression of lung by the heart
 But not all ARDS is same - effects of proning are more marked in Primary, lobar ARDS,
and less marked in secondary, diffuse ARDS
 Also, obese pts have much better response to proning since they have more collapsed
lung
 PEEP titrated using ARDSNET PEEP table, allows lower PEEP when prone due to
improvement in P/F
 Use v strict low TV, with NMBs
 Who benefits - Severe ARDS (P/F < 150 on PEEP 5), Lobar ARDS, Obese
 When - earlier is better, recruitability reduces with time
 How long - more than 12-16hrs
 Note - proning assoc. with increased sedation use, therefore may need to titrate stopping
criteria , however proning for 8hrs not associated with benefit ( Gattinoni 2001)

Plateau Pressure

Limitation of Pplat - Pro

 Inflection pt for increased mortality at Pplat 28

 Vt/FRC as a stress index, correlates well with Pplat
 Mortality correlates well with Pplat
 Note - ECCO2R plus Pplat vent => improved outcome in severe ARDS (P/F <150) but
not moderate ARDS (P/F>150)
Limitation of Pplat - Con

 Pplat strongly influenced by chest wall compliance (Ccw)

 Can still get VILI at Pplat 30, 25 is a safer threshold
 Using stress index to guide Ventilation ( ie prevent tidal hyperinflation), get reduction in
IL-6
 Stress index more sensitive , but less specific, at detecting tidal hyperinflation, compared
to Pplat 25
 Pplat dependent on Ccw, if abnormal (eg obese pts), then Pplat threshold may be
insufficient, so must take into account transpulmonary pressure
o Note - no correlation between Pplat and transpulmonary pressure
o However, does mean that Pplat threshold likely to be lung protective( since assoc
with reduced transpulmonary pressure)
 Of 14 pts referred for ECMO, 7 found to have reduced transpulmonary pressure. When
vent. Adjusted for this, oxygen index improved, and pts no longer required ECMO
 Stress index is less influenced by chest wall mechanics, and has much better correlation
with trans pulmonary pressure

Minimize Transpulmonary Pressure

 Plateau pressure is the pressure required to distend both lung and chest wall
 In obese patients, use of low TV may still require very high Pplateau due to poor chest
wall compliance
 For BMI > 30, Pplat may increase by 6-8cmH2O
 Transpulmonary pressure (TPP) is the pressure required to distend the lung alone
 It is this pressure which relates to barotrauma
 It can be determined if oesophageal pressure is known (as surrogate marker of chest wall
compliance)
 Pplat = Plung + Pchest wall (Pchest wall = Poesoph)
 Hence Plung = Pplat - Poesoph
 Some evidence that reducing transpulmonary pressure for a TV < 6ml/kg IBW associated
with improved outcomes
 In normal lung, diaphragm contraction => equal spread of negative pressure throughout
lung since lung acts as a liquid body
 But when lung has heterogeneous atelectasis / consolidation, then get unequal pressure
distribution => pendeluft since can get very high transpulmonary pressures near areas of
consolidation => differential lung stress
 In normal lung, lung compliance and chest wall compliance are roughly equal
o In ARDS with stiff lungs and low TV , 75% is lung, 25% chest wall
o In ARDS with stiff lungs and high TV , 90% is lung, 10% chest wall
 Swings in Pes linked to pt effort during active breathing, so can track WoB
 Talmor trial of PEEP titration (NEJM 2008) - negative TPP implies compressive forces
and thus potential for tidal opening and closing => titrating PEEP until TPP positive
helped to prevent this
 As IAP increases, get increased risk of negative TPP. Can offset using PEEP
 Ideally, should use TPP instead of Pplat to determine true driving pressure
 Oesophageal pressure near diaphragm most accurately represents TPP near dependent,
poorly compliant lung in ARDS
o With 30 degree head up position, Gravity increases Pes by 5cm H2O
o Also affected by weight of heart and active expiration
 Transpulmonary pressure can be optimized by:
o Lung recruitment - Hi PEEP, APRV, Prone positioning
o Titrate PEEP to Pplat of 28cmH2O ( using 4-6ml/kg IBW TV )
o Titrate PEEP using oesophageal pressure monitoring
o Early use of NMBs to minimize TVs early in course of ARDS
 If unable to measure Poesoph, can optimize chest wall compliance by:
o Treating Intra abdominal Hypertension
o Reducing chest wall oedema via negative fluid balance
o Escharotomy in patients with inhalational lung injury and circumferential chest
Burns
 Monitoring Poesoph
o Oesoph press balloon - lower third of oesoph, inflated with 0.5ml of air
 o Regional pressure measurement, affected by posn, weight of heart etc.
o Helps determine transpulmonary pressure, an end insp assessment
o And PEEPopt, an end exp assessment
o Lung stress is transpulmonary press, lung strain is volume change in response to
stress (=TV/FRC)
o TPP should be <25-27 to prevent VILI, strain ( as measured by TV/FRC) should
be < 2
o Negative end exp TPP indicates collapse of unstable lung units, titrate PEEP to
maintain positive TPP at end exp

3) Reduce duration of ventilation

a) Achieve a negative fluid balance as soon as possible

 Once pt cardiovascularly stable i.e. minimal vasopressor requirement, aim for natriuresis
o Frusemide
o Amiloride
o Thiazides
o Spironolactone
o Aminophylline infusion (beware Tachycardia)
o ? Nesiritide (Natriuretic peptide)
 If the above fail, consider early CVVH to achieve negative fluid balance
 Note, however, FACTT trial follow up - Mikkelson AJRCCM 2012 - conservative fluid
strategy and Hypoxia both strongly assoc with neurocognitive decline later, also poor
glycemic control

b) Encourage synchronized spontaneous breathing once P/F improved

 Advantages of spontaneous Ventilation (ie allowing patient to breathe spontaneously) :

o improved Ventilation to peri diaphragmatic areas, where much dependent blood
flow occurs, hence improving V/Q matching
o helps exercise diaphragmatic muscles, preventing resp. muscle atrophy
 o allows reduction in sedation
 Disadvantages of spontaneous Ventilation
o in diseased lung, develop negative intrathoracic pressure gradients eg -20 at
dependent lung base, -5 at open lung apex
o this pressure differential may cause a pendeluft effect, with gas moving from non-
dependent to dependent lung => minimal net gain in tidal volume
o negative intra thoracic pressure may also => negative pressure pulmonary oedema
o negative intra thoracic pressure + increased dependent blood flow + lung damage
may => haemorrhagic lung injury due to increased microvasc pressure gradient
o SV => increased afterload
o Hering Brewer reflex in diseased lung may => rapid spont. Resp rate => assoc.
risk of VILI
 Hence institution of spontaneous Ventilation must be carefully timed and monitored
o institute after initial 24-48hrs depending on improvement in P/F, institution of
neutral fluid balance
o ensure patient breathing synchronized with ventilator
o consider using a volume guaranteed mode to prevent excessive TVs with SV +
Pressure Support
o consider insertion of oesophageal pressure balloon to determine transpulmonary
pressure if concerns re: VILI with spont. Breathing
 Ventilator induced diaphragm dysfunction :
o excessive ventilatory support causes disuse atrophy of diaphragm
o insufficient ventilatory support causes diaphragmatic fatigue and exhaustion
o may present as inability to trigger ventilator
o prevent by using pressure curve to diagnose excess work of breathing or
insufficient triggering, and then titrate PS and PEEP to optimize
o prevent air hunger (causing increased work of breathing) by ensuring peak insp
flow at least 60l/min
Failure to Respond 
Have Low threshold for performing Echo, BAL and chest CT
Consider alternative pathologies :

 ARDS Mimics:

- Wegeners vasculitis => interstitial lung disease => use ECMO early, get low CRP response cf
IPPV, ? ECMO rests lung and reduces inflammation response
- Eosinophilic pneumonia - eosinophils may not be raised initially, only after 48hrs. In severe
pneumonia, should not have any eosinophils since suppressed by endogenous steroids
- Acute Interstitial Pneumonia - often linked to myosotis - request ANA, ENA and Myositis
specific ENA ( often positive when ANA, ENA negative ). Present with progressive single organ
failure

 If ongoing infection in presence of interstitial lung disease

- can give IVIg, which is good against vasculitis and infection

- always check CMV if previous Hx of immunosuppressive Rx
- be suspicious if single organ failure,

 Check CMV, vasculitis screen, eosinophilia count, CT ? Peri lobular, periphery sparing
( indicates diffuse alveolar Haemorrhage )
  Distant Sepsis, particularly CVC related infection and Sinusitis
 Lung Sepsis - as well as VAP, consider viral pneumonia and check NPA +/- Tracheal
aspirates for HSV, CMV, H1N1
 Chest Ultrasound if patient too sick for transfer to CT - looking for fluid, occult
Pneumothorax, evidence of basal collapse or aeration, consolidation
 Early CT scan - as well as 1o vs. 2o ARDS, may help direct BAL and exclude
Pneumothorax, PE, Empyema/abscess, Interstitial Pneumonitis (as differential of ARDS),
late stage fibrosis
o If pleural effusions present, little point in draining them unless underlying lung is
aerated, since if collapsed/consolidated, very unlikely that removal of pleural fluid
will => re-expansion
 If no pathogen isolated, consider early BAL
o esp. if immunosupressed - PCP, TB, Aspergillus, CMV, HSV
o ?eosinophils, increased l'cytes, haemosiderin laden macrophages , all suggestive
of UIP (Interstitial Pneumonitis)
o also biochemical evidence of early fibrosis
 As last resort, some centres perform Lung Biopsy if diagnosis still unclear ( can change
Mx in up to 50% cases )
 IAH common - if present, Pplat may significantly overestimate transpulmonary pressure

<RV Failure

 Acute Cor Pulmonale occurs in 22% of pts during protective lung Ventilation - ACP
assoc with hi CO2, pneumonia, high driving pressure and low PF ratio - score out of 4
helps guide echo diagnosis
 Rx - Reduce Pplat / pCO2 if possible, iNO, Recruitment trial, Prone position. Consider
Sildenafil
 If RV dilation due to hypercapnia, best treatment is VV ECMO => reduce pCO2 and
increase pO2 in attempt to normalise pulmonary vascular resistance

Steroids in ARDS 
  Consider steroids if
o Patient not improving, infection excluded and day 7 - 14
o Persistent high inflammatory markers
o Cultures persistently negative inc. BAL
o Negative virology esp CMV / HSV
 ? Hx of Aspiration / CAP - potential benefit of early steroids day 1-7
 Check for Eosinophilia , consider autoimmune screen
 Perform CTPA, BAL, Echo
 ? CT Abdo also to exclude occult abdo Sepsis / ischaemia
 CT chest also excludes established extensive fibrosis which might be a contraindication
to steroids
 Ensure adequate gastric cover and that steroids given in the morning to prevent sleep
disturbance
 Dosing of Steroids
o Methylprednisolone used for lung penetration and prolonged residence time
o Day 1-6 - use 1mg/kg
o Day 7-14 use 2mg/kg, then :
o Slow tapering over 14 days
o Ensure pt screened regularly for VAP, CVC infection, CMV/HSV
o Steroids unsuitable in patients who are pregnant, have AIDS or require skin grafts
(Burns)

Persistent Hypoxaemia 
 Aim Hb > 10g/dL
 Consider keeping Albumin > 20g/dL
 Consider reducing physiological targets -
o O2 Sats >85% (>80% if young pt.)
o pH > 7.2
 Trial bolus NMB 63RM + avoid de-recruitment
  HiPEEP post RM if Pt Recruitable
 Consider Transpulmonary Pressure
o Might be lower than expected if raised IAP or severe obesity
o May thus get cyclical derecruitment on expiration
o Solution may be much higher PEEP, ideally directed by assessment of TPP by
measurement of oesophageal pressure
 Consider Aggressive Diuresis +/- CVVHF
 Consider HFO if Pplat > 30
 Consider Prone Positioning
 Consider NO / Flolan nebulizer ( ? B2 agonists )
 Consider ILA if pH < 7.15
 Consider ECMO if < 7days ventilated
o early referral if clear by day 3 that patient not improving

Persistent Hypercapnia 
Effects of Hypercapnia

 Physiological Effects:
o Raises intracranial pressure by vasodilation
o Stimulates respiration centrally
o Shifts oxyhaemoglobin curve to right hence offloading more oxygen for a given
pO2
o Indirect sympathomimetic stimulating increased cardiac output
o Peripheral vasodilation improving distal perfusion
o Pulmonary vasoconstriction at high levels => RV failure
 Cellular effects:
o Hypercapnia may attenuate ALI by inhibition of endogenous Xanthine Oxidase
o Also, when gut made ischaemic, get reduced secondary lung vascular
permeability with high CO2
 o BUT - in presence of pneumonia, get increased proliferation of bacteria in lung
with high CO2 due to suppression of neutrophil activity, akin to Hypothermia
o High CO2 impairs mitochondrial function which is good if tissue requires rest eg
acute phase, but not in convalescent phase when require tissues to proliferate to
aid recovery
o Overall, high CO2 appears immunosuppressant, which is good if host response is
main villain, but not necessarily in acute infection, when host response required to
get rid of bacteria
o CO2 as well as suppressing certain enzymes, may increase expression of certain
genes and thus enzymes eg Vit E transfer to protein , which is protective against
tissue injury and thus may mediate protective effect of high CO2 , since Vit E
inhibits production of strong chemokines esp. leucotriene B4

Management

 Consider partially blocked ETT ( Suction catheter may still pass down ETT if plugged
with viscous secretions)
 If high BMR causing increased CO2 production, consider :
o cooling
o increased sedation
o paralysis if Ventilator Dysynchrony
 If wheeze present, consider reducing resp. rate (? Air trapping)
 Consider carinal oxygen flush
 Consider extra corporeal CO2 removal ( see ECLS section )
 If persistent resp. acidosis, consider use of NaHCO3 infusion (corrects acidosis by
increasing Strong Ion Gap due to high concentration of Na)
o In chronic hypercapnoea, HCO3 is increased
o Hypercapnoea protects lung from ischaemia - reperfusion injury
o However, more difficult to correct Resp acidosis with HCO3 than metab acidosis
since with Resp acidosis, HCO3 is already high, and need to increase it much
more to normalise pH
 o In metab acidosis, HCO3 is low, so require far less HCO3 to correct
o Effectively, to correct Resp acidosis, will get increased Na and an increased SID,
which may also cause fluid overload.
o If given, never give as bolus ( since will increase CO2 which cannot be got rid of
in a short space of time due to the increased deadspace assoc. with ARDS), so
always give as an infusion slowly

Spontaneous Breathing 
The Problem

 Spontaneous breathing in severe ARDS assoc with increased Transpulmonary pressure

 This may not be recognized due to Pendeluft
o Pendeluft is interalveolar transfer of gas
o This may cause alveolar overdistension and VILI, but may not be recognised
since TV and Pplateau will remain unchanged
o It is particularly associated with increased diaphragmatic movt during spont.
Breathing

How to monitor

 Lose Pplat if pt breathing actively, but not Poes, so can still calculate TPP in actively
breathing pt much more easily than Delta P
 Get much larger swings in Ppleural than Poes in dependent areas of lung during SV,
hence may need to set lower safe threshold values to protect dependent lung areas during
SV
 Major determinant of TPP Delta P is pt effort, not ventilator, during SV

Potential Solutions

 Temporary paralysis
o Only use in severe ARDS
o Only use for 24-48hrs at initial presentation
  Increased PEEP
o Prevents excessive 'doming' of diaphragm, hence limiting it's ability to contract
o May be effective during BiPAP Ventilation
 APRV Ventilation
o Pts able to breathe spontaneously but TV's limited by high PEEP
 Volume Control Ventilation
o Pt able to breathe spontaneously but since flow is fixed, applied pressure
decreases to compensate for negative intrathoracic pressure hence maintaining
transpulmonary pressure

Timing of transition to SV

 SV reduces IL6 levels in ARDS in animal models, yet may also cause high transthoracic
pressures => worse VILI
 Timing of transition from IPPV to PS based on -
o P/F
o improving inflamm markers
 ? does TV change when PS changes ?
o If so, stay with PS
o If not then pt is compensating for reduced PS with increased diaphragmatic movt.
and therefore may not be ready for PS
o APRV may have a role here

Transpulmonary Pressure Measurement 

Oesophageal pressure balloon placement

 Aim for distal 2/3 of oesophagus ( first 1/3 get too many airway artefacts )
 Insert into stomach, inflate 4-6ml depending on catheter type, then pull back while
transduction get pressure, looking for negative deflection indicating SV, or sudden
increase in pressure if full IPPV indicating intrathoracic position.
  If getting increased cardiac artefacts ( which also implies good position ), by cautious
filling of balloon can optimise trace, by doing an inspiratory hold and progressively fill
balloon looking at Delta P with arterial pressure for both Pplat and Oesoph Pressure ( aim
ratio 0.8-1.2) or increase filling against TV, looking for sudden increase ( implying
balloon is overfilled and pressure measured is due to overdistension, not true oesoph
pressure )
 Esophageal pressure measured = Ppleural + Poesoph. Can minimise effect of Poes if
using large balloon by assuming Poes = 1cmH2O for each 1ml filling of balloon
 At Pplateau, measuring Poes Max, and then on expiration, measuring Poes Min, gives
most info about overdistension and atelectasis during tidal Ventilation.
 Many uses for oesoph pressure measurement inc guidance of vent dysynchrony, weaning,
diaphragm dysfunction etc.

How to set PEEP and Driving Pressure

 Despite a pressure gradient from neg to positive from top to bottom of lung in supine pt,
oesoph pressure correlates with mid lung which is a good average point
 Aim to titrate PEEP so that TPP remains positive during exhalation - this signifies that
there is no end expiratory collapse - particularly useful in obese patients or patients with
raised intra-abdominal pressure
 Good correlation between TPP and EIT
 With PEEP optimisation using TPP, get a smaller than deltaPEEP increase in Pplat =>
reduced transpulmonary pressure.
 Benefit of PEEP depends on whether pt is recruitable or not. The reduction in driving
pressure for an increase in PEEP may assess recruitability in a more effective way than
other recruitment tests, and TPP driving pressure rather than Pplat-PEEP driving pressure
may be a more appropriate driving pressure target
 The only problem is that Poes measures mid lung pressure, so it overestimates Ppleural in
dependent lung, and overestimates Ppleural at top of lung. So when setting PEEP, though
may prevent atelectasis, may risk overdistension of 'normal' lung units.
 Refer for ECMO if, despite lung protective Ventilation, unable to get decent oxygen sats /
excessive pCO2
How to monitor spont breathing pts with ARDS

 Lose Pplat if pt breathing actively, but not Poes, so can still calculate TPP in actively
breathing pt much more easily than Delta P
 Get much larger swings in Ppleural than Poes in dependent areas of lung during SV,
hence may need to set lower safe threshold values to protect dependent lung areas during
SV
 Major determinant of TPP Delta P is pt effort, not ventilator, during SV
 How to reduce pt effort -
o ECMO to reduce pCO2
o Rocuronium low dose infusion to reduce muscle strength
o Use of Sighs intermittently, by reducing hypoxic drive and Hering Brewer reflex,
may reduce drive
o Higher PEEP reduces effort also ( worsens work force gradient, reduced coning of
diaphragm etc. )

High Frequency Oscillator Ventilation (HFOV) 

 2 recent, large RCTs have thrown doubt on the benefit of HFO in ARDS, demonstrating
no benefit
 May be related to lack of recruitability in the subject patient population, also possible that
some pts were resonated at their resonant frequency => barotrauma through increased
transmission of pressure wave through alveolar tree.
 What are the current indications for using HFO then ?
o Use if severe ARDS (P/F < 100) with no benefit from proning or unable to prone,
if lung protection cannot be provided with conventional vent - Pplat > 30
( corrected for chest wall compliance ), FiO2 60-70%
o If on HFO, P/F does not improve or vasopressor requt increases dramatically,
revert back to conventional Ventilation - allow 6-12 hrs
o Use Recruitment Manouvre => Max. Mean Airway Pressure of 30 ( prior use of
RM important )
o Use for minimum time possible, ideally < 48hrs ?
  Avoid in :
o Lobar ARDS ( increased incidence of over distension, non recruitable )
o PCP ( fragile lungs, increased barotrauma )
 If patient is not Recruitable, then HFO not useful, so useful to check recruitability
beforehand
 Increased RV Failure with HFO if use MAP > 5 above Pplat - check Echo, CO2
clearance, ensure good secretion control, avoid NMBs if possible
 Perhaps current lung protection so good that added benefit of HFO is not there, only harm
( increased vasopressor requt, RVF etc )

Mechanism of action

 Uses multiple mechanisms inc. bulk flow for both oxygenation and CO2 removal
 By minimizing bulk flow movt, aim is to minimize VILI
 Pressure swing in HFO is attenuated down the airway, unlike with IPPV
o Pressure attenuated 60 (mouth) => 1 (small airways) with HFO
o Pressure attenuated 60 (mouth) => 40 (small airways) with IPPV

Initial Settings :

•AIM TO LIMIT MAP < 30

• FiO2 = 1. , conventional mPAW + 5cmH2O
• Frequency 8Hz
• Cycle Vol. 175ml
• Bias Flow 20l/min

 Ensure chest 'wiggle' is seen during Ventilation

Cautions

 Beware overdistension and barotrauma esp. if mPaw > 35cmH2O

o Can diagnose overdistension from CXR ( flattened diaphragm )
 Avoid suction for first 12-24hrs to prevent de-recruitment
o After this, trial suction 4-6hrly if no desaturation off HFO
 Contra-Indications - Raised ICP, COPD

Oxygenation (Lung Recruitment)

Target PaO2 > 8 kPa (FiO2 = 1.0)

Increase mPaw by 2 cmH2O and do ABG after 20 mins

Keep increasing mPaw by 2 cmH2O every 20 mins until O2 target achieved or mPaw = 40
cmH2O

Ventilation (to clear CO2)

Target : pH 7.25

Better High f and low Cycle volume if possible

Increase Cycle volume by 10 ml every 20 mins until max. for a given f
Reduce f by 1 Hz every 20 mins until f = 5 Hz or pH > 7.25
If pH still < 7.25 - Introduce cuff leak - will need to increase bias flow

Weaning - Target PaO2 > 8 kPa

 1 st reduce mPaw by 2 cm H2O every 4 hours until mPaw = 30 cm H2O

 Next reduce FiO2 by 0.1 every 4 hour until FiO2 = 0.4
  Net reduce mPaw by 2 cm H2O every 4 hours until mPaw = 18 cm H2
 Consider weaning from HFO to conventional Ventilation when:
o CXR improved
o Duration of HFO > 4/7 ( to rest lung )
o MAP 18-24, FiO2 0.4
 Transition to Conventional Vent.
o SIMV - PC is suggested
o PEEP + 10/12 cm H2O
o Adjust PC to give same mPaw as on HFOV

ECMO 
 Aim is to rest lungs, to allow lung healing, avoiding VILI
 Main determinant of oxygenation is blood flow, needs to be at least 60% of cardiac
output
 Sweep gas flow only affects CO2 clearance, use FiO2 1.0
 VA ECMO => used in cardiogenic Shock, get blue head red legs, brain gets low sat
blood from heart, legs get oxygenated blood from ECMO circuit, so cannot rest lungs
therefore do not use for lung failure
 Hence use VV ECMO for acute resp. failure in ARDS, VA ECMO for acute cardiac
failure
 Cannulation under US guidance, short and wide cannula to optimise flow
 Best combo for oxygenation is to drain from IVC (29FG) and re-inject via SVC (21FG)
 Main problem is re-circulation of freshly oxygenated blood - made worse by low CO,
hypovolaemia, proximity of catheter tips, increased pump flows - best to use Avalon
cannula to minimise this
 Ventilator settings - use, PEEP 12-16, Pplat 20-24, VT 1-4ml/kg IBW, APRV or BiPAP,
RR < 20, FiO2 < 50%
 Predictors of mortality in ECMO - age, lactate on ECMO, Pplat level
 Monitoring - usual plus ? ROTEM, platelets, APTT, fibrinogen, serum free Hb, ABGs
 Heparin bonded lines, APTT 44-55secs, Aspirin if platelets > 400
  Average LoS 20 days
 Mortality reduced in high volume (>20/yr) centres

Brain MRI findings after ARDS 

 Neuropsychological sequelae - deficiencies clearly correlate with degree and duration of
desaturation
 Functional disability at 2 and 5 years even in young patients - Herridge et al NEJM 2011
 ? Assoc with structural changes on MRI brain ? - haemosiderin deposits are remnants of
previous bleeds, can see on SWI (susceptibility weighted imaging) imaging, and see this
after HACE in mountaineers
 See similar changes in pts who have suffered multiple Hypoxaemia events
 7/17 ECMO pts and 3/5 ARDS no ECMO pts show theses changes
 However, clear causality with Hypoxaemia not proven yet

Evidence based recommendations 

 Low dose steroids for 14 days in first 2 weeks with gradual taper may improve outcome
in patients with ARDS due to Community Acquired Pneumonia
 The use of the NMB Cisatracurium in the first 48hrs after intubation for pts with ARDS
may improve outcome, potentially by reducing transpulmonary pressures and preventing
spontaneous Ventilation, and hence secondary barotrauma . No clear evidence of
increased Neuropathy associated with it's use
 Use of higher levels of PEEP improves outcome in pts with severe ARDS but not mild
ARDS
 Titrating PEEP against transpulmonary pressures using an oesophageal pressure monitor
can improve outcome in ARDS
 Recruitment manoeuvres and Hi PEEP may improve lung compliance and oxygenation in
some, but cause alveolar overdistension in others, due to heterogeneity in ARDS, hence
consider a trial of recruitability first
 Prone positioning for up to 16hrs per session may significantly improve outcome in
severe ARDS patients, but not mild ARDS patients
  Inhaled NO and Prostacyclin improve oxygenation but not outcome
 ECMO may be of benefit for pts with severe ARDS who are referred to an ECMO centre
in the early stages of the disease

ARDS Mx mnemonic - iPRONE 

 i - Investigate and treat cause of ARDS, exclude differential diagnoses
 P - Paralyse early in severe ARDS, accept Permissive hypercapnia, minimise Pplat
 R - assess for Recuitability => use hi PEEP if recruitable, consider prone positioning
 O - consider use of Oesophageal pressure / electrical monitoring to aid PEEP titration
 N - aim for Negative fluid balance once CVS stable
 E - give early consideration to referral for Extra Corporeal Oxygenation / CO2 removal

Recent Papers 
2017

The ART Trial - Effect of Lung Recruitment and Titrated Positive End-Expiratory
Pressure (PEEP) vs. Low PEEP on Mortality in Patients With Acute Respiratory Distress
Syndrome. A Randomized Clinical Trial. JAMA 2017;318(14):1335-1345
This randomised, controlled trial of 1013 patients with severe ARDS (P/F < 26.6kPa) compared
a strategy of recruitment maneuvers combined with PEEP adjusted to the optimal respiratory
system compliance, with a low-PEEP strategy. Control patients were ventilated as per the
ARMA trial low tidal volume group - 6 ml/kg predicted body weight, plateau pressures < 30 cm
H2O and PEEP set by the ARDSnet PEEP/FiO2 table.
There was a significantly increased 28-day mortality in the intervention group (55.3% vs. 49.3%;
P = 0.041). This persisted at 6 months (65.3% vs. 59.9%; P = 0.04) and was consistent across
sensitivity analyses. Although there was no difference in refractory hypoxaemia, the
interventional group suffered more barotrauma (5.6% vs. 1.6%; P = 0.001), had more
pneumothoraces requiring drainage (3.2% vs. 1.2%; P = 0.03) and had a higher mortality rate
within the first 7 days. Despite this, there were no differences in ICU (60.6% vs. 55.8%; P =
0.13) or hospital mortality (63.8 vs. 59.3; P = 0.15). Of note, in the ART trial, despite having
significantly higher driving pressures, the control group had better outcomes.
APRV - Early application of Airway Pressure Release Ventilation may reduce the duration
of mechanical Ventilation in acute respiratory distress syndrome. Intensive Care Med
2017;43(11):1648-1659
138 pts with moderate to severe ARDS (P/F <250) were randomised to receive either APRV or
standard low TV lung protective Ventilation. Patients in the APRV group had significantly more
ventilator free days by day 28 than those in the LTV group (primary outcome; median 19 (8-22)
days vs. 2 (0-15) days; P < 0.001). More patients receiving APRV were successfully extubated
(66% vs. 39%; P=0.001) and fewer required Tracheostomy (13% vs. 30%, P = 0.013). There was
no difference in the incidence of Pneumothorax; 3 vs. 7 in the APRV vs LTV groups,
respectively (P = 0.199). Neuromuscular blockade, prone positioning, nitric oxide or HFOV was
required in 23 (34%) patients in the LTV arm and 6 (8%) receiving APRV. Length of stay was
significantly reduced in ICU (APRV vs. LTV 15 vs. 20 days, P = 0.015) but not hospital (21 vs.
27 days, P = 0.06). ICU mortality (20% vs. 34%; P = 0.06) and hospital mortality (24% vs. 37%;
P = 0.09) were not significantly reduced with APRV.

2016

The LUNGSAFE Study. Epidemiology, Patterns of Care, and Mortality for Patients With
ARDS in 50 Countries. JAMA. 2016 Feb 23;315(8):788-800

 This was an international, multi-centre, prospective cohort study which set out to assess
the epidemiology, clinician recognition and management interventions used in ARDS. In
terms of severity, 30% were mild, 46% were moderate, and 23.4% of cases were severe.
60.2% of ARDS cases were clinician recognised; recognition was more likely for severe
ARDS (78.5%) than for mild ARDS (51.3%). At the time of fulfilment of ARDS criteria
only 34.0% were recognised by clinicians pointing towards diagnostic delay.
 On the first day of ARDS, 63.7% of the patients received lung protective Ventilation
(tidal volume 61 8 mL/kg predicted body weight (PBW) and plateau pressure 61 30 cmH
2O). 35.1% of patients with ARDS received tidal volumes > 8 mL/kg PBW.
 There was no relationship between PEEP and PaO2/FIO2 or FiO2 but an inverse
relationship between FiO2 and SpO2. Mean PEEP in severe ARDS was 10cmH2O. This
suggests Hypoxia was managed with increased oxygen not PEEP.
  In patients with severe ARDS, prone positioning was used in 16.3% , neuromuscular
blockade in 37.8% and high dose corticosteroids 23.3%.
 The following hospital mortality rates were observed; mild ARDS; moderate ARDS,
40.3%; severe ARDS, 46.1%. Patients who had a driving pressure > 14 cmH 20 had a
higher mortality than those who had a driving pressure of 61 14 cmH 20 (P=0.02).
However, driving pressure could only be calculated in the 40.1% of patients who had
plateau pressure reported.

LIPS-A Trial. JAMA 2016;315(22): 2406-2414

Aspirin, when started in the ED in pts at high risk for ARDS, does not appear effective in
preventing ARDS

2015

Driving Pressure - Amato et al, NEJM 2015 Feb 19;372(8):747-55

For lung protective Ventilation, using TV's limited by pressure ( and hence limited by patient's
own lung compliance characteristics) rather than a set volume determined by patient's height,
might provide a more individualised and hence safer approach. Using multilevel mediation
analysis, individual data from 3562 patients with ARDS enrolled in nine previously reported
randomized trials was analyzed to examine whether the driving pressure ( Pplat - PEEP ) or 63P,
was an independent variable associated with survival.
Trials examining the effect of tidal volume interventions were used as part of a derivation cohort,
trials into high PEEP were used as a validation cohort. In all patients (irrespective of treatment
allocation), a one standard deviation increase in 63P (equating to 7 cmH2O) measured at day 1
was associated with increased mortality (relative risk, 1.41; 95% CI, 1.32 to 1.52; P<0.001).
When analysing only patients who received lung protective Ventilation; those who had a driving
pressure less than or equal to the median (13 cmH2O) had an improved survival when compared
to those with driving pressure > 13 cmH 2O (relative risk, 1.36; 95% CI, 1.17 to 1.58; P <
0.001). In mediation analysis 63P was responsible for 75% of the treatment benefit seen in the
tidal volume trials (P = 0.004) and 45% of the benefits seen in the PEEP trials (P = 0.001). 63P >
7cm H2O was found to increase mortality by up to 41%, even in patients receiving "protective"
plateau pressures and VT. Individual changes in VT or PEEP after randomization were not
independently associated with survival; they were associated only if they were among the
changes that led to reductions in 63P

HARP-2 trial, NEJM 2015

In 540 patients diagnosed with ARDS randomly assigned to either Simvastatin 80mg od or
placebo, Simvastatin therapy, although safe and associated with minimal adverse effects, did not
improve clinical outcomes

2013

PROSEVA trial, NEJM 2013

In 466 patients with severe ARDS, early application of prolonged prone-positioning sessions
significantly decreased 28-day and 90-day mortality. The 28-day mortality was 16.0% in the
prone group and 32.8% in the supine group (P<0.001). Unadjusted 90-day mortality was 23.6%
in the prone group versus 41.0% in the supine group (P<0.001). The incidence of complications
did not differ significantly between the groups, except for the incidence of cardiac arrests, which
was higher in the supine group.

OSCAR trial, NEJM 2013

The use of HFOV had no significant effect on 30-day mortality in patients undergoing
mechanical Ventilation for ARDS. There was no significant between-group difference in the
primary outcome, which occurred in 166 of 398 patients (41.7%) in the HFOV group and 163 of
397 patients (41.1%) in the conventional-Ventilation group (P=0.85 by the chi-square test).
Similar results were seen in the OSCILLATE trial of HFOV in Canada, in which 548 pts were
randomised to either HFOV or conventional lung protective Ventilation. Mortality was 47% in
HFOV grp vs 35% in control grp. The trial was stopped early before target recruitment was
reached.

2012
BALTI-2 trial, The Lancet 2012
326 patients randomly assigned within 3 days of ARDS diagnosis, to either Salbutamol infusion
(15mcg/kg/hr) or placebo for 7 days. One patient in each group withdrew consent. Recruitment
was stopped after the second interim analysis because of safety concerns. Salbutamol increased
28-day mortality (55 [34%] of 161 patients died in the Salbutamol group vs 38 (23%) of 163 in
the placebo group. Treatment with intravenous Salbutamol early in the course of ARDS was
poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes.