This document discusses rescue therapies for refractory hypoxemia in acute respiratory distress syndrome (ARDS). It reviews evidence on inhaled nitric oxide (iNO), prone positioning, recruitment maneuvers and positive end-expiratory pressure (PEEP) titration, high frequency oscillatory ventilation (HFOV), and extracorporeal membrane oxygenation (ECMO). Prone positioning and iNO are first-line therapies that improve oxygenation but iNO does not reduce mortality. Recruitment maneuvers combined with PEEP titration may provide a survival benefit in severe ARDS. HFOV and ECMO are second-line therapies that can facilitate lung-protective ventilation but their effects on outcomes are unclear.

1. Hypoxaemic Rescue Therapies
In
ARDS
Review of the evidence
Muhammad Abdelmoneim
PSMMC-ICU

3. Is she in refractory hypoxemia?

4. Refractory Hypoxemia
O Most studies in a general ARDS population
and many clinicians define refractory hypoxia
as either
O PaO2/FIO2 ratio < 100
Or
O SaO2 < 88%
Or
O PaO2 < 60 mmHg
With a plateau airway pressure > 30 cm H2O with
a FIO2 > 0.8

5. Lines of rescue therapies
O First line
O iNO
O Proning
O HFOV
O Alveolar recruitment maneuvers
To prevent critical hypoxia, to allow ‘protective’
ventilation and to minimize organ failure
• Second line >> ECMO

6. Inhaled Nitric Oxide (iNO)
iNO showed no effects on mortality, regardless of hypoxemia
severities.
Crit Care Med. 2014 Feb;42(2):404-12. doi: 10.1097/CCM.0b013e3182a27909.

7. iNO
O However iNO proved by many studies that
it improves oxygenation
O Mostly started at 5 ppm and titrated up to
40 ppm to achieve optimal effect
O Optimal effect on oxygenation can usually
be achieved with lower doses (5–10 ppm),
whereas optimal effect on pulmonary
artery pressure may require higher doses
(up to 40 ppm)

8. Prone positioning
O Patients with severe trauma and ARDS
O Often spend prolonged time in the supine
position, this tends to increase atelectasis
and consolidation in the gravitational-
dependent lung regions
O ARDS increases lung weight collapsing the
dorsal regions of the lungs under the
weight of the ventral regions

9. Prone positioning
• Prone positioning shifts the gravitational forces and
reduces the cardiac compression of the lungs.
• Higher percentage of the lungs’ alveolar units are open
to ventilation in the prone position than in the supine
position.
• Air is distributed more homogeneously throughout the
lungs, and stress and strain are decreased
• Enhanced drainage of secretions from the posterior
lung segments
Prone Positioning Effect

10. PROSEV
A
The 28-day mortality was 16.0% in the prone group and 32.8% in the
supine group (P<0.001). The hazard ratio for death with prone
positioning was 0.39 (95% confidence interval [CI], 0.25 to 0.63) NNT 6
Prone positioning

11. When to stop proning
O The criteria for stopping prone treatment are any of
the following (PROSEVA protocol):
O Improvement in oxygenation (defined as a
PaO2:FiO2 ratio of ≥150 mm Hg, with a PEEP of
≤10 cm of water and an FiO2 of ≤0.6; in the prone
group, these criteria had to be met in the supine
position at least 4 hours after the end of the last
prone session);
O A decrease in the PaO2:FiO2 ratio of more than
20%, relative to the ratio in the supine position,
before two consecutive prone sessions; or
complications occurring during a prone session
and leading to its immediate interruption. proseva
protocol.pdf
Prone positioning

12. Prone positioning
Complications leading to the immediate interruption of
prone treatment included :
O Nonscheduled extubation,
O Main-stem bronchus intubation,
O Endotracheal-tube obstruction,
O Hemoptysis
O Oxygen saturation of less than 85% on pulse oximetry
O PaO2 of less than 55 mm Hg for more than 5 minutes
when the FiO2 was 1.0
O Cardiac arrest
O Heart rate of less than 30 beats per minute for more than
1 minute,
O Systolic blood pressure of less than 60 mm Hg for more
than 5 minutes
O Any other life-threatening reason for which the clinician
decided to stop the treatment.

13. Recruitment maneuvers and
PEEP titration
O The most common RM used in protective
ventilation strategies was a static RM of 40 cm
H2O pressure for 40 s
O However this RM method can be
uncomfortable, may induce circulatory
depression and has not been associated with
improved outcomes in patients with ARDS

14. For patients with acute lung injury and acute respiratory distress
syndrome, a multifaceted protocolized ventilation strategy designed to
recruit and open the lung resulted in no significant difference in all-
cause hospital mortality or barotrauma compared with an
established low-tidal-volume protocolized ventilation strategy. This
"open-lung" strategy did appear to improve secondary end points
related to hypoxemia and use of rescue therapy
RM-PEEP

15. O Current evidence suggests that high PEEP
regimes may have a survival benefit in patients
with severe ARDS but there is insufficient
evidence to establish the long term effects of
recruitment maneuvers
O Recruitment maneuvers and PEEP titration are
inexpensive, readily available and should be
considered prior to other expensive or invasive
rescue therapies in patients with refractory
hypoxaemia
RM-PEEP

16. High frequency oscillatory
ventilation (HFOV)

17. OSCILLATE
Conclusions In adults with moderate-to-severe ARDS, early application
of HFOV, as compared with a ventilation strategy of low tidal volume
and high positive end-expiratory pressure, does not reduce, and may
increase, in-hospital mortality.
(HFOV)
Saudi Arabia: Riyadh: King Saud Bin Abdulaziz University for Health Science – Y.M. Arabi, H. Tlayjeh, O.
Trinidad, O. Abahussein; Riyadh Armed Forces Hospital – Y. Mandourah, A. Abu Daya, G. Hood, Q.
Weber.

18. (HFOV)

19. (HFOV)
OSCAR

20. (HFOV)

21. O Limitations
O expense of a separate ventilator
O The need for specific training in the use of
HFOV and circuit set-up
O Impaired clearance of pulmonary secretions
O The need for heavy sedation and
neuromuscular blockade
(HFOV)

22. O Currently the place of oscillation in the rescue of
hypoxaemic ARDS patients is unclear but it is usually
commenced after other rescue therapies have been
unsuccessful (iNO, RMs, PEEP).
O Depending on local experience and training many
centers would then choose between prone
positioning and oscillation as an additional rescue at
this point?
O Although there is some evidence that oscillation
when prone may also be efficacious, future studies
are required to determine the true clinical place of
such a strategy.
(HFOV)

23. Extra-corporeal membrane
oxygenation (ECMO)

24. provide non-pulmonary oxygen delivery and carbon
dioxide removal and may also facilitate lung
protective ventilation in ARDS
(ECMO)

25. CESAR
(ECMO)

26. O The aim of CEZAR trial is to assess whether
for patients with severe, but potentially
reversible, respiratory failure, ECMO will
increase the rate of survival without severe
disability by six months post randomisation
and will be cost effective from the viewpoints
of the NHS and society, compared to
conventional ventilatory support.
(ECMO)

27. O During ECMO, ventilator settings are gradually reduced to
allow lung rest, i.e. peak inspiratory pressure 20 cm H2O, end
expiratory pressure 10 cm H2O, rate 10 breaths per minute
and FIO2 30%. ( 30,20,10,10)
O Anticoagulation is maintained with heparin to keep the
activated clotting time (ACT) between 160 and 220 seconds.
Patients are fed enterally or parenterally into the circuit, as
indicated.
O Invasive procedures are avoided to reduce the risk of
haemorrhage, and therefore any additional venous access
necessary, e.g. for haemofiltration, is achieved via the circuit.
O Patients are diuresed to dry weight.
O Haemoglobin concentrations are maintained at 14 g/dl, and
platelet counts are kept >100,000 per ml.
O Patients are weaned from ECMO and decannulated when
chest X-ray appearance and lung compliance have improved,
and adequate gas exchange without excessive ventilation
(peak pressure less than 30 cmH2O, and FIO2 less than 60%)
can be demonstrated during a 'trial-off' ECMO.
(ECMO)
CEZAR protocol

28. O Main conclusions:
O 6 month survival without disability: 63% ECMO
group vs. 47% conventional group NNT 6.
O Quality-adjusted life years at 6 months ('confined to
bed' and 'unable to wash or dress'): ECMO group
showed a gain of 0.03 gain
(ECMO)

29. ANZ-ECMO
During June to August 2009 in Australia and New Zealand, the ICUs
at regional referral centers provided mechanical ventilation for many
patients with 2009 influenza A(H1N1)-associated respiratory failure,
one-third of whom received ECMO. These ECMO-treated patients
were often young adults with severe hypoxemia and had a 21%
mortality rate at the end of the study period
(ECMO)