The Stroke Oxygen Supplementation Study

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The Stroke Oxygen Supplementation Study
www.so2s.co.uk

• Chief Investigator Dr Christine Roffe
• Trial Manager Dr Sarah Pountain
• North Staffordshire Combined Healthcare Trust

Funded by National Institute For Research
Research for Patient Benefit
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Hypoxia
ABG kPa Saturation Normal 12.6
0.1 97 2 Mild hypoxia 9.3
lt95 Moderate hypoxia 8.0 lt92 Severe
hypoxia 6.7 lt85 Life threatening 5.3 lt75
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Normal oxygen saturation in healthy older adults
(age 65-90)
Ogburn-Russell, J Gerontol Nurs 19901626-30
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Adverse effects of hypoxia after stroke IEarly
deterioration
381 consecutive patients with acute
stroke Oxygen saturation lt90 doubles risk of
early deterioration.
Silva et al, Cerebrovasc Dis 200111(suppl 4)70
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Adverse effects of hypoxia after stroke II
Increased mortality

• N153 assessed from arrival and during transfers
  till ward admission
• Hypoxia defined as SpO2lt90 for gt10 of assessment
  phase
• Oxygen saturation lowest during transfers
• Hypoxic pts are more likely to have a history of
  chest problems
• Hypoxia associated with 2x increase in mortality,
  but no longer significant if corrected for NIHSS
• No effect on long-term disability
• Rowat et al. Cerebrovasc Dis 200621166-172.

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Adverse effects nocturnal hypoxia after stroke
Increased level of disability
10 desaturations/h
gt10 desaturations/h
Good, Stroke 199627252-259
Silva,Cerebrovasc Dis 200111(suppl 4)70,
Sandberg, JAGS 200149391-397.
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When to start oxygen?Views of British Stroke
Physicians
Arora et al, Br J Cardiol 200512456-458.
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National and international Stroke Guidelines
UK National Clinical Guidelines for Stroke
Arterial oxygen concentration should be
maintained within normal limits 2004 Give Oxygen
to maintain oxygen saturation at or above 95
2008 European Stroke Initiative Recommendations
for Stroke Management 2-4L/min when indicated in
2003 Oxygen if saturationlt92 in 2007 American
Stroke Association Guidelines Oxygen if
saturation lt95 in 2003 and 2005 Oxygen if
saturation lt/92 in 2007
National Clinical Guidelines for Stroke. RCP
2004, 2008, NICE 2008, EUSI 2004, ESO 2007
ASA, Stroke. 200334(4)1056-83,
200536916-23, 2007381655-1711.
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Oxygen saturation on arrival in hospital
Oxygen Saturation ()
Age (years)
n105 Mean age 74.0 years (SD 9.6 years) Mean
oxygen saturation 96.3 (SD 1.6)
Stroke Oxygen pilot Study in progress, baseline
demographic data,
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Oxygen saturation in stroke in in patients with
acute stroke
Roffe et al, Stroke 2003342641-2645.
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Unexpected nocturnal hypoxia in stroke patients
Time spent with an oxygen saturation lt90 at
night 52 more than 5 minutes 23 more than 30
minutes 15 more than 1 hour
Roffe et al, Stroke 2003342641-2645
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Experimental Evidence (mice) Hyperoxia
increases O2 delivery in ischaemic core

• Oxi-Hb concentration in ischaemic zone doubled
• Reduction in the area of cortex with lt20
  residual CBF
• Infarct size at 2 days reduced by 45

Shin, H. K. et al. Brain 2007 1301631-1642.
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Experimental evidence (rat)

• 95 O2 during 90 min MCAO
• Reduced neurological deficit
• Reduced infarct size
• Reduced penumbral conc. of ROS and MMP expression
• Liu et al J Cereb Blood Flow Metab.
  2006261274-84.

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Routine oxygen supplementation
No oxygen
Oxygen
No oxygen
Oxygen
Oxygen
No oxygen
All strokes
Mild strokes SSSgt40 (top) Severe strokes SSS 40
(bottom)
Ronning and Guldvog, Stroke 1999302033-37.
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Selective high dose short burst oxygen
supplementation

• Methods
• acute stroke lt12 h and perfusion-diffusion
  "mismatch" on MRI
• RCT of high-flow oxygen via mask for 8 hours
  (n9) vs room air (n7)
• Results
• Oxygen tended to improve stroke scale scores at 4
  h and 1 week, and significantly at 24 h, but
  there was no significant difference at 3 months.
• MRI lesion volumes were significantly reduced at
  4 hours, but not subsequent time points.
• Cerebral blood volume and blood flow within
  ischemic regions improved
• More petechial hemorrhages (50 w oxygen vs 17 w
  room air)

Singhal et al . Stroke. 200536797-802.
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Potential adverse effects of oxygen
Formation of toxic free radicals Masking of an
important warning sign of underlying
pathology Stress imposed by the mask or
cannula Drying of mucous membranes Hospital
acquired infection through the plastic
tubing Immobilisation of the patient Unintended
effects on staff attitude to the
patient Respiratory depression in patients with
severe COPD
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Central changes in respiratory drive
Normal respiratory pattern Cheyne-Stokes
respiration Hyperventilation Most common
Hypoventialtion, apnoea Rare except in brain
stem strokes and pre-termially
Vingerhoets, Clin Chest Med. 199415729-37. Rowat
et al, JNNP 200778277-9.
Lee, Stroke 19745612-616.
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Complications
SpO2 ()
100
90
80
68 year old male with left hemiparesis and
pneumonia.

• Airway Obstruction
• Aspiration
• Pneumonia
• Pulmonary emboli
• Fluid overload

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Upper airway obstruction?
Tongue? Secretions? Positioning?
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Aspiration

• 40-50 of strokes have dysphagia
• Silent in 60
• Assoc. w. desaturations of ³ 2 during water
  swallow
• May also occur if nil by mouth.

Mann et al, Cerebrovasc Dis. 200010380-6. Daniel
s et al, Arch Phys Med Rehabil 19987914-9. Smith
et al, Age Ageing 200029495-9. Colodny,
Dysphagia 200116(1)48-57.
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Conclusion

• Hypoxia is common after acute stroke, and often
  intermittent
• It is more likely to occur at night
• Routine oxygen supplementation may or may not
  improve outcome
• More evidence is needed to guide oxygen treatment
  after stroke

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Stroke Oxygen Study
Main Hypothesis Fixed dose oxygen treatment
during the first 3 days after an acute stroke
improves outcome after stroke. Secondary
hypothesis Restricting oxygen supplementation to
night time only is more effective than continuous
supplementation.
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The Team

• Trial Management Committee

• Trial Steering Committee

• Dr Christine Roffe
• Prof. Peter Jones
• Prof. Peter Crome
• Prof. Richard Gray
• Mr Peter Mrs Linda Handy (Strokes R Us)

• Prof. Richard Lindley
• Prof. Martin Dennis
• Prof. Lalit Kalra
• Prof. Sian Prothero
• Jane Daniels
• Mrs Peta Bell

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• Data Monitoring Safety Committee

• International Advisory Committee

• Prof. S Jackson
• Prof. T Robinson
• Dr Martyn Lewis
• User Representatives
• Peter Linda Handy
• Mrs Peta Bell

• Prof. Richard Lindley
• Funder
• Research for Patient Benefit
• Sponsor
• North Staffordshire Combined Healthcare NHS Trust

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Stroke Oxygen Study

• Multi-centre study
• prospective, randomised, open, blinded-endpoint
  (PROBE)
• About 1000 patients will be sufficient to show a
  moderate (0.5 Rankin point) effect
• About 6000 patients will have to be recruited to
  show a small effect (0.2 Rankin point)

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Eligibility for the study

• Inclusion criteria
• Adult patients with acute stroke
• No definite indications or definite
  contraindications for O2 treatment
• Within 24 hours of admission
• Exclusion criteria
• Potential indications for O2 treatment
• O2 saturation on air lt90
• dyspnoea
• Medical indications for oxygen (PE, severe
  pneumonia, acute asthma)
• Patients on long term oxygen for chronic lung
  disease
• If the stroke is not the main clinical problem
• Serious life threatening illness

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Randomisation

• Randomisation form
• Baseline O2 saturation demographics
• Date time of event
• Glasgow Coma Scale
• NIHSS
• Predictors of outcome
• Log on or phone to randomise
• www.so2s.co.uk
• Tel [phone]
• Assigned to a treatment group

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1 week post recruitment

• Local, trained, research team member
• 7 days 1 day after enrolment or at discharge
• Confirm diagnosis
• Document death
• NIHSS
• Compliance with the intervention
• Complications
• Data entered online

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3, 6 12 month post recruitment

• Centrally by SOS team
• Questionnaire sent to patient
• Deaths
• Discharge status
• Modified Rankin Score
• Barthel ADL score
• Nottingham EADL score
• EuorQuol score
• Memory
• Sleep
• Speech

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Study Centres

• No. of active centres 1
• No. of interested centres 47
• No. of centres completing SSI forms 41
• No. of centres awaiting REC approval 7
• No. of centres with REC approval 5

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Cumulative Recruitment
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Study Contacts

• SOS Study Manager
• Dr Sarah Pountain
• E-mail sarah.pountain_at_northstaffs.nhs.uk
• Tel [phone]
• SOS Chief Investigator
• Dr Christine Roffe
• E-mail christine.roffe_at_northstaffs.nhs.uk
• Tel [phone]
• Springfield Unit, City General Hospital,
  Stoke-on-Trent ST4 6QG

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Treatment of hypoxia after stroke
?
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Management of Hypoxia

• First, and most importantly
• Clear mouth and airway
• In drowsy or dysphagic patients suction may be
  required
• Sit the patient out, if possible, or elevate the
  head of the bed
• Chest physiotherapy
• Assess swallowing, and review oral foods/fluids
• If all this does not help
• Medical review to exclude/ treat pneumonia,
  bronchospasm, heart failure, or abnormal
  breathing patterns
• Stop sedative drugs
• Oxygen