Oxygen Targets

Supplemental oxygen administration is a ubiquitous therapy and cornerstone of medical therapy. Oxygen:

Principles

Aim to minimise the harm by balancing harms of hypoxia and hyperoxia:

Hypoxia is consistently defined as a PaO2 <60mmHg or SpO2 <90%. The threshold for hyperoxia is less clear, but a PaO2 >300mmHg is often used.

  • Overly-conservative target and subsequent hypoxia
    • Harm of hypoxaemia is well-established:
      • Organ dysfunction
      • ↑ ICP
      • ↑ PVR and PAP
    • Safety of mild hypoxaemia (e.g. SpO2 88-92%) is also well demonstrated:
      • Healthy subjects during sleep
      • Comorbid persons over long-distance flights
  • Overly-liberal target and subsequent hyperoxia
    Definition of harm is less-well characterised:
    • ↑ Reactive oxygen species
      • ↑ Infarct size in:
        • AMI
        • Stroke
      • Pneumonitis
      • Proliferative retinopathy
    • Hyperoxia-induced vasoconstriction
    • ↓ Seizure threshold

Practice

  • Use SpO2 as the preferred monitor
  • Set upper and lower bounds for all critically ill patients
    • General ICU patients
      • Titrate to SpO2 94-98%
        • Optimal target is unknown
        • An SpO2 of 100% hides signs of deterioration, as the PaO2 can ↓ with no observable change
    • Minimise supplemental oxygen
      More conservative approach favoured in groups where ↑ significantly harm with liberal oxygen:
      • Ischaemia
        Only used to correct ischaemia; supranormal oxygen may ↑ infarct size.
        • STEMI
        • CVA
      • Paraquat poisoning
      • Bleomycin exposure
    • Targeted or tolerated hyperoxia
      Groups where hyperoxia is therapeutic, or any hypoxia may be detrimental:
      • Cardiac arrest resuscitation
        With adjustment to normoxia once ROSC is achieved and oxygenation can be reliably monitored.
      • CO poisoning
      • Decompression injury
        Prior to HBOT.
      • Simple pneumothorax
      • Severe pulmonary hypertension
  • FiO2 challenge
    A failure to significantly increment SpO2 in response to ↑ FiO2 is diagnostic of a shunting or diffusion-limited pathology.

Excessive supplemental oxygen may mask deterioration in pulmonary function, as a fall in SpO2 will only manifest once the P/F ratio has fallen to a dangerous degree.

Key Studies

General ICU patients:

  • Hypoxia is known to be harmful

  • Some observational data suggests harm from hyperoxaemia

    • Confounded by acuity of patients receiving high oxygen targets
    • Higher target provides a margin of protection against hypoxaemia

  • Given the ubiquity of oxygen therapy, there is potential for a small mortality benefit to have large impact

  • CLOSE (2016)

    • 104 mechanically ventilated adults, with clinical equipoise to oxygenation target
    • Multicentre (4), parallel group, RCT
    • SpO2 88-92% vs. ≥96% SpO2
      • FiO2 titrated by bedside nurse, PEEP by patient
    • Primary outcome of mean AUC for oxygenation metrics
    • 14% time-off-target in conservative arm vs. 3% in liberal arm
    • Established general feasibility of oxygenation target trials

  • OXYGEN-ICU (2016)

    • 434 adult Italians admitted to a single ICU
      • ~66% mechanically ventilated
    • Single-centre, allocation concealed, non-blinded RCT
    • 660 patients provides 80% power for 6% ARR in mortality (!!), with control mortality of 23%
    • Stopped early for slow recruitment
    • Conservative vs. standard oxygen therapy
      • Conservative:
        • Target SpO2 94-98%
        • PaO2 70-100mmHg with lowest possible FiO2
      • Standard:
        • Target SpO2 97-100%
        • FiO2 >0.4 and PaO2 <150mmHg
    • Significant ↓ mortality (24.2% vs. 33.9%) and ventilation time (72 vs. 48 hours) in conservative group
    • Woefully underpowered for an overly ambitious mortality benefit

  • ICU-ROX (2019)

    • 965 Australasian adults <2 hours from ventilation, expected to be ventilated for over 1 day
    • Allocation concealed, unblinded, multicentre (21), RCT
    • Conservative vs. usual oxygen
      • Conservative
        SpO2 titrated to 91-96% using lowest possible FiO2.
      • Usual
        SpO2 titrated >90% with no upper limit, discouraging FiO2 <0.3.
    • No difference in 28 day ventilator-free days
    • No difference in secondary outcomes
    • Small differences between groups in actual oxygen received

  • PILOT (2022)

    • ~3000 mechanically ventilated ICU patients from one ICU in Tennessee
    • FiO2 adjusted to maintain target oxygen saturation in 3 groups:
      • Low: SpO2: 88-92%
        Average saturation was 93%; FiO2 ↓ to minimum of 0.21.
      • Intermediate: 92-96%
        Average saturation 94%.
      • High: 96-100%
        Average saturation 97%.
    • No significant difference in days alive and free of mechanical ventilation
    • No difference in pre-specified secondary endpoints
    • Reasonable group separation

References

  1. Semler MW, Casey JD, Lloyd BD, et al. Oxygen-Saturation Targets for Critically Ill Adults Receiving Mechanical Ventilation. New England Journal of Medicine. 2022;387(19):1759-1769. doi:10.1056/NEJMoa2208415
  2. Conservative Oxygen Therapy during Mechanical Ventilation in the ICU. N Engl J Med. 2020;382(11):989-998. doi:10.1056/NEJMoa1903297
  3. Angus DC. Oxygen Therapy for the Critically Ill. New England Journal of Medicine. 2020;382(11):1054-1056. doi:10.1056/NEJMe2000800