PILOT
Oxygen-Saturation Targets for Critically Ill Adults Receiving Mechanical Ventilation
Semler. N Engl J Med 2022; 387:1759-1769. DOI: 10.1056/NEJMoa2208415
Clinical Question
- In patients receiving invasive mechanical ventilation, does a target oxygen saturation of 90%, 94%, or 98% increase days alive and free of mechanical ventilation at 28 days?
Background
- Despite the ubiquity of oxygen therapy in the critical care setting, the optimal oxygenation target remains elusive
- Higher oxygen targets provide a degree of protection against hypoxaemia, but expose patients to the potential harms of a high fraction of inspired oxygen (FiO2)
- Even a small survival difference could result in a significant reduction in mortality, given the vast numbers of patients treated with mechanical ventilation
- A number of trials have compared restrictive and liberal oxygen therapy, with more recent trials showing equipoise between the two groups
Design
- Single centre, cluster-randomised, cluster-crossover trial
- Non-blinded
- Patients assigned to trial from emergency department (ED) or intensive care unit (ICU) at first receipt of invasive mechanical ventilation
- Cluster design meant ED and ICU switched to one of three targets every 2 months, in a randomly generated sequence
- The three oxygen targets were defined as
- lower (SpO2 90%; range 88-92%)
- intermediate (SpO2 94%; range 92-96%)
- higher (SpO2 98%; range 96-100%)
- The final 7 days of each period were considered a wash-out period, and were not included in the primary analysis
- Primary outcome defined as days alive and ventilator free at 28 days
- Sole secondary outcome defined as in-hospital death at 28 days
- 2250 patients would provide 92% power at alpha level of 0.05 to detect absolute difference of 2 ventilator-free days between any two of the three groups
Setting
- Single centre in Nashville USA
- Data collection occurred from July 1st 2018 to August 31st 2021
- There was a 2 month pause due to Covid-19 during April and May 2020
Population
- Inclusion:
- All adult patients (>18 years of age)
- Located in ED or ICU
- Requiring mechanical ventilation
- Exclusion:
- Pregnant
- Incarcerated
- Patients with Covid-19 were managed on a separate ICU. Those with a laboratory confirmed diagnosis were not included in the primary analysis
- 2987 patients enrolled
- 446 (14.9%) excluded due to enrolment during washout period, or Covid-19 diagnosis
- Baseline characteristics of lower vs intermediate vs higher target groups were broadly similar
- Age: 57 vs 59 vs 59
- Female: 44.7% vs 44.8% vs 46.8%
- Comorbidities
- COPD: 18.3% vs 20.4% vs 19.3%
- Coronary artery disease: 17.9% vs 17.7% vs 20.4%
- Acute illness
- Cardiac arrest: 15.5% vs 11.6% vs 12.5%
- Myocardial infarction: 16.8% vs 16.1% vs 16.6%
- Sepsis: 34% vs 28.8% vs 32.4%
- Received vasopressors: 19.8% vs 19.9% vs 17.5%
- Median time from initiation of ventilation to enrolment: 0.0 vs 0.0 vs 0.0hr
- Separation of SpO2 and FiO2 between trial groups occurred
Intervention
- Lower oxygen target
- Target SpO2 90%; range 88-92%
- Intermediate oxygen target
- Target SpO2 94%; range 92-96%
Control
- Higher oxygen target
- Target SpO2 98%; range 96-100%
Management common to both groups
- Only the changes in FiO2 were mandated by the trial protocol
- FiO2 was titrated by respiratory therapists within 15 minutes of assignment to trial
- All other aspects of patient care, including ventilatory parameters and PEEP, were left to the discretion of the treating clinician
Outcome
- Primary outcome: number of days alive and free of mechanical ventilation at 28 days – no significant difference
- 20 days in lower; 21 days in intermediate and higher
- Odds Ratios
- Lower vs intermediate: 0.95 (95% CI 0.79-1.13)
- Intermediate vs higher: 1.00 (95% CI 0.84-1.19)
- Lower vs intermediate: 0.95 (95% CI 0.78–1.14)
- Secondary outcome: No significant difference in secondary outcome or numerous prespecified exploratory outcomes
- Comparing lower vs intermediate vs higher targets
- No significant difference in 28 day mortality
- 34.8% vs 34.0% vs 33.2%
Authors’ Conclusions
- Among critically ill patients receiving mechanical ventilation, days alive and ventilator free did not differ among groups in which lower, intermediate and higher oxygenation targets were used
Strengths
- Very large numbers considering this was a single centre trial
- Excellent separation between the three groups
- Average sats achieved for each group 93%, 94% and 97% respectively
- Average FiO2 administered for each group 0.31, 0.37 an 0.45 respectively
- Use of SpO2 rather than PaO2 allowed for vast, highly granular data set
- Nearly 8 million individual saturation readings
- Excellent overall adherence to SpO2 targets
- Cluster crossover format reduces selection bias and reduces time to enrolment
- Sequential randomisation over the study period reduces risks of bias due to seasonality
- Patient-centred primary outcome with face validity – that is, it is relevant to the intervention being tested
- The choice of primary outcome allows a greater degree of discrimination between interventions than a simple mortality outcome
Weaknesses
- A few factors reduce the generalisibility of these results
- Single centre trial
- The ICU involved did not have surgical patients
- The trial intervention was implemented by respiratory therapists, a role not present in some settings
- Some unusual baseline characteristics for the patients
- For example, 14% on home oxygen and 3% of patients chronically ventilated. This last group of patients could never achieve the primary outcome
- Though separation was good, the target saturations for the lower group were not really met overall, increasing the risk of a beta error
- This is likely due to reaching an FiO2 of 0.21, as occurred in around a 3rd of patients in the lower group
- There is a chance that the use of different FiO2s may have introduced clinician bias, affecting their decision to attempt a spontaneous breathing trial and extubation
- The primary outcome does not discern between dying and being ventilated for 28 days, a difference which would clearly matter to patients
The Bottom Line
- In this trial of low, intermediate and high oxygen targets, no significant difference was found in days alive and ventilator free at 28 days
- This excellent trial has challenged my prior inclination towards lower oxygen saturation targets and lower FiO2s. I remain confident in my belief that unnecessarily high FiO2s are harmful, but I will be less aggressive in reducing the FiO2 in the absence of hyperoxia
- Those who use higher targets will be reassured. The chance that there is a large treatment benefit to any particular oxygen target is extremely low
- I will continue to aim for the equivalent of an intermediate target of oxygenation, except in a research setting
- I await the results of Mega-ROX with great anticipation
External Links
- article Oxygen-Saturations Targets for Critically Ill Adults Receiving Mechanical Ventilation
- further viewing Critical Care Reviews PILOT trial presentation
- further reading Conservative Oxygen Therapy during Mechanical Ventilation in the ICU
Metadata
Summary author: Omar Jundi @bi0marker
Summary date: 01/12/22
Peer-review editor: @davidslessor
Image by Defence-Imagery from Pixabay
Thanks for the review.
Don’t forget to eagerly await the results of our very own UK ROX trial too, we are recruiting 18,000 patients UK wide
Yes of course! We’re actively recruiting at my site. Very keen to see the results.