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The ICU-ROX Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group
Oxygen is a vital element in medical practice and among the most universally used agents for the treatment of critically ill patients. Guidelines for the provision of oxygen give recommendations for target oxygen saturations and for the weaning of oxygen therapy. Despite this, the titration of supplemental oxygen in mechanically ventilated patients is infrequent with resultant hyperoxia being common in the intensive care unit (ICU).
Hyperoxia can be defined as a state in which supraphysiological levels of oxygen are inspired and/or reach the arterial circulation. A formal definition for arterial hyperoxia does not exist, but a partial pressure of arterial oxygen (PaO2 ) higher than 120 mmHg (>16 kPa) has previously been characterised as mild hyperoxia and PaO2 >200 mmHg (26.7 kPa) as severe hyperoxia.
Physiologic Rationale –
Conservative oxygen therapy may contribute to acclimatisation and cellular adaptation to the lower ranges of normoxia, which may result in improved efficiency of ATP production and protection of mitochondria. From a physiological point of view, this makes perfect sense as the human body has evolutionarily adapted to successfully maintain aerobic metabolism with a fraction of inspired oxygen (FiO2 ) of 21% in ambient air at sea level. It provides the ideal environment for the eukaryotic cell that is perfectly capable of efficient oxygen consumption at partial pressures of arterial oxygen of 75-100 mmHg (10-13.3 kPa) and corresponding mitochondrial oxygen concentrations of approximately 11 mmHg (1.5 kPa).
The side effects of supraphysiological oxygenation can be roughly subdivided in cell damage, inflammation, pulmonary complications, neurological symptoms and vascular effects.
As we know, oxygen delivery and tissue oxygen tension not only depend on the arterial oxygen tension but also on perfusion and oxygen consumption.
What’s Known –
Despite this evidence, there is a lack of good clinically directive data regarding strategies for oxygen administration in adults undergoing mechanical ventilation.
conservative oxygen therapy would result in more ventilator free days than usual oxygen therapy in adults who were expected to undergo mechanical ventilation in the ICU beyond the day after recruitment.
Design: Randomized clinical trial across 21 ICUs in Australia and New Zealand conducted by the ICU-ROX investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Randomization using computer-generated random numbers; block randomization in a 1:1 ratio and stratified by trial center.
Eligibility: ≥18 years of age who were expected to receive mechanical ventilation in the ICU beyond the day after recruitment. Less than 2 h of invasive or non-invasive ventilation. Those not enrolled within the 2-hour time window were categorized as missed.
Exclusion criteria: Hyperoxia appropriate in the judgment of the physician (e.g., CO poisoning)
Hyperoxia needs to be avoided (e.g., COPD, paraquat poisoning, etc)
Death imminent, no active measures of treatment
Life expectancy less than 90 d due to the underlying medical condition
Drug overdose, including alcohol intoxication
Long term NIV dependence
Neurological conditions: Guillain–Barré syndrome, cervical cord injury above C5, muscular dystrophy, or motor neuron disease
In the “best interests” of the patient, non-enrollment was appropriate
Enrolled in previous studies
Intervention: “Conservative group”: The alarm was set to sound when the Spo2 was 97%. Exposure to a Spo2 of 97% or was higher minimized.
Control: “Usual care”: No specific methods to limit the Fio2 or the Spo2. No upper alarm limits for Spo2. Fio2 of less than 0.3 during invasive ventilation was discouraged.
Care common to both groups: Minimum SaO2 of 90%; minimum PO2 of 60 mm Hg (regardless of SaO2). FiO2 titrated accordingly. Other aspects of care, including ventilator weaning and extubation practices, were at the discretion of the treating clinician. No restriction on oxygen when transported outside the ICU; an increase in FiO2 was considered standard practice for procedures including as bronchoscopy, suctioning, or tracheostomy. Usual oxygen therapy while on ECMO. Assigned oxygen-therapy strategy until discharge from the ICU or 28 days after randomization, whichever was earlier.
Statistical analysis: Ventilator-free days assumed to be16.4±11.3 days. The absolute difference of 2.6 ventilator-free days was assumed at day 28. 1000 patients for 90% power, an alpha level of 0.05. Analysis- the intention to treat basis.
8 did not consent
1510 missed the window
Con: 484; Lib: 481 (after refusal for evaluation of primary endpoint)
Baseline characteristics: well matched
Clear separation of FiO2 between groups:
Time on a FiO2 of 0.21: Median 29 hours (5 to 78) vs. 1 hour (interquartile range, 0 to 17)
Time with SaO2 97% or less: Median 27 hours (11 to 63.5) and 49 hours (interquartile range, 22 to 112)
The mean FiO2 during the first 10 days of mechanical ventilation in the ICU and the lowest and highest FiO2 values until day 28
Time-weighted mean Pao2 values during the first 10 days of mechanical ventilation
Both were lower in the conservative group.
Primary outcome: Ventilator-free days from randomization till day 28. Patients who died: 0 ventilator-free days.
Median: Conservative vs. liberal: 21.3 (0.0 to 26.3) vs. 22.1 (0.0 to 26.2)
Mean: 15.5±11.8 vs. 16.0±11.5
No. of days of ventilation among survivors: 2.95 (2.61 to 3.33)
3.11 (2.76 to 3.51)
All-cause mortality at 90 d: 166/479 (34.7) vs. 156/480 (32.5); odds ratio, 95% CI: 1.10 (0.84 to 1.44)
All-cause mortality at 180 d: 170/476 (35.7) vs. 164/475 (34.5); 1.05 (0.81 to 1.37)
Rate of unemployed patients at 180 days, among those who were employed prior to the illness: No difference between groups
Cognitive function at 180 d, assessed using the Telephone Interview for Cognitive Status (TICS) questionnaire. Higher scores, better cognitive status. No difference between groups
Health-related quality of life at 180 d assessed using the five-level EuroQol five dimensions (EQ-5D-5L). In the mobility and personal-care domains of the quality-of-life assessment, greater frequency of moderate problems and a lower frequency of severe problems than with usual-oxygen; no difference in other domains.
The Glasgow outcome score was used in patients with a primary neurological problem.
Ventilator-free days at 28 d in patients with HIE: 87 (18.0%) vs. 79 (16.4%) patients. 21.1 (0 to 26.1) days vs. 0 (0 to 26) (p=0.007)
Post-hoc analysis of HIE: 37 of 86 patients (43%) in the conservative-oxygen group vs. 46 of 78 (59%) in the usual-oxygen group (relative risk, 0.73; 95% CI, 0.54 to 0.99; hazard ratio, 0.67; 95% CI, 0.43 to 1.03);
Unfavorable outcome on the Extended Glasgow Outcome Scale: 43 of 78 patients (55%) vs. 49 of 72 (68%), respectively (relative risk, 0.81; 95% CI, 0.63 to 1.05).
Patients who had acute brain pathologies other than acute ischemic hypoxic encephalopathy appeared to do better with usual care oxygen
Patients with sepsis also did better in the usual care oxygen group (Day 180 death 25.9% vs 20.1%)
In many of the previous trials, liberal oxygen interventions were considerably more liberal than the oxygen regimen used in the usual-care group, and relatively few of the patients were critically ill. Different results may also be found with different regimens for conservative oxygen therapy.
Much needed RCT
Challenged the dogma of minimum 30-40% FiO2 in all ICU patients on mechanical ventilation
Interesting Subgroup analysis which will need further exploration.