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Randomized Controlled Trial
. 2023 Mar 1;24(3):e137-e146.
doi: 10.1097/PCC.0000000000003175. Epub 2023 Jan 19.

Randomization to a Liberal Versus Conservative Oxygenation Target: Redox Responses in Critically Ill Children

Gareth A L Jones  1   2 , Simon Eaton  3 , Michael Orford  3 , Samiran Ray  1   2 , Daisy Wiley  4 , Padmanabhan Ramnarayan  5   6 , David Inwald  6 , Michael P W Grocott  7 , Michael Griksaitis  7   8 , John Pappachan  7   8 , Lauran O'Neill  2 , Paul R Mouncey  4 , David A Harrison  4 , Kathryn M Rowan  4 , Mark J Peters  1   2 ; Oxy-PICU Investigators of the Paediatric Critical Care Society Study Group (PCCS-SG)
Affiliations
Randomized Controlled Trial

Randomization to a Liberal Versus Conservative Oxygenation Target: Redox Responses in Critically Ill Children

Gareth A L Jones et al. Pediatr Crit Care Med. .

Abstract

Rationale: Optimal systemic oxygenation targets in pediatric critical illness are unknown. A U-shaped relationship exists between blood oxygen levels and PICU mortality. Redox stress or iatrogenic injury from intensive treatments are potential mechanisms of harm from hyperoxia.

Objectives: To measure biomarkers of oxidative status in children admitted to PICU and randomized to conservative (oxygen-hemoglobin saturation [Sp o2 ] 88-92%) versus liberal (Sp o2 > 94%) peripheral oxygenation targets.

Design: Mechanistic substudy nested within the Oxygen in PICU (Oxy-PICU) pilot randomized feasibility clinical trial ( ClinicalTrials.gov : NCT03040570).

Setting: Three U.K. mixed medical and surgical PICUs in university hospitals.

Patients: Seventy-five eligible patients randomized to the Oxy-PICU randomized feasibility clinical trial.

Interventions: Randomization to a conservative (Sp o2 88-92%) versus liberal (Sp o2 > 94%) peripheral oxygenation target.

Measurements and main results: Blood and urine samples were collected at two timepoints: less than 24 hours and up to 72 hours from randomization in trial participants (March 2017 to July 2017). Plasma was analyzed for markers of ischemic/oxidative response, namely thiobarbituric acid-reactive substances (TBARS; lipid peroxidation marker) and ischemia-modified albumin (protein oxidation marker). Total urinary nitrate/nitrite was measured as a marker of reactive oxygen and nitrogen species (RONS). Blood hypoxia-inducible factor (HIF)-1a messenger RNA (mRNA) expression (hypoxia response gene) was measured by reverse transcription- polymerase chain reaction. Total urinary nitrate/nitrite levels were greater in the liberal compared with conservative oxygenation group at 72 hours (median difference 32.6 μmol/mmol of creatinine [95% CI 13.7-93.6]; p < 0.002, Mann-Whitney test). HIF-1a mRNA expression was increased in the conservative group compared with liberal in less than 24-hour samples (6.0-fold [95% CI 1.3-24.0]; p = 0.032). There were no significant differences in TBARS or ischemia-modified albumin.

Conclusions: On comparing liberal with conservative oxygenation targets, we show, first, significant redox response (increase in urinary markers of RONS), but no changes in markers of lipid or protein oxidation. We also show what appears to be an early hypoxic response (increase in HIF-1a gene expression) in subjects exposed to conservative rather than liberal oxygenation targets.

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Conflict of interest statement

The remaining authors have disclosed that they do not have any potential conflicts of interest. Drs. Jones’, Eaton’s, Ray’s, Harrison’s, and Peters’ institutions received funding from the Great Ormond Street Hospital Children’s Charity. Drs. Jones’ and Harrison’s institutions received funding from the U.K. National Institute for Health Research (NIHR). Dr. Jones was funded by the National Institute for Health Research Academic Clinical Fellowship scheme. Dr. Eaton’s institution received funding from Vitaflo; he disclosed that he is an inventor on a patent licensed to Vitaflo and University College London. Dr. Ray received support for article research from the NIHR Great Ormond Street Hospital Biomedical Research Centre; he disclosed consultancy work with La Roche Ltd. Dr. Grocott disclosed that he is a coinvestigator of the Intensive Care Unit Randomized Trial Comparing Two Approaches to OXygen Therapy (UK-ROX) in critically ill adults. Dr. Griksaitis is part funded though the National Institute for Health Research (NIHR) Senior Investigator scheme and via Southampton NIHR Biomedical Research Centre. Drs. Mouncey’s and Rowan’s institutions received funding from the U.K. NIHR Health Technology Assessment program. Dr. Mouncey received support for article research from the U.K. NIHR. Dr. Peters’ institution received funding from the Pediatric Critical Care Society; he received funding from the U.K. NIHR Health Technology Assessment Program. The remaining authors have disclosed that they do not have any potential conflicts of interest.

References

    1. Numa A, Aneja H, Awad J, et al.: Admission hyperoxia is a risk factor for mortality in pediatric intensive care. Pediatr Crit Care Med. 2018; 19:699–704
    1. Raman S, Prince NJ, Hoskote A, et al.: Admission Pa o 2 and mortality in critically ill children: A cohort study and systematic review. Pediatr Crit Care Med. 2016; 17:e444–e450
    1. Sznycer-Taub NR, Lowery R, Yu S, et al.: Hyperoxia is associated with poor outcomes in pediatric cardiac patients supported on venoarterial extracorporeal membrane oxygenation. Pediatr Crit Care Med. 2016; 17:350–358
    1. Balcarcel DR, Coates BM, Chong G, et al.: Excessive oxygen supplementation in the first day of mechanical ventilation is associated with multiple organ dysfunction and death in critically ill children. Pediatr Crit Care Med. 2022; 23:89–98
    1. Barrot L, Asfar P, Mauny F, et al.: Liberal or conservative oxygen therapy for acute respiratory distress syndrome. N Engl J Med. 2020; 382:999–1008

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