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    2 Comments for this article
    Iso-shunt relationship between FiO2-PaO2 and potential "confounding by indication"
    Robert Tasker, MA, MBBS, MD | Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, & Harvard Medical School, Boston
    The authors describe an association between PaO2 ≥300 mmHg and death in patients undergoing arterial blood gas (ABG) analysis while requiring treatment in a pediatric intensive care unit (PICU). They also find – compared to patients with PaO2 <300 mmHg – increasing odds of death with increasing numbers (1, 2 and ≥3) of ABGs with PaO2 ≥300 mmHg, and ≥3 hours apart from one another. In reconciling the meaning of this work, the information in the paper’s Figure is helpful. From first principles, using the iso-shunt relationship between FiO2 and PaO2 in a way that takes account of both ventilation-perfusion (V-Q) mismatch and scatter, and intrapulmonary shunt, we think of three hypothetical conditions:

    1. In those with normal gas exchange (i.e., normal V-Q mismatch scatter and shunt 0%), the steps in PaO2 300 mmHg to ≥550 mmHg could be achieved with steps in FiO2 from 0.45 to ≥0.75. In this state, PaO2 100 mmHg should be achieved with FiO2 0.21–0.25.
    2. In those with some abnormality in gas exchange (i.e., V-Q mismatch scatter and shunt ≤5%), the steps in PaO2 300 mmHg to ≥550 mmHg could be achieved with steps in FiO2 from 0.60 to 1.00. In this state, PaO2 100 mmHg should be achieved with FiO2 0.30.
    3. In those with clearly abnormal gas exchange (i.e., V-Q mismatch scatter and shunt 20%), FiO2 1.00 would be required to achieve PaO2 300 mmHg. In this state, PaO2 100 mmHg should be achieved with FiO2 0.60.

    Setting aside any interaction between the FiO2–PaO2 relationship and positive end-expiratory pressure (PEEP) in the mechanically ventilated patient, under what circumstances would the hypothetical patients described above knowingly have their baseline ideal FiO2 increased from 0.21, or 0.30, or 0.60 to, at most, 1.00 – and have serial ABGs whilst doing so? The authors mention in their discussion the problem of “confounding by indication”, i.e., higher FiO2 being used during resuscitation with the sickest patients receiving a FiO2 1.00. There are, however, three other examples of this problem that may be of systematic significance with the data analysis. First, similar to the author’s resuscitation example, is the patient with severe traumatic brain injury and brain swelling and, at worst, some abnormality in gas exchange (Example 2 above), who has episodes of raised intracranial pressure. It is not uncommon for these patients to require repeated episodes of bag-manual-ventilation with FiO2 1.00. In this circumstance any number of ABGs may be carried out to check that PaCO2 is not too low. Second, the patient undergoing apnea testing as part of the assessment of Death by Neurological Criteria (DNC). Typically, the test is started after a period of pre-oxygenation (10-minutes with FiO2 1.00) with an ABG confirming an appropriate starting PaCO2. At least two tests are carried out separated by many hours. Last, in the potential lung organ donor, the so-called “standard criteria” for choosing lungs are to ventilate with FiO2 1.00 and PEEP 5 cmH2O and then check that PaO2 >300 mmHg (i.e., lungs better than the third of the hypothetical cases described above).

    Are the associations between PaO2 ≥300 mmHg and death still present when the above circumstances are considered? Can the dataset be edited to exclude ABGs from the time of DNC determination, or organ transplant assessment? Alternatively, perhaps consider clustering of FiO2, PaCO2 and PaO2 and work out whether this information really is about PICU patients being exposed to higher than necessary FiO2 for their state of VQ mismatch scatter and shunt.
    Observations re: presence of arterial line and SpO2/PaO2 relationship
    Hari Krishnan, MD | Birmingham Children's Hospital, UK
    The authors must be congratulated on a very well conducted study. The detailed analysis plan, including not just the maximum PaO2, but also using number of hyperoxaemic blood gases, time distribution between the samples, and using mPELOD2 (excluding PF ratio) to derive observed-expected mortality data for various PaO2 thresholds certainly add to the strength of association between hyperoxaemia and mortality.

    1. Given that this is a single centre study, it may be useful to provide some information about the centre's oxygen saturation/PaO2 targeting practices as context to understanding the ~28% of patients with a PaO2 with hyperoxaemia.

    2. Presence of an arterial line as a marker of severity of illness is illustrated by the lower mortality rate of only 0.5% in those without an arterial line (74% of the whole population), compared with 6.5% in patients with an arterial line (26% of the whole population). This also illustrates the reason further sensitivity analysis and testing for unknown confounders are useful.

    3. The authors suggest "A wide range of PaO2 values was observed within 20 minutes of documented SpO2 and FIO2 values; therefore, we did not attempt to use measurements of SpO2 and FIO2 as surrogates for arterial oxygen tension (eTable 12 in the Supplement)."

    It is unsurprising that the authors did not find a correlation between SpO2 and PaO2 values. The analysis seems to have been restricted to the "plateau" part of oxygen dissociation curve (SpO2=100 in eTable 12) where any correlation is not expected. This does not diminish the potential utility of oxygen saturation targeting as the best strategy to prospectively limit exposure to hyperoxemia at the bedside.

    Many congratulations once again on this well designed study .
    Original Investigation
    Critical Care Medicine
    August 21, 2019

    Association of Severe Hyperoxemia Events and Mortality Among Patients Admitted to a Pediatric Intensive Care Unit

    Author Affiliations
    • 1Department of Pediatrics, University of Pittsburgh School of Medicine; UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
    • 2Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
    • 3Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
    • 4Health Informatics for Clinical Effectiveness, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
    JAMA Netw Open. 2019;2(8):e199812. doi:10.1001/jamanetworkopen.2019.9812
    Key Points español 中文 (chinese)

    Question  Is severe hyperoxemia (arterial oxygen tension ≥300 mm Hg) associated with mortality among critically ill children?

    Findings  In this cohort study of 23 719 intensive care encounters from 2009 to 2018 at a children’s hospital, 6250 patients had at least 1 measured arterial oxygen tension value. After adjusting for covariates, severe hyperoxemia appeared to be independently associated with in-hospital mortality, and a stepwise increase in the adjusted odds of mortality was observed with more episodes of severe hyperoxemia.

    Meaning  Severe hyperoxemia appeared to be associated with mortality in a large, single-center cohort of critically ill children; prospective data are needed to assess causality.


    Importance  A high Pao2, termed hyperoxemia, is postulated to have deleterious health outcomes. To date, the association between hyperoxemia during the ongoing management of critical illness and mortality has been incompletely evaluated in children.

    Objective  To examine whether severe hyperoxemia events are associated with mortality among patients admitted to a pediatric intensive care unit (PICU).

    Design, Setting, and Participants  A retrospective cohort study was conducted over a 10-year period (January 1, 2009, to December 31, 2018); all 23 719 PICU encounters at a quaternary children’s hospital with a documented arterial blood gas measurement were evaluated.

    Exposures  Severe hyperoxemia, defined as Pao2 level greater than or equal to 300 mm Hg (40 kPa).

    Main Outcomes and Measures  The highest Pao2 values during hospitalization were dichotomized according to the definition of severe hyperoxemia and assessed for association with in-hospital mortality using logistic regression models incorporating a calibrated measure of multiple organ dysfunction, extracorporeal life support, and the total number of arterial blood gas measurements obtained during an encounter.

    Results  Of 23 719 PICU encounters during the inclusion period, 6250 patients (13 422 [56.6%] boys; mean [SD] age, 7.5 [6.6] years) had at least 1 measured Pao2 value. Severe hyperoxemia was independently associated with in-hospital mortality (adjusted odds ratio [aOR], 1.78; 95% CI, 1.36-2.33; P < .001). Increasing odds of in-hospital mortality were observed with 1 (aOR, 1.47; 95% CI, 1.05-2.08; P = .03), 2 (aOR, 2.01; 95% CI, 1.27-3.18; P = .002), and 3 or more (aOR, 2.53; 95% CI, 1.62-3.94; P < .001) severely hyperoxemic Pao2 values obtained greater than or equal to 3 hours apart from one another compared with encounters without hyperoxemia. A sensitivity analysis examining the hypothetical outcomes of residual confounding indicated that an unmeasured binary confounder with an aOR of 2 would have to be present in 37% of the encounters with severe hyperoxemia and 0% of the remaining cohort to fail to reject the null hypothesis (aOR of severe hyperoxemia, 1.31; 95% CI, 0.99-1.72).

    Conclusions and Relevance  Greater numbers of severe hyperoxemia events appeared to be associated with increased mortality in this large, diverse cohort of critically ill children, supporting a possible exposure-response association between severe hyperoxemia and outcome in this population. Although further prospective evaluation appears to be warranted, this study’s findings suggest that guidelines for ongoing management of critically ill children should take into consideration the possible detrimental effects of severe hyperoxemia.