DISCUSSION
In this retrospective cohort study of PARDS patients with clinically obtained echocardiograms, there was no association between AVDSf at PARDS onset and RV systolic dysfunction or pulmonary hypertension within 24 hours of PARDS diagnosis. AVDSf was, however, associated with measures of oxygenation at PARDS onset, suggesting that the primary determinant of AVDSf was ventilation-perfusion mismatch from pulmonary overdistension or increased intrapulmonary shunt rather than reduced pulmonary blood flow from increased pulmonary vascular resistance.
In pediatrics, elevated AVDSf, RV systolic dysfunction, and PH have all been independently associated with mortality and worse outcomes in PARDS6,7,10,11. As alveolar dead space is increased in low cardiac output states and in intrapulmonary shunt, elevated AVDSf likely reflects a combination of these physiologies. Our primary hypothesis was that higher AVDSf would be associated with echocardiographic evidence of RV systolic dysfunction and PH due to an increase in pulmonary vascular resistance. However, this was not demonstrated in this cohort of patients who had clinical echocardiograms performed a median of 1.2 hours from the qualifying arterial blood gas.
AVDSf at onset also did not discriminate echocardiographic measures of RV dysfunction and PH. We did find associations between AVDSf and secondary outcomes of measures of oxygenation (OI, P/F ratio) at PARDS onset. It may be that very early during PARDS higher AVDSf could be more reflective of intrapulmonary shunt as positive pressure is being initiated and titrated to maximize lung recruitment. In one study of sheep models of early ARDS, increases in estimated AVDSf by PET scans were attributable primarily to redistribution of perfusion likely related to mechanisms including hypoxic pulmonary vasoconstriction and gravitational effects with redistribution of perfusion away from non-dependent lung regions with no change in mean pulmonary artery pressures15. Further, compared to other PARDS cohorts, our study cohort had a relatively high AVDSf at onset (median 0.2, IQR 0.1-0.3) and had a higher severity of illness. This may have created selection bias in our sample that could have biased toward the null hypothesis.
One recent adult study demonstrated that increases in AVDSf were associated with relative increases in echocardiographic surrogates for pulmonary vascular resistance over the course of ARDS12, suggesting that a changing and increasing AVDSf over time may be an indicator of those who may be at risk for RV systolic dysfunction. As new or persistent RV systolic dysfunction during the first 8 days of PARDS is associated with worse outcomes7, future studies in pediatric patients should investigate the longitudinal association of changing AVDSf as a marker or potential predictor of PARDS-related pulmonary hypertension or subsequent RV dysfunction. Similar to studies showing that oxygenation metrics and pulmonary mechanics early in PARDS are not associated with pulmonary injury and outcomes4,13,16, it is possible that using AVDSf at later time points or the trajectory of AVDSf will have more value, particularly as PARDS pathophysiology evolves into worsening hypoxemia and/or multiple organ dysfunction syndrome. As pulmonary arterial catheters are rarely used in modern PARDS management, prospective and protocolized echocardiograms may also allow for other non-invasive surrogates of elevated pulmonary vascular resistance or RV-pulmonary arterial coupling to be more fully investigated. Alternatively, it is possible that pulmonary, rather than vascular, physiology ultimately determines AVDSf. In either case, the clinical utility of AVDSf should be clarified in future studies.
Our study has limitations including its retrospective design and single-center cohort. We selected PARDS patients who had a clinically obtained echocardiogram and available PetCO2 data, which restricted our cohort to approximately 22% of the total patients from the PARDS database during the study timeframe. As discussed above, this resulted in a cohort with a higher severity of illness with bias toward patients more likely to have hemodynamic instability or specific diagnoses, such as sepsis. Therefore, generalizability to all PARDS patients may be limited. Another limitation from our retrospective design was the quality of ETCO2 data available for review. ETCO2 values were directly recorded from the electronic medical record using the closest value within an hour of the first qualifying blood gas at PARDS onset and had a median time from blood gas of 15 min. However, it is possible that the ETCO2 value may have changed at the time of the blood gas. Approximately one-third of the patients with echocardiograms did not have EtCO2 data available or had an EtCO2 recorded that yielded a negative AVDSf when calculated. Finally, ideally alveolar dead space as measured by volumetric capnography would also be included as the correlation of alveolar dead space estimated with that method compared to AVDSf is reduced in patients with hypoxemia8,9.
In this retrospective cohort study, alveolar dead space fraction at PARDS onset was not associated with RV systolic dysfunction or pulmonary hypertension identified by echocardiography within 24 hours of PARDS onset and may be more closely associated with ventilation-perfusion mismatch from pulmonary overdistension or increased intrapulmonary shunt. Future investigations should focus on clarifying the clinical utility of AVDSf in relation to existing metrics throughout the course of PARDS.