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.