Discussion
This study evaluated the prognostic value of pulmonary artery systolic
pressure (PASP) in predicting outcomes of weaning patients with COVID-19
from mechanical ventilation. The adjusted HR for a 1-mmHg increase in
PASP was 0.94 (95% CI 0.90‒0.97) for weaning (P < 0.001), and
PASP was negatively correlated with the PaO2:FiO2 (r = -0.48, P
< 0.01). The appropriate cutoff value of PASP for ventilator
weaning was 39.50 mmHg, with a sensitivity of 100% and a specificity of
96.15%
Epidemiological studies of COVID-19 have shown that the mortality rate
of critical patients is 49%, accounting for 5% of confirmed patients7.
Recent studies have revealed that the severity of the disease is an
independent predictor of a poor prognosis8. The effective and
appropriate treatment for critically ill patients seems to be a key for
decreasing mortality. Successful ventilator weaning often indicates a
good prognosis. At present, the conditions for clinical discontinuation
from mechanical ventilation are the minute ventilation volume, maximum
inspiratory pressure, respiratory frequency,
rapid shallow breathing index,
0.1-second airway closure pressure and so on9, 10. However, a previous
study showed that attempts at extubation failed in approximately 20% of
mechanically ventilated patients, and these patients spent more than
40% of the total mechanical ventilation time in the overall weaning
process11. Improper extubation time leads to hypoxemia, and can even
lead to a need for tracheal reintubation. On the other hand, prolonged
mechanical ventilation time increases the risk of related complications
(such as infection, gastrointestinal bleeding, deep vein thrombosis,
etc.)12. Due to the recurrent nature of the disease symptoms, many
patients had met the clinical indicators and were temporarily weaned off
the ventilator, but then required mechanical ventilation again.
Therefore, in order to ascertain the correct timing for weaning patients
off the ventilator, more accurate and specific predictors appropriate to
the characteristics of COVID-19 are needed.
In this study, we found statistically significant differences in
biochemical indicators (IL-6 and D-dimer) between the weaning success
and weaning failure groups. The former indicated that the immune
response of patients who failed to be weaned off the ventilator was
stronger, and the latter reflected the fibrinolytic dysfunction in these
patients. The levels of PCT and CRP were higher than the normal values,
without significant differences between the two groups, indicating that
both groups showed enhanced inflammation. In terms of myocardial injury
markers, the levels of TnI and myoglobin were significantly higher in
group II than in group I, indicating that patients in whom ventilator
weaning failed had more serious heart injury.
We also found that patients who failed to wean off the ventilator had a
thicker interventricular septum and a higher PASP on echocardiography,
which was consistent with a previous study13. The thickened
interventricular septum may be related to the cytokine storm associated
with COVID-19. In our study, the levels of IL-6 were significantly
elevated in both groups, and was higher in patients who were not
successfully weaned from the ventilator. The cytokine storm may increase
the permeability of the vascular wall and could lead to myocardial
edema14, 15. In addition, hypoxia can also lead to an early and
substantial inflammatory response and cell damage16, and may also lead
to some myocardial thickening and edema.
Among the echocardiographic measurements, PASP appeared to be most
related to the severity of the patients’ condition. Our research showed
that PASP had a moderate correlation with the OI, which indicated that
PASP could partly reflect the lung condition of COVID-19 patients. The
result of Cox analysis showed that PASP was an independent risk factor
of ventilator evacuation in critically ill COVID-19 patients. For every
1 mmHg increase in PASP, the risk of weaning from the ventilator was
0.94 times higher, even after adjusting for other risk factors. The ROC
curve showed that the best cutoff value for PASP for predicting the
success of weaning off the ventilator was 39.50 mmHg, with a sensitivity
of 100% and a specificity of 96.15% (P < 0.0001), and an AUC
is 0.99, which showed the good power of the test. We suggest that PASP
and other criteria for ventilator weaning should be considered together.
In critically ill patients, if the PASP is higher than 39.5 mmHg,
ventilator weaning should not be considered.
Other studies have also confirmed that PASP is related to prognosis in
patients with cardiovascular disease. One study showed that when PASP
> 45 mmHg, the prognosis of
acute decompensated heart failure
(ADHF) was poor; early right ventricular dilatation or dysfunction
suggested a poor prognosis, while LVEF or left ventricular diastolic
function could not predict prognosis17.
There are many reasons for the increased pulmonary artery pressure in
critically ill COVID-19 patients. Anatomic reasons include inflammation
of pulmonary arterioles involved in bronchitis and the surrounding
inflammation, accompanied by thickening, spasm, or fibrosis of the blood
vessel walls. Functional reasons include pulmonary vasoconstriction and
spasm caused by a neurohumoral mechanism, such as hypoxia and
respiratory acidosis, which increase pulmonary circulatory resistance.
In addition, secondary injury (emphysema) is caused by long-term
mechanical ventilation, which indirectly causes the rise of PASP.
Computed tomography angiography of one case in our study confirmed that
the spasticity and thrombus of pulmonary arterioles caused the PASP
elevation and that PASP fluctuates during anticoagulation and
vasodilation treatment. In addition to the pulmonary vasospasm caused by
the pathological changes in the lung itself, and the decrease in
pulmonary vascular compliance caused by pulmonary fibrosis, the
accompanying cardiac diseases also have a significant impact. Acute
virus replication in the myocardium and secondary inflammatory responses
can lead to acute myocardial injury, some of which can lead to left
ventricular systolic dysfunction and myocardial swelling18, that is,
ADHF, which can aggravate the pulmonary congestion. With the progression
in the disease course, the pulmonary artery pressure of these patients
increased gradually, which increased the burden of the right heart. In
the present study, two of the three patients who died showed a sudden
decrease in right heart function and pulmonary artery pressure several
days before death. Therefore, PASP elevation is a comprehensive
indicator of the interaction between systemic inflammation and
pathogen-mediated cardiovascular and respiratory system damage, which
may be the mechanism underlying the worse outcomes.
PASP measurements in this study could have been influenced by various
factors, such as nitric oxide (NO)
treatment and increased blood volume due to fluid retention. NO gas is
soluble in water and easily passes through a lipid membrane. NO can
relax vascular smooth muscle, inhibit platelet aggregation, affect
leukocyte chemotaxis, control inflammation, ease pain, regulate
immunity, eliminate oxygen free radicals, and protect the gastric
mucosa. NO can combine with hemoglobin in red blood cells and acts as a
potent vasodilator19. Three of our patients were treated with NO, which
temporarily reduced but did not reverse PASP.
Furthermore, hypoxia and hypercapnia can cause sympathetic nerve
excitability, renal vasoconstriction, and decreased renal blood flow,
resulting in water and sodium retention. The increased blood volume can
lead to increased pulmonary circulation resistance. However, the
patients in this study underwent strict volume management to avoid fluid
retention as far as possible, and the left atrial diameters were rarely
enlarged, as measured by echocardiography. A previous study also showed
no significant association between echocardiographic indices of filling
pressures and weaning failures20. Therefore, PASP in this study was less
affected by pre-pulmonary circulation load.
PASP did not significantly associated with success of ventilator weaning
in the logistic regression analysis; however, it showed an association
with the outcome in Cox regression analysis. This may be explained by
the addition of the time variable, for correction, in the Cox regression
analysis; this result shows that continuous pulmonary hypertension,
rather than temporary changes, may be more strongly related to the
prognosis.
In this study, estimation of pulmonary artery pressure was based on TRPG
plus RAP. The literature on mechanical ventilation
indicates that CVP is equivalent
to RAP; hence, we used CVP instead of RAP. For spontaneous respiration,
we used the American Society of Echocardiography guidelines for
estimation; sonographic measurement of the IVC diameter and
collapsibility was used to estimate RAP21. In terms of the effect of
mechanical ventilation on right atrial pressure, high positive
end-expiratory pressure (PEEP; 8‒10 cmH2O) will affect the flow from the
right heart to the left heart. However, the hemodynamics of the heart
mainly depend on changes in the internal pressure of the heart, and our
patients’ PEEPs were generally below 8‒10 cmH2O during mechanical
ventilation; thus, the increase in the external pressure likely had
little effect22.