Arterial partial pressure of carbon dioxide (PaCO₂) is a common parameter in blood gas analysis, reflecting lung ventilation function. Hyperventilation leads to a decrease in PaCO₂, while insufficient ventilation results in increased PaCO₂. In pulmonary embolism (PE) patients, decreased PaCO₂ is often observed and is currently attributed to pulmonary artery blockage by thrombi, which reduces alveolar surfactant, lung compliance, and alveolar diffusion capacity. This disrupts the ventilation/perfusion (V/Q) ratio, leading to pulmonary arteriovenous shunting, local atelectasis, pleural effusion, hypoxemia, and compensatory hyperventilation (resulting in decreased PaCO₂) (1, 2). However, we observed that some PE patients exhibited decreased PaCO₂, while others did not, even in cases with smaller thrombi. This suggests that other factors (e.g., nerve distribution in the lungs) may contribute to decreased PaCO₂. Pulmonary vessels have sympathetic and vagus nerve distribution. When the thrombus stimulates the pulmonary vessel wall, the sympathetic nerve is excited, which leads to vasoconstriction and increased pulmonary vascular pressure. Nevertheless, whether the stimulation of pulmonary nerves by thrombus leads to decreased PaCO₂, and the relationship between thrombus location and decreased PaCO₂ in PE patients is limited research.

This study retrospectively analyzed data from PE patients with decreased PaCO₂ to explore the causes of decreased PaCO₂ and its correlation with thrombus location and 90-day prognosis.

There are many factors affecting arterial partial pressure of carbon dioxide (PaCO₂). Changes in PaCO₂ may result from cardiopulmonary diseases or neurological and mental disorders. Chronic lung diseases such as chronic obstructive pulmonary disease (COPD) can lead to PaCO₂ retention, while idiopathic pulmonary fibrosis (IPF) can cause a decrease in PaCO₂. In this study, no statistically significant differences were observed in chronic lung diseases between the two groups. Additionally, vagus nerve (VN) excitation can increase PaCO₂, whereas sympathetic nerve (SN) excitation can increase the respiratory rate and decrease PaCO₂.

The lungs are innervated by both the sympathetic and parasympathetic nervous systems. The sympathetic nerves originate from the thoracolumbar segment of the spinal cord (T1–L2), emit postganglionic fibers after the sympathetic trunk, and form the anterior and posterior pulmonary plexuses with the vagus nerve. These nerves descend from the hilum of the lung along the trachea and pulmonary vessels, distributing around the bronchi and pulmonary vessel walls. Zhou et al. (5) found that the canine pulmonary sympathetic nerve bundle was primarily distributed in the posterior wall of the pulmonary trunk and the left pulmonary artery, with minimal distribution in the anterior wall of the pulmonary trunk and the right pulmonary artery. The longest and shortest distances between pulmonary artery nerve endings and the pulmonary artery lumen were 4,148 μm and 823 μm, respectively. Zhang et al. (6) reported that there were 2,160 sympathetic nerves around the pulmonary artery in dogs, with the largest concentration at the proximal end of the pulmonary artery bifurcation, accounting for 70 to 84% of the total. Most sympathetic nerves were distributed 1 to 3 mm below the intima at the beginning of the left and right pulmonary arteries and under the intima of the wall after the pulmonary artery bifurcation. Huang et al. (7) confirmed the presence of a large number of sympathetic nerves in the posterior wall of the main pulmonary trunk, the right wall, and the posterior wall of the pulmonary artery bifurcations. Wang et al. (8) found that the sympathetic nerve was overactivated in an animal model of pulmonary thrombosis, with significant increases in sympathetic neurotransmitters such as tyrosine hydroxylase and neuropeptide Y in lung tissue.

The results of this study showed that pulmonary thrombi were distributed in the right pulmonary arteries and/or the left lower pulmonary artery in the decreased PaCO₂ group, consistent with the distribution of pulmonary sympathetic nerves. Multivariate logistic regression analysis identified thrombosis in the right pulmonary artery and left lower lobe pulmonary arteries as risk factors for decreased PaCO₂. This may be due to the abundance of sympathetic nerves in the branches of the right and left pulmonary arteries, which are close to the vascular intima. Mechanical stimulation of the vascular wall by thrombi may activate para-pulmonary sympathetic nerves, leading to hyperventilation and decreased PaCO₂. However, this study was a retrospective case analysis, and sympathetic neurotransmitters such as tyrosine hydroxylase, neuropeptide Y, and norepinephrine were not measured in PE patients with decreased PaCO₂. Therefore, decreased PaCO₂ cannot be considered a predictor of pulmonary vascular sympathetic nerve excitability.

Pearson correlation analysis revealed a weak negative correlation between PASP and decreased PaCO₂. This may be due to the decrease in PaCO₂ leading to a reduction in H⁺ concentration in the blood, stimulating chemoreceptors and causing reflex vasoconstriction, thereby increasing PASP (9, 10). Additionally, Pearson correlation analysis showed a negative correlation between the pulmonary vascular obstruction index (PVOI) and decreased PaCO₂. Metafratzi et al. (11) demonstrated that a PaCO₂ value of 30 mmHg or lower was associated with an arterial bed obstruction index of >50%. The greater the degree of thrombus blockage, the higher the pulmonary vascular pressure, and the more pronounced the vascular sympathetic nerve and mechanical stimulation, which may contribute to the decrease in PaCO₂.

Spearman correlation analysis revealed a weak negative correlation between decreased PaCO₂ and CTS-defined risk PE. However, no correlation was observed between decreased PaCO₂ and the simplified Pulmonary Embolism Severity Index (sPESI). This may be because PASP and PVOI were higher in patients with decreased PaCO₂ compared to the non-decreased group, indicating larger thrombus volume and greater pulmonary artery blockage, resulting in impaired cardiac function and higher risk stratification. However, as a retrospective study, systolic blood pressure and heart rate could not be recorded in real time, and some patients had received oxygen therapy at the time of diagnosis, which may explain the lack of correlation between decreased PaCO₂ and sPESI scores. From these correlation studies, it is evident that decreased PaCO₂ can indicate increased PVOI blockage, leading to elevated PASP and higher CTS-defined risk PE.

Kotsiou et al. (9) followed PE patients with decreased PaCO₂ for 6 months and found that their 6-month survival rate was lower than that of patients with normal PaCO₂. In our study, patients with decreased PaCO₂ exhibited no hemodynamic instability, and the 90-day mortality in the decreased PaCO₂ group was 9 cases, compared to 10 cases in the non-decreased PaCO₂ group. Kaplan–Meier survival analysis indicated no correlation between decreased PaCO₂ and 90-day mortality. The discrepancy with previous findings may be due to the shorter observation period in this study. Additionally, the 90-day mortality in both groups primarily involved patients with chronic end-stage pulmonary diseases, such as interstitial pulmonary disease combined with pulmonary hypertension, right heart failure, and chronic obstructive pulmonary disease with poor pulmonary function. These patients were bed-bound for extended periods, making them more susceptible to pulmonary thrombosis or infection, which likely contributed to the increased mortality.

However, this study has several limitations. First, its retrospective, single-center design limits the generalizability of the findings. To strengthen the results, further research with a larger, prospective, multicenter cohort, incorporating comprehensive medical histories and long-term follow-up data, is necessary. Second, because the number of patients in high-risk was small, and many patients could not be diagnosed by CTPA examination, so it was excluded from this study. Third, Many PE patients have COPD, or pneumonia, interstitial lung disease, pleural effusion, etc., which may have an impact on arterial blood gas, but it is difficult to the inability to accurately quantify the extent or scope of lung lesions prevented an analysis of their impact on PaCO₂, so we did not include CT images in the manuscript.

The prevalence of decreased PaCO₂ was elevated among PE patients. Decreased PaCO₂ was associated with thrombosis in the right pulmonary artery and left lower lobe pulmonary arteries, consistent with the distribution of pulmonary sympathetic nerves. However, it remains unclear whether decreased PaCO₂ can indicate increased sympathetic sensitivity. Decreased PaCO₂ was negatively correlated with PVOI, PASP, and CTS-defined risk PE, indicating greater pulmonary vascular obstruction and higher risk stratification. However, decreased PaCO₂ did not correlate with 90-day mortality.