Efficacy observation of erythropoietin on sepsis complicated with acute respiratory distress syndrome

1. Introduction

Sepsis is a complex syndrome characterized by an excessive immune response to infection, leading to numerous life-threatening complications. Among these, acute respiratory distress syndrome (ARDS) is one of the earliest and most prevalent complications, particularly when induced by sepsis, characterized by its rapid onset and high mortality rates [1, 2]. Although the pathogenesis of ARDS remains partially understood, it is commonly attributed to diffuse pulmonary vascular endothelial damage and increased vascular permeability, resulting in pulmonary edema and infiltration of inflammatory cells within the lung tissue. Clinically, ARDS manifests as refractory hypoxemia and respiratory distress [3]. Current therapeutic strategies for ARDS, especially when secondary to sepsis, involve supportive care such as respiratory support, antibiotic therapy, anticoagulation and the administration of vasoactive drugs, and till present, there is a lack of specific targeted pharmacological interventions for these patients [4].

Erythropoietin (EPO), a cytokine belonging to the type I cytokine superfamily, exhibits a broad spectrum of tissue-protective effects, including anti-apoptotic, anti-inflammatory, and immunomodulatory actions [5]. Clinically, EPO is extensively used for treating renal anemia and has been shown to enhance cardiac function in heart failure patients [6, 7, 8]. Notably, EPO has demonstrated protective effects on lung tissue post-cardiopulmonary resuscitation [9]. Despite these findings, the application of EPO in the treatment of ARDS, particularly sepsis-induced ARDS, has been scarcely reported.

In this study, we explore the potential therapeutic role of EPO in treating patients with sepsis-associated ARDS to provide clinical insights for improving the management of these patients.

2. Research materials and methods

3. Results

3.6 Duration of mechanical ventilation and 28-day mortality

The mean duration of mechanical ventilation was 7.48 ± 1.80 days in the placebo group and significantly shorter in the EPO group at 5.47 ± 1.28 days (t = 6.434, p < 0.05). Within a 28-day hospitalization period, the EPO group experienced 8 deaths, resulting in a mortality rate of 16.00%, and an average survival time of 27.020 ± 0.364 days with a 95% confidence interval (CI) ranging from 26.307 to 27.733 days. Conversely, the placebo group had 17 deaths, translating to a mortality rate of 34.00%, and an average survival time of 25.300 ± 0.610 days, with a 95% CI between 24.104 and 26.469 days. A significant difference in survival rates between the two groups was identified (Log-Rank test, χ² = 4.651, p = 0.031), as demonstrated in Fig. 1.

Fig. 1.Survival curve within 28 days after hospitalization in the two groups. EPO: Erythropoietin.

4. Discussion

ARDS is a common critical illness in the intensive care unit (ICU). Available data suggest that over 10% of ICU admissions are due to ARDS, with a mortality rate ranging between 30% and 50% [12, 13]. Survivors often endure irreversible cerebral damage, leading to cognitive impairment, diminished lung capacity, and reduced exercise tolerance, significantly impacting their quality of life [14]. The association between sepsis and the progression of ARDS, particularly in critically ill patients, has been well-documented. The incidence of ARDS secondary to sepsis is higher, with mortality rates potentially reaching 70% to 90%, substantially exceeding those associated with non-septic ARDS [15]. The heterogeneity of ARDS contributes to variable patient responses to treatment. Currently, the management of septic ARDS lacks a swift and effective protocol, with strategies limited to pharmacotherapy, supportive care, and targeted interventions [16]. EPO, a 30.4 kDa endogenous glycoprotein hormone, is renowned for its role in erythropoiesis and enhancing oxygen delivery. Furthermore, EPO has been attributed with organoprotective properties in various contexts, including ischemia-reperfusion injury, neural damage, inflammation, and trauma across both animal studies and clinical trials [17, 18, 19]. Notably, EPO has shown the potential to reduce lung injury in pneumonia models by inhibiting neutrophil extracellular trap (NET) formation. This study employs normal saline as a placebo to contrast with EPO treatment, aiming to elucidate EPO’s effects on septic ARDS, focusing particularly on alterations in blood gas parameters, lung volumes, and levels of inflammatory markers in patients.

Sepsis-associated ARDS often results in elevated capillary permeability, diminishing lung compliance, leading to decreased lung volume and subsequent hypoxemia; thus, enhancing respiratory mechanics and addressing the hypoxic condition are essential for lowering mortality in these patients [20]. The findings of this study indicated no significant differences in heart rate and mean arterial pressure between patients treated with EPO and those given the placebo, suggesting minimal impact of EPO on patient hemodynamics. However, blood gas analysis revealed improved PaO₂, PaCO₂ and oxygenation index levels in the EPO group compared to the placebo group on treatment days 7 and 14. EPO, an oxygen-regulated hormone, enhances erythropoiesis by activating hypoxia-inducible factors that stimulate the proliferation, differentiation, and maturation of erythroid progenitor cells in the bone marrow, thereby ameliorating the hypoxic state [21]. In addition, our results showed that the lung volume and FRC of patients in the EPO group were significantly increased compared with that in the placebo group, suggesting that the alveolar compliance of patients in the well-ventilated area was better, and combined with the improvement of compliance and oxygenation indicators, it can be observed that the pulmonary function of patients was better. Inflammatory factor infiltration is an important factor related to the progression of sepsis-induced diseases. The sepsis-mediated inflammatory cascade can lead to alterations in the alveolar-capillary endothelial barrier’s permeability, precipitating significant respiratory system damage. Thus, the administration of active anti-inflammatory and anticoagulant therapies is beneficial in the management of ARDS triggered by sepsis [22, 23]. Our study results demonstrated that the levels of TNF-α, IL-10 and CRP were significantly lower in the EPO group compared to the placebo group at both the 7th and 14th days of treatment, indicating that EPO effectively enhances the anti-inflammatory response, thereby diminishing neutrophil infiltration and the subsequent inflammatory injury caused by adhesion. These findings align with prior research indicating that EPO can reduce neutrophil infiltration into lung tissue [24, 25]. Nevertheless, the precise mechanism behind EPO’s anti-inflammatory effects warrants further investigation. Additionally, we evaluated the average duration of mechanical ventilation and the mortality rate within 28 days of hospitalization among patients receiving either treatment regimen and observed that the EPO group had a significantly shorter duration of mechanical ventilation and a lower mortality rate compared to the placebo group, suggesting that this treatment regimen aids more effectively in disease recovery and decreases the short-term mortality associated with sepsis and ARDS, which could be related to EPO’s role in ameliorating hypoxemia and diminishing the inflammatory response.

5. Conclusions

In this study, we explored the effects of EPO, and our findings demonstrate that EPO enhances the therapeutic outcomes in patients with sepsis-associated ARDS by improving blood gas metrics, augmenting lung volume functionality and attenuating serum levels of inflammatory mediators. As a multifunctional endogenous regulator, EPO could be a promising therapeutic agent for sepsis-induced ARDS. Nevertheless, concerns regarding the safety, optimal dosing and protective mechanisms of EPO remain to be addressed, urging the need for further comprehensive trials and clinical investigations.

Availability of data and materials

The authors declare that all data supporting the findings of this study are available within the paper and any raw data can be obtained from the corresponding author upon request.

Author contributions

LJ and XX—designed the study and carried them out. LJ, XX, WXZ and JQC—supervised the data collection, analyzed the data, interpreted the data. LJ, XX, WXZ, JQC, JHY and WZ—prepared the manuscript for publication and reviewed the draft of the manuscript. All authors have read and approved the manuscript.

Ethics approval and consent to participate

Ethical approval was obtained from the Ethics Committee of Sir Run Run hospital of Nanjing Medical University (2022-SR-S037). Written informed consent was obtained from legally authorized representatives for anonymized patient information to be published in this article.

Acknowledgment

Not applicable.

Funding

This work was supported by Research Project on Elderly Health of Jiangsu Provincial Health Commission (Grant No. LKM2022009) and Jiangsu Provincial Health Commission Research Project (Grant No. M2022033).

Conflict of interest

The authors declare no conflict of interest.