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Effects of acetaminophen use on mortality of patients with acute respiratory distress syndrome: secondary data mining based on the MIMIC-IV database

BMC Pulmonary Medicine volume 24, Article number: 568 (2024) Cite this article

Abstract

Background

Acetaminophen is a commonly used analgesic after surgery, and its impact on prognosis in patients with acute respiratory distress syndrome (ARDS) has not been studied. This study explores the association between the use of acetaminophen and the risk of mortality in patients with ARDS.

Methods

In this retrospective cohort study, 3,227 patients with ARDS who had or had not received acetaminophen were obtained from the Medical Information Mart for Intensive Care IV, patients were divided into acetaminophen and non- acetaminophen groups. In-hospital mortality of ARDS patients was considered as primary end point. We used univariate and multivariate Cox regression analyses to assess the relationship of acetaminophen use and in-hospital mortality in patients with ARDS. Subgroup analysis was performed according to age, gender, and severity of ARDS.

Results

Of the total patients, 2,438 individuals were identified as acetaminophen users. The median duration of follow-up was 10.54 (5.57, 18.82) days. The results showed that the acetaminophen use was associated with a decreased risk of in-hospital mortality [hazard ratio (HR) = 0.67, 95% confidence interval (CI): 0.57–0.78]. Across various subgroups of patients with ARDS based on age, gender, and severity, acetaminophen use exhibited an association with reduced risk of in-hospital mortality.

Conclusion

Acetaminophen use was associated with in-hospital mortality of patients with ARDS. Acetaminophen therapy may represent a promising therapeutic option for ARDS patients and warrants further investigation.

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Background

Acute respiratory distress syndrome (ARDS) is a condition characterized by non-cardiogenic pulmonary edema, leading to acute respiratory failure [1], which imposes a significant disease burden on the intensive care unit (ICU) due to its high morbidity and mortality rates [2]. Clinicians treating patients with ARDS often consider low tidal volume ventilation (LTVV) and adjunctive therapies (including prone positioning and neuromuscular blockade) [3]. The efficacy of several other interventions, such as high-frequency oscillatory ventilation and neuromuscular blockers, in treating ARDS may be limited [4]. Investigations indicate that the in-hospital mortality rate for ARDS remains high, ranging from 34.9% to 46.1% [5].

The pathogenesis of ARDS involves dysregulated inflammatory response, excessive recruitment and activation of neutrophils (polymorphonuclear leukocytes), and the formation of neutrophil extracellular traps (NETs) [6]. Acetaminophen, a commonly used analgesic after surgery, in inhibiting lipid peroxidation has recently garnered attention [7, 8]. A vitro experiments demonstrated that acetaminophen exhibits a mitigating effect on the formation of NETs in lung epithelial cells derived from patients suffering from severe pneumonia [9]. Moreover, some evidence indicated that the presence of free hemoglobin can cause lung injury and dysfunction of other organs in ARDS potentially through mechanisms such as inflammation and oxidative damage [10, 11]. In a retrospective observational study, elevated concentrations of circulating cell-free hemoglobin were found to be independently associated with an increased risk of mortality in critically ill patients with sepsis, and acetaminophen may exert a protective effect by mitigating oxidative injury induced by cell-free hemoglobin [12]. Therefore, we hypothesized that the acetaminophen use in the ICU might exert an influence on the prognosis of patients with ARDS.

In this study, we obtained a large quantity of patient data from Medical Information Mart for Intensive Care IV (MIMIC-IV) database to explore the association between the use of acetaminophen and the risk of mortality in patients with ARDS.

Methods

Study population

In this retrospective cohort study, we gathered data from the MIMIC-IV database. MIMIC-IV is a large, single-center, publicly available, and de-identified patient database, covering over 70,000 ICU admissions in Beth Israel Deaconess Medical Center, United States from 2008 to 2019 [13]. This database recorded each patient’s length of stay, laboratory tests, medication treatment, vital signs, and other comprehensive information. All personal information is de-identified by utilizing a randomized code to substitute patient identification [14]. The requirement of ethical approval for this was waived by the Institutional Review Board of The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), because the data was accessed from MIMIC-IV database (a publicly available database). The need for written informed consent was waived by the Institutional Review Board of The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College) due to retrospective nature of the study. One author (TW) obtained the necessary certification to access the database, and subsequently made the data extraction process. All methods were performed in accordance with the STROBE guidelines.

We screened all patients in the database, and included only those who satisfied the following criteria: (1) age older than 18 years; (2) diagnosed with ARDS upon ICU admission; (3) hospitalized in the ICU for more than 24 h. The diagnostic criteria for ARDS adhere to the Berlin definition [15]: acute onset, presence of bilateral infiltrates on chest radiograph, arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2) ≤ 300 mmHg, positive end-expiratory pressure (PEEP) ≥ 5 cmH2O, and absence of heart failure. We excluded some patients who lacked information on acetaminophen use (n = 0) or mechanical ventilation use (n = 121). In addition, patients with liver failure (total bilirubin ≥ 12 mg/dL) (n = 4,336) [16], and those with incomplete survival data (n = 2) were also excluded. After applying the inclusion and exclusion criteria, a total of 3,227 patients diagnosed with ARDS were included for further analysis (Fig. 1).

Fig. 1
figure 1

Flow chart illustrating the exclusion and inclusion criteria

Full size image

Acetaminophen use

To identify the acetaminophen use, prescriptions for acetaminophen during ICU stay were identified by analyzing the medication records in the MIMIC-IV database.

Outcomes and follow-up

In-hospital mortality of ARDS patients was considered as primary end point for this study. The date of the patient’s first hospitalization time was considered as the starting point for follow-up, and the median duration of follow-up was 10.54 (5.57, 18.82) days.

Data collection

We extracted baseline parameters of all eligible patients: age (years), gender, race/ethnicity, marital status, insurance status, weight (kg), systolic blood pressure (SBP, mmHg), diastolic blood pressure (DBP, mmHg), mean arterial pressure (MAP, mmHg), heart rate (bpm), respiratory rate (insp/min), temperature (℃), oxygen saturation (SpO2, %), tidal volume (mL), arterial carbon dioxide tension (PaCO2), PaO2 (mmHg), FiO2 (mmHg), PaO2/FiO2 (mmHg), PEEP, (cmH2O), severity of ARDS (mild, moderate, severe), prothrombin time (PT, seconds), pneumonia, acute kidney injury (AKI), sepsis, vasopressor, propofol, midazolam, dexmedetomidine, opiates, ICU type, Simplified Acute Physiology Score II (SAPSII), Sequential Organ Failure Assessment (SOFA) score, Glasgow Coma Score (GCS), Charlson comorbidity index (CCI), white blood cell (WBC, K/μL), platelet (K/μL), red cell distribution width (RDW, %), hemoglobin (g/dL), hematocrit (%), total bilirubin (mg/dL), lactate (mmol/L), bicarbonate (mEq/L), PH, creatinine (mg/dL), epidermal growth factor receptor (eGFR, mL/min/1.73m2), blood urea nitrogen (BUN, mg/dL), glucose (mg/dL), international normalized ratio (INR, %), sodium (mEq/L), potassium (mEq/L), and chloride (mEq/L). The patients were categorized into mild, moderate, and severe ARDS based on their PaO2/FiO2 levels: mild (200 mmHg < PaO2/FiO2 ≤ 300 mmHg), moderate (100 mmHg < PaO2/FiO2 ≤ 200 mmHg), and severe (PaO2/FiO2 ≤ 100 mmHg) [17, 18]. The Kidney Disease: Improving Global Outcomes (KDIGO) criteria were employed to ascertain the occurrence of AKI in patients with ARDS during their hospitalization [19]. Sepsis was diagnosed according to sepsis-3 criteria: patients with documented or suspected infection and an acute change in total SOFA score of ≥ 2 points [20].

Statistical analysis

Multiple imputation was performed for missing variables, and sensitivity analysis was conducted before and after data interpolation (Supplementary Table 1). Skewness and kurtosis methods were used for assessing the distribution of continuous variables, and Levene’s test was used for homogeneity of variance. Continuous variables with normal distribution were presented as Mean and standard deviation [Mean (± SD)], and t test was used for comparison between groups with equal variance, and t 'test was used for uneven variance. Continuous variables with non-normal distribution were described as median and interquartile spacing [M (Q1, Q3)], and Wilcoxon rank sum test was used for comparison between groups. Categorical variables were presented as the number of cases and composition ratio [n (%)]. The groups were compared using the Chi-squared test or Fisher’s exact test. P < 0.05 was considered to indicate a statistically significant difference.

Univariate and multivariate Cox regression analysis was employed to screen out potential confounding factors associated with in-hospital mortality among ARDS patients (Supplementary Table 2). Subsequently, we used univariate and multivariate Cox regression analyses to assess the relationship of acetaminophen use and the risk of in-hospital mortality in patients with ARDS. We employed propensity score matching (PSM) analysis to ensure the robustness of the findings and balance potential influencing factors in research populations. The matching was established in a 1:1 ratio with a caliper width of 0.02. Hazard ratio (HR) with 95% confidence interval (CI) was calculated. Lastly, subgroup analysis was performed according to age, gender, and severity of ARDS. All statistical analyses were conducted using R version 4.2.3 software.

Results

Population characteristics

For this study, a total of 3,227 individuals diagnosed with ARDS were selected. In the whole cohort, the mean age of patients was 59.41 (± 15.89) years old, with 1,312 (40.66%) females and 1,915 (59.34%) males. Among these, 2,438 individuals were identified as acetaminophen users. Table 1 exhibited characteristics of all participants and participants in acetaminophen and non- acetaminophen groups. Compared with the non- acetaminophen group, the acetaminophen group had higher heart rate, respiratory rate, temperature, PEEP, pneumonia, AKI, sepsis, vasopressor, platelet, bicarbonate, PH, and eGFR, more white ethnicity, lower SAPS II score, SOFA score, CCI, RDW, total bilirubin, lactate, BUN, and potassium.

Table 1 Characteristics of all participants and participants in acetaminophen use and non-acetaminophen use groups
Full size table

Association between acetaminophen use and in-hospital mortality

As shown in Supplementary Table 2, potential confounding factors included race/ethnicity, marital status, temperature, PEEP, vasopressor, propofol, midazolam, dexmedetomidine, ICU type, SAPSII, GCS, platelet, RDW, total bilirubin, lactate, bicarbonate, BUN, and INR. We evaluated the link between acetaminophen use and in-hospital mortality in patients with ARDS (Table 2). The result of univariate Cox regression analysis indicated that the acetaminophen use was found to be associated with a decreased risk of in-hospital mortality compared to non-use (HR = 0.52, 95%CI: 0.45–0.60, P < 0.001). After adjusting all confounding factors, this correlation stayed statistically significant (Model 2: HR = 0.67, 95%CI: 0.57–0.78, P < 0.001). We employed a 1:1 PSM analysis to further validate the findings. A total of 1494 patients with ARDS were enrolled after PSM. After PSM, the matching scores of the samples were uniformly distributed (Supplementary Fig. 1). As shown in Supplementary Fig. 2, the standardized mean difference (SMD) of variables were all within the range of ± 0.1 after PSM, indicating a balance of variables between the groups. Interestingly, the relationship between acetaminophen use and in-hospital mortality remained consistent after PSM (Model 2: HR = 0.70, 95%CI: 0.58–0.84, P < 0.001).

Table 2 Association between acetaminophen use and in-hospital mortality
Full size table

Subgroup analysis

A stratified analysis was conducted to investigate the influence of acetaminophen use on in-hospital mortality among different population. As shown in Table 3, there is a significant relationship between acetaminophen use and in-hospital mortality among individuals aged < 65 years (HR = 0.65, 95% CI: 0.51–0.82) and aged ≥ 65 years (HR = 0.70, 95% CI: 0.56–0.87) in full adjusted model, as well as among males (HR = 0.66, 95% CI: 0.53–0.82) and females (HR = 0.68, 95% CI: 0.54–0.86), and individuals with moderate ARDS (HR = 0.64, 95% CI: 0.50–0.82), and severe ARDS (HR = 0.61, 95% CI: 0.44–0.83). The relationship between acetaminophen use and in-hospital mortality remains consistent in direction. In addition, we also found that acetaminophen use was associated with decreased risk of in-hospital mortality with a marginal significance in patients with mild ARDS (P = 0.051). In short, it can be inferred that acetaminophen use exhibited an association with reduced risk of in-hospital mortality across various subgroups of patients with ARDS.

Table 3 Subgroup analysis
Full size table

Discussion

This study focused on the association between acetaminophen use and in-hospital mortality in critically ill patients with ARDS. Our findings revealed a significant association between acetaminophen use and a reduction in in-hospital mortality. Importantly, these findings remained consistent across various subgroups of patients with ARDS. Therefore, our study provides evidence supporting the potential benefits of acetaminophen use to improve the outcome in individuals with ARDS.

Acetaminophen is widely utilized as a popular analgesic and antipyretic medication globally [21]. Its antipyretic effect is attributed to its inhibition of cyclooxygenase-3 and prostaglandin synthesis in the central nervous system, thereby readjusting the heat-regulating center in the hypothalamus [22]. Some prior studies have investigated the impact of acetaminophen administration on prognosis in critically ill patients. In a multicenter retrospective observational study, the use of paracetamol (acetaminophen) was found to be significantly associated with a reduction in in-hospital mortality among patients in the ICU [23]. While Lee BH et al., reported that treatment with acetaminophen was associated with a significant increase in 28-day mortality for critically ill patients with sepsis (adjusted odds ratio = 2.05, P = 0.01), but not for critically ill patients without sepsis (adjusted odds ratio: 0.58, P = 0.63) [24]. In addition, the study conducted by Janz et al. suggested that acetaminophen may exert a protective effect in critically ill patients with sepsis, potentially through its ability to mitigate oxidative damage caused by acellular hemoglobin [12]. An Ascorbate in Sepsis: Targeted Therapy to Enhance Recovery (ASTER) platform Randomized Clinical Trial pointed out that intravenous acetaminophen was safe for adults with sepsis, and further revealed that patients treated with acetaminophen were less likely to develop ARDS [25]. ARDS is a severe pulmonary disorder with a high mortality rate, and pharmacologic intervention appears to be a viable approach for patients diagnosed with ARDS [26]. However, the impact of acetaminophen therapy on clinically relevant outcomes in ARDS patients remains unclear. In our study, after adjusting potential confounding factors, we observed a significant correlation between the use of acetaminophen and decrease in in-hospital mortality among patients with ARDS. Furthermore, the association was also robust across various subgroups.

The precise mechanisms for patients with ARDS benefiting from acetaminophen administration remain unknown. The pathogenesis of ARDS is caused by the oxidative stress dysregulation and neutrophil recruitment [27]. Acetaminophen treatment may attenuate oxidative stress and suppress the exaggerated innate immune response, thereby facilitating tissue repair [28, 29]. In addition, acetaminophen also exhibits potent inhibition of lipid peroxidation mediated by blood proteins [30]. The pathophysiological mechanisms of acetaminophen on ARDS prognosis require further investigation.

To the best of our knowledge, this study represents the first investigation into the association between the acetaminophen use and in-hospital mortality among ARDS patients, providing evidence for treatment options and clinical management of patients with ARDS. Additionally, we adjusted for additional confounding factors and performed subgroup analysis, which enhances the reliability and robustness of our findings. However, it is important to acknowledge several noteworthy limitations in this study. Firstly, this was a single-center retrospective cohort study. Consequently, there exists the potential for selection bias, which may limit the generalizability of the findings to all patients with ARDS. Secondly, the MIMIC-IV database lacks the information regarding the criteria and timing for acetaminophen administration, potentially introducing bias in assessing the association between acetaminophen use and in-hospital mortality. But we utilized PSM analysis to ensure the robustness of the findings and balance potential influencing factors in research populations. Thirdly, this retrospective study was conducted using the MIMIC-IV database. Despite efforts to mitigate potential confounding factors, there remain unidentified variables that may introduce confusion, such as etiology of ARDS, serum albumin levels, and the dosage of acetaminophen used. Furthermore, MIMIC-IV only contains the records of ICU patients at the Beth Israel Deaconess Medical Center between the years 2008 and 2019, but there may be new developments in the management of ARDS patients currently. Lastly, this study focused on patients with ARDS, excluding those who may develop ARDS shortly after admission. In short, although we have discovered an association between acetaminophen and the prognosis of patients with ARDS in this study, current accepted interventions solely encompass LTVV, prone positioning and neuromuscular blockade. More in-depth studies with prospective design are required to validate and further expand our findings.

Conclusion

In conclusion, the present study demonstrates that acetaminophen use was associated with in-hospital mortality of patients with ARDS. Acetaminophen therapy may represent a promising therapeutic option for ARDS patients and warrants further investigation.

Data availability

The datasets used and/or analyzed during the current study are available from the MIMIC-IV database, https://mimic.physionet.org/iv/.

Abbreviations

ARDS:

Acute respiratory distress syndrome

ICU:

Intensive care unit

NETs:

Neutrophil extracellular traps

MIMIC-IV:

Medical Information Mart for Intensive Care IV

SBP:

Systolic blood pressure

DBP:

Diastolic blood pressure

MAP:

Mean arterial pressure

SpO2 :

Oxygen saturation

PaCO2 :

Arterial carbon dioxide tension

PT:

Prothrombin time

AKI:

Acute kidney injury

SAPSII:

Simplified Acute Physiology Score II

SOFA:

Sequential Organ Failure Assessment

GCS:

Glasgow Coma Score

CCI:

Charlson comorbidity index

eGFR:

Epidermal growth factor receptor

BUN:

Blood urea nitrogen

INR:

International normalized ratio

KDIGO:

Kidney Disease: Improving Global Outcomes

SD:

Standard deviation

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Acknowledgements

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Funding

This work was supported by the Anhui Province Natural Science Foundation (2108085MH300) and Anhui Province Clinical Medical Research Translation Special Project (202304295107020006, 202304295107020001).

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Authors and Affiliations

  1. Anhui Medical University, Hefei, Anhui Province, 230022, China

    Tong Wang & Weihua Lu

  2. Department of Critical Care Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui Province, 241000, China

    Tong Wang, Hongzhen Yin, Guanggui Shen, Yingya Cao, Xuemei Qin, Qiancheng Xu, Yupeng Qi & Xiaogan Jiang

  3. Department of Critical Care Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Anhui Province Clinical Research Center for Critical Respiratory Medicine, No.2 West Road of Zheshan, Jinghu District, Wuhu, Anhui Province, 241000, China

    Weihua Lu

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Contributions

TW and WL designed the study. TW wrote the manuscript. HY, GS, YC, XQ, QX, YQ, and XJ collected, analyzed, and interpreted the data. WL critically reviewed, edited, and approved the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Weihua Lu.

Ethics declarations

Ethics approval and consent to participate

The requirement of ethical approval for this was waived by the Institutional Review Board of The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), because the data was accessed from MIMIC-IV database (a publicly available database). The need for written informed consent was waived by the Institutional Review Board of The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College) due to retrospective nature of the study. All methods were performed in accordance with the relevant guidelines and regulations. One author (TW) has become a credentialed used on PhysioNet and that they have signed the data use agreement (https://physionet.org/content/mimiciv; https://doiorg.publicaciones.saludcastillayleon.es/10.13026/kpb9-mt58; https://doiorg.publicaciones.saludcastillayleon.es/10.1038/s41597-022-01899-x).

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Supplementary Information

Supplementary Material 1: Supplementary Fig. 1. The propensity scores of the samples before and after PSM.

12890_2024_3379_MOESM2_ESM.pdf

Supplementary Material 2: Supplementary Fig. 2. The standardized mean difference (SMD) of variables before and after PSM.

Supplementary Material 3.

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Wang, T., Yin, H., Shen, G. et al. Effects of acetaminophen use on mortality of patients with acute respiratory distress syndrome: secondary data mining based on the MIMIC-IV database. BMC Pulm Med 24, 568 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12890-024-03379-x

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Keywords

BMC Pulmonary Medicine

ISSN: 1471-2466

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