Sepsis is a life-threatening condition arising from an abnormal response to infection, which results in organ dysfunction. It remains a significant cause of death among critically ill patients (1, 2). Even though sepsis-related mortality has reduced recently, it still impacts over 30 million people every year, potentially leading to 6 million deaths (3, 4). Alarmingly, remarkable disparities exist between regions. Patients in low to middle-income countries face higher mortality rates from sepsis than those in developed countries (5, 6). Consequently, sepsis treatment and management persist to be significant obstacles.

Acetaminophen, also known as an over-the-counter medication, is deemed safe at therapeutic doses. It exhibits pain-relieving and fever-reducing properties similar to aspirin (7, 8). Nowadays, it is standard in the intensive care unit (ICU) to use acetaminophen to reduce body temperature for patients presenting with fever and potential infections (9, 10). Most patients diagnosed with sepsis show symptoms of fever (11, 12). In severe sepsis cases, hemolysis occurs, leading to the production of free hemoglobin, reactive oxygen species, and lipid peroxidation, which ultimately cause cell damage (13, 14). Study outcomes have demonstrated that acetaminophen reduces free radicals in iron protoporphyrin-free hemoglobin and hinders lipid peroxidation (15, 16). Thus, employing acetaminophen may be beneficial to sepsis patients. However, its use in sepsis treatment does not have universal agreement within the scholarly community. Some experts champion the idea of reducing body temperature, identifying fever as a harmful factor (17). Conversely, there’s a belief among others that fever during an infection can enhance survival (18, 19). Moreover, studies indicate no impact on the number of ICU-free days when acetaminophen is administered early to treat fever resulting from a probable infection (20).

Due to the lack of high-level evidence, ICU physicians currently face uncertainty regarding the benefits, effectiveness, or potential harm of acetaminophen treatment for fever in cases of sepsis (21). To address this uncertainty, we conducted a retrospective cohort study based on the MIMIC-IV database. The aim was to assess the association between acetaminophen use and in-hospital mortality, 30-day mortality, length of hospital stay, and ICU stay in sepsis patients. To be more specific, our hypothesis posits that compared to patients not using acetaminophen, the use of acetaminophen can lower short-term mortality.

We utilized Navicat Premium v16.1.7 to gather data from the MIMIC-IV database v2.2, specifically focusing on sepsis patients who either did or did not use acetaminophen. This publicly accessible database provides real-world data on more than 73,000 patients who were admitted to the ICU at Beth Israel Deaconess Medical Center between 2008 and 2019 (22). Author Shilin Sun secured authorization to utilize this database (Certification Number: 12281929). All reporting in this study adheres to the guidelines stipulated by the Strengthening the Reporting of Observational Studies in Epidemiology (23).

Our research reveals that administering acetaminophen has a link to a lower in-hospital mortality in patients with critical sepsis. The outcomes from this group also imply that acetaminophen can potentially lower 30-day mortality from sepsis and expedite hospital discharge and ICU discharge. These results maintain their strength even following adjustments for risk factors and the application of PSM for comparison. Our findings endorse the use of acetaminophen in sepsis treatment, suggesting a promising therapeutic option for clinical practice and inviting further research in this area.

Our study aligns with early clinical trials suggesting that acetaminophen could improve lipid peroxidation and kidney function in septic patients (37). An earlier observational study found a correlation between acetaminophen use and decreased in-hospital deaths in critically unwell septic patients. This implies a protective effect by reducing oxidative damage caused by cell-free hemoglobin (38). Moreover, some researchers have noted that giving acetaminophen within the first 24 h of ICU admission can lessen oxidative damage and enhance kidney function in severely septic adults. This is particularly true when cell-free hemoglobin is detectable in the blood plasma (14) .

A controlled study examined 700 patients with fever, indicating that the early use of acetaminophen to treat potential infection neither impacted the length of ICU stays nor affected survival rates at the 28-day and 90-day milestones (20). However, our research, unlike the study mentioned above, focused specifically on sepsis patients. This approach provided a clearer view of acetaminophen’s role in sepsis management. The study concluded that administrating acetaminophen to sepsis patients can shorten time spent in the ICU and lower short-term mortality rates.

In a cohort study of 606 sepsis patients, researchers observed a notable link between the use of acetaminophen and increased mortality among those who had a fever (39). What makes our study unique is our wider scope. We did not focus solely on fever patients but on various forms of sepsis for all reasons. We utilized the Sepsis-3 criteria to define sepsis, incorporating a more diverse range of subjects for a complete depiction of the sepsis patient population. Unlike past results, our study indicates a significant correlation between the use of acetaminophen and a reduction in mortality.

In a past study, researchers examined 46 pediatric sepsis patients aged 7 to 18. They found no link between acetaminophen use and increasing organ dysfunction or mortality rates (40). Unlike this study, our research primarily targets adult patients due to the higher occurrence of sepsis in adults versus children. Moreover, our study involves a larger sample size, rendering our results more clinically relevant.

Research indicates that the common anti-inflammatory and antioxidant medication, acetaminophen, shows noteworthy potential in treating sepsis (13). Essentially, acetaminophen might provide a safeguard by minimizing oxidative damage instigated by cell-free hemoglobin. It can connect to ferrous iron (Fe^{4 +}) in cell-free hemoglobin at clinically relevant doses, altering it to a less reactive ferric iron (Fe^{3 +}) (38, 41, 42). In lab tests, some studies have suggested that acetaminophen eases sepsis-induced cognitive impairment by reducing iron-induced cell death via the GPX4 and FSP1 signal pathways (43, 44). Other research hints that it reduces the effect of endotoxins on pulmonary circulation in sedated pigs, which could be crucial in severe systematic inflammation (45). Moreover, the CYP3A5 gene has been proposed as a potential significant biomarker for acetaminophen metabolism. Understanding certain genotypes linked to acetaminophen reactions could lead to more tailored treatment methods for handling sepsis and septic shock (46). Looking forward, more research is required to understand the molecular mechanics and biochemical responses of acetaminophen in sepsis treatments, gathering evidence for its positive effects in clinical contexts.

While this study offers significant findings, it is not without constraints. First, as with all retrospective analyses, potential confounding elements like a patient’s underlying medical conditions, lifestyle, and personal habits could influence results. We minimized these influences by adjusting for possible confounders using PSM. Second, our study only considered drugs like acetaminophen, disregarding other treatment interventions. The multi-faceted nature of sepsis treatment warrants further research comparing different methods. Third, our analysis only included patients treated with acetaminophen within 48 h of admission, leaving the effects of delayed use uncertain. More research is needed in this area. Fourth, the MIMIC-IV database, which does not record death causes, has some data limitations, hampering our ability to conduct a competing risk analysis. Lastly, our study is single-center, necessitating validation through multicenter trials. Given these constraints, future research should explore acetaminophen’s exact role in sepsis treatment and provide more comprehensive analyses to confirm our findings.

Acetaminophen use may be linked to lower short-term mortality in critically ill septic patients, according to our study’s findings. This implies that the careful use of acetaminophen can benefit such patients. However, more comprehensive studies, like multicenter randomized controlled trials, are needed to validate and confirm this correlation further.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by the Massachusetts Institute of Technology and Beth Israel Deaconess Medical Center. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

SS: Conceptualization, Data curation, Writing – original draft, Writing – review & editing. HL: Data curation, Writing – original draft. QL: Conceptualization, Writing – review & editing, Writing – original draft. YY: Data curation, Writing – original draft. XC: Data curation, Writing – original draft. BZ: Data curation, Writing – original draft.