Septic shock refers to sepsis with hypotension and blood lactate level of >2.0 mmol/l that cannot be corrected by positive fluid therapy (1). Current epidemiological data have shown an increased incidence of septic shock and a mortality rate ranging from 26 to 42% (2, 3). Vasopressors are the cornerstones of shock treatment (4). Specifically, norepinephrine (NE) is used as first-line vasopressor therapy (5). Theoretically, the sympathetic nervous system (SNS) plays a vital role in septic shock by enabling patients to maintain smooth muscle cell contraction (6). However, prolonged activation of the SNS in septic shock patients may elevate levels of circulating catecholamines (7), causing down-regulation and desensitization of α-adrenergic receptors on the surface of smooth muscle cells (8). This can make patients hyposensitive or insensitive to exogenous catecholamines, leading to deterioration due to refractory shock (9). There is an urgent need to reduce vasopressor requirements because some studies have revealed that the need for NE is one of the indicators of severity in patients with septic shock (10–12).

Data from animal studies have shown that dexmedetomidine (DEX) may reduce NE requirements in septic shock settings (13, 14). Recent clinical studies have also revealed that DEX for sedation may lower vasopressor requirements in septic shock patients, among them, the sample size is relatively small and the observation time is relatively short (15–18). A crossover trial included only 38 patients and was observed for 12 h, showing a decrease in NE doses 4 h after DEX only administration (17), however, the duration of DEX infusion was limited to 4 h. A retrospective study including 83 patients found that DEX was associated with lower vasopressor requirements to maintain target MAP in the first 48 h (15), however, this study could not eliminate the confounding effects of other sedatives (19). Moreover, a randomized trial recruited 66 patients and found that DEX- only sedation tended to reduce NE compared to normal saline (16). Inconsistent with the above three studies, a comparative study enrolled a small sample size of 24 patients and reported that sedation with DEX + propofol required a similar amount of NE as midazolam + propofol (18), and the relationship between DEX and NE in this study could not eliminate the confounding effects of propofol. It is important to note that the time window for reversing shock and reducing NE is also very important, nearly half of the deaths attributable to septic shock occur within the first 72 h (20, 21). However, previous studies have reported that DEX sedation for more than 24 h may cause withdrawal syndrome with sudden cessation (22, 23), thus the long-term effects as long as 72 h of DEX-only sedation in septic shock patients remain unclear. Herein, we investigated the long-term use of a DEX-only sedation regimen for hemodynamic changes, especially vasopressor requirements in septic shock patients, using a large sample size from the public database Medical Information Mart for Intensive Care IV (MIMIC-IV).

We utilized the MIMIC-IV critical care database, which includes ICU patient data from 2008 to 2019. MIMIC-IV was established by the Massachusetts Institute of Technology (Cambridge, MA) and Beth Israel Deaconess Medical Center (Boston, MA), and all patient data were collected with IRB approval. Author Zhou was responsible for data extraction from the database (certification number 35931520).

In this retrospective study, we found that DEX-only regimen may be associated with decreased vasopressor requirements, improved AST and PaO₂/FiO₂ levels, and reduced 90-day mortality in patients with septic shock. Our study highlights the hemodynamic advantage of dexmedetomidine for as long as 72 h after drug exposure, which suggests that DEX might be preferred for septic shock treatment.

Current literature suggests that DEX administration could lower vasopressor requirements in patients with septic shock (15–17). Mechanistically, some animal studies speculated that DEX’s sympatholytic effect (25) reduced plasma catecholamine levels in a time-dependent (26, 27) and dose-dependent manner (28) through its highly selective α2-adrenergic receptor agonist function (29), and patients with refractory shock usually show excessive catecholamine release (7). From this perspective, DEX may help reduce the resistance of vascular smooth muscle cells to catecholamines, thereby reducing the demand for vasopressor drugs. In addition, a study revealed that a low plasma concentration of DEX acts on α2A receptors in vascular smooth muscle cells, leading to vasodilatory effects, whereas high concentrations of DEX would directly activate α2B receptors, which exert vasoconstrictive effects and increase blood pressure (28). To be more objective in explaining vasopressor effects in this retrospective study, we chose NEq/MAP ratio (a higher ratio indicates higher vasopressor requirements to maintain a certain MAP) (15) as our primary endpoint to account for differences in target MAP between DEX and non-DEX groups. After PSM and GLMM analyses with adjustment for MAP and other confounders, our study revealed that there was still an association between DEX and reduction in NEq/MAP in the first 72 h after sedation. Our analysis is based on a large population focusing on longer observation durations, as long as 72 h. Further, we compared different timepoints after DEX/non-DEX sedation. The present study is the first to compare the potential roles of DEX and other sedatives in reducing vasopressor requirements in septic shock patients, and to evaluate the impact on vasopressor needs during sedation based on horizontal comparisons.

Inconsistent with our study, a multicenter randomized trial (DESIRE trial) included 201 sepsis patients requiring mechanical ventilation and found no statistically significant improvement in mortality or ventilator-free days in DEX group, despite the possibility of underpowered mortality (30). Although our study was retrospective, we believe that our study has certain strengths: first, compared to the DESIRE trial, our study focused on vasopressor reactivity (a key physiological effect). Second, the study population of the DESIRE trial included patients with sepsis, and only a subset with septic shock. Our study included patients with septic shock, which decreased the heterogeneity. Third, our study analyzed various hemodynamic parameters and organ biochemical markers at different time points during the first 72 h of shock. Fourth, to avoid the influence of other sedatives, we included DEX-only versus other sedatives to more directly and objectively reflect the impact of DEX on vasopressor demand. Our previous study revealed that DEX administration showed no significant difference in vasopressor requirements in patients with sepsis associated AKI (SA-AKI) (31), which was inconsistent with the results of the present study and might be due to the different study populations of the two studies. Our study focused on septic shock patients with mechanical ventilation, whereas Hu et al. (31) included patients with SA-SKI.

Several factors may contribute to elevated HR during septic shock, including hypovolemia and septic cardiomyopathy (32, 33). Studies have shown that treatments that reduce HR in septic shock significantly improve outcomes (29). DEX has been found to reduce HR, likely through its sympatholytic properties (25). In studies investigating the effects of DEX in healthy individuals, DEX was found to decrease CO, presumably by decreasing the heart rate (28). In our study, we revealed that both the heart rate and CO decreased at 24 h, but as time passed, the heart rate gradually recovered to the baseline level and CO tended to be stable at 72 h, which indicated that DEX might have hemodynamic advantages in septic shock patients.

DEX has been confirmed to have various organ protective roles in several animal studies (34–40). However, whether DEX has multiple organ-protective effects in patients with septic shock is unknown. In this study, we found that DEX might be related to improvements in AST and PaO₂/FiO₂ levels. Since the parameters that we selected in the study only partly reflected organ functions, other parameters, such as residual renal function, were not recorded in the database. Further clinical trials are needed to confirm the relationship between DEX and multi-organ functions. Unexpectedly, we showed that DEX-only sedation was associated with a longer length of hospital stay, and a lower 90-day mortality rate in septic shock patients with mechanical ventilation. One of the reasons for this might be that the longer survival time in DEX group indicated that patients would be hospitalized longer. That is, patients in DEX group had both lower 90-day mortality and in-hospital mortality within 90 days in univariate analysis after PSM, the lower in-hospital mortality within 90 days meant that patients in DEX group had longer hospitalizations, which contributed to the longer LOS in hospital. In addition, further analysis of survivors in the two groups also revealed that survivors in DEX group, which had a lower 90-day mortality, had a longer LOS in ICU and hospital, although the difference was not statistically significant. As for 28-day mortality and 28-day in hospital mortality, a similar tendency was observed, but without a significant difference. Similarly, a study (41) showed improved patient outcomes such as reduced mortality, and less delirium/coma. The possible benefits of DEX may be related to its intrinsic α2-adrenergic receptor agonist characteristics and reduced moderate inflammatory reactions and the effects of DEX sedation and auxiliary analgesia (42–44). However, the specific mechanisms need to be studied further.

The limitations of this study originate from its retrospective nature, there might be measurement bias because of the long time period, which ranged from 2008 to 2019, although PSM analysis was applied to reduce selection bias. The results of this study only showed a statistical association between DEX and reduced vasopressor requirements, which requires further randomized controlled trials to confirm this. The costs of DEX/non-DEX group were not recorded, and specific DEX doses used in each patient were not explored in the present study, thus we were unable to analyze the economic benefits and any dose-dependent effects of DEX. Additionally, with progress in the treatment of septic shock, many other advances, such as how to use the ventilators, fluids, or nutrition management (45), would also influence the correlations between DEX and vasopressor requirements. Moreover, some small clinical trials have demonstrated that the association between DEX and reduced vasopressor requirements was evidenced in patients with more severe sepsis or refractory septic shock (16, 17, 30), and we only included patients with septic shock and failed to distinguish refractory septic shock from them. Therefore, conclusions regarding the beneficial effects of DEX should be made cautiously.

Among septic shock patients on mechanical ventilation, DEX may be associated with decreased vasopressor requirements, improved AST and PaO₂/FiO₂ levels, and reduced 90-day mortality in septic shock patients up to 72 h after drug exposure.

The use of DEX in septic shock patients on mechanical ventilation in critical care settings warrants further study.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

LL helped to analyze the data and wrote the manuscript. XS analyzed datasets. MX helped to reviewed and modify the manuscript. KK helped to modify the manuscript. ZC helped to design the work. SZ extracted data from the database. ZZ helped to write the manuscript. SA analyzed the data and reviewed the data result. BX designed the work and reviewed the manuscript. All authors read and approved the final manuscript.

This work was supported by the Clinical Research Program of NanFang Hospital, Southern Medical University [grant number 2018CR047]. The National Natural Science Foundation of China [Grant number 62076253] and the Natural Science Foundation of Guangdong Province [Grant number 2021A1515010077].

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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