
==== Front
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Front Med (Lausanne)
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Frontiers in Medicine
2296-858X
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10.3389/fmed.2024.1415425
Medicine
Original Research
Effect of propofol versus midazolam on short-term outcomes in patients with sepsis-associated acute kidney injury
Li Yuanjie 1 †

Guo Taipu 1 †
Yang Zhenkun 2 †

Zhang Rui 1
Wang Zhi 3
Li Yize 1 4 *

1Anesthesiology Research Laboratory, Tianjin Medical University General Hospital, Tianjin, China
2Cardiovascular Disease Research Laboratory, Tianjin Medical University General Hospital, Tianjin, China
3Anesthesiology Research Laboratory, Erdos Central Hospital, Ordos, China
4Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States
Edited by: Harish Ramakrishna, Mayo Clinic, United States

Reviewed by: Liping Zhuang, The First People Hospital of Mudanjiang City, China

Jingjing Yuan, First Affiliated Hospital of Zhengzhou University, China

*Correspondence: Yize Li, liyizelisa@126.com
†These authors have contributed equally to this work

06 9 2024
2024
11 141542517 4 2024
30 8 2024
Copyright © 2024 Li, Guo, Yang, Zhang, Wang and Li.
2024
Li, Guo, Yang, Zhang, Wang and Li
https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Background

Propofol and midazolam are commonly used sedative drugs in mechanically ventilated patients in the Intensive Care Unit (ICU). However, there is still a lack of relevant studies exploring the influence of midazolam and propofol on the prognosis of patients with Sepsis-associated Acute Kidney Injury (S-AKI).

Patients and methods

A statistical analysis was conducted on 3,745 patients with S-AKI in the Medical Information Mart for Intensive Care IV database. The patients’ baseline characteristics were grouped based on the use of either propofol or midazolam as sedatives. Cox proportional hazards models, logistic regression models, and subgroup analyses were used to compare the effects of propofol and midazolam on the short-term prognosis of S-AKI patients, including 30-day mortality, ICU mortality, and duration of mechanical ventilation.

Results

In the statistical analysis, a total of 3,745 patients were included, with 649 patients using midazolam and 3,096 patients using propofol. In terms of the 30-day mortality, compared to patients using midazolam, S-AKI patients using propofol had a lower ICU mortality (hazard ratio = 0.62, 95% confidence interval: 0.52–0.74, p < 0.001), lower 30-day mortality (hazard ratio = 0.56, 95% confidence interval: 0.47–0.67, p < 0.001), and shorter mechanical ventilation time (odds ratio = 0.72, 95% confidence interval: 0.59–0.88, p < 0.001). Kaplan–Meier curves showed lower survival probabilities in the midazolam group (p < 0.001). Subgroup analyses showed that propofol was strongly protective of short-term prognosis in older, male, smaller SOFA score CCI score, no heart failure, and comorbid chronic kidney disease patients with S-AKI.

Conclusion

Compared to midazolam, propofol was considered a protective factor for short-term mortality risk and ICU mortality risk in S-AKI patients. Additionally, S-AKI patients using propofol had a lower risk of requiring prolonged mechanical ventilation. Overall, propofol may be more beneficial for the short-term prognosis of S-AKI patients compared to midazolam.

MIMIC-IV
sepsis-associated acute kidney injury
propofol
midazolam
mortality
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article. section-at-acceptanceIntensive Care Medicine and Anesthesiology
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pmcIntroduction

Sepsis, a systemic inflammatory response syndrome triggered by infection, significantly impacts global health (1). S-AKI is a form of acute kidney injury that arises within the context of sepsis. This kidney injury typically results from the systemic inflammatory response and hemodynamic alterations induced by sepsis, leading to insufficient renal perfusion and/or direct renal cellular damage (2). In 2017, there were an estimated 48.9 million sepsis cases globally, resulting in 11 million sepsis-related deaths, accounting for 19.7% of all worldwide fatalities (3). Sepsis remains the primary cause of morbidity and mortality in ICUs globally, coupled with significant economic repercussions (4, 5). A multicenter prospective cohort study revealed an AKI incidence of 51% among 1,177 sepsis patients (6–9). Consequently, S-AKI is a prevalent complication among critically ill ICU patients. The mortality rate is markedly higher in sepsis patients who develop AKI compared to those without AKI (10).

Appropriate sedation management using sedative drugs is nearly universal for mechanically ventilated ICU patients, enhancing their tolerance to mechanical ventilation and effectively reducing psychological stress in critically ill ICU patients (11). Propofol and midazolam are commonly used sedatives for mechanically ventilated ICU patients, including those with sepsis (12–14). The 2013 Pain, Agitation, and Delirium Guidelines recommend propofol over midazolam for mechanically ventilated adult ICU patients due to its association with reduced mechanical ventilation duration, ICU length of stay, and delirium (15). The same meta-analysis indicated that, compared with midazolam, propofol use can shorten intubation time in critically ill patients (16). Additionally, studies have found that compared to midazolam, critically ill patients receiving propofol have a lower risk of AKI in the first 7 days in the ICU and a reduced rate of renal replacement therapy potentially linked to propofol (17). The beneficial effects of propofol on renal ischemia–reperfusion injury are associated with its inhibition of pro-inflammatory cytokines (18, 19).

Thus, the critical importance of appropriate sedation for critically ill patients, significant gaps remain in the existing literature, especially regarding the comparative effects of midazolam and propofol on the prognosis of S-AKI patients. This study for the first time compared the short-term prognostic impacts of propofol and midazolam, focusing on critical outcomes such as 30-day mortality, ICU mortality, and the duration of invasive mechanical ventilation in patients diagnosed with S-AKI.

Methods

Study population

This study is a single-center, retrospective cohort analysis utilizing data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The MIMIC-IV database is an extensive, publicly accessible resource, developed and maintained by the Massachusetts Institute of Technology (MIT) Computational Physiology Laboratory. It contains a substantial collection of medical records for ICU patients at Beth Israel Deaconess Medical Center from 2008 to 2019 (20). Utilization of the MIMIC-IV database was sanctioned by the Institutional Review Board of both MIT and Beth Israel Deaconess Medical Center. This project adhered to the principles outlined in the Declaration of Helsinki. The ethics committee approved the utilization of the data, citing the anonymized nature of the participants and the standardized formatting of the dataset.

One of the authors, Zhenkun Yang, secured access to the MIMIC-IV database and acquired the necessary certifications (ID: 57121385). Sepsis was diagnosed using the Sepsis-3.0 criteria (1), Among these sepsis patients, those with acute kidney injury were identified based on the Kidney Disease Improving Global Outcomes (KDIGO) criteria (21). Inclusion criteria were as follows: (1) Age ≥ 18 years; (2) Diagnosed with S-AKI (sepsis and AKI onset within 0–48 h of ICU admission); (3) Sedation with propofol or midazolam during ICU stay; (4) Availability of survival data. Exclusion criteria were: (1) Absence of mechanical ventilation; (2) ICU stay less than 48 h. Ultimately, 3,745 patients met the inclusion criteria for statistical analysis (Figure 1).

Figure 1 Flow of included patients through the trial. AKI, acute kidney injury; ICU, intensive care unit; MIMIC-IV, Medical Information Mart for Intensive Care-IV.

Variables extraction

We extracted data information by using Structured Query Language running with the software Navicat Premium (version 16). Such as demographic characteristics: age, gender, race, weight; vital signs: mean arterial pressure (MAP), heart rate, temperature, respiratory rate, urine output, comorbidities: heart failure, chronic obstructive pulmonary disease (COPD), diabetes, chronic kidney disease (CKD), liver disease; laboratory tests: red blood cell distribution width (RDW), glucose, creatinine, platelet, white blood cell counts (WBC), hemoglobin, hematocrit, blood urea nitrogen (BUN), lactate, bicarbonate, sodium, potassium, chloride, PaCO2, PaO2, FiO2, international normalized ratio (INR), plasma prothrombin time (PT); hospitalization treatment measures: opiates, vasopressor, antibiotics, and renal replacement therapy (RRT); scoring systems: Sepsis-Related Organ Failure Assessment Score (SOFA), Charlson Comorbidity Index (CCI) score. Where MAP = diastolic blood pressure(DBP) + 1 / 3 [systolic blood pressure (SBP)—DBP]. For those with multiple admission records, only the first admission data is extracted. For those with multiple values, the first measurement value within 24 h after admission to the ICU is selected. Concerning missing values, as illustrated in Supplementary Table S1, the highest percentage of missing data was approximately 8.8%. Sensitivity analyses before and after interpolation of missing variables are shown in Supplementary Table S2.

Study outcomes

The primary endpoints of our study were: (1) 30-day mortality, defined as death within 30 days of ICU admission; (2) ICU mortality, defined as death occurring ICU admission; (3) duration of invasive mechanical ventilation, limited to patients receiving this intervention, categorized by median duration into two groups: < 3 days and ≥ 3 days.

Statistical analysis

Normality of measurement data was assessed using the Shapiro–Wilk test. Normally distributed data were expressed as mean ± standard deviation (Mean ± SD). Group comparisons were conducted using the independent sample T-test; non-normal data were represented as median. Count data and interquartile range [M (Q1, Q3)] were reported, with group comparisons made using the Mann–Whitney U test. Enumeration data were summarized by number of cases and composition ratio N (%), with comparisons conducted via chi-square test. The rank sum test was utilized for ordinal data. All statistical analyses were two-sided, with a significance level of α = 0.05. A two-sided p < 0.05 was deemed statistically significant. Data management and analyses were conducted using SPSS Statistics (version 27) and R (version 4.3.2).

Patients receiving midazolam and propofol were categorized into respective groups, and their baseline characteristics were compared. The midazolam group served as the reference group. Univariate and multivariate analyses were then employed to investigate the effects of midazolam and propofol on various outcomes. To assess the independent associations of midazolam and propofol in S-AKI patients, we utilized the Cox proportional hazards model and Logistic regression model, adjusting for potential confounders. Results were expressed as odds ratios (OR) or hazard ratios (HR) with 95% confidence intervals (CI). Model I: unadjusted; Model II: adjusted for demographic variables; Model III: adjusted for demographic variables and variables with p < 0.05 in univariate analysis. Kaplan–Meier survival analysis was conducted to evaluate the impact of the two sedative drugs on 30-day and ICU mortality, respectively. Differences between the two groups were assessed using the log-rank test. After controlling for multiple confounders using propensity score matching, the effects of the two drugs on different outcomes were again explored. Further stratified analyses were performed based on age (≥ 65 years vs. < 65 years), gender, SOFA score (≥ 3 vs. < 3), CCI (≥ 3 vs. < 3), heart failure, and chronic kidney disease. The objective is to evaluate the consistency of the prognostic values of the two sedative drugs.

Results

Baseline characteristics

This study involved 3,745 patients with no loss to follow-up. They were divided into propofol and midazolam groups for sedation (Table 1). Patients had an average age of 65.25 ± 14.77 years; 1,466 (39.15%) were male, and 67.64% were White. The midazolam group showed higher heart and respiratory rates, lower urine output on admission, and higher incidences of heart failure, COPD, and liver disease, with elevated SOFA and CCI scores. Except for lactate, potassium, PaCO2, INR, and PT, other lab parameters differed significantly. Additionally, the midazolam group used more RRT and opiates, excluding vasopressors and antibiotics. In S-AKI patients, midazolam sedation correlated with higher 30-day and ICU mortality rates, and longer mechanical ventilation durations (≥ 3 days) compared to propofol (p < 0.001, Table 2). Propofol group had shorter median ICU follow-up durations (9.11 vs. 11.14 days for midazolam).

Table 1 Baseline characteristics of the propofol group and midazolam group.

Categories	All (n = 3,745)	Midazolam (n = 649)	Propofol (n = 3,096)	p value	
Age, years	65.25 ± 14.77	64.60 ± 15.52	65.39 ± 14.61	0.237	
Gender, n (%)				0.017	
Female	1,466 (39.15)	281 (43.30)	1,185 (38.28)		
Male	2,279 (60.85)	368 (56.70)	1911 (61.72)		
Weight, kg	83.01 (69.35, 98.88)	84.20 (67.86, 101.00)	83.00(69.78, 98.39)	0.580	
Race, n (%)				0.092	
Black	253 (6.76)	50 (7.70)	203 (6.56)		
White	2,533 (67.64)	415 (63.94)	2,118 (68.41)		
Other	370 (9.88)	64 (9.86)	306 (9.88)		
Unknown	589 (15.73)	120 (18.49)	469 (15.15)		
Vital signs	
Heart rate, bpm	88.09 ± 19.83	95.31 ± 23.58	86.58 ± 18.61	< 0.001	
MAP, mmHg	83.42 ± 18.15	83.97 ± 20.20	83.30 ± 17.69	0.430	
Respiratory rate, bpm	17.00 (14.00, 21.00)	20.00 (16.00, 25.00)	16.00(14.00, 20.00)	< 0.001	
Temperature, Deg.C	36.58 ± 0.98	36.62 ± 1.19	36.57 ± 0.93	0.306	
Urine output, mL	3150.00 (2030.00, 4400.00)	2434.00 (1454.00, 3875.00)	3257.00 (2177.50, 4501.50)	< 0.001	
Comorbidities	
Heart Failure, n (%)	1,216 (32.47)	280 (43.14)	936 (30.23)	< 0.001	
COPD, n (%)	584 (15.59)	138 (21.26)	446 (14.41)	< 0.001	
Diabetes, n (%)	1,216 (32.47)	210 (32.36)	1,006 (32.49)	0.946	
CKD, n (%)	644 (17.20)	124 (19.11)	520 (16.80)	0.156	
Liver disease, n (%)	640 (17.09)	180 (27.73)	180 (27.73)	< 0.001	
Laboratory tests	
RDW, %	15.13 ± 2.26	15.56 ± 2.30	15.04 ± 2.25	< 0.001	
Platelet, K/uL	175.00 (126.00, 239.00)	209.00 (141.00, 278.00)	171.00 (124.00, 231.00)	< 0.001	
WBC, K/uL	12.30 (8.90, 16.90)	12.80 (8.60, 19.30)	12.20 (9.00, 16.50)	0.039	
Hemoglobin, g/dL	10.36 ± 2.38	11.01 ± 2.49	10.22 ± 2.33	< 0.001	
Hematocrit, %	31.43 ± 7.13	33.74 ± 7.48	30.95 ± 6.96	< 0.001	
Glucose, mg/dL	139.00 (114.00, 175.00)	148.00 (114.00, 209.00)	138.00 (114.00, 170.00)	< 0.001	
Creatinine, mg/dL	1.00 (0.80, 1.50)	1.30 (0.80, 2.10)	1.00 (0.70, 1.40)	< 0.001	
BUN, mg/dL	20.00 (14.00, 31.00)	28.00 (18.00, 47.00)	19.00 (14.00, 28.00)	< 0.001	
INR	1.30 (1.20, 1.60)	1.30 (1.20, 1.70)	1.30 (1.20, 1.60)	0.261	
PT, sec	14.80 (13.00,17.20)	14.80 (13.10,18.20)	14.80 (13.00,17.10)	0.083	
Arterial blood gases	
Lactate, mmol/L	2.00 (1.30, 2.90)	1.90 (1.30, 3.00)	2.00 (1.30, 2.90)	0.786	
Bicarbonate, mEq/L	22.71 ± 4.54	22.20 ± 5.59	22.81 ± 4.28	0.009	
Sodium, mEq/L	137.59 ± 4.76	138.26 ± 5.49	137.45 ± 4.59	< 0.001	
Potassium, mEq/L	4.41 ± 0.86	4.37 ± 0.87	4.41 ± 0.85	0.260	
Chloride, mEq/L	104.68 ± 6.01	104.05 ± 6.77	104.81 ± 5.82	0.008	
PaCO2, mmHg	41.00 (36.00, 47.00)	41.00 (35.00, 49.00)	41.00(36.00, 46.00)	0.133	
PaO2, mmHg	187.00 (102.00, 326.00)	112.00 (80.00, 188.00)	213.00 (113.00, 342.00)	< 0.001	
FiO2, %	100.00 (50.00, 100.00)	80.00 (50.00, 100.00)	100.00 (50.00, 100.00)	0.001	
Intervention	
RRT, n (%)	505 (13.48)	131 (20.18)	374 (12.08)	< 0.001	
Vasopressor, n (%)	2,794 (74.61)	483 (74.42)	2,311 (74.64)	0.906	
Antibiotics, n (%)	3,673 (98.08)	638 (98.31)	3,035 (98.03)	0.642	
Opiates, n (%)	3,224 (86.09)	623 (95.99)	2,601 (84.01)	< 0.001	
CCI	3.00 (1.00, 4.00)	3.00 (2.00, 5.00)	2.00 (1.00, 4.00)	< 0.001	
SOFA	3.00 (1.00, 5.00)	4.00 (1.00, 6.00)	3.00 (1.00, 5.00)	< 0.001	
MAP, mean arterial pressure; COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease; RDW, red cell distribution width; WBC, white blood cells; BUN, blood urea nitrogen; INR, international normalized ratio; PT, plasma prothrombin time; RRT, renal replacement therapy; CCI, Charlson Comorbidities Index; SOFA, Sequential Organ Failure Assessment. Data are mean (SD), n (%), or median (IQR).

Table 2 Three outcomes’ characteristics between propofol group and midazolam group.

Categories	All (n = 3,745)	Midazolam (n = 649)	Propofol (n = 3,096)	P value	
30-day mortality, n (%)				< 0.001	
No	3,035 (81.04)	417 (64.25)	2,618 (84.56)		
Yes	710 (18.96)	232 (35.75)	478 (15.44)		
ICU mortality, n (%)				< 0.001	
No	3,083 (82.32)	435 (67.03)	2,648 (85.53)		
Yes	662 (17.68)	214 (32.97)	448 (14.47)		
Ventilation duration, n (%)				< 0.001	
< 3 days	1882 (50.25)	225 (34.67)	1,657 (53.52)		
≥ 3 days	1863 (49.75)	424 (65.33)	1,439 (46.48)		
30-day follow-up time (days)	30.00 (30.00, 30.00)	30.00 (12.41, 30.00)	30.00 (30.00, 30.00)	< 0.001	
Hospital follow-up time (days)	9.37 (6.08, 16.84)	11.14 (6.41, 18.23)	9.11 (6.04, 16.33)	< 0.001	

Impact of sedatives on 30-day mortality in S-AKI patients

According to Table 3, after adjusting for confounders, exclusive propofol sedation reduced the 30-day mortality risk in S-AKI patients by 44% (HR = 0.56, 95% CI: 0.47–0.67, p < 0.001), indicating it is an effective protective factor. Kaplan–Meier curves showed lower 30-day survival probabilities in the midazolam group (Figure 2A).

Table 3 Analysis of the association between sedative agents and three outcomes.

Sedatives	Model I	Model II	Model III	
HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value	
30-day Mortality	
Midazolam	Ref		Ref		Ref		
Propofol	0.38 (0.32, 0.44)	< 0.001	0.50 (0.42, 0.58)	< 0.001	0.56 (0.47, 0.67)	< 0.001	
ICU mortality	
Midazolam	Ref		Ref		Ref		
Propofol	0.48 (0.41, 0.57)	< 0.001	0.55 (0.47, 0.65)	< 0.001	0.62 (0.52, 0.74)	< 0.001	
Sedatives	Model I	Model II	Model III	
OR (95% CI)	P value	OR (95% CI)	P value	OR (95% CI)	P value	
Invasive mechanical ventilation	
Midazolam	Ref		Ref		Ref		
Propofol	0.46 (0.39, 0.55)	< 0.001	0.57 (0.48, 0.69)	< 0.001	0.72 (0.59, 0.88)	0.002	
30-day mortality: Model I: Unadjusted; Model II: Adjusted for age, gender, race, heart rate, respiratory rate, mean arterial pressure, urine output; Model III: Model II further adjusted by Charlson Comorbidity index, Sequential Organ Failure Assessment, red cell distribution width, glucose, creatinine, white blood cells, hematocrit, blood urea nitrogen, lactate, bicarbonate, sodium, potassium, chloride, PaO2, FiO2, international normalized ratio, plasma prothrombin time, heart failure, chronic obstructive pulmonary disease, chronic kidney disease, liver disease, renal replacement therapy, vasopressor, opiates. ICU mortality: Model I: Unadjusted; Model II: Adjusted for age, gender, race, heart rate, respiratory rate, mean arterial pressure, urine output; Model III: Model II further adjusted by temperature, Charlson Comorbidity index, Sequential Organ Failure Assessment, red cell distribution width, glucose, creatinine, white blood cells, hematocrit, blood urea nitrogen, lactate, bicarbonate, sodium, PaO2, international normalized ratio, plasma prothrombin time, heart failure, chronic obstructive pulmonary disease, chronic kidney disease, liver disease, Renal Replacement Therapy, vasopressor. Invasive mechanical ventilation: Model I: Unadjusted; Model II: Adjusted for age, gender, race, heart rate, respiratory rate, mean arterial pressure, urine output; Model III: Adjusted for age, gender, race, heart rate, respiratory rate, urine output, Charlson Comorbidity index, Sequential Organ Failure Assessment, red cell distribution width, glucose, creatinine, platelet, hematocrit, hemoglobin, blood urea nitrogen, lactate, bicarbonate, sodium, potassium, chloride, PaCO2, PaO2, FiO2, heart failure, chronic obstructive pulmonary disease, chronic kidney disease, liver disease, Renal Replacement Therapy, vasopressor, antibiotics. HR, hazard ratio; OR, odds ratio; CI, confidence interval.

Figure 2 Kaplan-Mill survival analysis of different drugs in sepsis-associated acute kidney injury patients with 30-day mortality (A) and ICU mortality (B).

Impact of sedatives on ICU mortality in S-AKI patients

According to Table 3, after adjusting for confounders, exclusive propofol sedation reduced ICU mortality risk in S-AKI patients by 38% (HR = 0.62, 95% CI: 0.52–0.74, p < 0.001), indicating propofol also was an effective protective factor against ICU mortality in S-AKI. Kaplan–Meier survival curves showed a less pronounced decline in in-hospital survival probabilities over time in the propofol group (Figure 2B).

Impact of sedatives on duration of invasive mechanical ventilation in S-AKI patients

According to Table 3, after adjusting for confounders, exclusive propofol sedation reduced the risk of invasive mechanical ventilation lasting more than 3 days in S-AKI patients by 28% (OR = 0.72, 95% CI: 0.59–0.88, p = 0.002). Figure 3 illustrated the effects of the two drugs on duration of invasive mechanical ventilation. The propofol group exhibited lower OR values and shorter duration of mechanical ventilation in S-AKI patients.

Figure 3 The distribution of two drugs on odds ratio (A) and duration of invasive mechanical ventilation (B) in patients with sepsis-related acute kidney. OR, odds ratio; CI, confidence interval.

Impact of sedatives on three outcomes after propensity score matching analysis

According to Table 4, after propensity score matching analysis, multifactorial Logistic regression and COX regression showed that propofol remained more protective than midazolam against ICU death (HR = 0.67, CI: 0.53–0.84, p < 0.001), 30-day death (HR = 0.58, CI; 0.46–0.72, p < 0.001), and invasive mechanical ventilation (HR = 0.75, CI: 0.58–0.96, p = 0.021) in patients with S-AKI.

Table 4 Association between sedative agents and three outcomes after propensity score matching.

Sedatives	Model I	Model II	Model III	
HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value	
30-day Mortality	
Midazolam	Ref		Ref		Ref		
Propofol	0.64 (0.51, 0.77)	< 0.001	0.58 (0.47, 0.72)	< 0.001	0.58 (0.46, 0.72)	< 0.001	
ICU mortality	
Midazolam	Ref		Ref		Ref		
Propofol	0.71 (0.57, 0.89)	0.002	0.68 (0.54, 0.85)	< 0.001	0.67 (0.53, 0.84)	< 0.001	
Sedatives	Model I	Model II	Model III	
OR (95% CI)	P value	OR (95% CI)	P value	OR (95% CI)	P value	
Invasive mechanical ventilation	
Midazolam	Ref		Ref		Ref		
Propofol	0.80 (0.64, 1.01)	0.067	0.81 (0.64, 1.02)	0.074	0.75 (0.58, 0.96)	0.021	
30-day mortality: Model I: Unadjusted; Model II: Adjusted for age, gender, race, heart rate, respiratory rate, mean arterial pressure, urine output; Model III: Model II further adjusted by Charlson Comorbidity index, Sequential Organ Failure Assessment, red cell distribution width, glucose, creatinine, white blood cells, hematocrit, blood urea nitrogen, lactate, bicarbonate, sodium, potassium, chloride, PaO2, FiO2, international normalized ratio, plasma prothrombin time, heart failure, chronic obstructive pulmonary disease, chronic kidney disease, liver disease, renal replacement therapy, vasopressor, opiates. ICU mortality: Model I: Unadjusted; Model II: Adjusted for age, gender, race, heart rate, respiratory rate, mean arterial pressure, urine output; Model III: Model II further adjusted by temperature, Charlson Comorbidity index, Sequential Organ Failure Assessment, red cell distribution width, glucose, creatinine, white blood cells, hematocrit, blood urea nitrogen, lactate, bicarbonate, sodium, PaO2, international normalized ratio, plasma prothrombin time, heart failure, chronic obstructive pulmonary disease, chronic kidney disease, liver disease, Renal Replacement Therapy, vasopressor. Invasive mechanical ventilation: Model I: Unadjusted; Model II: Adjusted for age, gender, race, heart rate, respiratory rate, mean arterial pressure, urine output; Model III: Adjusted for age, gender, race, heart rate, respiratory rate, urine output, Charlson Comorbidity index, Sequential Organ Failure Assessment, red cell distribution width, glucose, creatinine, platelet, hematocrit, hemoglobin, blood urea nitrogen, lactate, bicarbonate, sodium, potassium, chloride, PaCO2, PaO2, FiO2, heart failure, chronic obstructive pulmonary disease, chronic kidney disease, liver disease, Renal Replacement Therapy, vasopressor, antibiotics. HR, hazard ratio; OR, odds ratio; CI, confidence interval.

Subgroup analysis

We conducted risk stratification analyses for 30-day mortality in S-AKI patients based on age, gender, SOFA scores, CCI scores, heart failure, and chronic kidney disease history (Figure 4). Propofol was linked to lower 30-day mortality risks in patients aged ≥65 years (HR = 0.51, 95% CI: 0.41–0.64), male (HR = 0.53, 95% CI: 0.42–0.67), with SOFA scores <3 (HR = 0.54, 95% CI: 0.40–0.74), CCI scores <3 (HR = 0.49, 95% CI: 0.36–0.68), without heart failure (HR = 0.51, 95% CI: 0.40–0.64), and with chronic kidney disease (HR = 0.37, 95% CI: 0.25–0.53). The effects of propofol on ICU mortality mirrored those on 30-day mortality. However, propofol did not show significant effects on the duration of mechanical ventilation in patients aged <65 years, female, with CCI scores <3 and without heart failure.

Figure 4 Forest plots of 30-day mortality (A) and ICU mortality (B) and ventilation duration (C) in different subgroups. HR, hazard ratio; OR, odds ratio; CI, confidence interval; CCI, charlson comorbidity index; CKD, chronic kidney disease; SOFA, Sequential Organ Failure Assessment.

Discussion

This study was a single-center, retrospective cohort analysis designed to elucidate the risks associated with propofol and midazolam sedation. Utilizing both univariate and multivariate analyses, we demonstrated that in patients with sepsis-associated acute kidney injury (S-AKI), midazolam sedation, compared to propofol, was linked to higher 30-day mortality, increased ICU mortality, and prolonged durations of invasive mechanical ventilation. Sedatives are routinely administered to critically ill patients requiring invasive mechanical ventilation to minimize patient-ventilator asynchrony and alleviate anxiety and stress (15). Both propofol and midazolam have the potential to suppress respiratory drive, induce immunosuppression, and lead to profound sedation (22, 23).

A previous systematic review showed that compared to midazolam, propofol sedation improved clinical outcomes in ICU patients, decreased ICU stay and duration of mechanical ventilation in patients undergoing acute surgery, and shortened weaning time in critically ill patients (16). Similarly, in a multi-center observational cohort study, propofol sedation was associated with lower hospital mortality rates, shorter hospital stays, and shorter duration of invasive mechanical ventilation compared to midazolam sedation in patients with acute respiratory distress syndrome (24). A Canadian study also showed faster extubation for mechanically ventilated patients receiving propofol versus those receiving midazolam (25). In another observational propensity score matched cohort study, propofol sedation reduced vasopressor dosing, mortality rates, and bleeding events compared to midazolam in patients with cardiogenic shock (26).

Our data and other experiments above proved that propofol was more friendly to the short-term prognosis of S-AKI patients than midazolam, including 30-day mortality, in-hospital mortality, and mechanical ventilation time. Prolonged mechanical ventilation was associated with adverse outcomes and can increase patient mortality (27, 28). Therefore, we preferred patients to receive a shorter duration of invasive mechanical ventilation. Compared to benzodiazepines like midazolam, propofol had shorter recovery times to arousable mental status, allowing patients to be liberated from the ventilator more quickly with adequate respiratory drive to breathe spontaneously (29, 30), consistent with our conclusions. Additionally, due to pharmacokinetic properties, propofol can rapidly awaken patients. Propofol had a rapid onset, short duration of action, taking effect in seconds to minutes, and is quickly redistributed to peripheral tissues, along with a large volume of distribution, allowing early recovery of consciousness (31). Midazolam was a lipophilic drug not easily metabolized in adipose tissues, leading to its accumulation and longer persistence in the body (32). Prolonged midazolam sedation can also lead to neurological injury (33). Clinical ICU analgesia and sedation practice guidelines (e.g., PADIS guidelines 26) also emphasize shortened time on ventilators and early rehabilitation (34). For S-AKI patients specifically, propofol has been shown to act as a scavenger of oxygen free radicals (OFRs), reducing lipid peroxidation in the kidneys (35), and modulate ischemia/reperfusion injury (IRI) with organ-protective potentials as a measure to improve patient outcomes (36). Therefore, in S-AKI patients, propofol was an effective strategy with superior outcomes compared to midazolam.

In subgroup analyses, the propofol group exhibited protective effects on 30-day mortality compared to the midazolam group across various subgroups, including age, gender, SOFA scores, CCI scores, heart failure, and chronic kidney disease. Comparable outcomes were observed for in-hospital mortality. Specifically, in S-AKI patients aged ≥65 years [HR = 0.51 (95% CI: 0.41–0.64)], propofol was associated with superior short-term outcomes compared to midazolam. In an additional randomized controlled trial involving elderly patients, propofol sedation demonstrated significant advantages over midazolam sedation, particularly in reducing the incidence of post-operative cognitive dysfunction (37). Propofol showed no statistically significant effects compared to midazolam on duration of mechanical ventilation in S-AKI patients aged <65 years [OR = 0.79 (95% CI: 0.56–1.06)], females [OR = 0.86 (95% CI, 0.63–1.17)], without heart failure [OR = 0.83 (95% CI, 0.61–1.13)], and with CCI scores <3 [OR = 0.84 (95% CI, 0.65–1.08)]. These findings underscore the need for further exploration into the optimal selection of first-line sedatives for populations at various stages of illness.

This study presented three significant strengths. Firstly, it was the first to explore the impact of various sedatives on short-term outcomes in patients with S-AKI, offering crucial insights for the optimal selection of sedative agents in this specific population. Secondly, the study’s substantial sample size guaranteed robust statistical power. Lastly, the study encompassed crucial variables pertinent to clinical practice in ICU management of sepsis-related acute kidney injury, including severity, prognosis, complications, and a comprehensive range of laboratory indicators. Nonetheless, our study had certain limitations. First, as a retrospective analysis, the study may have been subject to inherent selection bias. Moreover, the analysis exclusively concentrated on patients’ initial hospital admissions, potentially overlooking the influence of dynamic changes in indicators on the study’s outcomes. Finally, due to the limitations in available sedative data, we were unable to ascertain the impact of sedative duration on the study outcomes. Although a meticulous multi-factorial analysis was employed to mitigate confounding variables, further validation of our findings through large-scale multi-center studies and randomized controlled trials remains imperative.

Conclusion

Propofol has been identified as a protective factor for short-term and ICU mortality in S-AKI patients. Additionally, S-AKI patients receiving propofol had a lower risk of prolonged mechanical ventilation compared to those receiving midazolam. These findings suggested that propofol may offer greater short-term benefits for S-AKI patients than midazolam.

We would like to extend our gratitude to the investigators at Tianjin Medical University General Hospital who provided assistance that greatly contributed to this work.

Data availability statement

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

Author contributions

YuL: Conceptualization, Data curation, Investigation, Methodology, Resources, Software, Writing – original draft, Writing – review & editing. TG: Conceptualization, Investigation, Methodology, Visualization, Writing – original draft. ZY: Investigation, Software, Writing – original draft. RZ: Visualization, Writing – original draft. ZW: Investigation, Writing – original draft. YiL: Writing – original draft, Writing – review & editing.

Conflict of interest

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.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2024.1415425/full#supplementary-material
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References

1. Singer M Deutschman CS Seymour CW Shankar-Hari M Annane D Bauer M . The third international consensus definitions for Sepsis and septic shock (Sepsis-3). JAMA. (2016) 315 :801–10. doi: 10.1001/jama.2016.0287 26903338
2. Bellomo R Kellum JA Ronco C . Acute kidney injury. Lancet. (2012) 380 :756–66. doi: 10.1016/s0140-6736(11)61454-2 22617274
3. Rudd KE Johnson SC Agesa KM Shackelford KA Tsoi D Kievlan DR . Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the global burden of disease study. Lancet. (2020) 395 :200–11. doi: 10.1016/s0140-6736(19)32989-7 31954465
4. Cecconi M Evans L Levy M Rhodes A . Sepsis and septic shock. Lancet. (2018) 392 :75–87. doi: 10.1016/s0140-6736(18)30696-2 29937192
5. Rello J Valenzuela-Sánchez F Ruiz-Rodriguez M Moyano S . Sepsis: a review of advances in management. Adv Ther. (2017) 34 :2393–411. doi: 10.1007/s12325-017-0622-8 29022217
6. Bagshaw SM Uchino S Bellomo R Morimatsu H Morgera S Schetz M . Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol. (2007) 2 :431–9. doi: 10.2215/cjn.03681106 17699448
7. Bouchard J Acharya A Cerda J Maccariello ER Madarasu RC Tolwani AJ . A prospective international multicenter study of AKI in the intensive care unit. Clin J Am Soc Nephrol. (2015) 10 :1324–31. doi: 10.2215/cjn.04360514 26195505
8. Hoste EA Bagshaw SM Bellomo R Cely CM Colman R Cruz DN . Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. (2015) 41 :1411–23. doi: 10.1007/s00134-015-3934-7 26162677
9. Uchino S Kellum JA Bellomo R Doig GS Morimatsu H Morgera S . Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. (2005) 294 :813–8. doi: 10.1001/jama.294.7.813, PMID: 16106006
10. Morrell ED Kellum JA Pastor-Soler NM Hallows KR . Septic acute kidney injury: molecular mechanisms and the importance of stratification and targeting therapy. Crit Care. (2014) 18 :501. doi: 10.1186/s13054-014-0501-5 25575158
11. Patel SB Kress JP . Sedation and analgesia in the mechanically ventilated patient. Am J Respir Crit Care Med. (2012) 185 :486–97. doi: 10.1164/rccm.201102-0273CI 22016443
12. Hughes CG Mailloux PT Devlin JW Swan JT Sanders RD Anzueto A . Dexmedetomidine or Propofol for sedation in mechanically ventilated adults with Sepsis. N Engl J Med. (2021) 384 :1424–36. doi: 10.1056/NEJMoa2024922 33528922
13. Marler J Mohrien K Kimmons LA Vandigo JE Oliphant CS Boucher AN . Effects of propofol on vasopressor use in patients with sepsis and severe sepsis: a pilot study. J Crit Care. (2016) 35 :155–60. doi: 10.1016/j.jcrc.2016.05.015 27481752
14. Tekwani KL Watts HF Sweis RT Rzechula KH Kulstad EB . A comparison of the effects of etomidate and midazolam on hospital length of stay in patients with suspected sepsis: a prospective, randomized study. Ann Emerg Med. (2010) 56 :481–9. doi: 10.1016/j.annemergmed.2010.05.034 20828877
15. Barr J Fraser GL Puntillo K Ely EW Gélinas C Dasta JF . Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. (2013) 41 :263–306. doi: 10.1097/CCM.0b013e3182783b72 23269131
16. Garcia R Salluh JIF Andrade TR Farah D da Silva PSL Bastos DF . A systematic review and meta-analysis of propofol versus midazolam sedation in adult intensive care (ICU) patients. J Crit Care. (2021) 64 :91–9. doi: 10.1016/j.jcrc.2021.04.001, PMID: 33838522
17. Leite TT Macedo E Martins Ida S Neves FM Libório AB . Renal outcomes in critically ill patients receiving Propofol or midazolam. Clin J Am Soc Nephrol. (2015) 10 :1937–45. doi: 10.2215/cjn.02330315, PMID: 26342046
18. Hsing CH Chou W Wang JJ Chen HW Yeh CH . Propofol increases bone morphogenetic protein-7 and decreases oxidative stress in sepsis-induced acute kidney injury. Nephrol Dial Transplant. (2011) 26 :1162–72. doi: 10.1093/ndt/gfq572, PMID: 20864551
19. Yang S Chou WP Pei L . Effects of propofol on renal ischemia/reperfusion injury in rats. Exp Ther Med. (2013) 6 :1177–83. doi: 10.3892/etm.2013.1305 24223641
20. Johnson AEW Bulgarelli L Shen L Gayles A Shammout A Horng S . MIMIC-IV, a freely accessible electronic health record dataset. Sci Data. (2023) 10 :1. doi: 10.1038/s41597-022-01899-x 36596836
21. Khwaja A . KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. (2012) 120 :c179–84. doi: 10.1159/000339789 22890468
22. Devlin JW Roberts RJ . Pharmacology of commonly used analgesics and sedatives in the ICU: benzodiazepines, propofol, and opioids. Anesthesiol Clin. (2011) 29 :567–85. doi: 10.1016/j.anclin.2011.09.001 22078910
23. Devlin JW Skrobik Y Gélinas C Needham DM Slooter AJC Pandharipande PP . Clinical practice guidelines for the prevention and Management of Pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. (2018) 46 :e825–73. doi: 10.1097/ccm.0000000000003299 30113379
24. Hu AM Zhong XX Li Z Zhang ZJ Li HP . Comparative effectiveness of midazolam, Propofol, and Dexmedetomidine in patients with or at risk for acute respiratory distress syndrome: a propensity score-matched cohort study. Front Pharmacol. (2021) 12 :614465. doi: 10.3389/fphar.2021.614465, PMID: 33867980
25. Hall RI Sandham D Cardinal P Tweeddale M Moher D Wang X . Propofol vs midazolam for ICU sedation: a Canadian multicenter randomized trial. Chest. (2001) 119 :1151–9. doi: 10.1378/chest.119.4.1151 11296183
26. Scherer C Kleeberger J Kellnar A Binzenhöfer L Lüsebrink E Stocker TJ . Propofol versus midazolam sedation in patients with cardiogenic shock - an observational propensity-matched study. J Crit Care. (2022) 71 :154051. doi: 10.1016/j.jcrc.2022.154051 35526506
27. Blackwood B Alderdice F Burns KE Cardwell CR Lavery G O'Halloran P . Protocolized versus non-protocolized weaning for reducing the duration of mechanical ventilation in critically ill adult patients. Cochrane Database Syst Rev. (2010) 5 :Cd006904. doi: 10.1002/14651858.CD006904.pub2, PMID: 20464747
28. Wolkewitz M Palomar-Martinez M Alvarez-Lerma F Olaechea-Astigarraga P Schumacher M . Analyzing the impact of duration of ventilation, hospitalization, and ventilation episodes on the risk of pneumonia. Infect Control Hosp Epidemiol. (2019) 40 :301–6. doi: 10.1017/ice.2018.360 30773159
29. Carson SS Kress JP Rodgers JE Vinayak A Campbell-Bright S Levitt J . A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients. Crit Care Med. (2006) 34 :1326–32. doi: 10.1097/01.Ccm.0000215513.63207.7f 16540958
30. Kress JP O'Connor MF Pohlman AS Olson D Lavoie A Toledano A . Sedation of critically ill patients during mechanical ventilation. A comparison of propofol and midazolam. Am J Respir Crit Care Med. (1996) 153 :1012–8. doi: 10.1164/ajrccm.153.3.8630539 8630539
31. Sahinovic MM Struys M Absalom AR . Clinical pharmacokinetics and pharmacodynamics of Propofol. Clin Pharmacokinet. (2018) 57 :1539–58. doi: 10.1007/s40262-018-0672-3 30019172
32. Spina SP Ensom MH . Clinical pharmacokinetic monitoring of midazolam in critically ill patients. Pharmacotherapy. (2007) 27 :389–98. doi: 10.1592/phco.27.3.389, PMID: 17316150
33. McKenzie CA McKinnon W Naughton DP Treacher D Davies G Phillips GJ . Differentiating midazolam over-sedation from neurological damage in the intensive care unit. Crit Care. (2005) 9 :R32–6. doi: 10.1186/cc3010 15693964
34. Chanques G Drouot X Payen JF . 2008-2018: ten years of gradual changes in the sedation guidelines for critically ill patients. Anaesth Crit Care Pain Med. (2018) 37 :509–11. doi: 10.1016/j.accpm.2018.10.014, PMID: 30580774
35. Jin YC Kim W Ha YM Shin IW Sohn JT Kim HJ . Propofol limits rat myocardial ischemia and reperfusion injury with an associated reduction in apoptotic cell death in vivo. Vasc Pharmacol. (2009) 50 :71–7. doi: 10.1016/j.vph.2008.10.002
36. Kato R Foëx P . Myocardial protection by anesthetic agents against ischemia-reperfusion injury: an update for anesthesiologists. Can J Anaesth. (2002) 49 :777–91. doi: 10.1007/bf03017409, PMID: 12374705
37. Li WX Luo RY Chen C Li X Ao JS Liu Y . Effects of propofol, dexmedetomidine, and midazolam on postoperative cognitive dysfunction in elderly patients: a randomized controlled preliminary trial. Chin Med J. (2019) 132 :437–45. doi: 10.1097/cm9.0000000000000098 30707179
