The preventive effect of dexmedetomidine on acute kidney injury after major abdominal surgery : a propensity score matched cohort study

doi:10.21203/rs.3.rs-4495167/v1

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The preventive effect of dexmedetomidine on acute kidney injury after major abdominal surgery : a propensity score matched cohort study

https://doi.org/10.21203/rs.3.rs-4495167/v1

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Background: Major abdominal surgery, which defined as intraperitoneal approach performed under general anesthesia with duration no less than 120min, is a kind of high-risk surgery type for postoperative acute kidney injury (AKI among non-cardiac surgeries. Based on the apparent renal protective effect of dexmedetomidine demonstrated in cardiac surgery and animal study, this study assumed that the dexmedetomidine could prevent the postoperative AKI after major abdominal surgery.

Method: Patients undergoing elective major abdominal surgery from January 2019 to July 2021 in West China Hospital were enrolled. According to whether exposure to intravenous use of dexmedetomidine, patients were divided to Dex group and Control group. The primary outcome was the incidence of AKI in the postoperative 7 days. Secondary outcomes included urine output during operation, renal function on the first day after surgery, length of hospital stays, incidence of postoperative dialysis; mortality in hospital; incidence of hypotension and bradycardia during operation, and incidence of positive inotropic agents and vasopressors use.

Main results: After propensity score matching with ratio of 1:1, a total of 8836 patients were successfully matched. The dexmedetomidine administration has no association with incidence of postoperative AKI, dialysis, intraoperative hypotension, ICU admission , in-hospital mortality and length of hospital stays, but has association with increased urine output (450.00 (250.00, 700.00) vs. 400.00 (200.00, 600.00) ml; P<0.001) and higher value of eGFR (97.33±15.95 vs. 96.13±16.35 ml/min/1.73m2, P<0.001) on the first day after surgery and incidence of bradycardia (37.0% vs. 30.6%; P<0.001) during operation in the matched cohort. In loading dose subgroup, the use of dexmedetomidine decreased the incidence of AKI (OR: 0.44, 95% CI (0.23, 0.76), P=0.006). The association between dexmedetomidine and AKI was absence in subgroups of high or low infusion rate and no loading dose using.

Conclusion: Dexmedetomidine might have a dose-dependent preventive effect on AKI after major abdominal surgery. The use of dexmedetomidine with loading dose could reduce the incidence of postoperative AKI and had the function of renal protection.

dexmedetomidine

adult

acute kidney injury

major abdominal surgery

Surgery is a major cause of acute kidney injury (AKI) in hospitalized patients, accounting for up to 40% of in-hospital AKI cases[1]. Postoperative AKI occurs most frequently following cardiac surgery, with major abdominal surgery also being notable contributor[2]. The incidence of AKI following major abdominal surgery varies, ranging from 6.8% to 35%[3, 4]. The pathogenesis of AKI after major abdominal surgery involves large shifts in volume, intraperitoneal factors that may impair renal blood flow, inflammation, and increased intra-abdominal pressure[5]. AKI is linked to adverse outcomes, including chronic kidney disease, end-stage renal disease, and multiorgan dysfunction. These complications lead to prolonged hospital stays, reduced quality of life, and increased mortality, thereby increasing societal burden[6, 7]. Furthermore, research by Kork et al. indicates that even minor increase in the level of creatinine, not meeting AKI criteria, is associated with increased mortality and longer hospital stays, particularly in patients undergoing non-cardiac surgery[8]. Therefore, it is crucial to raise awareness of AKI following major abdominal surgery[7].

Dexmedetomidine is a kind of selective α adrenoreceptor agonist known for its sedative, analgesic and sympathetic nerve activity reduction properties[9]. Pre-clinical experiments showed dexmedetomidine alleviates ischemia-reperfusion renal injury, lipopolysaccharide-induced renal injury and cisplatin-induced renal injury by attenuating inflammation, oxidative stress and apoptosis through various pathway[10-12]. Clinical studies has also been conducted to investigate the renal protective effects of dexmedetomidine. A study revealed that dexmedetomidine reduced the incidence of postoperative AKI and increased intra-operative urine output in patients undergoing cardiac valve replacement under cardiopulmonary bypass (CPB)[13]. Additionally, a meta-analysis that included randomized controlled trials in cardiac surgery indicated that dexmedetomidine has a beneficial effect in preventing AKI and in reducing the length of intensive care unit (ICU) stays[14]. However, the impact of dexmedetomidine on renal protection following major abdominal surgery remains unclear.

Consequently, this retrospective study was designed to examine the impact of dexmedetomidine administration on the incidence of postoperative AKI and other postoperative outcomes following major abdominal surgery in a matched cohort sample. The authors posited that dexmedetomidine administration would reduce the occurrence of postoperative AKI and have dose-effect during the operation in patients undergoing major abdominal surgery.

1. Study design and data source

This retrospective, single-center study received approval from the Institutional Ethics Committee of West China Hospital and was registered on the Chinese Clinical Trial Registry (ChiCTR2300073505, registration date: July 12th 2023). This study was designed and reported using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Data were extracted from the electronic medical records of patients at West China Hospital, encompassing demographic information, anesthetic records, laboratory findings, diagnoses, etc. West China Hospital, affiliated with Sichuan University in Chengdu, China, stands as one of the largest single-center hospitals in the country, with 4,300 beds and over 14,000 employees. In 2022, the hospital handled 207,500 surgeries, accommodated 8.79 million outpatient visits, and discharged 302,300 patients.

2. Patient inclusion and exclusion criteria

The study included patients aged 18 and above who underwent elective abdominal surgery at West China Hospital. The major abdominal surgery was defined as intraperitoneal approach (including biliary tract, gastric, intestinal, liver surgeries, liver transplantation, pancreatic, and splenic surgeries) performed under general anesthesia with duration no less than 120min[15]. Due to the study's retrospective nature, the requirement for signing informed consent was waived. The exclusion criteria were as follows: (1) Patients classified as Grade V and VI according to the American Standards Association (ASA) classification; (2) Dexmedetomidine administration not conducted intravenously; (3) Missing data regarding serum creatinine (Scr) levels before or after surgery; (4) Incomplete data on hospital discharge; (5) missing data of dexmedetomidine dosage; (6) Patients with chronic renal disease or estimated glomerular filtration rate (eGFR) less than 60 ml·min·1.73 m² prior to surgery[16]¹⁶. Data collection spanned from January 2019 to July 2021.

3. Exposure variables

The exposure variable in our study was the administration of dexmedetomidine via intravenous route during surgery (Dex group) without restriction of dose, while the control variable was the absence of dexmedetomidine administration during surgery (Control group).

4 Confounding variables

We included a range of potential variables that could influence postoperative acute renal injury, as follows (shown in Supplementary Fig1): patient demographics, ASA classification, and comorbidities (such as hypertension, diabetes, cardiac dysfunction, cirrhosis, respiratory diseases, and peripheral vascular disease). Preoperative laboratory variables included hemoglobin, albumin and Scr concentrations. Anesthesia-related variables encompassed anesthesia duration, type (general anesthesia, general anesthesia combined with thoracic epidural anesthesia, general anesthesia combined with peripheral nerve block, general anesthesia combined with paravertebral block), and surgery duration. Surgical variables covered surgery type (biliary tract surgery, gastric surgery, intestinal surgery, liver surgery, liver transplantation, pancreatic surgery, or splenic surgery) and method (open or laparoscopic surgery). Intraoperative variables included fluid infusion (measured in ml/kg/h), colloid ratio, transfusion of blood products, use of Non-steroid anti-inflammatory drugs (NSAIDS), maximum concentration of lactic acid, and minimum hemoglobin concentration during surgery[17].

4. Outcomes and measurement

The primary outcome was the incidence of AKI within the first 7 days postoperatively, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. AKI is identified based on the following criteria: an increase in Scr by ≥0.3 mg/dL (≥26.5 µmol/L) within 48h, or an increase in SCr to ≥1.5 times the baseline value recorded in the previous seven days, or a urine output (UO) of less than 0.5 mL/kg/h for 6h[18]. The secondary outcomes include the level of Scr and eGFR on the first day after surgery, intraoperative urine output, length of hospital stay, in-hospital mortality, incidence of dialysis, incidence of ICU admission, and incidence of hypotension (defined as a minimum mean arterial pressure (MAP) of less than 60 mmHg), bradycardia (defined as a minimum heart rate (HR) of less than 50 bpm) and use of inotropic and vasopressor durgs during surgery.

5. Statistical analysis

Sample size calculation was performed by PASS 22.0 software. Assuming the incidence of postoperative AKI as 6.8% according to previous studies for abdominal surgery, a 30% reduction in the incidence of AKI was considered clinically significant. Considering the ratio of Dex group and control group was 1:1 and a data missing rate of 20%, each group would require 2564 patients.

For the assessment of continuous variables, the Kolmogorov-Smirnov test was utilized to evaluate normality. Continuous data adhering to a normal distribution were presented as mean ± standard deviation, while data with an abnormal distribution were reported as medians (Interquartile Range, IQR). Categorical variables were summarized by case counts (frequency). Certain continuous variables underwent transformation into clinically meaningful categories to better reflect the realities of clinical documentation accuracy. The unpaired t-test was applied to continuous variables with a normal distribution, and the Mann-Whitney U-test was used for those with an abnormal distribution. X² or Fisher’s exact tests was used for categorical variables.

Given the inherent selection bias in non-randomized studies, we aimed to minimize potential bias in our cohort study through propensity-score matching (PSM)[19]. In this process, each case receiving dexmedetomidine was matched to a control case within a 0.2 caliper. The propensity-scores were generated using a multivariate logistic regression model, taking into account covariables with standardized mean differences (SMD)≥0.1 as well as age, sex, BMI, and ASA classification. The balance between the two groups was assessed using SMD, with an SMD < 0.1 indicating appropriate balance[19].

Continuous variables with normally distribution were compared by Student’s t test while variables with non-normally distribution were compared by Mann-Whitney U test. Categorical variables were compared by Pearson’s chi-squared test or Fisher’s exact probability test both before and after PSM. Univariate analyses were adopted to assess the associations between dexmedetomidine and categorical outcome variables, conducted both pre- and post-PSM. If covariables with SMD≥0.1 persisted after PSM, they were included in a multivariable conditional regression model to explore the relationship between dexmedetomidine use and outcomes. Adjusted odds ratios with 95% confidence intervals were reported.

Sensitivity analyses evaluated the robustness of the primary outcome.First, the association between dexmedetomidine administration and AKI was estimated by using two additional statistic methods except for PSM to control the confounding factors. In the analysis adjusted for propensity score, the score was included as an additional covariate in the multivariate logistic regression model. In the inverse-probability- weighted(IPW) analysis, the predicted probabilities from the propensity-score model were used to calculate stabilized inverse-probability-weighting weights following Rubin’s rules[20]. A logistic regression model employing these weights was reported. Second, a prespecified subgroup analysis was conducted based on the infusion rate of dexmedetomidine and the use of a loading dose, to explore dose-related effects of dexmedetomidine on AKI: loading dose subgroup, no loading dose subgroup, low dose subgroup (infusion rate ≤ 0.4 ug/kg/h), high dose subgroup (infusion rate > 0.4 ug/kg/h).

For missing data regarding dexmedetomidine use and Scr levels before and after surgery, we initially filled the missing values manually. Cases without data on dexmedetomidine use and Scr levels were excluded, as outlined in the inclusion and exclusion criteria. Variables with more than 20% missing data were discarded, while multiple imputation was used for variables with less than 20% missing data[21].

Data processing and analysis were performed using R version 4.3.0, along with Storm Statistical Platform (www.medsta.cn/software). All hypothesis tests were two-sided, with a significance threshold set at p ≤ 0.05.

Characteristics of the cohort

A total of 16,431 patients undergoing major abdominal surgery met the inclusion criteria. Of the eligible cases, 4 were excluded due to an ASA grade of V or VI, 171 because dexmedetomidine was not administered intravenously, 1,118 for lacking data on Scr concentration, 153 for missing information about hospital discharge, and 1924 for missing dosage of dexmedetomidine. Additionally, 605 cases were excluded due to chronic kidney disease or a preoperative GFR of less than 60 ml/min/1.73m². Among the remaining cases, 12,456 were eligible for matching (Fig. 1).

Before matching, 5,354 patients received dexmedetomidine, while 7,102 did not. Nine covariates (ASA classification, preoperative Hb, preoperative Alb, preoperative Scr, surgery type, surgery method, fluid infusion, colloid ratio and use of NSAIDS) exhibited a standardized difference of more than 0.10. Following 1:1 propensity score matching for covariates with a SMD of more than 0.1, 8,836 patients were matched, with 4,418 in each study group. A balance of preoperative and intraoperative covariates between the two groups was achieved (as detailed in Tables 1 and 2). The missing data rate for the studied population was under 20%. The distribution of the estimated propensity scores for receiving dexmedetomidine in both the unmatched and matched populations was depicted in Fig. 2. The differences between the two groups were less pronounced in the matched cohort compared to the unmatched cohort.

Table 1

Demographics, medical comorbidities and preoperative experimental data before and after propensity score matching
Characteristic n(%) or median(IQR)	Before Matching			After Matching
Characteristic n(%) or median(IQR)	Dex (n = 5354)	Control (n = 7102)	SMD	Dex (n = 4418)	Control (n = 4418)	SMD
Age,years	55.80 (47.50, 65.20)	56.60 (48.50, 65.90)	0.067	56.00 (47.80, 65.60)	56.30 (48.40,65.50)	0.015
Sex,female	1979 (37.0)	2687 (37.8)	0.018	1641(37.1)	1656 (37.5)	0.007
BMI,kg/m²	22.89 (20.11,25.96)	22.87 (20.06,26.22)	0.026	22.99 (20.20, 26.08)	22.85 (20.07,26.04)	0.016
ASA classification			0.180			0.007
I	29 (0.5)	15 (0.2)		13 (0.3)	12 (0.3)
II	3936 (73.5)	4706 (66.3)		3154 (71.4)	3162 (71.6)
III	1362 (25.4)	2302 (32.4)		1224 (27.7)	1216 (27.5)
IV	27 (0.5)	80 ( 1.1)		27 (0.6 )	28 (0.6)
hypertension	787 (14.7)	1032 (14.5)	0.005	689 (15.6)	603 (13.6)	0.055
diabetes	518 (9.7)	689 ( 9.7)	0.001	434 (9.8)	415 (9.4)	0.015
cardiac dysfunction	8 (0.1)	10 ( 0.1)	0.002	8 (0.2)	4 (0.1)	0.025
cirrhosis	555 (10.4)	739 (10.4)	0.001	464 (10.5)	464 (10.5)	< 0.001
respiratory disease	48 (0.9)	77 ( 1.1)	0.019	42 (1.0)	52 (1.2)	0.022
Peripheral vascular disease	95 ( 1.8)	174 ( 2.5)	0.047	78 (1.8)	88 (2.0)	0.017
preoperative Hb,g/L	132.00 (118.00,146.00)	130.00 (115.00,143.00)	0.139	132.00 (117.00, 144.00)	132.00 (117.00, 145.00)	0.003
preoperative Alb, g/L	42.10 (39.30, 44.60)	41.60 (38.70, 44.10)	0.129	41.90 (39.10, 44.40)	41.80 (39.10, 44.40)	0.001
preoperative Scr, g/L	69.00 (58.00, 80.00)	71.00 (60.00, 81.00)	0.128	69.00 (59.00, 81.00)	69.00 (59.00, 80.00)	0.008
Abbreviations: BMI, body mass index; ASA, American Standards Association; Hb, hemoglobin; Alb, albumin; Scr, serum creatine.

Table 2

Intraoperative characteristics of patients in unmatched cohort and propensity score-matched cohort
Characteristic n(%) or median(IQR)	Before Matching			After Matching
Characteristic n(%) or median(IQR)	Dex (n = 5354)	Control(n = 7102)	SMD	Dex (n = 4418)	Control (n = 4418)	SMD
anesthetic duration,h	4.77 (3.92, 5.92)	4.75 (3.92, 5.89)	0.001	4.74 (3.91,5.89)	4.83 (3.98,5.93)	0.021
surgery duration,h	3.53 (2.76,4.57)	3.42 (2.67,4.43)	0.046	3.50(2.75,4.50)	3.50(2.75,4.50)	0.024
anesthetic type			0.081			0.072
GA	5318 (99.3)	7081 (99.7)		4392 (99.4)	4408 (99.8)
GA + TEA	6 ( 0.1)	13 ( 0.2)		4 ( 0.1)	5 (0.1)
GA + PNB	26 ( 0.5)	8 ( 0.1)		19 ( 0.4)	5 (0.1)
GA + PVB	4 ( 0.1)	0 ( 0.0)		3 (0.1)	0 (0.00)
surgery type			0.233			0.031
biliary tract surgery	283 ( 5.3)	474 ( 6.7)		264 ( 6.0)	286 (6.5)
gastric surgery	952 (17.8)	880 (12.4)		682 (15.4)	683 (15.5)
intestinal surgery	1140 (21.3)	1914 (27.0)		1031 (23.3)	1052 (23.8)
liver surgery	2040 (38.1)	2420(34.1)		1649 (37.3)	1644 (37.2)
liver transplantation	64 ( 1.2)	200 ( 2.8)		64 ( 1.4)	63 (1.4)
Pancreatic surgery	779 (14.5)	1084 (15.3)		645 (14.6)	613 (13.9)
Splenic surgery	96 ( 1.8)	130( 1.8)		83 ( 1.9)	77 (1.7)
Surgery method (laparoscopic)	1297 (24.2)	2401 (33.8)	0.212	1181(26.7)	1188(26.9)	0.004
fluid balance, ml/kg · h	8.18 (6.58,10.20)	9.26 (7.15,12.09)	0.373	8.39 (6.70,10.42)	8.37 (6.66,10.41)	0.001
colloid ratio	0.29 (0.23,0.37)	0.25 (0.16,0.33)	0.393	0.29 (0.22,0.36)	0.29 (0.21,0.37)	0.004
transfusion	911 (17.0)	1445 (20.3)	0.086	785 (17.8)	752 (17.0)	0.020
NSAIDS	1281 (32.1)	2733 (51.0)	0.391	2039 (46.2)	1996 (45.2)	0.020
concentration of Lacmax	1.60 (1.30,2.30)	1.60 (1.30,2.30)	0.060	1.60 (1.30,2.30)	1.60 (1.30,2.30)	0.014
Concentration of Hbmin	109.40 (91.80,123.00)	109.40 (91.80,123.00)	0.074	109.46 (93.50,122.60)	110.80 (95.30,123.90)	0.060
Abbreviations: GA, general anesthesia; TEA, thoracic epidural anesthesia;PNB, peripheral nerve block; PVB, paravertebral block༛Lacmax, The maximum value of lactic acid in the blood gas analysis during operation; NSAIDS, Non-steroid anti-inflammatory drugs; Hbmin, The minimum value of hemoglobin in the blood gas analysis during operation.

Postoperative acute kidney injury

In the crude cohort (n = 12456), postoperative AKI developed in 469 patients (3.8%). Among them, the majority of AKI cases were classified as grade 1, accounting for 370 patients (78.9%). In the matched cohort (n = 8,836), postoperative AKI developed in 299 patients (3.38%). Among them, the majority of AKI cases were classified as grade 1, accounting for 238 patients (79.6%).

Before mathcing, the incidence of postoperative AKI was significantly lower in the Dex group compared to the control group (3.3% vs. 4.1%, P = 0.036). However, in the matched cohort, there was no significant difference in the incidence of postoperative AKI between the two groups (3.4% vs. 3.3%, P = 0.769), shown on Fig. 3A.

Secondary outcomes

In the matched cohort, patients in the Dex group exhibited greater urine output during the operation than those in the control group (450.00 (250.00, 700.00) vs. 400.00 (200.00, 600.00)ml, P < 0.001)((Fig. 3B). Furthermore, the eGFR value in the Dex group was higher than controle group (97.33 ± 15.95 vs. 96.13 ± 16.35 ml/min/1.73m², P<0.001) in the first postoperative day(Fig. 3D). After matching, no significant difference was found in the concentration of Scr between the two groups (68.89 ± 17.96 vs. 68.54 ± 19.06 µmol/L, P = 0.368)(Fig. 3C)

There was no difference between the Dex group and the control group about the incidence of postoperative dialysis (0.1% vs. 0.1%, P = 1.000), postoperative ICU admission (7.4% vs. 7.2%, P = 0.744), in-hospital mortality rate (0.2% vs. 0.2%, P = 0.466), length of hospital stay (9.25 (8.00, 12.00) vs. 9.00 (8.00, 12.00), P = 0.057) (Table 3).

Table 3

secondary outcomes before and after propensity matching
	before PSM			after PSM
Outcomes, n (%) or median(IQR)	Dex (n = 5354)	Control (n = 7102)	P	Dex (n = 4418)	Control (n = 4418)	P
postoperative dialysis	3 (0.1)	10 (0.1)	0.242	3 (0.1)	3 (0.1)	1
ICU admission	352 (6.6)	719 (10.1)	<0.001	328 (7.4)	320 (7.2)	0.744
in-hospital mortality	12 (0.2)	13 (0.2)	0.760	10 (0.2)	7 (0.2)	0.466
Hospital stays, days	9.00 (8.00,12.00)	9.00 (8.00,12.00)	0.153	9.25 (8.00,12.00)	9.00 (8.00,12.00)	0.057
intraoperative hypotension	1011 (18.9)	1306 (18.4)	0.498	855 (19.4%)	836 (18.9%)	0.607
intraoperative bradycardia	1994 (37.2)	2265 (31.9)	<0.001	1634 (37.0%)	1354 (30.6%)	<0.001
Positive inotropic agents use	75 (1.4)	172 (2.4)	<0.001	70 (1.6)	72 (1.6)	0.866
Vasopressors use	634 (11.8)	988 (13.9)	<0.001	527 (11.9)	474 (10.7)	0.075
Abbreviations: AKI, acute kidney injury; ICU, intention care unit; PSM, propensity-score matching.

No between-group differences were found in the rates of intraoperative hypotension (19.4% vs. 18.9%, P = 0.607), use of positive inotropic agents () and vasopressors (1.6% vs. 1.6%, P = 0.866). Nonetheless, the incidence of intraoperative bradycardia in the Dex group was significantly higher than the control group (37.0% vs. 30.6%, P < 0.001) (Table 3).

Sensitivity analysis

Prespecified additional statistical analyses were performed and yielded results similar to the PSM analysis. In the crude cohort, the univariable analysis showed patients who received dexmedetomidine exhibited a lower risk of postoperative AKI than control group (OR = 0.81, 95% CI: 0.67 to 0.98, P = 0.032). In the propensity-matched cohort, the univariable analysis showed there was no significant association between dexmedetomidine use and postoperative AKI (OR = 1.04, 95% CI: 0.82 to 1.36, P = 0.769). Similarly, the univariable analysis in the inverse probability weighting cohort showed there was no significant association between dexmedetomidine and postoperative AKI (OR = 0.98, 95% CI: 0.86 to 1.12, P = 0.771). In the multivariable logistic model, which included the propensity score as an additional covariate, there was also no significant association between dexmedetomidine use and postoperative AKI (OR = 0.99, 95% CI: 0.81 to 1.22, P = 0.953) (Fig. 4).

In the matched cohort, it was found that 5.3% of patients in the Dex group were administered dexmedetomidine at an infusion rate of more than 0.4 µg/kg/h. Meanwhile, a loading dose was applied in 18.1% of patients in the Dex group. Subgroup analysis was performed to explore the association between dexmedetomidine use and AKI in subgroups based on the infusion rate and the application of a loading dose of dexmedetomidine in the matched cohort.

In the loading dose subgroup, the use of dexmedetomidine significantly reduced the incidence of postoperative AKI (OR = 0.44, 95% CI: 0.23 to 0.76, P = 0.006). However, in the non-loading dose sugroup (OR = 1.17, 95% CI: 0.93 to 1.49, P = 0.183), high-dose subroup (OR = 0.75, 95% CI: 0.29 to 1.58, P = 0.505) and low-dose subgroup (OR = 1.05, 95% CI: 0.83 to 1.33, P = 0.674), the use of dexmedetomidine showed no association with postoperative AKI (Fig. 5).

In this extensive population-based cohort study, AKI was observed in 3.80% of all patients undergoing selective major abdominal surgery. Within the crude cohort, the incidence of AKI in the Dex group was significantly higher than the control group. After PSM, dexmedetomidine did not demonstrate a significant association with AKI, but had close relationship with more urine output during operation and higher level of eGFR one the fist day after surgery. Furthermore, dexmedetomidine decreased the incidence of postoperative AKI in the loading dose subgroup significantly (OR = 0.44, 95% CI: 0.23 to 0.76) in the matched cohort.

In the matched cohort, although this study observed significantly more urine output during surgery and higher eGFR levels on the first day after surgery in the Dex group, it did not observe the preventive effect of dexmedetomidine on postoperative AKI. Several meta-analyses, including RCTs in patients undergoing cardiac surgery, offered consistent findings that dexmedetomidine could decrease the incidence of AKI[14, 22]. However, previous retrospective cohort studies in non-cardiac surgery settings showed inconsistent results[23, 24]. Paredes-Flores et al. defined the exposure of dexmedetomidine as infusion at 0.3 µg/kg/h and found no association between dexmedetomidine and AKI in patients undergoing non-cardiothoracic cancer surgery[23]. Nonetheless, Zhu et al defined the exposure as loading dose with 0.5-1.0 µg/kg or infusion rate with 0.2–0.7 µg/kg/h, and found the use of dexmedetomidine related to lower incidence of postoperative AKI in patients undergoing major joint replacement[24]. Some RCTs in non-cardiac surgery revealed renal protection by dexmedetomidine based on renal injury biomarkers, without reporting the occurrence of AKI[25, 26]. Our study failing to find the association between exposure of dexmedetomidine use and postoperative AKI might has several reasons. First, we did not restrict the usage of exposure variable (dexmedetomidine administration). Therefore, patients with low dose of dexmedetomidine were also included in the Dex group, leading to the overall renal protective effect was not obvious in the Dex group. Second, since most patients undergoing major abdominal surgeries planned to remove their tracheal tubes after surgery as soon as possible, dexmedetomidine was stopped before the end of surgery. However, dexmedetomidine was administrated for more than 24 h for patients underwent cardiac surgery or patients in ICU[27]. Therefore, the duration of dexmedetomidine administration in major abdominal surgery was shorter than that in cardiac surgery. Third, the pathogenesis of postoperative AKI after major abdominal surgery was multifaceted and differs from that in cardiac surgery. AKI following cardiac surgery tends to show relative homogeneity, characterized by renal ischemia, inflammatory responses, and sympathetic hyperactivation associated with cardiopulmonary bypass (CPB)[28], which decreased variability[29]. Conversely, the mechanism of AKI after major abdominal surgery encompasses a variety of factors such as fluid loss, bleeding, neuroendocrine responses to anesthesia and surgery, damage-associated molecular pattern (DAMP)-induced inflammation, as well as issues related to urinary obstruction and intra-abdominal pressure[4, 5]. These differences in patient populations and the pathophysiological aspects of postoperative AKI in cardiac versus major abdominal surgeries may influence the renal protective effects of dexmedetomidine.

Considering the potential dose-dependency of dexmedetomidine's renal protective effects[30] and unrestricted usage of dexmedetomidine administration in our study, we conducted a subgroup analysis. Similar to other retrospective study[24], it was not possible to unify the usage method of dexmedetomidine due to observation study design. Subgroup analysis in meta-analysis involving cardiac surgery showed dexmedetomidine took effect of preventing postoperative AKI regardless of loading dose use. However the preventive effect of dexmedetomidine was weakened with the infusion rate ≤ 0.4 µg/kg/min[14]. A research about ICU related sepsis-associated AKI indicated that dexmedetomidine with infusion rate ranging from 0.3 to 1.0 µg/kg/h could prevent AKI[27]. However, there was no RCTs directly comparing the preventive effects of different administration of dexmedetomidine. In our subgroup analysis, dexmedetomidine significantly reduced the incidence of AKI in loading dose subgroup, with a reduction rate of over 50%. However, neither the high infusion rate subgroup (> 0.4 µg/kg/min) nor the low infusion rate subgroup (≤ 0.4 µg/kg/min) showed no association between dexmedetomidine and postoperative AKI. The different dose-effect of dexmedetomidine on the prevention of AKI among patients undergoing major abdominal surgery, cardiac surgery and critically ill patients with sepsis might relate to the varying characteristics of dexmedetomidine administration in different clinical settings. In order to extubate endotracheal tube after major abdominal surgery as soon as possible, dexmedetomidine did not administrated continuously after surgery. However, dexmedetomidine usually administrated persistently after cardiac surgery because patients were ventilated for a period time. Therefore, the duration of dexmedetomidine administration was shorten in major abdominal surgery than cardiac surgery and loading dose had larger effect on total dose. According to the subgroup analysis, administration of dexmedetomidine with loading dose reduced the incidence of postoperative AKI significantly.

The comparison of safety endpoints showed a higher incidence rate of bradycardia in the Dex group after surgery, but there was no difference in the incidence rate of hypotension between the two groups. Previous retrospective study conducted in joint surgeries also got similar results[24]. Long-term hypotension persisting can lead to tissue hypoperfusion and affect organ function, which is a high-risk factor for postoperative AKI[31]. However, transient bradycardia has a mild effect on tissue perfusion[24]. Additionally, the proportion of patients treated with vasopressors and positive inotropic agents did not differ significantly between the Dex group and the control group. This finding was consistent with previous studies and meta-analyses[24, 26]. These findings showed that the use of dexmedetomidine during major abdominal surgery was safe

Strengths and limitations

Our research possesses several notable strengths. Firstly, to the best of our knowledge, this study is the first observational research for dexmedetomidine involving over 10,000 cases undergoing major abdominal surgery. Due to the large sample size, we were able to fully consider a wide range of important confounding factors during the analysis process, including demographic characteristics, preoperative comorbidities, intraoperative management, and so on. Secondly, we explored the potential dose-effect of dexmedetomidine on renal protection for the first time, which was often overlooked in non-cardiac surgeries. The usage of drug administration had a significant impact on its efficacy. Our finding could provide a foundation for finding the optimal usage of dexmedetomidine. Third, although cohort studies are inherently subject to selection bias, we utilized PSM to mitigate confounders. Moreover, we conducted sensitivity analyses by using other propensity-score methods to control the confounding factors.

However, our study was not without limitations. Firstly, we defined postoperative AKI solely based on changes in Scr, excluding urine output due to a lack of postoperative data. While this definition is widely accepted for post-surgery AKI in retrospective research, it may underestimate the actual incidence[32]. Secondly, as a retrospective cohort study, selection bias was an inherent issue. Despite extensive adjustments for confounders, there might still be unmeasured factors, such as hemorrhage volume and hypotension duration[16], affecting the results.

In conclusion, our study found there might be dose effect on the preventive effect of dexmedetomidine on postoperative AKI after major abdominal surgery, and the use of loading dose could significantly prevent the occurrence of postoperative AKI. The retrospective design of this study limits the generalization of these results to clinical practice. Well-designed randomized controlled trials are needed to further explore the renal protective effects of dexmedetomidine in major abdominal surgery.

Ethics approval and consent to participate

The ethics committee of the West China Hospital of Sichuan University approved this study, the approval number: 2022(1329). The study was registered on the Chinese Clinical Trial Registry (ChiCTR2300073505, registration date: July 12th 2023)

Consent for publication

All authors have provided their final approval for the version to be published and are committed to being responsible for all aspects of this work.

Availability of data and materials

No.

Competing interests

The authors declare no conflicts of interest.

Funding declaration

None.

Authors’ contributions

Study design: all authors

Data acquisition: QL, TJ

Data analysis: LHB, LR

Drafting of the manuscript: all authors

Revision of manuscript: all authors

Acknowledgments

The authors acknowledge the Biostatistics Center at West China Hospital of Sichuan University for their support in data acquisition and analysis.

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No competing interests reported.

supplementaryFig.jpeg
Supplementary Fig.1 Directed acyclic graph for the association between dexmedetomidine (exposure) and postoperative acute kidney injury (outcome) Blue color variables indicate ancestors of the outcome and red color variables indicate ancestors of both the exposure and outcome. Abbreviations: ASA, American Society of Anesthesiologists; Alb, Albumin; Hb, hemoglobin; Scr, serum creatine; Lacmax, The maximum value of lactic acid in the blood gas analysis during operation; NSAIDS: Non-steroid anti-inflammatory drugs; Hbmin, The minimum value of hemoglobin in the blood gas analysis during operation; AKI, acute kidney injury.

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The preventive effect of dexmedetomidine on acute kidney injury after major abdominal surgery : a propensity score matched cohort study

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Postoperative acute kidney injury

Secondary outcomes

Sensitivity analysis

Discussion

Strengths and limitations

Conclusion

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