# Effects of Different Doses of Dex Anesthesia on Inflammatory Factors and Hemodynamics in Patients Undergoing Neurosurgery and Its Relationship with RSS Score

Authors: Qiaoling Lu; Chengwei Wu; Zhenhua Wu; Xinbin Wang; Hao Cheng
Journal: BioMed Research International
 (2022)

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## Abstract

The effects of different doses of dexmedetomidine (Dex) anesthesia on inflammatory factors and hemodynamics in patients undergoing neurosurgery and its relationship with RSS scores are analyzed. A total of 102 patients who received neurosurgery in our hospital from March 2021 to March 2022 are selected. According to different intraoperative Dex dose, the enrolled patients are randomly divided into low-, medium-, and high-dose groups, 34 patients in each group. In this study, hemodynamic indexes, inflammatory factors, anesthesia effect, and the Ramsay sedation scale (RSS) score are compared in each groups. The experimental results show that in neurosurgery, compared with low-dose Dex, high-dose Dex can better maintain patients’ intraoperative hemodynamic parameters and effectively inhibit postoperative inflammatory response, but postoperative awakening time is also relatively prolonged, while medium-dose Dex can effectively control patients’ awakening time.


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## Body

## 1. Introduction

In the process of neurosurgery, especially those involving craniocerebral functional areas, due to the great difficulty of the operation, it is easy to cause postoperative limb dysfunction or paraplegia and other serious complications if the operation is not handled properly [1]. Ideal neurosurgical anesthesia requires rapid and stable anesthesia induction, adequate intraoperative analgesia, stable hemodynamics, and rapid recovery after drug withdrawal without agitation, respiratory depression, and residual drug effects [2]. Dexmedetomidine (Dex) is a new class of anesthetics, which belongs to α2 adrenergic receptor agonists. The mechanism of action of Dex in surgery is to activate α2 adrenergic receptors in the presynaptic membrane of the locus, reduce the release of norepinephrine, and then reduce the excitability of synaptic structures [3]. Adrenergic nerve fibers from the locus coeruleus nuclear have the function of regulation of the cerebral cortex awakening response in the mi and application of general anesthesia right beauty [4–6]. It can play the drug to the locus coeruleus nuclear adrenergic nerve to adjust action, inhibit the awakening of the brain response, and thus ensure the exact effect of anesthesia and anesthesia awakening period smoothly. It also reduces the risk of agitation during awakening [7–9]. At present, the dose selection of Dex remains to be further clarified.This study compared the effects of different doses of Dex on inflammatory factors, hemodynamics, and sedation scores of patients undergoing neurosurgery, to further clarify the influence of the choice of Dex dose on the quality of recovery from general anesthesia.The rest of this paper is organized as follows: Section2 discusses the related work, followed by patients’ information and intervention methods designed in Section 3. Section 4 shows the experimental results and analysis, and Section 5 is the conclusion and relevant appraisement for the whole study.


## 2. Related Work

In recent years, Dex has become a routine drug used in general intravenous anesthesia, which can play a synergistic effect with conventional anesthesia drugs and play a good central sedation effect without obvious respiratory inhibition effect [10–12]. At present, the dose of Dex used in clinical practice is 0.2~1.0 μg/(kg h), and there is no clear unified standard for the selection of dose [13]. Some studies believe that selecting a large dose of Dex can achieve a more precise sedation effect and avoid the occurrence of agitation in the wake period, but other studies believe that a large dose of Dex can prolong the wake time and affect the recovery of cognitive function after anesthesia [14, 15]. Therefore, the selection of appropriate dose of Dex for general anesthesia is one of the key clinical topics. The ideal drug dose should be able to achieve the desired sedation effect, prevent the occurrence of agitation in the recovery stage, not affect the recovery process, and not prolong the recovery time of anesthesia.Recovery mainly includes the degree of restlessness and recovery time. In this study, the recovery time of breath, eye-opening time of breath, and extubation time were shorter in the low-dose group and the medium-dose group, and there was no statistical significance between the two groups, suggesting that the recovery time of low-dose and medium-dose groups was similar and shorter than that of the high-dose group [16]. By comprehensive comparison, among the three different doses, middle-dose Dex had the advantages of good sedation effect and weak agitation degree at high dose and short awakening time at low dose. In the wake period of anesthesia, the ideal sedation effect can prevent the occurrence of agitation in the wake period and thus avoid the fluctuation of vital signs in the wake period [17–19]. In this study, HR, CI, and RPP of the medium-dose and high-dose groups were lower than those of the low-dose group, and RSS scores of the medium-dose and high-dose groups were significantly higher than those of the low-dose group, which further confirmed the exact sedative effect of high-dose Dex, and the effect of stabilizing vital signs was consistent with that of high-dose Dex.In neurosurgery, intravenous anesthesia is the most commonly used anesthesia method, but patients are easily excited by the sympathetic adrenergic system due to endotracheal intubation, extubation, and other measures, resulting in accelerated heart rate and increased blood pressure [20]. In addition, during surgical treatment, patients will release peptides from the monocyte-macrophage system and activate the complement system due to surgical trauma, resulting in damage to the intima of blood vessels. Meanwhile, C-reactive protein receptors on monocytes will be activated due to the massive release of C-reactive protein, resulting in vascular injury. In addition, the trauma caused by surgery will also lead to an increase in the inflammatory response of patients [21]. In this study, inflammatory factors in each group were significantly increased 3 days after surgery. Serum CRP and IL-6 levels in each group decreased with the increase of Dex dose (all P<0.05), which also reflected the advantages of medium- and high-dose Dex in clinical application. In addition, further analysis of this study showed that serum inflammatory factors including CRP and IL-6 levels in neurosurgery patients were closely correlated with RSS score, suggesting that monitoring of inflammatory factors in patients undergoing neurosurgery has positive effects on clarifying patient sedation effect and adjusting anesthesia plan.


## 3. Patients’ Information and Intervention Methods

### 3.1. Patients’ Information

A total of 102 patients who received neurosurgery in our hospital from March 2021 to March 2022 are selected, including 56 cases of intracranial tumor resection, 28 cases of skull defect repair, and 18 cases of intracranial aneurysm clipping. All patients are in line with disease diagnosis and surgical indications. All patients enrolled in the study are aware of relevant matters and gave informed consent. Patients with serious organic functional diseases such as liver and kidney, psychiatric history, long-term use of large doses of sedative drugs, and allergic constitution are excluded. All patients included in this study included 59 males and 43 females, aged from 34 to 63 years, with an average of48.51±8.12 years. Body mass index (BMI) ranged from 18.23 kg/m2 to 26.35 kg/m2 with an average of 22.26±2.43 kg/m2. According to the American Society of Anesthesiologists, there are 65 grade II patients and 37 grade III patients. According to different intraoperative Dex dose, the enrolled patients are randomly divided into low-, medium-, and high-dose groups, 34 patients in each group, and Dex dose is 0.2 μg/(kg h), 0.4 μg/(kg h), and 0.8 μg/(kg h), respectively.


### 3.2. Intervention Methods

Patients in each group are given intravenous inhalation combined anesthesia. After entering the operating room, peripheral veins are routinely opened to establish invasive arterial pressure.Anesthesia induction plan is as follows: sufentanil 0.3μg/kg, vecuronium 0.1 mg/kg, etomidate 0.2 mg/kg, and propofol 1-3 mg/kg. After endotracheal intubation, ventilator parameters are adjusted as follows: respiration ratio 1 : 2, tidal volume 8 mL/kg, ventilation frequency 12 times/min, oxygen flow 2 L/min. Intraoperatively, sevoflurane is inhaled for anesthesia maintenance and vecuronium is intermittently injected intravenously to maintain muscle relaxation, with BIS values ranging from 35 to 45. Dex loading dose 1.0 μg/kg is slowly pumped 15 min after induction of anesthesia, which is completed within 10 min. Intraoperative are given 0.2 μg/(kg h), 0.4 μg/(kg h), and 0.8 μg/(kg h) right beautiful mi on micropump injection. During the operation, if the systolic blood pressure is lower than 90 mmHg, dopamine is injected intravenously (2 mg/time), and atropine is injected intravenously (0.5 mg/time) when the heart rate is lower than 50 times/min.


### 3.3. Observation Indicators

There are six observation indicators as follows:(1)
Comparison of baseline data of patients in each group is as follows: gender, age, body mass index, and disease grade are compared in each group(2)
Changes of hemodynamic indexes in each group during awakening are compared as follows: During awakening, changes of heart rate (HR) are recorded in all patients, and cardiac index (CI), heart rate, and rate pressure product (RPP) are calculated(3)
Compare the changes of serum inflammatory factor indexes in different time periods in each group: 5 mL of fasting elbow venous blood is extracted from each group before and 3 d after surgery, and centrifuge is used for centrifuge operation (centrifuge parameters are set to 3500 r/min, centrifuge radius is 10 cm, and continuous centrifuge time is 15 min). The levels of C-reactive protein (CRP) and interleukin-6 (IL-6) are detected by double-antibody sandwich enzyme-linked immunosorbent assay (ELISA)(4)
The postoperative sedation score of each group is compared as follows: the sedation score of the two groups is observed, and the sedation evaluation is carried out according to the Ramsay sedation scale (RSS) [13]. RSS has 5 grades as follows: level 1: the patient’s consciousness is 0, and the patient has no response to pat call and will respond to injurious stimuli; level 2: the patient’s consciousness is not completely lost, with slight fuzzy consciousness and no response to loud calls; level 3: blurred consciousness, responding to the call to beat; level 4: slightly clear consciousness, clear response when tapping and calling; and level 5: conscious and able to respond to medical staff’s questions(5)
The recovery of each group is observed, including the recovery time of respiration, eye-opening time of exhalation, and extubation time(6)
The correlation between RSS scores and inflammatory factors is analyzed


### 3.4. Statistical Processing

All data collected in this study are input into SPSS 26.0 for analysis and processing, in which the measurement data are subjected to normal test, represented byx̅±s, variance comparison between groups, independent sample t test, percentage (%), and χ2 for counting data. The correlation between sedation score and inflammatory factors in patients undergoing neurosurgery is completed by Pearson’s correlation coefficient analysis. P<0.05 confirmed statistical difference in data comparison.


## 3.1. Patients’ Information

A total of 102 patients who received neurosurgery in our hospital from March 2021 to March 2022 are selected, including 56 cases of intracranial tumor resection, 28 cases of skull defect repair, and 18 cases of intracranial aneurysm clipping. All patients are in line with disease diagnosis and surgical indications. All patients enrolled in the study are aware of relevant matters and gave informed consent. Patients with serious organic functional diseases such as liver and kidney, psychiatric history, long-term use of large doses of sedative drugs, and allergic constitution are excluded. All patients included in this study included 59 males and 43 females, aged from 34 to 63 years, with an average of48.51±8.12 years. Body mass index (BMI) ranged from 18.23 kg/m2 to 26.35 kg/m2 with an average of 22.26±2.43 kg/m2. According to the American Society of Anesthesiologists, there are 65 grade II patients and 37 grade III patients. According to different intraoperative Dex dose, the enrolled patients are randomly divided into low-, medium-, and high-dose groups, 34 patients in each group, and Dex dose is 0.2 μg/(kg h), 0.4 μg/(kg h), and 0.8 μg/(kg h), respectively.


## 3.2. Intervention Methods

Patients in each group are given intravenous inhalation combined anesthesia. After entering the operating room, peripheral veins are routinely opened to establish invasive arterial pressure.Anesthesia induction plan is as follows: sufentanil 0.3μg/kg, vecuronium 0.1 mg/kg, etomidate 0.2 mg/kg, and propofol 1-3 mg/kg. After endotracheal intubation, ventilator parameters are adjusted as follows: respiration ratio 1 : 2, tidal volume 8 mL/kg, ventilation frequency 12 times/min, oxygen flow 2 L/min. Intraoperatively, sevoflurane is inhaled for anesthesia maintenance and vecuronium is intermittently injected intravenously to maintain muscle relaxation, with BIS values ranging from 35 to 45. Dex loading dose 1.0 μg/kg is slowly pumped 15 min after induction of anesthesia, which is completed within 10 min. Intraoperative are given 0.2 μg/(kg h), 0.4 μg/(kg h), and 0.8 μg/(kg h) right beautiful mi on micropump injection. During the operation, if the systolic blood pressure is lower than 90 mmHg, dopamine is injected intravenously (2 mg/time), and atropine is injected intravenously (0.5 mg/time) when the heart rate is lower than 50 times/min.


## 3.3. Observation Indicators

There are six observation indicators as follows:(1)
Comparison of baseline data of patients in each group is as follows: gender, age, body mass index, and disease grade are compared in each group(2)
Changes of hemodynamic indexes in each group during awakening are compared as follows: During awakening, changes of heart rate (HR) are recorded in all patients, and cardiac index (CI), heart rate, and rate pressure product (RPP) are calculated(3)
Compare the changes of serum inflammatory factor indexes in different time periods in each group: 5 mL of fasting elbow venous blood is extracted from each group before and 3 d after surgery, and centrifuge is used for centrifuge operation (centrifuge parameters are set to 3500 r/min, centrifuge radius is 10 cm, and continuous centrifuge time is 15 min). The levels of C-reactive protein (CRP) and interleukin-6 (IL-6) are detected by double-antibody sandwich enzyme-linked immunosorbent assay (ELISA)(4)
The postoperative sedation score of each group is compared as follows: the sedation score of the two groups is observed, and the sedation evaluation is carried out according to the Ramsay sedation scale (RSS) [13]. RSS has 5 grades as follows: level 1: the patient’s consciousness is 0, and the patient has no response to pat call and will respond to injurious stimuli; level 2: the patient’s consciousness is not completely lost, with slight fuzzy consciousness and no response to loud calls; level 3: blurred consciousness, responding to the call to beat; level 4: slightly clear consciousness, clear response when tapping and calling; and level 5: conscious and able to respond to medical staff’s questions(5)
The recovery of each group is observed, including the recovery time of respiration, eye-opening time of exhalation, and extubation time(6)
The correlation between RSS scores and inflammatory factors is analyzed


## 3.4. Statistical Processing

All data collected in this study are input into SPSS 26.0 for analysis and processing, in which the measurement data are subjected to normal test, represented byx̅±s, variance comparison between groups, independent sample t test, percentage (%), and χ2 for counting data. The correlation between sedation score and inflammatory factors in patients undergoing neurosurgery is completed by Pearson’s correlation coefficient analysis. P<0.05 confirmed statistical difference in data comparison.


## 4. Experimental Results and Analysis

### 4.1. Comparison of the Baseline Data in each Group

Table1 shows the comparison of baseline data in each group. It can be seen from Table 1 that there are no significant statistical differences in baseline data of each group, including gender, age, BMI, and disease grade (P>0.05).Table 1
Comparison of baseline data in each group.
GroupGender (n, %)Age (years)BMI (kg/m2)Disease classificationMaleFemaleIIIIILow-dose group (n=34)18 (52.94)16 (47.06)48.82±8.2022.42±2.4722 (64.71)12 (35.29)Medium-dose group (n=34)20 (58.82)14 (41.18)48.85±8.0722.36±2.4419 (55.88)15 (44.12)High-dose group (n=34)21 (61.76)13 (38.24)47.85±8.3022.01±2.4224 (70.59)10 (29.41)F0.5410.5040.6911.581P0.4620.6160.4920.209


### 4.2. Comparison of Changes of Hemodynamic Indexes in Different Time Periods

Table2 shows the comparison of changes of hemodynamic indexes in groups with different doses of Dex. In Table 2, ∗ represents P<0.05 compared with the low-dose group. The levels of HR, CI, and RPP in the low-dose group are increased significantly than those in the medium-dose group and the high-dose group (P<0.05), and there are no significant differences in the levels of each indicator between the medium-dose group and the high-dose group (P>0.05).Table 2
Comparison of changes of hemodynamic indexes in groups with different doses of Dex.
GroupHR (times/min)CI (L/(min·m2))RPP (×103)Low-dose group (n=34)94.71±5.444.14±0.3912.41±0.90Medium-dose group (n=34)85.41±6.28∗3.09±0.30∗9.60±0.61High-dose group (n=34)83.44±5.97∗3.04±0.29∗9.51±0.60F5.1446.1985.633P<0.001<0.001<0.001


### 4.3. Changes of Serum Inflammatory Factor Indexes in Different Time Periods

Table3 shows the comparison of changes in serum inflammatory factors at different time periods. In Table 3, △ represents compared with before surgery, P<0.05; ∗ represents P<0.05 compared with the low-dose group; # represents P<0.05 compared with the medium-dose group. It can be seen from Table 3 that there are no significant differences in serum inflammatory factors among all groups (P>0.05) before operation. 3 days after operation, serum inflammatory factors in each group are significantly increased. Serum CRP and IL-6 levels in each group decrease with the increase of Dex dose (all P<0.05).Table 3
Comparison of changes in serum inflammatory factors at different time periods.
GroupCRP (mg/L)IL-6 (pg/ml)Before the operation3 d after the operationBefore the operation3 d after the operationLow-dose group (n=34)27.18±2.0442.83±4.36△36.03±2.5758.58±2.82△Medium-dose group (n=34)27.58±2.1535.73±2.50△∗36.23±2.4750.04±2.49△∗High-dose group (n=34)27.46±2.2327.70±3.78△∗#36.12±2.6642.01±2.63△∗#F0.7876.4270.3277.056P0.434<0.0010.745<0.001


### 4.4. Comparison of Postoperative Sedation Scores

Table4 shows the comparison of postoperative sedation scores. In Table 4, ∗ represents P<0.05 compared with the low-dose group. It is clearly evident from Table 4 that the RSS score of the low-dose group decreases significantly than that of the medium-dose group and the high-dose group (P<0.05), and there is no significant difference in RSS score between the medium-dose group and the high-dose group (P>0.05).Table 4
Comparison of postoperative sedation scores.
GroupRSS scoreLow-dose group (n=34)1.56±0.50Medium-dose group (n=34)2.35±0.48∗High-dose group (n=34)2.59±0.50∗F5.494P<0.001


### 4.5. Observation of the Recovery of each Group

Table5 shows the comparison of indicators related to recovery. In Table 5, ∗ represents P<0.05 compared with the low-dose group; # represents P<0.05 compared with the medium-dose group. It can be seen from Table 5 that the respiratory recovery time, eye-opening time, and extubation time in high-dose group increase significantly than those in the low-dose group and medium-dose group (P<0.05). No significant statistical difference is found between the low-dose group and the medium-dose group (P>0.05).Table 5
Comparison of indicators related to recovery.
GroupRespiratory recovery time (min)The opening time of the breath (min)Extubation time (min)Low-dose group (n=34)3.88±0.885.00±0.826.85±0.82Medium-dose group (n=34)4.00±0.825.03±0.836.94±0.89High-dose group (n=34)8.24±0.89∗#9.41±1.05∗#11.15±1.60∗#F7.1458.3348.946P<0.001<0.001<0.001


### 4.6. Analysis of the Correlation between RSS Scores and Inflammatory Factors

Figure1 shows the correlation between CRP index and RSS score. Figure 2 shows the correlation between the IL-6 index and RSS score. Through the above experimental results, it can be observed that Pearson’s correlation coefficient analysis shows that serum inflammatory factors including CRP and IL-6 levels are significantly negatively correlated with RSS scores in neurosurgery patients (all P<0.05).Figure 1
Correlation between the CRP index and RSS score.Figure 2
Correlation between the IL-6 index and RSS score.


## 4.1. Comparison of the Baseline Data in each Group

Table1 shows the comparison of baseline data in each group. It can be seen from Table 1 that there are no significant statistical differences in baseline data of each group, including gender, age, BMI, and disease grade (P>0.05).Table 1
Comparison of baseline data in each group.
GroupGender (n, %)Age (years)BMI (kg/m2)Disease classificationMaleFemaleIIIIILow-dose group (n=34)18 (52.94)16 (47.06)48.82±8.2022.42±2.4722 (64.71)12 (35.29)Medium-dose group (n=34)20 (58.82)14 (41.18)48.85±8.0722.36±2.4419 (55.88)15 (44.12)High-dose group (n=34)21 (61.76)13 (38.24)47.85±8.3022.01±2.4224 (70.59)10 (29.41)F0.5410.5040.6911.581P0.4620.6160.4920.209


## 4.2. Comparison of Changes of Hemodynamic Indexes in Different Time Periods

Table2 shows the comparison of changes of hemodynamic indexes in groups with different doses of Dex. In Table 2, ∗ represents P<0.05 compared with the low-dose group. The levels of HR, CI, and RPP in the low-dose group are increased significantly than those in the medium-dose group and the high-dose group (P<0.05), and there are no significant differences in the levels of each indicator between the medium-dose group and the high-dose group (P>0.05).Table 2
Comparison of changes of hemodynamic indexes in groups with different doses of Dex.
GroupHR (times/min)CI (L/(min·m2))RPP (×103)Low-dose group (n=34)94.71±5.444.14±0.3912.41±0.90Medium-dose group (n=34)85.41±6.28∗3.09±0.30∗9.60±0.61High-dose group (n=34)83.44±5.97∗3.04±0.29∗9.51±0.60F5.1446.1985.633P<0.001<0.001<0.001


## 4.3. Changes of Serum Inflammatory Factor Indexes in Different Time Periods

Table3 shows the comparison of changes in serum inflammatory factors at different time periods. In Table 3, △ represents compared with before surgery, P<0.05; ∗ represents P<0.05 compared with the low-dose group; # represents P<0.05 compared with the medium-dose group. It can be seen from Table 3 that there are no significant differences in serum inflammatory factors among all groups (P>0.05) before operation. 3 days after operation, serum inflammatory factors in each group are significantly increased. Serum CRP and IL-6 levels in each group decrease with the increase of Dex dose (all P<0.05).Table 3
Comparison of changes in serum inflammatory factors at different time periods.
GroupCRP (mg/L)IL-6 (pg/ml)Before the operation3 d after the operationBefore the operation3 d after the operationLow-dose group (n=34)27.18±2.0442.83±4.36△36.03±2.5758.58±2.82△Medium-dose group (n=34)27.58±2.1535.73±2.50△∗36.23±2.4750.04±2.49△∗High-dose group (n=34)27.46±2.2327.70±3.78△∗#36.12±2.6642.01±2.63△∗#F0.7876.4270.3277.056P0.434<0.0010.745<0.001


## 4.4. Comparison of Postoperative Sedation Scores

Table4 shows the comparison of postoperative sedation scores. In Table 4, ∗ represents P<0.05 compared with the low-dose group. It is clearly evident from Table 4 that the RSS score of the low-dose group decreases significantly than that of the medium-dose group and the high-dose group (P<0.05), and there is no significant difference in RSS score between the medium-dose group and the high-dose group (P>0.05).Table 4
Comparison of postoperative sedation scores.
GroupRSS scoreLow-dose group (n=34)1.56±0.50Medium-dose group (n=34)2.35±0.48∗High-dose group (n=34)2.59±0.50∗F5.494P<0.001


## 4.5. Observation of the Recovery of each Group

Table5 shows the comparison of indicators related to recovery. In Table 5, ∗ represents P<0.05 compared with the low-dose group; # represents P<0.05 compared with the medium-dose group. It can be seen from Table 5 that the respiratory recovery time, eye-opening time, and extubation time in high-dose group increase significantly than those in the low-dose group and medium-dose group (P<0.05). No significant statistical difference is found between the low-dose group and the medium-dose group (P>0.05).Table 5
Comparison of indicators related to recovery.
GroupRespiratory recovery time (min)The opening time of the breath (min)Extubation time (min)Low-dose group (n=34)3.88±0.885.00±0.826.85±0.82Medium-dose group (n=34)4.00±0.825.03±0.836.94±0.89High-dose group (n=34)8.24±0.89∗#9.41±1.05∗#11.15±1.60∗#F7.1458.3348.946P<0.001<0.001<0.001


## 4.6. Analysis of the Correlation between RSS Scores and Inflammatory Factors

Figure1 shows the correlation between CRP index and RSS score. Figure 2 shows the correlation between the IL-6 index and RSS score. Through the above experimental results, it can be observed that Pearson’s correlation coefficient analysis shows that serum inflammatory factors including CRP and IL-6 levels are significantly negatively correlated with RSS scores in neurosurgery patients (all P<0.05).Figure 1
Correlation between the CRP index and RSS score.Figure 2
Correlation between the IL-6 index and RSS score.


## 5. Conclusion

The effects of different doses of dexmedetomidine (Dex) anesthesia on inflammatory factors and hemodynamics in patients undergoing neurosurgery and its relationship with RSS scores are analyzed. In neurosurgery, compared with low-dose Dex, high-dose Dex can better maintain patients’ intraoperative hemodynamic parameters and effectively inhibit postoperative inflammatory response, but postoperative awakening time is also relatively prolonged. In contrast, medium-dose Dex can effectively control patients’ awakening time. Therefore, Dex dose can be selected according to the individual requirements and constitution of patients during clinical application.



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