If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
1 These authors contributed equally to this work and should be considered co-first authors.
Yu-Peng Qi
Footnotes
1 These authors contributed equally to this work and should be considered co-first authors.
Affiliations
Department of Critical Care Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, Anhui, ChinaAnhui Provincial Clinical Research Center for Critical Respiratory Disease, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, Anhui, China
Department of Critical Care Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, Anhui, ChinaAnhui Provincial Clinical Research Center for Critical Respiratory Disease, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, Anhui, China
Department of Critical Care Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, Anhui, ChinaAnhui Provincial Clinical Research Center for Critical Respiratory Disease, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, Anhui, China
Department of Critical Care Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, Anhui, ChinaAnhui Provincial Clinical Research Center for Critical Respiratory Disease, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, Anhui, China
Department of Critical Care Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, Anhui, ChinaAnhui Provincial Clinical Research Center for Critical Respiratory Disease, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, Anhui, China
Corresponding author. Department of Critical Care Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), No. 2 Zheshan West Road, Wuhu, Anhui, China.Tel.: +8605535739734; fax: +8605535739731.
Department of Critical Care Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, Anhui, ChinaAnhui Provincial Clinical Research Center for Critical Respiratory Disease, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, Anhui, China
Gastrointestinal failure results in death in critically ill patients. This study aimed to explore the effect of dexmedetomidine (DEX) on intestinal barrier function and its mechanism in critically ill patients undergoing gastrointestinal surgery.
Methods
Patients undergoing gastrointestinal surgery were randomized into the DEX group (n = 21) or midazolam (MID) group (n = 21). Sufentanil was used for analgesia in both groups. In the DEX group, DEX was loaded (1 μg/kg) before sedation and infused (0.7 μg/kg/h) during sedation. In the MID group, MID was loaded (0.05 mg/kg) before sedation and infused (0.1 mg/kg/h) during sedation. The mean arterial pressure , heart rate , borborygmus resumption time , first defecation time, length of intensive care unit stay, and length of hospital stay were observed. The diamine oxidase (DAO), D-lactate , TNF-α, IL-6, and α7nAChR levels in plasma or hemocytes were detected before the start of sedation (0 h) and after sedation (24 h).
Results
No significant differences in age, sex, body mass index, Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were noted (P > 0.05). The mean arterial pressure between 0 h and 24 h showed no significant difference between the groups (P > 0.05), but the heart rate was significantly lower in the DEX group (P = 0.042). The borborygmus resumption time was significantly earlier in the DEX group (P = 0.034). The lengths of intensive care unit stay (P = 0.016) and hospital stay (P = 0.031) were significantly shorter in the DEX group. The TNF-α level in the DEX group was lower at 24 h than 0 h. The D-lactate level was significantly lower in the DEX group than the MID group at 24 h (P = 0.016). The expression of α7nAChR in the DEX group was significantly higher at 24 h than 0 h (P < 0.05).
Conclusions
DEX maintained intestinal barrier integrity in patients undergoing gastrointestinal surgery through the cholinergic anti-inflammatory pathway.
The gastrointestinal tract provides the most extensive storage of bacterial organisms and endotoxins and is very sensitive to ischemia and hypoperfusion. Intestinal epithelial tissue serves as a barrier to resist pathogen invasion, produces and secretes antimicrobial peptides, and maintains homeostasis.
Many stress factors can destroy the intestinal barrier, disturb homeostasis of the intestinal flora, disrupt immune function, and release intestinal bacteria. Simultaneously, the bacterial metabolites enter the blood, causing gut origin sepsis.
When the gut is damaged, interferon gamma (IFN-γ, tumor necrosis factor alphaTNF-α, and interleukin-1 beta IL-1β) inflammatory factors activate myosin light streptokinase through the NF-κB pathway. Functional changes in a variety of protein components constituting the tight junctions of intestinal epithelial cells, such as junction adhesion molecule-1, occludin, and claudin, cause functional changes and ultimately destroy the integrity of tight junctions.
Therefore, the key to maintaining intestinal barrier function is inhibiting the inflammatory response. The serum D-lactate (D-LAC) and diamine oxidase (DAO) levels are often used as important reference indicators for evaluating intestinal barrier function.
Activation of central alpha 7 nicotinic acetylcholine receptor reverses suppressed immune function of T lymphocytes and protects against sepsis lethality.
have shown that the cholinergic anti-inflammatory pathway (CAP) is a neuroimmune regulatory pathway with obvious anti-inflammatory effects. The CAP is mainly composed of the vagus nerve, α7nAChR, and muscarinic receptors, which play different anti-inflammatory roles. Activation of the CAP can effectively reduce the release of TNF-α, IL-6, and IL-1β and significantly inhibit the inflammatory reaction caused by various local and systemic causes.
Tak PP Role of the cholinergic nervous system in rheumatoid arthritis: aggravation of arthritis in nicotinic acetylcholine receptor α7 subunit gene knockout mice.
As an essential target in the CAP, α7nAChR has been a popular research topic in recent years.
Dexmedetomidine (DEX) and midazolam (MID) are the most commonly used sedative drugs in the intensive care unit (ICU) given their minimal effects on hemodynamics and apparent sedative effects.
Midazolam and propofol used alone or sequentially for long-term sedation in critically ill, mechanically ventilated patients: a prospective, randomized study.
have shown that DEX has a definite anti-inflammatory effect. This effect is similar to that of direct electrical stimulation of the vagus nerve, but whether DEX can further decrease intestinal permeability in patients with gastrointestinal surgery is unclear.
Therefore, our study was conducted to investigate whether DEX could protect the intestinal barrier in gastrointestinal surgery and explore its possible mechanism.
Methods
Study subjects
This randomized, double-blinded, prospective, controlled study was performed with adherence to the principles of the Declaration of Helsinki, approved by the Institutional Review Board (IRB) of the First Affiliated Hospital of Wannan Medical College (approval number: WAN 2015-18), and registered with the Chinese Clinical Trial Registry at www.chictr.org (registration number: ChiCTR1900024367).
Patients were recruited according to the following criteria: 1) patients admitted to the ICU after undergoing elective gastrointestinal surgery, 2) patients who received mechanical ventilation via intubation through the oral trachea with an estimated ventilation time of more than 24 h; 3) patients who required analgesia and sedation; and 4) patients who gave an informed consent for participating in this study. Patients who met any of the following criteria were excluded: 1) women who were pregnant or lactating, 2) patients younger than 18 years old, 3) patients with a heart rate (HR) less than 55 bpm, 4) patients with a high atrioventricular block without a cardiac pacemaker, 5) patients diagnosed with an acute liver failure, 6) patients diagnosed with a cerebrovascular accident, and 7) patients diagnosed with dementia.
Using a computer-generated random number table, patients were randomly assigned to the DEX group or the MID group. DEX was loaded (1 μg/kg) before sedation and was infused (0.7 μg/kg/h) during sedation. MID was loaded (0.05 mg/kg) before sedation and infused (0.1 mg/kg/h) during sedation. Analgesia and sedation were performed according to the following procedure: the Richmond Agitation Sedation Scale score was maintained at −2 to 1
On the basis of retrospective data from our institution (mean D-LAC value at 24 h: 33.50 μmol/mL, standard deviation (SD): 5.68 μmol/mL), a power analysis was performed using the mean value of D-LAC at 24 h as the primary variable. A total of 22 patients were required in each group to detect a difference of 5.0 μmol/mL between the groups at a level of 0.05, with a power of 80%, expecting an SD of 5.68 μmol/mL. Considering 10% loss, 25 patients were enrolled in each group between June 2017 and May 2019.
Procedure
To eliminate any possible effects of the surgical technique, all of the procedures were performed by the same surgical group. To maintain blinding, the clinicians who prepared the materials and performed the procedures for sedation and analgesia were not involved in management or assessments unless an emergency occurred (mean arterial pressure (MAP) < 65 mmHg or HR < 50 bpm). The investigators and patients were blinded to the intervention.
The patients' sex, age, weight, diagnosis, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, hourly HR and blood pressure (BP), borborygmus resumption time (BRT), first defecation time (FDT), length of ICU stay, and length of hospital stay were recorded.
Blood was collected before sedation (0 h) and after sedation (24 h). The blood was centrifuged at 3000 rpm for 15 min. The supernatant was carefully absorbed into a 2-mL Eppendorf (EP) tube with a transfusion gun (avoiding absorbing blood cells) to detect TNF-α, D-LAC, and IL-6. The contents of D-LAC, DAO, TNF-a, and IL-6 in blood were detected strictly using enzyme linked immunosorbent assay kits (Nanjing JianCheng, China) according to the manufacturer's instructions. Blood cells were collected to detect the changes in α7nAChR mRNA using real-time polymerase chain reaction (PCR).
(α7nACHR-F: 5′-AGGCGAGTTCCAGAGGAAGC-3′;
α7nACHR-R: 5′-CTTCTCCCTGAGCCTCCTGC-3′;
β-actin-F: 5′-GGCACTCTTCCAGCCTTCCT-3′;
β-actin-R: 5′-CCTGTACGCCAACACAGTGC-3′)
Outcomes
The primary outcomes included the D-LAC, DAO, TNF-α, IL-6, and α7nAChR levels in plasma or hemocytes.
The secondary outcomes included the MAP, HR, BRT, FDT, length of ICU stay, and length of hospital stay.
Statistical analysis
SPSS software version 22.0 (Chicago, IL, USA) was used for data analysis. All of the data were tested for a normal distribution and homogeneity of variance. Measurement data with a normal distribution are expressed as the mean ± SD ( ± s). The Mann–Whitney-U non-parametric test was used to compare the data and rates of a non-normal distribution. Measurement data with a non-normal distribution are expressed as the median interquartile range.
P < 0.05 was considered statistically significant.
Results
A total of 50 patients were included in this study. Four patients refused follow-up in the middle of the study. Four patients were excluded because of in complete follow-up data. Finally, the remaining 42 patients were included in the statistical analysis (Fig. 2).
Fig. 2Flow chart of patient inclusion. B I: Billroth's I subtotal gastrectomy, B II: Billroth's II subtotal gastrectomy.
Demographic and clinical characteristics of the DEX and MID groups
All patients were administered parenteral nutrition within the first 24 h after the operation, with energy of 20-25 kcal/kg. The antibiotics included ceftazidime (2 g, every 8 h) and metronidazole (1 g, every 24 h).
No significant differences in age, sex, body mass index, diagnosis, comorbidities, or APACHE II, SOFA, or Richmond Agitation Sedation Scale scores were noted between the DEX and MID groups (P > 0.05).
No significant difference in blood pressure was noted between the two groups (P > 0.05), but the HR in the DEX group was significantly lower than that in the MID group (P = 0.042). The BRT in the DEX group was significantly shorter than that in the MID group (P = 0.034), and there was no significant difference in the FDT between the two groups (P > 0.05). Compared with the MID group, the DEX group had a significantly shorter ICU stay (P = 0.016) and hospital stay (P = 0.031) (Table 1).
Table 1Demographic and clinical characteristics of the DEX and MID groups.
DEX group (n = 21)
MID group (n = 21)
P
Age (y)
69.19 ± 8.52
69.38 ± 9.18
0.945
Sex (male/female)
16/5
16/5
-
BMI (kg/m2)
20.40 ± 2.77
21.70 ± 3.60
0.196
APACHE II score
15.86 ± 3.62
15.67 ± 4.07
0.323
SOFA score
9.15 ± 2.35
9.25 ± 3.02
0.910
RASS score
−0.33 ± 1.11
−0.48 ± 1.08
0.675
Diagnosis
-
-
-
Gastric Tumor
4 (19.05%)
3 (14.29%)
0.679
Pancreatic tumor
5 (23.81%)
8 (38.10%)
0.317
Small bowel tumor
10 (47.62%)
8 (38.10%)
0.533
Colonic tumor
2 (9.52%)
2 (9.52%)
1.000
Co-morbidities
-
-
-
Hypertension
3 (14.29%)
7 (33.33%)
0.147
COPD
3 (14.29%)
5 (23.81%)
0.432
Cardiac disease
8 (38.10%)
10 (47.62%)
0.895
Sepsis
9 (42.86%)
11 (52.38%)
0.537
MAP (mm Hg)
87.20 ± 9.70
87.98 ± 9.66
0.795
HR (bpm)
72.63 ± 8.21
81.51 ± 17.31
0.042
BRT (h)
70.8 ± 23.28
90.24 ± 32.88
0.034
FDT (h)
6.24 ± 2.10
7.38 ± 2.00
0.077
Length of hospital stay (d)
18.86 ± 8.12
24.74 ± 8.91
0.031
Length of ICU stay (d)
2.76 ± 0.77
3.71 ± 1.56
0.016
BRT = borborygmus resumption time; FDT = first defecation time; BMI = body mass index; APACHE II = acute physiology and chronic health evaluation; SOFA = sequential organ failure assessment; RASS = richmond agitation and sedation scale; MAP = mean arterial pressure; HR = heart rate; Length of hospital stay = time of postoperative hospitalization stay; Length of ICU stay = time of ICU hospitalization stay; COPD = chronic obstructive pulmonary disease.
Changes in indicators of intestinal inflammation and permeability in the DEX and MID groups
In the DEX group, the TNF-α level was lower at 24 h than 0 h, but the IL-6 level did not change significantly. In the MID group, the TNF-α and IL-6 levels did not change significantly from 0 h to 24 h. There was no significant difference in the TNF-α or IL-6 level between the DEX and MID groups at 0 h (P > 0.05). Compared to the MID group, the DEX group showed decreased production of TNF-α (P = 0.044) at 24 h, but no significant difference in IL-6 production was noted between the two groups.
The DAO and D-LAC serum levels in the DEX group were significantly different at 0 h compared with 24 h (P < 0.05), but no significant differences were noted in the MID group between 0 h and 24 h (P > 0.05); furthermore, the DAO and D-LAC serum levels in the DEX group were not significantly different from those in the MID group at 0 h (P > 0.05). DEX induced a greater reduction in D-LAC production than MID at 24 h versus 0 h (P < 0.05) (Table 2).
Table 2Changes in the indicators of intestinal inflammation and permeability in the DEX and MID groups.
Comparison of the α7nAChR level between the two groups at 0 h and 24 h
The level of α7nAChR in the DEX group was significantly higher than that in the MID group (P < 0.05), but there was no significant change in the level of α7nAChR in the MID group between 0 h and 24 h (P > 0.05). There was no significant difference in the α7nAChR level between the DEX and MID groups at 0 h, and the α7nAChR level in the DEX group was significantly higher than that in the MID group at 24 h (P = 0.015) (Table 3).
Table 3Changes in α7nAChR levels before and after treatment in the two groups.
The present study demonstrated that DEX administration in patients undergoing gastrointestinal surgery benefited postoperative intestinal barrier integrity in patients. These results might be attributed to the fact that DEX usage was associated with less gastrointestinal injury reflected by a shorter time to BRT than MID. Furthermore, DEX produced stable hemodynamic effects and shortened the hospital stay.
The gastrointestinal mucosa is susceptible to injury, and gastrointestinal surgery always destroys the intestinal mechanical barrier. Simultaneously, the gastrointestinal muscle layer is filled with macrophages, many of which are released when stimulated, further promoting the release of cell factors, prostaglandins, and other factors. Therefore, when mucosal injuries occur, these factors can cause local and systemic inflammatory responses and even sepsis, resulting in postoperative gastrointestinal dysfunction.
have suggested that the intestinal tract is the first organ involved in sepsis and is the “initiating organ” of sepsis. Approximately, 30% of sepsis patients who die of multiple organ dysfunction syndrome (MODS) do not clinically exhibit a focus on primary infection. Nevertheless, bacteria similar to intestinal bacteria can be found in their blood cultures.
The gastrointestinal tract is often involved earlier and recovers later in the disease course. The study found that abdominal distension, intra-abdominal pressure, and the time to recover intestinal function were significantly delayed in sepsis patients. The injury mechanism might be that the gastrointestinal mucosa and villi are rich in blood flow, sensitive to ischemia and hypoxia, and vulnerable to damage under hypoperfusion. When sepsis occurs, the circulatory blood volume decreases, and the intestinal blood flow decreases significantly. When the systemic circulatory blood volume decreases by 10%, gastrointestinal blood perfusion decreases by approximately half. Long-term hypoperfusion can cause intestinal mucosal cell oedema, villous degeneration and necrosis, damage or even loss of tight junctions between cells, and increased intestinal permeability. If not controlled in time, this condition will eventually result in MODS.
Therefore, managing inflammatory reactions, maintaining intestinal function, protecting intestinal barrier integrity, and avoiding intestinal bacteria and endotoxin release into the blood are critical points for preventing MODS.
The gastrointestinal tract is the largest organ innervated by nerve fibres. The inflammatory reflex formed by the vagus nerve could play an essential role in intestinal immune regulation. Studies
The permeability of these receptors to calcium ions increases when activated, facilitating the inflow of calcium ions without causing cell membrane depolarization. Therefore, α7nAChR can participate in regulating calcium-related events conveniently and quickly. Research has shown that the CAP mainly plays a role through α7nAchR.
Directional knockout of the α7nAChR gene or vagotomy can reduce CAP activity and aggravate the inflammatory reaction in various inflammatory model animals. A preliminary study based on clinical sepsis patients showed that high α7nAChR expression in peripheral blood mononuclear cells was associated with reduced inflammation and an improved prognosis.
Usefulness of α7 nicotinic receptor messenger RNA levels in peripheral blood mononuclear cells as a marker for cholinergic antiinflammatory pathway activity in septic patients: results of a pilot study.
As a representative benzodiazepine, MID exhibits various pharmacological effects, including anxiolytic, sedative, hypnotic and anticonvulsive effects, as well as muscle relaxation and anterograde amnesia. In addition, MID shows rapid onset, has little impact on hemodynamics, and is widely used in multidisciplinary clinical fields.
Midazolam and propofol used alone or sequentially for long-term sedation in critically ill, mechanically ventilated patients: a prospective, randomized study.
demonstrated that MID can protect the liver from lipopolysaccharide (LPS)-induced immune-mediated liver injury by inhibiting inflammation and immune activation in liver macrophages. DEX is a new type of α2-adrenergic receptor agonist that can simultaneously act on the central and peripheral nervous systems, regulate autonomic nervous activity, and produce dose-dependent sedative, hypnotic and anxiolytic effects. In addition, DEX can reduce the incidence of delirium in patients and has been widely used in the sedation of critically ill patients.
Nestor JE Dexmedetomidine for Long-Term Sedation Investigators Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials.
Dexmedetomidine for prevention of postoperative delirium in older adults undergoing oesophagectomy with total intravenous anaesthesia: a double-blind, randomised clinical trial.
Our study found that DEX had no significant effect on blood pressure at a shallow depth of sedation compared to MID. Moreover, DEX also reduced the length of ICU stay.
on acute inflammation have shown that DEX significantly inhibits the release of high levels of TNF-α, IL-1β, IL-6, and other inflammatory factors. Clinical studies
Effect of dexmedetomidine on perioperative inflammatory response and cellular immune in patients undergoing radical operation of thoracoscopic lung cancer.
have also found that DEX use in general anaesthesia can significantly reduce the levels of plasma inflammatory factors in perioperative patients. Especially in patients with severe sepsis caused by intestinal obstruction, DEX treatment can reduce the release of inflammatory factors and the increased intra-abdominal pressure of sepsis patients. Our study found that the BRT in the DEX group was significantly shorter than that in the MID group. Thus, DEX is beneficial for the recovery of intestinal function.
Dexmedetomidine-induced cardioprotection is mediated by inhibition of high mobility group box-1 and the cholinergic anti-inflammatory pathway in myocardial ischemia-reperfusion injury.
have shown that DEX exerts its anti-inflammatory effects by activating the CAP of the vagus nerve and the α-2 adrenergic receptor. CAP activation is achieved mainly by activating α7nAChR.
Our study found that the TNF-α level in the DEX group was significantly reduced, demonstrating that the clinical sedative dose of DEX could produce an apparent anti-inflammatory effect and block the inflammatory cascade reaction. In addition, our study found that DEX increased α7nAChR expression in peripheral blood mononuclear cells. It follows that the sedative dose of DEX can inhibit the inflammatory reaction through the CAP in patients undergoing gastrointestinal surgery. Some studies
have also shown that inhibition of the inflammatory response is a crucial factor in maintaining intestinal barrier function.
When the intestinal mucosa or tight junctions of intestinal cells are damaged, intestinal mucosa permeability is increased. D-LAC, a metabolite of bacteria, is present in the intestine and may then enter the blood. Therefore, the serum D-LAC level can reflect the degree of damage to the intestinal mucosal barrier and the change in intestinal permeability. DAO, a highly active catalyst for the oxidation of diamine in the upper villi of the intestinal mucosa, is relatively stable under normal conditions. When intestinal permeability increases, the serum DAO level increases. Therefore, the serum DAO level can indirectly reflect the degree of intestinal mucosal injury.
Our study showed that the D-LAC level decreased significantly in the DEX group, indicating that DEX could substantially decrease intestinal permeability in patients undergoing gastrointestinal surgery. Combined with the increased expression of α7nAChR in peripheral blood mononuclear cells, these findings suggest that the mechanism might be related to α7nAChR activation, increased CAP activity, inhibition of the intestinal inflammatory response, and decreased intestinal permeability.
Conclusions
As a sedative, DEX is more suitable for patients undergoing gastrointestinal surgery based on its protection of the intestinal barrier. The mechanism is potentially related to α7nAChR activation, increased CAP activity, inhibition of the intestinal inflammatory response, and decreased intestinal permeability.
Author Contributions
WHL and ZW conceived and designed the study. YPQ, YYC, and WJM performed the experiments and wrote the paper. XS, QC, QCX, and YYC contributed essential materials, and YPQ and YYC analyzed and interpreted the data. All of the authors read and approved the final manuscript.
Acknowledgments
Grateful acknowledgment is made to my supervisors Mr. Weihua Lu and Mr. Zhen Wang, who gave me considerable help through suggestions, comments, and criticism. Their encouragement and unwavering support have sustained me through frustration and depression. Without their pushing me ahead, completing this thesis would be impossible. Besides, I sincerely appreciate this thesis's contribution made in various ways by my friends and colleagues
Disclosure
None declared.
Funding
The Key Laboratory of Noncoding RNA Transformation Research of Anhui Higher Education Institution (RNA201910).
Anhui Province Natural Science Foundation for Youth (1908085QH360).
Funding of “Peak” Training Program for Scientific Research of Yijishan Hospital, Wannan Medical College (GF2019G08).
Availability of Data
The datasets generated during the current study are available from the corresponding author on reasonable request.
Approval and Consent to Participate
The study was approved by the local ethics committee (Ethics Committee of the First Affiliated Hospital of Wannan Medical College, protocol number 201518, date of approval November 18, 2015).
References
Neal M.D.
Sodhi C.P.
Dyer M.
et al.
A critical role for TLR4 induction of autophagy in the regulation of enterocyte migration and the pathogenesis of necrotizing enterocolitis.
Activation of central alpha 7 nicotinic acetylcholine receptor reverses suppressed immune function of T lymphocytes and protects against sepsis lethality.
Tak PP Role of the cholinergic nervous system in rheumatoid arthritis: aggravation of arthritis in nicotinic acetylcholine receptor α7 subunit gene knockout mice.
Midazolam and propofol used alone or sequentially for long-term sedation in critically ill, mechanically ventilated patients: a prospective, randomized study.
Usefulness of α7 nicotinic receptor messenger RNA levels in peripheral blood mononuclear cells as a marker for cholinergic antiinflammatory pathway activity in septic patients: results of a pilot study.
Dexmedetomidine for prevention of postoperative delirium in older adults undergoing oesophagectomy with total intravenous anaesthesia: a double-blind, randomised clinical trial.
Effect of dexmedetomidine on perioperative inflammatory response and cellular immune in patients undergoing radical operation of thoracoscopic lung cancer.
Dexmedetomidine-induced cardioprotection is mediated by inhibition of high mobility group box-1 and the cholinergic anti-inflammatory pathway in myocardial ischemia-reperfusion injury.
00180-9&id=gr1.jpg){kind=link}
00180-9&id=gr2.jpg){kind=link}