| With the development of modern medical technology,the rate of cesarean section has increased gradually all over the world in recent years.When it comes to China,which has been affected by policy that a couple is encouraged to raise two children,the increasing trend of cesarean section is particularly prominent.In some critical condition,cesarean sections were operated under general anesthesia,rather than spinal anesthesia.However,compared with spinal anesthesia,general anesthesia increases the risk of reflux,aspiration,tracheal intubation failure and hypoventilation in women undergoing cesarean section,especially in emergency situations.The advantages of cesarean section under intraspinal anesthesia(epidural anesthesia,subarachnoid block,combined spinal and epidural block anesthesia)are higher safety of the mother and the protection of the newborn from the exposure of general anesthesia drugs.It also allows the fetus to contact with the mother after delivery and start breastfeeding earlier to promote uterine contraction and milk secretion.Compared with other spinal anesthesia techniques,CSEA has been widely used in lower abdominal surgery because of its low cost,rapid onset,less drug consumption,effective analgesia and muscle relaxation effect.Most of the cesarean section can be completed under simple subarachnoid block anesthesia.The short duration of subarachnoid local anesthesia and early postoperative pain weaken the above advantages.Therefore,in order to prolong the pain relief during the operation to the post operation,anesthesiologists have been exploring to add various adjuvants to the subarachnoid local anesthetics,such as morphine,buprenorphine,fentanyl,clonidine and ketamine.All kinds of adjuvants can help patients get out of bed early and prolong the time of analgesia,but they are faced with various side effects.Therefore,the search for effective adjuvants is still in progress.Dexmedetomidine is a new type of a2 adrenergic receptor agonist with high selectivity.The affinity of dexmedetomidine with α2 and ai is 8 times that of clonidine(1620:1 vs.220:1).Many studies in China and abroad have confirmed the safety and effectiveness of dexmedetomidine for subarachnoid anesthesia.When combined with bupivacaine for intrathecal injection,dexmedetomidine can shorten the onset time of local anesthetics,prolong the duration of sensory and motor block,and then increase the effectiveness of postoperative analgesia.In addition,it can reduce the neurotoxicity of local anesthetics and reduce the incidence rate of adverse reactions.However,there is no consensus on the dose of dexmedetomidine for intrathecal injection at present.In addition,the relationship between the drug dose and the adverse reactions is not clear.Finally,can intrathecal application of dexmedetomidine play the role of sedation and amnesia?How effective is it?And whether the polymorphism of α2A adrenergic receptor(ADRA2A)C-1291G gene can affect its sedative and analgesic effects?There is also a lack of clinical research reports.In our study,different doses of dexmedetomidine combined with fixed doses of bupivacaine were used to observe the anesthetic effect and sedative effect when they were used in intrathecal injection,to explore the best combination dose of dexmedetomidine,and to further explore the effect of different additives(dexmedetomidine,clonidine,fentanyl)combined with bupivacaine on the anesthetic effect The relationship between the polymorphism of α2A adrenergic receptor(ADRA2A)C-1291G gene in the promoter region and the clinical effect(sedation and hemodynamic effect)of dexmedetomidine was studied,which provided strong evidence for the accurate clinical application of dexmedetomidine.Our study includes three parts:Part I:The clinical study of bupivacaine combined with different dose of dexmedetomidine for spinal anesthesia in parturientsObjective:Our research aimed to evaluate different doses of dexmedetomidine as an adjuvant combined with bupivacaine for obstetric subarachnoid block,observe sensory and motor blockade effect,hemodynamics and neonatal score,etc.Methods:This prospective,randomized,double-blind clinical study was approved by the Ethical Committee of Yantai Yuhuangding Hospital,Qingdao university.One hundred and twenty parturients undergoing elective cesarean section with CSEA were randomly divided into 4 groups(n=30 per group),the dose of dexmedetomidine in D1,D2,D3 were 5ug,7.5ug and 10ug,respectively,and no dexmedetomidine was added in control group(group C).All the four groups combined with 0.75%bupivacaine 1.5ml and diluted with normal saline into 3ml.Hemodynamic data,Ramsay score,VAS score,Apgar score,the modified-Bromage score and adverse reactions was recorded.In addition,the sensory block was defined by pin-prick,and the onset time and duration of sensory and motor block were also recorded.The CSEA were performed by the same anesthesiologist,and the cesarean section were operated by the same group of obstetricians.Results:1.1 Demographic data and clinical characteristics.There were no significant differences in four groups(P>0.05)as regard to age,height of parturients and weight both in parturients and the newborns.1.2 Hemodynamic data.There were no significant differences in four groups(P>0.05)of MABP and HR in T1.Compared with group C,MABP and HR in group D1,D2,D3 showed a downward trend in T2,T3,T4 and T5,and were decreased significantly especially in T3,T4,T5(P<0.05).Compared with T1 in group C,MABP and HR in T3,T4,T5 were significantly decreased(P<0.05).1.3 VAS score.The VAS score of group D1,D2,D3 in 24 hours was significantly lower than that in group C(P<0.05).The VAS score of D3group was significantly lower than the control group(C)(P<0.05),after 8 hours,12 hours and 24 hours.1.4 Sedation.Both the Ramsay score and bispectral index(BIS)showed no significant difference in four groups(P>0.05).1.5 Sensory and motor block.Compared with group C,the onset time of sensory block and motor block in group D1,D2,D3 were significantly shortened,and the duration prolonged(P<0.05).Compared with group D1,the onset time of sensory block and motor block in group D2,D3 were significantly shortened,and the duration prolonged(P<0.05).Besides,the onset time of sensory block and motor block in group D3 was the fastest and the duration was the longest among the four groups(P<0.05).1.6 Neonatus.No respiratory depression has been observed and the heart rate of all the neonates were more than100 beats per minute.There was no significant difference of Apgar score both in 1min and 5min(P>0.05).1.7 Adverse reactions.Compared with group C,the incidence of nausea and vomiting in the experimental group was significantly reduced(P<0.05);and the incidence of bradycardia in the D3 group was higher than that in the control group(P<0.05).No obvious neurological complications occurred in the four groups of patients.Part Ⅱ:Bupivacaine combined with different adjuvants such as clonidine,fentanyl and dexmedetomidine in parturients undergoing cesarean section with CSEA-A double-blinded,randomized,controlled clinical study.Objective:Our randomized controlled study research aimed to evaluate different(classic opioids fentanyl,traditional α2 adrenergic receptor agonists clonidine and new potent α2 adrenergic receptor agonists dexmedetomidine)drug as an adjuvant combined with bupivacaine for obstetric subarachnoid block,observe sensory and motor blockade effect,hemodynamics and neonatal score,etc.Methods:This prospective,randomized,double-blind clinical study was approved by the Ethical Committee of Yantai Yuhuangding Hospital,Qingdao university.After written informed consent,84 parturients,ASA I-II,term primiparity,aged20-35years,weighted 50-100 kg,with the height of 150-180cm,who were scheduled for elective cesarean section with CSEA in our hospital from September 2014 to October 2014 were randomly divided into 4 groups(n=21 per group),group BF:0.75%bupivacaine 1.5ml combined with fentanyl with the dose of 15ug;group BC:0.75%bupivacaine 1.5ml combined with clonidine with the dose of 75 ug;group BD:0.75%bupivacaine 1.5ml combined with dexmedetomidine with the dose of 10ug;the control group(group B):0.75%bupivacaine 1.5ml only and all the solutions were diluted with normal saline into 3ml.Hemodynamic data,Ramsay score,VAS score,Apgar score,the modified-Bromage score and adverse reactions was recorded.In addition,the sensory block was defined by pin-prick,and the onset time and duration of sensory and motor block were also recorded.The CSEA were performed by the same anesthesiologist,and the cesarean section were operated by the same group of obstetricians.Results:1.1 Demographic data and clinical characteristics.There were no significant differences in four groups(P>0.05)as regard to age,height,weight,gestational,ASA classification and operation time of parturients and neonatal weight.1.2 Hemodynamic data.There were no significant differences in four groups(P>0.05)of MABP and Incidence of low blood pressure in every time point.1.3 Sensory and motor block.The onset time of sensory block in group BD and group BC were 3.1 min and 3.2 min,respectively.There were significant differences when comparing with groupB and group BF(P<0.05).The duration of sensory block in group BD was 225.73±47.88min,while in group BC was 205.25±38.25 min.The duration of sensory block in group BD was extended for about 20 min than group BC and there were significant differences between BD and BC(P=0.04).We also found that the time of sensation subsided to T10 showed significant differences in four groups(P=0.002),among which the highest was group BD of 155.9±19.85 min and the lowest was groupB of 107.35±16.15min.The first time for additional analgesics postoperatively in group BD and group BC were 360.52±29.57min and f 349.84±25.12min,respectively.There were significant differences when comparing with groupB and group BF(P=0.02).1.4 VAS score.The VAS score of group BD and group BC 1h and 2h after surgery showed significant differences in contrast to groupB and group BF(P<0.05).1.5 Comparison of adverse reactions.The incidence of shivering in group gB and gBF was 14.2%and 4.7%,significantly higher than group BC and group BD(P<0.05).1.6 Neonatus.No respiratory depression has been observed and the heart rate of all the neonates were more thanl00 beats per minute.There was no significant difference of Apgar score in lmin and 5min(P>0.05).There were no significant differences in four groups as regard to partial pressure of oxygen,carbon dioxide partial pressure and pH value of umbilical artery(P>0.05).Part III The effect of α2A adrenergic receptor gene polymorphism on dexmedetomidine for obstetric anesthesia and postoperative analgesiaObjective:To observe the effect of α2A-AR gene polymorphism and dexmedetomidine combined with bupivacaine on obstetric subarachnoid anesthesia and the level of sedation and analgesia after operation.Methods:This study was approved by the Ethics Committee of Yantai Yuhuangding Hospital Affiliated to Qingdao University(ethics number:2018125),and informed consent was signed after thorough communication with patients and their families.A total of 96 women who required elective cesarean section from October 2018 to December 2018 were included in our hospital.American Society of Anesthesiologists(ASA)grade Ⅰ～Ⅱ,primipara,age 23-35 years old,both Han nationality,height 150-175cm,weight 50-90kg,BMI body mass index(BMI)18～35 kg/m2.The included patients were divided into C1291C(CC group),C1291G(CG group),and G1291G(GG group)according to the results of ADRA2A C1291G gene test.The intraoperative anesthetic drug regimen was:bupivacaine(0.75%,1.5ml)+dexmedetomidine lOug,all diluted with normal saline to 3ml;postoperative analgesia was used:sufentanil 1.5ug/Kg and dexmedetomidine 3ug/Kg was diluted with normal saline to 100ml.Anesthesia and surgery are performed by the same anesthesiologist and deputy chief physician in obstetrics,respectively.Unblinding will be performed when the patient grouping results are to be counted.During the operation,anesthesia information system was used to record the patient’s blood pressure,heart rate,BIS,SPO2 and other data.At the same time,the Apgar score,modified Bromage score,maintenance of the onset of sensory blockade,and the number of adverse events during the operation were recorded.Postoperative VAS scores and Ramsay scores were collected at different time and followed up for complications.Results:1.1 ADRA2A C1291G gene is polymorphic,and the frequencies of each group are C1291C(CC group 38 cases,39.58%),C1291G(CG group 46 cases,47.92%)and G1291G(GG group 12 cases,12.5%).The statistical data is in line with Hardy-Weinberg balance,and the number of included cases is representative of the group.1.2 The comparison of general data.There was no significant difference in age,height,weight,abdominal circumference,gestational age,ASA grade,neonatal weight and duration of surgery among the three groups.1.3 The effect of ADRA2A C1291G gene polymorphism on hemodynamics.There was no significant difference in MABP and HR among the three groups at each time.1.4 The effect of ADRA2A C1291G gene polymorphism on sensory and motor nerve block.There was no significant difference in sensorimotor block among the three groups(P>0.05).1.5 The effect of ADRA2A C1291G gene polymorphism on the BIS of parturients at different time points during operation.At T2,T3,T4 and T5 time point,the BIS of CC group was significantly lower than that of CG group and GG group,and there was significant difference compared with CG group and GG group(P(0.0011,0.0014,0.0012,0.001)<0.05)1.6 ADRA2A C1291G gene polymorphism was used to compare the VAS scores of postpartum women at different time points.At 8h,12h,24h after operation,the VAS score of CC group was significantly lower than that of CG group and GG group,and there was significant difference compared with CG and GG group.1.7 The comparison of ADRA2A C1291G gene polymorphism on Ramsay scores of postpartum women at different time.At 2 hours and 4 hours after operation,the Ramsay score of C1291C group was significantly higher than C1291G and G1291G groups,and there was significant difference compared with C1291G and G1291G groups.1.8 The comparison of adverse reactions.The incidence of adverse events(including bradycardia,hypotension,itching,nausea,shivering,respiratory depression,etc.)was similar among the three groups,with no statistical difference among them(P>0.05).Conclusion:1.The intrathecal injection of bupivacaine combined with different dose of dexmedetomidine shorten the onset time of sensory and motor motor block,prolong the duration,provide valid postoperative analgesia and reduce adverse reactions.2.The effect of dexmedetomidine depends on its dosage.The effect of sensory and motor block was enhanced with the increase of dexmedetomidine dose in our study.3.The application of bupivacaine combined with dexmedetomidine for intrathecal injection significantly reduce the incidence of nausea,vomiting,chills,pruritus and respiratory depression during perioperative period.4.The intrathecal injection of bupivacaine combined with clonidine and dexmedetomidine in comparement with fentanyl provides perfect postoperative analgesia.5.Dexmedetomidine significantly prolonged the duration of sensory and motor block compared with clonidine and fentanyl.6.Dexmedetomidine and clonidine prevent postoperative shivering,and dexmedetomidine provide adequate sedative effect.Dexmedetomidine with the dose of 10 ug can be used as an adjvant safely in spinal anesthesia.7.This study found that there is a genetic polymorphism at the rs 1800544 locus of the ADRA2A gene in the Chinese Han population.8.In this study,the polymorphism of the rs1800544 locus of the ADRA2A gene was associated with the level of sedation and analgesia of dexmedetomidine.Patients with the C1291C gene were more sensitive to dexmedetomidine and the polymorphism of the ADRA2A gene is one of the genetic factors that cause individual differences in the sedative and analgesic effects of dexmedetomidine.In conclusion,Dexmedetomidine can be used as an adjunct to local anesthetics for subarachnoid blockade.Compared to clonidine,dexmedetomidine adjuvant local anesthetic has been shown to be a more desirable drug,significantly enhanced Intrathecal local anesthetics block sensory movement and can last longer.The polymorphism of the rs 1800544 locus of the ADRA2A gene is associated with the level of dexmedetomidine sedation and analgesia.The genetic variation in the gene encoded by ADRA2A has an effect on the level of pain and sedation.Mididine has important clinical significance.The main innovations of the thesis:(1).For the first time,different doses of dexmedetomidine combined with bupivacaine for subarachnoid anesthesia were compared,and their blockade effects,adverse reactions and complications were compared.The optimal dose of Dex,intramedullary can produce a sedative effect.(2)Compare the effects of different additives on the lumbar anesthesia of local anesthetics.Compared with clonidine and fentanyl,Dex is proved to be the best choice.Dex can significantly enhance the block of sensory movement of intrathecal local anesthetics,and the side effects are minimal,medications within the spinal canal can produce a sedative effect.(3)For the first time,the rs1800544 gene polymorphism of the ADRA2A gene was closely related to the sedative and analgesic level of dexmedetomidine.The C1291C type was more sensitive to the sedative response of dexmedetomidine.The polymorphism of the ADRA2A gene caused the right One of the genetic factors for the individual differences in the sedative and analgesic effects of medetomidine. |
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