| BackgroundVisual loss after anesthesia and surgery is a rare but very serious complication with an estimated incidence of 0.0008%to 0.003%.In some special surgeries,such as spine operation in prone position,the odds of visual loss may be 1/500.The closed cases analysis by the American Society of anesthesiologists?American Society of Anesthesiologists,ASA?shows that the eye injury accounted for only 3%,but the compensation is relatively higher,which indicates the severity of perioperative permanent blindness.In recent years,people have payed more attention to visual impairment that may occur after non-ocular surgery,however,the incidence of it is still increasing.In the last decade,minimally invasive surgery which can promote postoperative rehabilitation,reduce postoperative pain,shorten hospitalization time,provide a more ideal operative field and decrease intraoperative bleeding and so on,is greatly favored in the development process of the surgical department.In gynecological surgery,minimally invasive surgery is usually carried out under the steep Trendelenburg position?ST?.Only in this way can the abdominal contents rely on gravity to move to the other side,so as to provide an excellent surgical field.Usually the patient will be remained in this position for several hours,or even longer which has adverse effects on patients especially on eyes.However,little attention has been given to the effects of this non physiological position on the patient.Early studies suggested that the ST position may lead to central venous pressure,pulmonary capillary wedge pressure and pulmonary arterial pressure increase during surgery,in the meantime,it also reduces cardiac output.In addition,this position can lead to intraocular pressure elevation.The elevation of intraocular pressure of patients with glaucoma correlated greatly with tilt angle in this position,and the elevation of intraocular pressure?IOP?increases the risk of patients with advanced glaucoma.The majority of current studies on intraocular pressure were focused on the urology surgery,especially radical prostatectomy,due to the prolonged steep Trendelenburg position.Weber et al reported 2 patients suffered ischemic optic neuropathy after the laparoscopic radical prostatectomy under ST position.Molloy et al.investigated the ST position and its related intraocular pressure elevation and carried out 3 years follow-up visits to the patients with visual loss after surgery.Among these 43 patients,some of them underwent laparoscopic radical prostatectomy,some others experienced laparoscopic radical resection of colon cancer,while the others were subjected to panhysterectomy,however,the increase of intraocular pressure seems not to correlate a lot with the surgery categories,while the prolonged ST position can increase intraocular pressure and reduce the perfusion pressure of the eye,which may be the risk factors leading to postoperative visual function injury.Except for ketamine,many general anesthetics have the characteristics of decreasing IOP,including propofol,sevoflurane and remifentanil.Propofol is a powerful and short acting sedative and hypnotic anesthetic with characteristics of fast metabolism,high lipophilicity,and relatively short half-life time,which makes it very suitable for target-controlled infusion?TCI?.The TCI model is able to achieve individual drug use,maintain the stability of hemodynamics and appropriate depth of anesthesia.In the last few decades,propofol has become the most popular anesthetic.Intravenous infusion of propofol perioperatively can reduce intraocular pressure more significantly,compared to sevoflurane,isoflurane and thiopental.Dexmedetomidine,which is a new,potent and highly selective alpha-2 adrenoceptor agonist and has the effects of sympathetic inhibition,sedation,amnesia,and analgesia,is an adjuvant drug of safe and effective in modern anesthesiology.An increasing number of reports have indicated that a loading dose and continuous infusion of dexmedetomidine can decrease the elevated intraocular pressure induced by tracheal intubation,laparoscopic surgery under St position.Both dexmedetomidine and propofol have the effect of lowering intraocular pressure,but whether the combination of these two agents have a stronger synergistic effect of reducing the intraocular pressure has not been reported at home and abroad.Noradrenergic neurons are distributed in locus coeruleus,which can be connected downward with synapses of brainstem,nucleus of solitary tract,dorsal horn of spinal cord,and upward projected to the cerebral cortex.It relates to sympathetic nervous activity and has a large number of 2-adrenergic receptors.2 adrenergic receptors belong to classical G protein-coupled receptors.Inhibition of adenylate cyclase can decrease the level of cyclic adenosine monophosphate?cAMP?in cells.To our knowledge,cAMP response element?CREB?is the phosphorylated substrate of many protein kinase in which protein kinase A?PKA?is the first identified and activated by cAMP to regulate cell function.PKA is widely distributed in nerve system,after activation,it can stimulate the downstream CREB and initiate the transcription in signaling pathway.cAMP acts as a second messenger to amplify signal by stimulating PKA.c-fos technique,which is short for c-fos protooncogene and a technique for nerve function positioning,is used in the study of central signal transduction pathways in brain by many researchers.c-fos protein is considered to be a symbol involved in the transduction and regulation of stimulating signals,and also as a third messenger involved in regulating the expression of target gene.The expression of c-fos protein in neurons increases due to the increase of stimulus,which differs in quantity and position in response to different stimulus.Studies show that retinal ischemia reperfusion injury can induce the transient expression of c-fos,the level of which positively correlates with the degree of retinal morphological damage.The first part of this study was to explore the effect of the joint of dexmedetomidine and propofol TCI on the intraocular pressure in patients undergoing laparoscopic extensive hysterectomy resection surgery under ST position using prospective,randomized,controlled,and double blind method;the second part was to study the effect of dexmedetomidine on intraocular pressure and the role of central alpha-2 adrenergic through different administration routes including intravenous and locus ceruleus microinjection and using the specific antagonist-yohimbine as the neuropharmacological analysis tool to explore the Central Mechanism of dexmedetomidine on IOP.Part?Role of Dexmedetomidine in Intraocular Pressure Elevation During Laparoscopic Hysterectomy of Patients in the Steep Trendelenburg Position under Propofol Anesthesia:A Randomized Controlled TrialBackground:Both the Dexmedetomidine and propofol can reduce IOP in patients under the Trendelenburg position.However,whether dexmedetomidine combined with propofol synergistically decreases the intraocular pressure is unknown.This study evaluated the role of dexmedetomidine combined with propofol in intraocular pressure during laparoscopic total hysterectomy of patients in steep Trendelenburg position.Methods Seventy patients were randomly assigned to two groups.The dexmedetomidine group?DEX,n=35?was treated with a loading dose of dexmedetomidine?1?g/kg?,infused intravenously over 15 min,followed by continuous infusion of dexmedetomidine?0.4?g/kg/h?until the end of procedure.The control group?Con,n=35?received an equal volume of normal saline.Anesthesia in the two groups was induced by propofol?2-4 mg/ml?and remifentanil?2-5 ng/ml?target-controlled infusion and injecting rocuronium intravenously?0.6 mg/kg?,followed by tracheal intubation and IPPV with PET CO2 at 33-36 mmHg,airway pressure at 11-23 cmH2O,in the meantime,anesthesia was maintained with propofol and remifentanil target-controlled infusion and constantly infusing cis-atracurium?1-3 ug/kg/min?.The pneumoperitoneum pressure of CO2 was set at 9-14 mmHg.Intraocular pressure was measured three times in each eye at 11 different time points,including 10 min after supine position?T1?,15 min after loading dose of DEX or saline?T2?,5 min after anesthesia induction?T3?,5 min after CO2pneumoperitoneum?T4?,5?30?60 and 120 min after ST position?T5-8?,5 and 60 min after extubation?T9-10?,and 24 h after surgery?T11?.Intraoperative data,including anesthesia time,operation time,steep Trendelenburg time,mean arterial pressure,heart rate,the dose of anesthetics and vasoactive agents,end-tidal CO2,BIS,complications,bleeding volume,urine volume and total volume of infusion were also measured.Results IOP at T9 and T10 in DEX group were significantly decreased compared to CON group?P<0.01 and P<0.05?,and the IOP in two groups at T3 were both reduced comparing with T1?P<0.01?,while it was elevated at T7 and T8?P<0.01 and P<0.05?.The BIS at T2 in DEX group was lower than that in CON group?P<0.01?,while the MAP at T6 in DEX group was higher than that in CON group?P<0.05?,in addition,the HR at T2,T3,T7 in DEX group were lower than that in CON group?P<0.05?.The concentration of TCI propofol in DEX group was markedly lower than that in CON group?P<0.05?.There was no significant difference among other data.Conclusion Dexmedetomidine combined with propofol have the similar effect of decreasing the intraocular pressure with propofol alone during laparoscopic hysterectomy of patients in the steep Trendelenburg position.Moreover,DEX also promoted the pressure recovery to the preoperative level during the immediate post-tracheal extubation period.Part ? Central Mechanism in the effect of Dexmedetomidine on Intraocular PressureBackground: Dexmedetomidine can reduce the intraocular pressure of patients undergoing laparoscopic hysterectomy under ST position in previous clinical trials,the present study was designed to explore the role of central alpha 2 adrenergic in DEX decreasing the IOP in rats subjected to CO2 pneumoperitoneum under ST position through different ways of infusion.Methods: The pneumoperitoneum by CO2 + Trendelenburg,LC microinjection animal model for different infusion routes were established in 48 Male SD rats,300 + 25 g.The experiment was divided into 2 parts: in the first part rats were randomly divided into 6 groups according to the different administration ways of dexmedetomidine:?1?control group?group C?;?2?intravenous infusion of dexmedetomidine?group ID?;?3?LC microinjection of dexmedetomidine set?Group LD?.And in the second part,according to the central use:?4?LC microinjection of yohimbine?group Y?;?5?LC microinjection of yohimbine followed by intravenous infusing dexmedetomidine?group YID?or LC injection of dexmedetomidine?group YLD?,respectively,the changes of intraocular pressure was recorded at 8 different time point,including prior to operation?T1?,10 minutes after pneumoperitoneum + ST position?T2?,10 minutes after locus coeruleus injection of yohimbine or artificial cerebrospinal fluid?T3?,10 minutes after intravenous or intralocular injection of DEX?T4?,60 minutes after pneumoperitoneum?T5?,90 minutes after pneumoperitoneum?T6?,120 minutes after pneumoperitoneum?T7?,and 150 minutes after pneumoperitoneum?T8?..Animals were sacrificed by air embolism at scheduled time.The samples of LC were subjected to fixing with 10% of paraformaldehyde,dehydrating,paraffin embedding,making sections,HE staining,light microscope to observe pathological changes,radioimmunoassay and WB to determine the expression of c AMP,PKA and CREB.Results: 1.Effect of dexmedetomidine on intraocular pressure after intravenous infusion Compared with the control group,the intraocular pressure was decreased rapidly at T4-6 time points?P<0.05,P<0.01?after dexmedetomidine administration intravenously,which indicated that intravenous infusion of dexmedetomidine has the effect of lowering intraocular pressure.2.Effect of dexmedetomidine on intraocular pressure through LC injection Compared with the control group,the IOP was decreased at T4-6 time points after infusion DEX in LC?P< 0.05,P< 0.01?,which suggested that DEX,the alpha-2 receptor agonist in LC,may be involved in the regulation of IOP in the central nervous system.3.Effect of yohimbine on intraocular pressure through intracerebroventricular microinjectionCompared with the control group,there were no differences of IOP between the two groups at all time points?P> 0.05?during continuous observation for 120 min after the LC was injected with yohimbine,indicating that there was no effect of LC microinjection on IOP.4.Effect of yohimbine on intraocular pressure in rats 10 min after LC injection followed by intravenous or LC injection of DEXAfter the rats were microinjected with yohimbine in lateral ventricles 10 min prior to intravenous infusion with 1ug/kg of DEX,the IOP in group YID did not decrease significantly comparing with the Y group 120 min after the above administration?P> 0.05?,while the IOP at T4,T5 in group YID were elevated when comparing with group ID?P< 0.05,P< 0.01?,which suggested that microinjection of yohimbine in lateral ventricles could reverse the effect of decreasing IOP by peripheral DEX infusion.In the meantime,the IOP in group YLD was neither decreased significantly 120 min after the same administration comparing with the Y group?P> 0.05?,while the IOP at T4,T5 in group YLD were elevated when comparing with group ID?P< 0.05,P< 0.01?,suggesting that microinjection of yohimbine in lateral ventricles could reverse the effect of decreasing IOP by DEX infusion in LC.5.c-fos positive cells: compared with group C,the expression of c-fos protein in LC in the group of ID and LD decreased significantly?P< 0.01?,while the change of c-fos in Y group had no statistical significance.The expression of c-fos protein was decreased in the group of YID,and the number of c-fos positive cells in the Y group was reduced from 62±13 / high magnification to 32±7 / high magnification?P< 0.05?,while the change of that in group YLD had no statistical significance.6.Radio-immunity assay showed the expressions of c AMP,PKA and CREB in ID and LD groups were markedly decreased as comparing with C group following intravenous or Locus Coeruleus infusion with DEX?P<0.01?,these protein in YID groups were reduced when comparing with Y group after microinjection with yohimbine in LC followed by intravenous infusion with DEX?P<0.05?,while they were elevated comparing with those in group ID;in the meantime,these protein in YLD groups did not altered when comparing with Y group after microinjection with yohimbine in LC followed by intravenous infusion with DEX?P>0.05?,while they were elevated comparing with those in group LD,indicating that Yohimbine infusion in lateral ventricle prior to DEX can reverse the DEX-induced reducing IOP effect.7.WB results showed the level of c AMP,PKA and CREB in ID and LD groups were also markedly decreased as comparing with C group following intravenous or Locus Coeruleus infusion with DEX?P<0.01?,and the difference of level of these protein among YLD,YID and Y groups were in keeping with the radio-immunity assay,which further suggests c AMP-PKA-CREB signaling pathway was involved in the DEX-mediated effect of reducing IOP.Conclusion:Dexmedetomidine may reduce the high intraocular pressure in rats under pneumoperitoneum combined with ST position by exciting the alpha 2 adrenoceptors in locus coeruleus,the pathway of c AMP-PKA-CREB and c-fos protein may be involved in this effect. |
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