Pharmacodynamic Interaction Of Combinated Etomidate With Dexmedetomideine Egarding Adrenal Suppression

Background:Both Etomidate（ETO） and Dexmedetomidine（DEX） are used as sedatives in clinical situation,but the indications are slightly different.ETO is often used for anesthesia induction period（also used to sedative ICU patients early）;DEX is mainly used to provide sedation for ICU patients.Due to some beneficial profiles of DEX on heart,nerve and renal protection,thus,DEX is now often used during anesthesia.As we know,ETO is the imidazole derivative,early clinical application have found that the drug had the effect of adrenal cortex inhibition,later studies confirmed that this kind of adrenocortical function suppression was mainly related to its chemical structure of imidazole ring.It is worth noting that the chemical structure of DEX also contains imidazole ring.Therefore,based on the known adrenocortical suppression of etomidate,we have good reason to suspect that DEX might also suppress adrenocortical function.The reported studies have found adrenal cortex inhibition effect in animals and cells in vitro,to some extent,although this has not been further confirmed in clinical application research.Especially it should be noted that,despite the different clinical indications,ETO and DEX are common used in combination in clinical situation.As a result,it is important to pay close attention to the nature of possible interaction and clinical significance.Usually,the interaction of both drugs might be defined as synergy,antagonism or addition,which is related to the biophase of drug.The interaction nature,with a combination of ETO and DEX regarding the function of adrenal cortex,has to be determined from the perspective of clinical safety.So far,however,the related information is limited.Therefore,the current srudy is designed to clarify the characteristics of the interaction of ETO and DEX regarding adrenal suppression for clinical anesthesia safety.The possible direct inhibition effects of steroidogenesis produced by individual or combination of ETO and DEX were investigated based on the secretion of cortisol and aldosterone of human the adrenal cortical cells.Methods:A primary human cortical cell lines,purchased from Sciencell Company,was cultured in vitro.On the third generation,the primary human cortical cells were cultured in plates with the density of 5×10⁵,then Hycolone culture solution without fetal bovine serum was added after 24h culture,and fresh fetal bovine serum culture solution was added again after 2～3h.Then,the cells were exposed to ETO,DEX with different concentration individually or combinations.The range of concentration of ETO and DEX were 0,10,30,100,1000,3000,10000,100000n M,and 0,10,30,100,1000,3000,10000n M respectively.Drug-induced changes in the production/release of cortisol（CORT） and aldosterone（ALDO） were measured by chemiluminescence method after 24h incubation,and the average production（unit:pg/h/10000 cell） was calculated within 1hour.The etomidate concentration-response（the average production of CORT,ALDO within 1h）with Hill equation（Sigmoid exposure-response curve） was fitted,and the pharmacodynamic parameters were estimated based on nonlinear mixed effect model.Subsequently,the effects of DEX on above pharmacodynamic parametes were explored with concentration-and non concentration-dependence.Results:A total of 19 batches of cells were tested in drugs stimulation with ETO and DEX individually or combination of both with different concentraion,and the results from10 batches of cells were used in the final analysis.When given in combination in vitro,their effect on production/release was complex.Pharmacodynamic analysis results suggest that DEX（alone or combined ETO） did not affect the adrenal cortical hormone secretion with lack of concetraion-response（CORT,ALDO） relationship in the concentration range studied.The ETO concentration-ALDO,CORT production relationship could be better described by Hill equation.In addition,the model of ETO concentration-CORT relationship was improved significantly when the DEX with dose-dependent was a covariate of E₀,with a decrease objection function value by 4.55（P<0.05）.However,the goodness of fit had no obvious improvement with a dose dependent manner of DEX as covarate of EC₅₀.The final pharmacodynamic model parameter values were as follows:as for ETO-ALDO,Emax=1.20,EC₅₀=9.74,E₀=1.33,gamma=18.5;as for ETO-CORT,the EC₅₀=9.49,Emax=8.16,EC₅₀=9.49,E₀=8.57,gamma=37.0 for ETO alone;while DEX is present,Emax=8.16,EC₅₀=9.49,E₀=8.57–0.0247×(C_DEX–4.6),gamma=37.0（all parameters except for gamma are the values of natural logarithm conversion）.Conclusions:To our knowledge,this is the first observation report of the interation of etomidate-dexmedetomidine regarding adrenal suppression.The results suggested that etomidate significantly suppress the ALDO and CORT production of human adrenal cortical cells.Although DEX alone did not affect the secretion of the CORT,it could reduce the E₀（base secretion production） of the ETO concentration-CORT secretion curve in a dose dependent way.That is,DEX additively increased the adrenal suppression of ETO.Backgroud: Etomidate（ETO） is a potential hypnotic with the rapid onset,short action time and the stable hemodynamics,which is preferable for pediatric anesthesia,especially used in the anesthesia induction for children with congenital heart disease;Dexmedetomidine（DEX）,widely used in clinical anesthesia and critical care medicine,is a highly selective α₂ adrenergic receptor agonists with the properties of sedation,analgesia,anti-sympathetic.Etomidate induced adrenal function suppression is related to its imidazole compound structure and dexmedetomidine is also a imidazole derivative.Therefore,we guessed that the children with congenital heart disease might be vulnerable to the adrenal suppression with dexmedetomidine administration.Previous studies have found that dexmedetomidine induced the adrenal cortex inhibition in animal and in vitro cell lines,however,which was unsuccessed to be confirmed in clinical research.Therefore,this study was designed based on tool drug of etomidate and dexmedetomidine administered preoperatively.The congenital heart surgery related risk factors and total serum cortisol concentration was observed,recorded and analyzed after heart surgery.Methods: Sixty-seven ASA physical status Ⅱ～Ⅲ pediatric patients aged 2～ 149 months,weighted 3.3 to 29.3 kg,scheduled for CHD corrected surgery children were recruited.The operation was undertaken in the moring.All patients randomly divided into two groups by computer random number distribution method.The children in group D received an infusion of dexmedetomidine（Dex）intravenously with a bolus dose of 0.5 μg·kg^-1 within 10 min during anesthesia induction,then followed with a maintenance dose of dexmedetomidine 0.5 μg·kg^-1·^h-1.The children in group E received etomidate（Eto）intravenously with a blous dose of 0.3 mg·kg^-1 without maintainence dose.Other induction drugs included sufentanil,midazolam and rocuronium.The suitable depth of anesthesia was maintained with sufentanil,sevoflurane and rocuronium.All kinds of possible preoperative risk factors associated with relative adreal insufficience were observed and recorded.The arterial samples were drawed and assyed for the total of plasma cortisol concentrations by chemiluminescence method according to preset time.The cortisol concentrations were compared between both groups.Preset time was as following: before anesthesia induction（T0）,at the end of induction（T1）,30 minutes after anesthesia induction（T2）,at the time of aortic and inferior vena catheteraization（T3）,180 min（T4） and 24 h（T5） after anesthesia induction.Data were analyzed by SPSS statistical software and EXCEL office software.Results: A total of 67 cases of children with congenital heart disease were included in the final data analysis.There was no statistically difference between both groups regarding age,gender,body weight,body surface area（P > 0.05）.There are also no statistically differences between groups regarding surgery related items.The cortisol concentration decreased gradually after anesthesia induction in both groups,and returned to baseline values after 24 hours.The cortisol concentration was significant lower in the children of group E than that of group D at 180 minutes after anesthesia induction.Conclusions: The plasma concentrations of cortisol decreased in the children with congenital heart disease after CPB and surgical repair,and returned to baseline after 24 hours of anesthesia induction.The adrenal cortex function inhibition induced by etomidate in CHD children is longer and more serious than that induced by dexmedetomidine（if any） during preoperative CHD children.