The Effects Of Dexmedetomidine Combined With Oxycodone For Patient-controlled Intravenous Analgesia After Video-assisted Thoracoscopic Surgery

Background and Objective:Lung cancer is a higher incidence malignant tumor in all over the world.Surgery resection is an important treatment.It is believed that traditional open thoracotomy causes severely surgical trauma and postoperative pain.But now it could be done under thoracoscopic procedure including lymph node clearance.Comparing with conventional open-chest procedure,there are many advantages for thoracoscopic surgery,such as minimal incision,decreased postoperative pain,less length of stay.Although it is minimal invasive procedure,stress response caused by surgery is existed.Undermanaged pain is still observed and few of them arc very severe,and it may last several months after surgery.Acute postoperative pain result to increased sympathetic tone and cardiovascular and cerebrovascular incident.It also causes many complications such as pneumonia and atelectasis,and prolongs hospitalization that is not benefit to patient recovery.So,postoperative analgesia is indispensable.Although we have many strategies for postoperative pain management,undermanaged pain is still observed.So,it is significant important to investigate the analgesia strategy af-ter video-assisted thoracoscopic procedure.Opioids are still the main drug for treatment of acute postoperative pain.But opioid-related adverse drug events,such as nausea,vomiting,pruritus,urinary retention,constipation,even respiratory depression are concerned by clinician and patients.These problems often need additional treatment.Therefore,innovative pain regimens that minimize or abandon opioid use are necessary.It is very important for patients with malignant tumor to maintain normal immune function.It has positive significance for those patients to reduce pro-inflammatory cytokines and maintain the balance between pro-inflammatory and anti-inflammatory.Both surgery trauma and postoperative pain can cause release of cytokines.Cytokines and immune system can regulate and affect each other through signaling transduction.Inflammatory cascade reactions are activated.And at last,those effects will improve or inhibit patient’s resistance and prognosis.High mobility group box 1 is an important inflammatory mediator involved in many kinds of inflammatory responses and causes release of pro-inflammatory cytokines.Studies showed that it is an upstream factor for inflammatory response.Once released,HMGB1 bind with receptor and activate several signaling pathway and cause injury of cell and tissue.However,inhibition the activation of signaling can decrease the release of cytokines and reduce inflammatory response.TNF-α and IL-6 are two important pro-inflammation cytokines.The increased expression of them always means inflammation and stress response and poor prognosis.IL-10 is an important anti-inflammatory cytokine and it can regulate immune function and is also involved in many kinds of inflammatory response.Dexmedetomidine is α2-adrenergic receptor(α2AR)agonist.The affinity of α2:α1 is 1620:1.It has many effects,including analgesia and sedation,and it also has anti-sympathetic and organ protective effects.Dexmedetomidine play its role through binding α2AR located at central and peripheral.In clinical practice,it has opioid-sparse effects whether used perioperatively or postoperatively.Previous studies showed that dexmedetomidine infusion during operation would reduce the inflammation response and decrease the release of cytokines.Oxycodone is a semi-synthetic opioid and a selective μ-and κ-receptor agonist,and it is characterized by a rapid onset and short duration of action.Studies have shown good efficacy of oxycodone in managing postoperative pain,especially compared with other opioids,it has few incidences of respiratory depression.When compared with morphine,it has similar analgesia and fewer side effects and it is mainly used for moderate and severe pain.Intravenous patient-controlled analgesia has few contraindications and its effect in pain management can be maintained continuously with a stable therapeutic concentration,it allows patients to administration by themselves.It is one of the choice to attenuate postoperative pain.There is no study to investigate whether dexmedetomidine combined with oxycodone for intravenous patient-controlled analgesia after video-assisted thoracoscopic lobectomy could alleviate postoperative pain and reduce inflammatory response after surgery.The aim of our study is to investigate the efficacy of dexmedetomidine combined with oxycodone for intravenous patient-controlled analgesia after thoracoscopic lobectomy and compare with oxycodone alone.We also evaluate the incidence of side effects.The serum levels of HMGB1,TNF-α,IL-6 and IL-10 are detected and analyzed.Methods:Patients with newly diagnosed lung cancer aged 18～75 years,ASA Ⅰ-Ⅲ,undergoing elective video-assisted thoracoscopic lobectomy in Shandong Cancer Hospital Affiliated to Shandong University between Jun 2014 and Dec 2015 were recruited and randomly allocated into two groups:oxycodone(O group);dexmedetomidine combined with oxycodone(DO group).Before induction,patients in DO group received 0.5μg/kg of dexmedetomidine diluted to 20 mL with physiologic saline infused intravenously for 10 minutes,and patients in O group received the same dose of physiologic saline.Anesthesia was induced with midazolam,propofol,fentanyl and rocuronium and maintained with propofol and sevoflurane.Analgesia and muscle relaxant was provided with fentanyl and rocuronium respectively.We monitored electrocardiogram(ECG).blood pressure(BP),heart rate(HR),pulse oxygen saturation(SpO2),partial pressure of carbon dioxide at end-tidal(PetCO2),bispectral index(BIS).A radial artery catheter and central venous line were inserted in all patients.The patient-controlled intravenous analgesia(PCIA)protocol was oxycodone 50mg in O group or dexmedetomidine 2.5μg/kg and oxycodone 50mg in DO group,diluted to 100 ml in 0.9%saline.In both of groups,background infusion was lml/h and bolus dose was 2ml followed by 15 min of lockout time.If patients complained pain,we recommended them press the PCA button,and if relief was not obtained,a rescue analgesic(30 mg of pethidine by intramuscular injection)was administered.The outcomes were as follows:Ramsay sedation score and VAS score at 4h,6h,24h,and 48 h postoperatively were assessed.The incidence of side effects was assessed and recorded in the general ward.HR and MAP were recorded at the following time points:arrival in the operating room(TO);before intubation(T1);after intubation(T2);30 minutes after incision(T3);at extubation(T4);arrival at the PACU(T5);1 day after surgery(T6);and 2 days after surgery(T7).The satisfaction with pain control was assessed at 48 h postoperatively after the PCA pump was removed.Number of PCA boluses and cumulative consumption of PCA oxycodone was recorded.The levels of serum HMGB1,TNF-α,IL-6 and IL-10 was detected at three time points:before surgery,postoperative day land day 2.All patients in the study were consented according to the ethical standards of the Helsinki Declaration of 1975.Results:1.There were no significant differences in the patients’ characteristics such as age,sex,height and body mass index.The intraoperative measurements,surgery time and consumption of fentanyl were also no significant differences between two groups(P=0.883,P=0.327 respectively).2.The changes of MAP and HR were no significant difference between two groups at different time points(P>0.05).3.The VAS scores at rest at 4,6 and 24 h postoperative were higher in O group than DO group(P<0.001).But there was no significant diffidence between two groups at 48h postoperatively(P=0.087).The VAS scores at movement at 4,6 and 24h were higher in O group than DO group(P≤0.001).But there was no significant diffidence between two groups at 48h postoperatively(P>0.05).No patients required rescue analgesia.The Ramsay sedation scores were no statistical differences between two groups at different time points(P>0.05).4.The incidence of nausea at 6h postoperatively was 50%in group O,while at the same time the value was7.5%in group DO,(P<0.001).The incidence of vomiting was 12.5%in O group,but the value was 0 in DO group(P=0.027).There were no patients suffered nausea and vomiting in both groups after 6h postoperatively.5.Number of PCA boluses and consumption of oxycodone in group O was higher than in group DO(P<0.01).6.The number of patients very satisf-actory was 5%in group O,while it was 15%in group DO.The number of’ patients satisfactory was 17.5%in group O,while it was 75%in group DO.Satisf-action with pain control was lower in group O than in group DO(P<0.001).7.There were no obvious differences in the levels of serum HMGB1 in the two groups before surgery(P=0.668).It was increased in both of groups at postoperative day 1 compared with before surgery(P<0.01).The values in O group were higher than DO group at postoperative day 1(P=0.008).At postoperative day 2,in O group,it was still higher than before surgery(P<0.01).But it was no statistical difference in DO group compared with before surgery(P=0.407).And the levels of HMGB1 in group O was higher than group DO at postoperative day 2(P<0.01).8.There were no obvious differences in the levels of serum TNF-a and IL-6 in the two groups before surgery,but these values increased at day 1 after surgery(P<0.05).And the values in O group were significance higher than in DO group(P<0.05).The levels of serum TNF-α and IL-6 in group O were increased at postoperative day 2 compared with before surgery(P<0.05).However,in group DO,the values at postoperative day 2 were no significant differences compared with before surgery(P>0.05).But the levels of TNF-a in group O was higher than in group DO at postoperative day 2(P<0.05).9.There were no obvious diff-erences in the levels of serum IL-10 between two groups before surgery(P=0.132).It was increased in both of groups at postoperative day 1 compared with before surgery(P<0.05).At postoperative day 2,It was no statistical difference in O group compared with before surgery(P=0.609).But in DO group,it was still higher than before surgery(P<0.01).There were no statistical difference between two groups at postoperative day 1 and day 2(P>0.05).Conclusions:Comparing with oxycodone alone,the combination of dexmedetomidine and oxycodone for intravenous patient-controlled analgesia following video-assisted thoracoscopic lobectomy enhance the analgesic effect,reduce the consumption of opioids,lower the incidence of side effects,associate with better satisfaction with postoperative pain control and reduce early inflammatory response after surgery.