Impact Of Circadian Rhythm On Postoperative Infections After Elective General Surgery And Its Mechanism

Backgrounds:Infection is one of the most common complications after surgery.The development of postoperative infection increases suffering for patients,results in prolonged hospital stay,extra costs,and seriously affect the quality of patients after surgery.It is important to control the incidence of postoperative infection.The studies of postoperative infections mainly focused on asepsis,surgical patterns,using antibiotics,controlling temperature and blood glucose in preoperative etc.,however,it did not significantly reduce the incidence of postoperative infections following improved these fields.Therefore,it is necessary to explore new mechanisms for postoperative infections.Mechanisms that contribute to the postoperative infections are complicated,the influence resulted by surgery and anesthesia,the stress responses and using drugs in perioperative period,the physical status of patient's and many other factors involve their regulation.Circadian rhythm is the inner rhythm of organism in the absence of external signals.It regulates many physiological functions via clock genes,melatonin and some endogenous chemicals.Circadian rhythm regulates the inflammatory reaction by regulating the recruitment of immune cells,the generation and migration of inflammatory cytokines.The increasing evidences in vivo indicate that susceptibility to endotoxic shock is dependent on the circadian rhythm.Further,the magnitude of response to pathogenic bacteria challenge may vary with the time of the day.Therefore,circadian rhythm may affect the occurrence of postoperative infection-related complications.However,the potential mechanism remains to be elucidated.Aims:The aim of this study was to determine the effect of operation timing on postoperative infections and provided a theoretical basis for the reasonnable arrangement operation.This study were divided into three parts: firstly,to evaluate the impact of operation timing on the incidence of postoperative inflammatory reactions and determinate the possible mechanism for regulating postoperative inflammatory reaction of circadian rhythm;secondly,to determine the impact of time of the operation on the incidence of postoperative infections and prognosis following colorectal cancer surgery;thirdly,to dectect circadian rhythm of the level of melatonin and clock genes,and the concertration of inflammatory cytokines in patients with sepsis and non-sepsis,and analyze the specific mechanism how circadian rhythm regulate inflammatory reaction in the sepsis patients.Methods:1.A total of 794 patients underwent laparoscopic or open surgery for colorectal cancer at the Department of Colorectal Surgery in the first affiliated hospital of Zhejiang University,school of medicine in the period between Junuary to December in 2014.Patients were divided into three groups according to the start time of surgery: CT1(07:00 to 12:00 hrs),CT2(12:01 to 18:00 hrs)and CT3(18:01 hrs to midnight).To investigate the possible mechanisms of circadian rhythm on postoperative inflammatory reactions according to the count of white blood cells,the concentration of CRP and biochemical indexes both preoperative and in 24 h after postoperative.To expore the mechansim of circadian rhythm and postoperative inflammatory reactions by detecting stress hormones including cortisol,epinephrine,and norepinephrine.2.To compare the incidence of postoperative infections in three group patients one month after postoperative,and the rate and type of infection for infected patients as well as the length of hospital stay,the length of ICU stay,duration of surgery etc.In addition,the incidence of postoperative complications and prognosis are compared in six months following surgery.3.The concentration of melatonin,the expression of clock genes cry-1 and per-2,and the release of two pro-inflammatory cytokines,TNF-? and IL-6,in the serum of 11 septic and 11 non-septic patients in ICU are assessed.Additionally,to explore the specific mechanism of circadian regulate infections in septic patients.Results:1.Out of 756 patients that were enrolled in the study.There was no significant difference on the preoperative indicators among the three groups.There was no significant difference of the concentration of hemoglobin,glutamyl transpeptidase,alanine aminotransferase,creatinin,the red blood cells and platelet counts,the levels of the sress hormones including cortisol,epinephrine and norepinephrine at 24 h after surgical procedure among three groups(p>0.05).However,compared with CT1 group the white blood cell counts in CT2 and CT3 groups were significantly decreased(p<0.05 and p<0.01,recepectly),the concentration of CRP in CT2 group was significantly decreased(p<0.05)while the concentration of glucose increased(p<0.01),the concentration of total bilirubin and indirct bilirubin in CT3 group were significantly decreased(p<0.05).Compared with CT2 group,CRP and the concentration of glucose was significantly decreased(p<0.01),while,the concentration of total bilirubin and indirct bilirubin were significantly decreased in CT3 group(p<0.05).2.Among 756 cases,118 developed postoperative infections in one month.The results from blood and pus culture showed 97.1% specimen was being pathogen-free.The overall incidence of postoperative infection was 14.5%(38 of 262),15.3%(46 of 300),and 17.5%(34 of 194)in the CT1,CT2 and CT3 group,respectively,with no significant inter-group differences(p>0.05).There was no significant difference of the length of hospital stay,the length of ICU stay,duration of surgery etc.(p>0.05).A total of 665 patients were followed.There was no significant difference the incidence of postoperative complications and prognosis in six months following surgery(p>0.05).3.The study revealed altered circadian rhythm of melatonin secretion,clock genes cry-1 and per-2 expression,pro-inflammatory cytokines TNF-? and IL-6 release in patients with sepsis.The altered circadian rhythm of pro-inflammatory cytokines in plasma were consistent with f melatonin secretion in septic patients.Conclusions:1.The level of inflammatory cytokines and biochemistry markers were correlated with circadian rhythm in postoperative,while,stress hormones were not related to regulate circadian rhythm in postoperative inflammatory reaction.2.The occurrence of postoperative infection and prognosis in patients undergoing colorectal cancer surgery were not associated with operation timing.3.Altered circadian rhythm of melatonin secretion and expression of clock genes was consistent with the levels of the pro-inflammatory cytokines.