Terlipressin In Septic Shock:a Randomized Double-blind Placebo-controlled Pilot Study

Backgrounds:Sepsis and septic shock are life-threatening conditions caused by a dysregulated immune response to infections,which may lead to tissue and organ injures and finally to death.Foreign epidemiological investigation showed that the mortality of sepsis has already surpassed the myocardial infarction,become another of the major causes of human noncardiac death and has the trend of increased year by year[1]?Despite advances in management,sepsis and septic shock still represent major healthcare problems worldwide leading to a substantial consumption of health-care resources.Septic shock is a distribution shock characterized by hypotension and vasodilation.The decrease in vascular tension may be mainly associated with endogenous NO formation,the decrease of calcium in cells and inflammatory media release.Aggressive volume resuscitation is the mainstay of initial shock management,when aggressive volume resuscitation is still unable to maintain an average arterial pressure of 65 mmHg,we usually use norepinephrine or dopamine to increase vascular tension.Norepinephrine and dopamine are catecholamine drugs,norepinephrine is alpha adrenal agonists,which increasing the mean arterial pressure by increasing the vascular resistance,dopamine is a precursor of norepinephrine,dopamine acts on alpha and beta adrenergic receptors and dopaminergic receptor,its vasoconstrictions are associated with the dose.The more secure and effective use of norepinephrine and dopamine has been a controversial issue and has not yet been confirmed by evidence-based medical documentation.In recent years,the guidelines recommend norepinephrine as a first-line vasoactive drug for septic shock[2].However,vascular hyporeactivity to catecholamines is common [3,4] suggesting the need to either use other vasopressor agents or combine catecholamines with other vasopressor agents.In fact,the present standard use of catecholamines is only based on empirical clinical evidence.In other words,it is unknown whether alternative approaches might be superior.It is important to find the plasma concentration of vasopressin in septic shock[ 5-7].The relative or absolute lack of vasopressin is an important reason for the decrease of vascular tension in septic shock.Vasopressin(VAP)is the adjuvant of norepinephrine for the treatment of septic shock[8].Terlipressin is a long-acting VAP,Its pharmacodynamic characteristics are similar to VAP,but the pharmacokinology is slightly different.Due to the current use of terlipressin in hepatorenal syndrome,portal hypertension and so on,the application of terlipressin for septic is still lacking.There are few reports on the efficacy and organ function of terlipressin in patients with septic shock.The purpose of this study was to compare the efficacy of terlipressin and norepinephrine on patients with septic shock and to focus on the organ function.Part ? Terlipressin in septic shock:A randomized double-blind placebo-controlled pilot study Objectives:To evaluate the efficacy and safety of terlipressin in treating septic shock.Methods:A randomized double-blind placebo-controlled pilot study performed in the first affiliated hospital of zhengzhou university general Intensive Care Unit from JUN 1,2015 to MAY 31,2016.All septic shock patients were diagnosed with the latest criteria of septic shock and after the standard fluid resuscitation,but vasoactive drugs were required to maintain a mean arterial pressure above 65 mmHg.All paitents were randomly divided into two groups: experimental group with 1 mg terlipressin treatment,control group treated by 11 mg norepinephrine,drugs were pumped through a 50 ml micropump,pump speed can be adjusted within the range 2-8 ml/h,aims to keep mean arterial pressure above 65 mmHg,if can't add with open label norepinephrine or other catecholamine drugs.The end of the study was shock correction,death or withdrawal.The main research indicators were 28-day,60-day survival rate and the secondary observation was the shock correction rate,the open label of norepinephrine requirement,the organ function,the duration of ICU,total length of hospital stay,mechanical ventilation time,hormone use time,vasoactive drug use time and the incidence of adverse events.Results:A total of 28 patients were enrolled,The baseline data of 28 patients were not significantly different.The 28-day survival rate of the experimental group and the control group was 61.5%(8/13)and 53.3%(8/15)respectively,and the difference was not statistically significant(P = 0.622).The 28-day survival curve was drawn by kaplan-meier method and the Log-Rank test results: ?2= 0.718,P= 0.397,the difference of survival curve of the two groups was not statistically significant.The shock correction rate was 61.5%(8/13)and 53.3%(8/15)respectively in the experimental group and the control group,and the difference was not statistically significant(P = 0.622).The open label norepinephrine requirements of the trial group and control group for the 0h?6h?12h?24h?48h time point were :(0.35 + 0.35)VS(0.39 + 0.58)g/kgmin,(0.87-2.09)VS(0.54 + 0.73)g/kgmin,(0.85-2.08)VS(0.60 + 0.97)g/kgmin,(0.43-0.77)VS(0.64 + 1.03)g/kgmin,(0.22-0.66)VS(0.86 + 1.49 g/kgmin,there was no statistically significant difference.In terms of hemodynamics,liver function,renal function,coagulation function and lung function,there was no statistically significant difference between the two groups(P > 0.05).There was no statistical difference between the two groups of patients in the duration of ICU,total length of hospital stay,mechanical ventilation time,hormone use time,vasoactive drug use time(P > 0.05).The incidence of adverse events in experiment group was 30.77%(4/13),including 2 cases of fingers ischemia,1 case of hyponatremia,1 case complicated with hyponatremia and intestinal ischemia,and the incidence of adverse events in control group was 6.67%(1/15),only 1 case occurred ischemia of fingers,There was no significant statistical difference in the incidence of adverse events between the two groups(P = 0.122).Conclusions:The efficacy and safety of terlipressin and norepinephrine for septic shock were comparable.Part ? The curative effect of vasoactive agents in patients with septic shock: A bayesian network meta-analysisObjective: To compare the curative effect of vasoactive agents as vasopressin,dopamine,epinephrine,norepinephrine,phenylephrine and terlipressin on septic shock and hope to obtain optimal treatment regimen.Methods:(1)Literature retrieval: the Pubmed database(http://www.ncbi.nlm.nih.gov/ pubmed),Embase database(http://www.embase.com)and Cochrane library(http://www.cochranelibrary.com)were used.The search words were “septic shock” OR “sepsis shock”,Dopamine OR phenylephrine OR vasopressor OR Vasopressin OR “antidiuretic hormone” OR terlipressin OR noradrenaline OR norepinephrine OR epinephrine OR randomized controlled trial.(2)Inclusion and exclusion criteria of studies: A study that met the following criteria was included: 1)The study was open published English randomized controlled trial regarding of the curative effect of vasoactive agents on septic shock;2)The outcomes of studies included the indicators such as heart rate(HT),ystemic vascular resistance index(SVRI),mean arterial pressure(MAP),mean pulmonary artery pressure(MPAP)and mortality rates at 28 day.However,a study was excluded if: 1)data was incomplete and was reused,2)it was a review,letter,report,comment or other non-treatise studies record,3)the study with small samples was excluded,which was less than 10 patients.(3)Network meta-analysis: The ADDIS software was used to perform the present meta-analysis,while node-splitting analysis was applied to assess inconsistency in network meta-analysis.Result:1.A total of 24 eligible studies were included in this meta-analysis,which included 6737 septic shock patients(vasopressin: 1850,dopamine: 1137;epinephrine: 411;norepinephrine: 2997,norepinephrine+dobutamine: 196;phenylephrine: 56 and terlipressin: 90).2.The overall quality of the present meta-analysis was high.3.The effect of terlipressin on HT was best,and the HT in terlipressin group was significantly reduced than in dopamine group(MD=-41.82,95%CI:-70.14,-11.96)and phenylephrine group(MD=-48.34,95%CI:-86.85,-8.02).4.The SVRI of patients in the vasopressin,dopamine,norepinephrine,phenylephrine and terlipressin groups were effectively enhanced,especially in terlipressin group,but there was no statistic difference between above groups.5.The effect of epinephrine on MAP was optimum,in which the MAP value was higher than in other group.In addition,the efficacy in epinephrine group was significantly improved than in dopamine group(MD=11.04,95%CI: 18.56,3.68)and norepinephrine group(MD=10.00,95%CI: 19.04,0.12).6.The effect of terlipressin on MPAP was best,which was lower in terlipressin group than in other group,however there was no remarkably different between groups.7.The mortality rates at 28 day in epinephrine group and norepinephrine+ norepinephrine+dobutamine group were lower than in other group,but it was statistically significant among groups.Conclusion: 1.Terlipressin acts as a new type of vasopressin,its curative effect on HT and SVRI are optimum compared with other drugs studied in present study and the HT in terlipressin group was significantly reduced than in dopamine and phenylephrine groups.2.Collectively,the curative effects of epinephrine,norepinephrine and terlipressin on septic shock patients were better than other vasoactive agents.