PK/PD Of Imipenem In Critically Ill Patients With Sepsis/septic Shock

Part One:Pharmacokinetics of imipenem in critically ill patients with sepsis/septic shockObjective:The aim of this study was to explore the pharmacokinetics of imipenem in critically ill patients with sepsis/septic shock.Methods:The eligibles are obtained from patients admitted to the ICU?Intensive care unit?of Zhongda Hospital Affiliated to Southeast University from May 2017 to Feb 2018,diagnosed sepsis or septic shock who received intravenous imipenem.Patients received imipenem 1.0g q8h according to the attending doctor.Each dose imipenem was continuously infused for 3 hours.Patient data collection:basic information?age,height and weight,diagnosis?,severity of illness[APACHE II?Acute physical and chronic health evaluation II?,SOFA?Sequential organ failure assessment?],laboratory examination[serum albumin concentrations?Alb?,Cr,lactate],clinical outcome?ICU mortality and 28 day mortality?.Blood samples with 2-ml every time to determine plasma imipenem concentrations on initial dosage on day1?initial dosage?,day 3 and day 7 were drawn predose,end of infusion,at 1,2,3 and 5 hours after drug infusion ended.Imipenem serum concentrations were measured by HPLC?High performance liquid chromatography?.Vd?Apparent volume of distribution?,clearance?CL?,t_1/2?Half-life time?was calculated by the software according to the imipenem serum concentrations.Results:?1?A total of 25 adult patients were enrolled in the study.in 25 patients:age 70±16years,height 168±6cm,IBW 63±8kg.Twenty-eight day mortality was 56%.Nine patients with sepsis and16 patients with septic shock.Between the sepsis group and septic shock group:age,height,IBW,site of infection,SOFA score and 28 day mortality had no significant difference?p>0.05?.?2?The comparison of PK of imipenem between the sepsis group and septic shock group:Vd:imipenem Vd?26.5±7.1L?on day 1 in the sepsis group was significantly lower than that?40.7±11.0L,p=0.001?in the septic shock group;Imipenem Vd?29.9±15.6L vs.22.8±15.3L,p=0.275?on day 3 and imipenem Vd?27.2±7.1L vs.28.7±19.8L,p=0.928?on day 7 had no significant difference between the sepsis group and septic shock group.T_1/2:on day 1,imipenem t_1/2?1.9±0.7h?in the sepsis group was lower than that?2.8±1.2 h,p=0.025?in the septic shock group.Imipenem t_1/2?2.0±0.8h?on day 3 and?1.6±0.7h?on day 7 in the sepsis group showed no significant difference comparing with that?1.8±1.0h,p=0.625?and?1.8±0.9 h,p=0.827?in the septic shock group.CL and C_max?Maximal concentration?on day 1,day 3 and day 7 had no significant difference between the two groups.?3?The analysis of the factors influencing on imipenem Vd in critically ill patients:Serum albumin concentrations:there was significant correlations between imipenem Vd and Alb on day 1?r=-0.517,p=0.008?.Imipenem Vd?35.5±11.4L?in Alb<30g/L group was higher than that?25.0±6.8L,p=0.031?in Alb?30g/L group.APACHE II score:there was significant correlations between imipenem Vd and APACHE II score on day 1?r=0.606,p=0.001?.Imipenem Vd?37.7±12.8L?in APACHE II?25 group was higher than that Vd?28.5±5.5L,p=0.036?in APACHE II<25 group.Multiple linear regression of analysis of the factors influencing on imipenem Vd in critically ill patients:Alb and APACHE II score on day 1 were identified as factors altering imipenem Vd?p<0.05?.?4?The correlations between the clinical outcome and imipenem Vd in critically ill patients:imipenem?Vd_3-1?1.7±21.5L?of the non-survivors was significantly higher than that?-13.1±11.4L,p=0.046?of the survivors.The area under the ROC?Receiver operating characteristic curve?of?Vd_3-1 in predicting death of the patients was 0.737?p=0.046?,with a sensitivity of 85.7%and a specificity of 54.4%.The value of cut off was-13.4L.Conclusions:APACHE II score and serum albumin concentrations were factors influence imipenem Vd in critically ill patients sepsis/septic shock;?Vd_3-1 is a predictor of survival for the sepsis/septic shock patients.Part Two: PD target attainment of imipenem in critically ill patients with sepsis/septic shockObjective: The aim of this study was to explore the imipenem target attainment in the critically ill patients with sepsis/septic shock and the factors influence on imipenem target attainment of PD.Methods: The eligibles are obtained from patients admitted to the ICU of Zhongda Hospital Affiliated to Southeast University from May 2017 to Feb 2018,who received intravenous imipenem.Patients received imipenem 1.0g q8 h or 0.5g q6 h according to the attending doctor.Patient data was collected: basic information?age,height and weight,diagnosis?,severity of illness?APACHE II score,SOFA score?,laboratory examination?Albumin,Creatinine,Lactate?,clinical outcome?ICU mortality,28 day mortality?.Each dose imipenem was continuously infused for 3 hours.Blood samples with 2-ml in the 1.0g q8 h group every time were drawn predose on the third day,end of infusion,at 1,2,3 and 5 hours.In the 0.5g q6 h group blood samples were drawn at predose,end of infusion,at 0.5,1,2 and 3 hours after drug infusion ended.Imipenem serum concentrations were measured by HPLC.The PK parameters of imipenem was calculated by software according to the imipenem concentrations.The attainment of two PK/PD targets was 100%f T>MIC and 50%f T >4×MIC.The patients were divided into sepsis group and septic shock group according to the severity of illness.Cr Cl was assessed by according to the Cockcroft-Gault equation and patients were divided into Cr Cl <60ml/min group and Cr Cl?60ml/min group.Results:?1?Patient data about basic information: a total of 50 critically ill patients were included,age 74±14 years,IBW 62±8 kg,thirty-four pulmonary infection patients,nine abdomen infection patients,three urinary infection patients,four patients of the other site of infection.Twenty-eight day mortality was 50.0%.Twenty-eight patients in the sepsis group and twenty-two patients in the septic shock group.Seventeen patients in the Cr Cl?60ml/min group and thirty-three patients in the Cr Cl<60ml/min group.?2?Imipenem target attainment of sepsis and septic shock patients: MIC ?1?g/ml,50%f T>4×MIC and 100%f T>MIC achieved were 100% respectively;MIC=2?g/ml,50%f T>4×MIC achieved and 100%f T>MIC achieved was 90.0% respectively;MIC=4?g/ml,50%f T>4×MIC achieved was 22.0%,100%f T>MIC achieved was 62.0%.?3?The comparison of imipenem target attainment between the sepsis group and septic shock group: MIC=2 ? g/ml,in the sepsis group 50%f T>4×MIC achieved 96.4% had no significantly difference comparing with that?81.8%,p=0.087?in the septic shock group.100 %f T>MIC achieved is 100% in the sepsis group,which is higher than that?77.3%,p=0.008?in the septic shock group.MIC=4?g/ml,there was no significantly difference about 50%f T>4×MIC achieved?28.6% vs.13.6%,p=0.206?between the sepsis group and septic shock group.In the septic shock group,100%f T>MIC achieved is lower than that?71.4%,p=0.035?in the sepsis group.?4?Cr Cl and imipenem target attainment: MIC=2?g/ml,in the Cr Cl ? 60ml/min group,50%f T>4×MIC achieved?26.0% vs.64.0%,p=0.022?was lower comparing with that in the Cr Cl <60ml/min group.100 %f T>MIC achieved?26.0% vs.62.0%,p=0.072?had no statistical difference between the two groups.MIC=4?g/ml,in the Cr Cl?60ml/min group 50%f T>4×MIC achieved?2% vs.20.0%,p=0.048?and 100%f T>MIC achieved?12.0% vs.50.0%,p=0.005?was lower comparing with that in the Cr Cl <60ml/min group.Conclusions: MIC?1?g/ml,imipenem target attainment in critically ill patients was high;MIC?2?g/ml,imipenem target attainment in critically ill patients was low.Imipenem target attainment was lower with the increasing of Cr Cl.