Effect of Midazolam on Inflammatory Response and Organ Function in Mechanically Ventilated Sepsis Patients With Different Immune Status

Effect of Midazolam on Inflammatory Response and Organ Function in Mechanically Ventilated Sepsis Patients With Different Immune Status.

ICU patients always experience all kinds of pain, discomfort and sleep disturbance,especially the sepsis patients. Appropriate sedation and analgesia is must,the newest sepsis guideline strongly recommend that mechanically ventilated sepsis patients need sedation therapy.

Recent studies show than immune dysfunction dose have an important effect on the occurrence and development of sepsis. When the body suffer from the pathogenic microorganism attacking and sepsis, it activate the systemic inflammatory response (SIRS) and compensatory anti-inflammatory response syndrome (CARS). When it is out of balance between SIRS and CARS, the inflammatory response, immune paralysis or immune dysfunction occurs and the mixed anti-inflammatory response syndrome (MARS) exists, and then the multiple organ dysfunction. So, immune dysfunction is thought to be the key factors on the development of the sepsis. Some studies show that the sedation drug such as midazolam, propofol, dexmedetomidine could suppress the inflammatory response effectively and then modulate the immune function.

Several recent studies show that midazolam has the immunoregulation effect and trend of suppress the inflammatory response, but the result is controversy, the possibly reason is the different immune status. Now there is the guideline about the different immune status: the normal immune function means that the value of mHLA-DR is more than 15000 monoclonal antibody; moderate-sever immune suppression means that the value of mHLA-DR is in the range of 5000 and 15000 monoclonal antibody; the immune paralysis means that the value of mHLA-DR is less than 5000 monoclonal antibody.

The purpose of the study is to explore the effect of midazolam to inflammatory response and organ function at mechanically ventilated sepsis patients who have different immune status.

Study Overview

• Status: Unknown
• Conditions: Sepsis; Inflammatory Disorder of Immune System
• Intervention / Treatment: Other: blood sample collection; Drug: Midazolam; Drug: Morphine; Procedure: Sedation interruption

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Mechanically ventilated ICU patients, sedation is needed.
2. Sepsis patients.
3. Age 18-80 yrs
4. Anticipated sedation duration is more than 3 days.
5. Agreed to participate the study and assigned the informed consent. -

Exclusion Criteria:

1. Allergic to the Benzodiazepine.
2. Hepatic dysfunction(Child-Pugh is C level).
3. Participated other study.
4. Bad prognosis and possibly become the major reason of patients death, such as sever craniocerebral injury,cardiopulmonary resuscitation,advanced malignant tumor,etc.
5. History of immune system disease, immune treatment (including hormone ) or treatment that could affect immune function (including continuous renal replacement therapy,CRRT).
6. Alcoholic and drug abuse.
7. Tendency for major mental disease or treatment of anti psychotics.
8. Pregnant,lactation woman.
9. Unwilling to assign the informed consent or bad compliance. -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Normal immune function; The value of monocyte human leukocyte antigen-DR (mHLA-DR) is equal to or more than 15000 monoclonal antibody.	Other: blood sample collection; Patients were included 1 hrs later(before the study drug is administrated), 3 d and 7 d after sedation with midazolam, blood sample is collected. Flow cytometry is performed to test the mHLA-DR and according the value of mHLA-DR, assign the participant to the 4 groups as described in the arm.; Drug: Midazolam; The loading dose of midazolam is 0.03-0.3 mg/kg, intravenous injected slowly for 10 minutes, then 0.04-0.2 mg/kg/h for maintenance of sedation.; Other Names: Liyuexi; Drug: Morphine; Morphine is the only analgesic drug that permitted to use. 2 mg morphine is given a bolus when the participant feel pain. If the pain is not alleviated, 0.4-1 mg/h morphine is maintained.; Procedure: Sedation interruption; Sedation interruption is performed at 8 am every morning.
Experimental: Moderate immunosuppression; The value of mHLA-DR is equal to or more than 10000 and less than 15000 monoclonal antibody.	Other: blood sample collection; Patients were included 1 hrs later(before the study drug is administrated), 3 d and 7 d after sedation with midazolam, blood sample is collected. Flow cytometry is performed to test the mHLA-DR and according the value of mHLA-DR, assign the participant to the 4 groups as described in the arm.; Drug: Midazolam; The loading dose of midazolam is 0.03-0.3 mg/kg, intravenous injected slowly for 10 minutes, then 0.04-0.2 mg/kg/h for maintenance of sedation.; Other Names: Liyuexi; Drug: Morphine; Morphine is the only analgesic drug that permitted to use. 2 mg morphine is given a bolus when the participant feel pain. If the pain is not alleviated, 0.4-1 mg/h morphine is maintained.; Procedure: Sedation interruption; Sedation interruption is performed at 8 am every morning.
Experimental: Sever immunosuppression; The value of mHLA-DR is equal to or more than 5000 and less than 10000 monoclonal antibody.	Other: blood sample collection; Patients were included 1 hrs later(before the study drug is administrated), 3 d and 7 d after sedation with midazolam, blood sample is collected. Flow cytometry is performed to test the mHLA-DR and according the value of mHLA-DR, assign the participant to the 4 groups as described in the arm.; Drug: Midazolam; The loading dose of midazolam is 0.03-0.3 mg/kg, intravenous injected slowly for 10 minutes, then 0.04-0.2 mg/kg/h for maintenance of sedation.; Other Names: Liyuexi; Drug: Morphine; Morphine is the only analgesic drug that permitted to use. 2 mg morphine is given a bolus when the participant feel pain. If the pain is not alleviated, 0.4-1 mg/h morphine is maintained.; Procedure: Sedation interruption; Sedation interruption is performed at 8 am every morning.
Experimental: Immune paralysis; The value of mHLA-DR is less than 5000 monoclonal antibody.	Other: blood sample collection; Patients were included 1 hrs later(before the study drug is administrated), 3 d and 7 d after sedation with midazolam, blood sample is collected. Flow cytometry is performed to test the mHLA-DR and according the value of mHLA-DR, assign the participant to the 4 groups as described in the arm.; Drug: Midazolam; The loading dose of midazolam is 0.03-0.3 mg/kg, intravenous injected slowly for 10 minutes, then 0.04-0.2 mg/kg/h for maintenance of sedation.; Other Names: Liyuexi; Drug: Morphine; Morphine is the only analgesic drug that permitted to use. 2 mg morphine is given a bolus when the participant feel pain. If the pain is not alleviated, 0.4-1 mg/h morphine is maintained.; Procedure: Sedation interruption; Sedation interruption is performed at 8 am every morning.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
T cell subset T Helper 1	T Helper 1(TH1) are tested before sedation, 3 d and 7 d after sedation with midazolam. The test method is Flow cytometry.	Change from baseline of T Helper 1 at 3 and 7 days.
T cell subset T Helper 2	T Helper 2(TH2) are tested before sedation, 3 d and 7 d after sedation with midazolam. The test method is Flow cytometry.	Change from baseline of T Helper 2 at 3 and 7 days.
T cell subset Regulatory T Cell	Regulatory T Cell are tested before sedation, 3 d and 7 d after sedation with midazolam. The test method is Flow cytometry.	Change from baseline of Regulatory T Cell at 3 and 7 days.
Interleukin-6	Levels of interleukin-6(IL-6) are tested before sedation, 3 d and 7 d after sedation with midazolam. The test method is Enzyme Linked Immunosorbent Assay（ELISA）.	Change from baseline of Interleukin-6 at 3 and 7 days.
Interleukin-10	Levels of interleukin-10(IL-10) are tested before sedation, 3 d and 7 d after sedation with midazolam. The test method is Enzyme Linked Immunosorbent Assay（ELISA）.	Change from baseline of Interleukin-10 at 3 and 7 days.
Tumo necrosis factor-α(TNF-α)	Levels of Tumo necrosis factor-α(TNF-α) are tested before sedation, 3 d and 7 d after sedation with midazolam. The test method is Enzyme Linked Immunosorbent Assay（ELISA）.	Change from baseline of TNF-α at 3 and 7 days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
duration of mechanical ventilation		from the begining of ventilation to weaning, up to 7 days.
Number of Participants with Serious and Non-Serious Adverse Events		up to 7 days
Mortality	Participants' mortality of 28 and 90 days is recorded, including state of survival, the date and the reason of death.	up to 28 days
Length of ICU stay		from ICU admmittion to discharge from ICU,up to 28 days.
Index of renal function	level of Blood Urea Nitrogen(BUN) and Creatinine(Cr).	baseline,the 3rd and 7th day after sedation
Index of myocardial enzyme	level of Brain Natriuretic Peptide(BNP).	baseline,the 3rd and 7th day after sedation
Index of hepatic function	level of glutamic-pyruvic transaminase(ALT),glutamic oxalacetic transaminase(AST),Total Bilirubin(Tbil).	baseline,the 3rd and 7th day after sedation
Index of endocrine function	level of cortisol and blood glucose.	baseline,the 3rd and 7th day after sedation
C-reaction protein	C-reaction protein(CRP)is tested before sedation, 3 d and 7 d after sedation with midazolam. The test method is Enzyme Linked Immunosorbent Assay（ELISA）.	baseline,the 3rd and 7th day after sedation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
mHLA-DR	Levels of mHLA-DR are tested before sedation, 3 d and 7 d after sedation with midazolam. The test method is Flow cytometry.	baseline,the 3rd and 7th day after sedation

Collaborators and Investigators

• Sponsor: Xiangya Hospital of Central South University
• Investigators: Principal Investigator: Yuhang Ai, Doctor., Xiangya Hospital of Central South University

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Anticipated): March 1, 2015
• Study Completion (Anticipated): March 1, 2015

Study Registration Dates

• First Submitted: April 29, 2014
• First Submitted That Met QC Criteria: May 7, 2014
• First Posted (Estimate): May 9, 2014

Study Record Updates

• Last Update Posted (Estimate): May 9, 2014
• Last Update Submitted That Met QC Criteria: May 7, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: sedation; organ function
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Immune System Diseases; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam; Morphine
• Other Study ID Numbers: 2014021801