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Influence of Age, Sepsis and SLCO1A2 Polymorphisms on Rocuronium Pharmacokinetics (ROCSEPSIS)

Primary Purpose

Sepsis, Systemic Inflammatory Response Syndrome, Septic Shock

Status
Completed
Phase
Phase 4
Locations
Brazil
Study Type
Interventional
Intervention
Serial blood sampling
Train of four monitoring
Blood testing for liver and renal function
General anesthesia
Small to medium sized surgery under general anesthesia
Sponsored by
Universidade Estadual Paulista Júlio de Mesquita Filho
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sepsis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Adult and elderly patients, both gender.
  • Patients submitted to small to medium-sized surgeries.
  • Patients who were induced with individual doses of rocuronium, fentanyl and propofol.
  • Patients with normal renal function (creatinine clearance > 60 mL/min).
  • Patients with normal liver function.

Exclusion Criteria:

  • Patients who were in use of fluoxetine, carbamazepine, aminoglycoside antibiotics, OATP1A2 inhibitors.
  • Patients with gastrointestinal and liver diseases, neuromuscular disorders.
  • Patients who were in chronic use of drugs which alter rocuronium effect.

Sites / Locations

  • Universidade Estadual Paulista Júlio de Mesquita Filho

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Experimental

Arm Label

Control group

Sepsis group

Elderly group

Arm Description

Adult patients(18-50 years old) ASA I-II without sepsis submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase).

Adult patients (18-50 years old) ASAII and III with sepsis, systemic inflammatory response syndrome or septic shock submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase).

Elderly patients (> 65 years old) ASA I-II without sepsis submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase).

Outcomes

Primary Outcome Measures

Determination of AUC/dose
Determination of area under the plasma concentration versus time curve (AUC)/dose of rocuronium will be estimated for pharmacokinetic analysis.

Secondary Outcome Measures

Determination of total clearance
Determination of total clearance of rocuronium will be estimated for pharmacokinetic analysis.
Determination of volume of distribution
Determination of volume of distribution of rocuronium will be estimated for pharmacokinetic analysis.
Determination of mean residence time
Determination of mean residence time of rocuronium will be estimated for pharmacokinetic analysis.
OATP1A2 genotyping using Real Time-PCR
The single nucleotide polymorphisms of SLCO1A2 gene (404A>T, 559G>A, 833delA at coding sequence and -1105G>A, -1032G>A, -715T>C, -361G>A e -189_-188insA at the non-coding sequence of SLCO1A2) are being evaluated in all included patients, using Real Time PCR.
Analysis of cytokine IL-1α in plasma
Plasma cytokine Interleukin-1α (IL-1α) will be evaluated in each patient.
Analysis of cytokine IL-1β in plasma
Plasma cytokine IL-1β will be evaluated in each patient.
Analysis of cytokine IL-6 in plasma
Plasma cytokine IL-6 will be evaluated in each patient.
Analysis of cytokine TNF-α in plasma
Plasma cytokine Tumor Necrosis Factor-α (TNF-α) will be evaluated in each patient.
Pharmacokinetic-Pharmacodynamic analysis: relationship between rocuronium plasma concentration and the neuromuscular blockade
The relationship between rocuronium plasma concentration and the neuromuscular blockade will be described by a sigmoid maximum effect model for each patient

Full Information

First Posted
March 2, 2015
Last Updated
January 24, 2017
Sponsor
Universidade Estadual Paulista Júlio de Mesquita Filho
Collaborators
University of Sao Paulo
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1. Study Identification

Unique Protocol Identification Number
NCT02399397
Brief Title
Influence of Age, Sepsis and SLCO1A2 Polymorphisms on Rocuronium Pharmacokinetics
Acronym
ROCSEPSIS
Official Title
Influence of Sepsis, Age and SLCO1A2 Genetic Polymorphisms on Rocuronium Pharmacokinetics-pharmacodynamics in ASA I-III Surgical Patients
Study Type
Interventional

2. Study Status

Record Verification Date
October 2016
Overall Recruitment Status
Completed
Study Start Date
February 2014 (undefined)
Primary Completion Date
December 2015 (Actual)
Study Completion Date
December 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Universidade Estadual Paulista Júlio de Mesquita Filho
Collaborators
University of Sao Paulo

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study aims to evaluate the influence of age and sepsis on in vivo activity of OATP1A2 using rocuronium (ROC) as a probe and evaluating the pharmacokinetics and pharmacodynamics in ASA I-III surgical patients. Thus, adult patients without sepsis (control group, n= 12), adult patients with sepsis (sepsis group, n= 12) and elderly patients without sepsis (elderly group, n= 12), all submitted to small to medium-sized surgeries who were induced with individual doses of rocuronium, fentanyl and propofol are being investigated.
Detailed Description
Rocuronium (ROC), a neuromuscular blocking agent used in surgical procedures, is primarily eliminated by biliary excretion. Its distribution to the liver, mediated the organic anion transporting polypeptide 1A2 (OATP1A2), is a determining factor for the duration of neuromuscular blockade. Age and release of cytokines during inflammation and infection processes of sepsis can alter expression of SLCO1A2 gene, encoding OATP1A2. The objective of this study is to evaluate the influence of age and sepsis on in vivo activity of OATP1A2 using ROC as a probe and evaluating the pharmacokinetics and pharmacodynamics in ASA I-III surgical patients. Adult patients without sepsis (control group, n=12), adult patients with sepsis (sepsis group, n=12) and elderly patients without sepsis (elderly group, n=12), all submitted to small to medium-sized surgeries are being investigated. All patients are being induced with individual doses of rocuronium, fentanyl and propofol. Serial blood samples are being collected up to 360 minutes after administration of ROC. Neuromuscular blockade induced by ROC is monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same times of blood sampling. The plasma concentration of ROC will be analyzed by liquid chromatography coupled to mass spectrometry with electrospray ionization using positive ion mode.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sepsis, Systemic Inflammatory Response Syndrome, Septic Shock

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
36 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Control group
Arm Type
Active Comparator
Arm Description
Adult patients(18-50 years old) ASA I-II without sepsis submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase).
Arm Title
Sepsis group
Arm Type
Experimental
Arm Description
Adult patients (18-50 years old) ASAII and III with sepsis, systemic inflammatory response syndrome or septic shock submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase).
Arm Title
Elderly group
Arm Type
Experimental
Arm Description
Elderly patients (> 65 years old) ASA I-II without sepsis submitted to small to medium sized surgery under general anesthesia are being recruited. All patients are being induced with individualized doses of rocuronium, midazolam, propofol and fentanyl. Serial blood sampling are being collected up to 6 h after administration of the drug for pharmacokinetic study. Neuromuscular blockade is being monitored by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF) at the same time as blood sampling. All patients are being submitted to blood testing for liver and renal function (creatinine, urea, albumin, aspartate aminotransferase and alanine aminotransferase).
Intervention Type
Procedure
Intervention Name(s)
Serial blood sampling
Intervention Description
Serial blood samples are being collected at times 0, 2, 5, 10, 15, 20, 30, 60, 120, 180, 240 and 360 minutes after rocuronium administration.
Intervention Type
Procedure
Intervention Name(s)
Train of four monitoring
Other Intervention Name(s)
TOF
Intervention Description
Neuromuscular blockade is being evaluated at the same time of blood sampling by stimulation of the adductor muscle of the thumb on the ulnar nerve through the train of four monitoring (TOF).
Intervention Type
Procedure
Intervention Name(s)
Blood testing for liver and renal function
Intervention Description
Blood testing: urea, creatinine, aspartate aminotransferase, alanine aminotransferase, albumin, glycemia
Intervention Type
Drug
Intervention Name(s)
General anesthesia
Other Intervention Name(s)
Midazolam, Rocuronium, Fentanyl, Propofol
Intervention Description
All patients were induced with individual intravenous doses of midazolam, rocuronium, fentanyl and propofol.
Intervention Type
Procedure
Intervention Name(s)
Small to medium sized surgery under general anesthesia
Intervention Description
Patients classified according American Society of Anesthesiologists (ASA) as ASA I-III and submitted to small-medium sized surgery under general anesthesia were recruited for the present investigation.
Primary Outcome Measure Information:
Title
Determination of AUC/dose
Description
Determination of area under the plasma concentration versus time curve (AUC)/dose of rocuronium will be estimated for pharmacokinetic analysis.
Time Frame
Up to 6h after rocuronium administration
Secondary Outcome Measure Information:
Title
Determination of total clearance
Description
Determination of total clearance of rocuronium will be estimated for pharmacokinetic analysis.
Time Frame
Up to 6h after rocuronium administration
Title
Determination of volume of distribution
Description
Determination of volume of distribution of rocuronium will be estimated for pharmacokinetic analysis.
Time Frame
Up to 6h after rocuronium administration
Title
Determination of mean residence time
Description
Determination of mean residence time of rocuronium will be estimated for pharmacokinetic analysis.
Time Frame
Up to 6h after rocuronium administration
Title
OATP1A2 genotyping using Real Time-PCR
Description
The single nucleotide polymorphisms of SLCO1A2 gene (404A>T, 559G>A, 833delA at coding sequence and -1105G>A, -1032G>A, -715T>C, -361G>A e -189_-188insA at the non-coding sequence of SLCO1A2) are being evaluated in all included patients, using Real Time PCR.
Time Frame
Up to 5 minutes before rocuronium administration
Title
Analysis of cytokine IL-1α in plasma
Description
Plasma cytokine Interleukin-1α (IL-1α) will be evaluated in each patient.
Time Frame
Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Title
Analysis of cytokine IL-1β in plasma
Description
Plasma cytokine IL-1β will be evaluated in each patient.
Time Frame
Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Title
Analysis of cytokine IL-6 in plasma
Description
Plasma cytokine IL-6 will be evaluated in each patient.
Time Frame
Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Title
Analysis of cytokine TNF-α in plasma
Description
Plasma cytokine Tumor Necrosis Factor-α (TNF-α) will be evaluated in each patient.
Time Frame
Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration
Title
Pharmacokinetic-Pharmacodynamic analysis: relationship between rocuronium plasma concentration and the neuromuscular blockade
Description
The relationship between rocuronium plasma concentration and the neuromuscular blockade will be described by a sigmoid maximum effect model for each patient
Time Frame
Up to 6h after rocuronium administration

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult and elderly patients, both gender. Patients submitted to small to medium-sized surgeries. Patients who were induced with individual doses of rocuronium, fentanyl and propofol. Patients with normal renal function (creatinine clearance > 60 mL/min). Patients with normal liver function. Exclusion Criteria: Patients who were in use of fluoxetine, carbamazepine, aminoglycoside antibiotics, OATP1A2 inhibitors. Patients with gastrointestinal and liver diseases, neuromuscular disorders. Patients who were in chronic use of drugs which alter rocuronium effect.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Natalia V. de Moraes, Prof.
Organizational Affiliation
Universidade Estadual Paulista Júlio de Mesquita Filho
Official's Role
Principal Investigator
Facility Information:
Facility Name
Universidade Estadual Paulista Júlio de Mesquita Filho
City
Araraquara
State/Province
São Paulo
ZIP/Postal Code
14801902
Country
Brazil

12. IPD Sharing Statement

Citations:
PubMed Identifier
24370612
Citation
de Moraes NV, Lauretti GR, Filgueira GC, Lopes BC, Lanchote VL. Analysis of rocuronium in human plasma by liquid chromatography-tandem mass spectrometry with application in clinical pharmacokinetics. J Pharm Biomed Anal. 2014 Mar;90:180-5. doi: 10.1016/j.jpba.2013.11.032. Epub 2013 Dec 7.
Results Reference
result
PubMed Identifier
28409297
Citation
Costa ACC, Coelho EB, Lanchote VL, Correia BV, Abumansur JT, Lauretti GR, de Moraes NV. The SLCO1A2 -189_-188InsA polymorphism reduces clearance of rocuronium in patients submitted to elective surgeries. Eur J Clin Pharmacol. 2017 Aug;73(8):957-963. doi: 10.1007/s00228-017-2243-1. Epub 2017 Apr 14.
Results Reference
derived

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Influence of Age, Sepsis and SLCO1A2 Polymorphisms on Rocuronium Pharmacokinetics

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