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NCT Number: NCT02399397

Influence of Age, Sepsis and SLCO1A2 Polymorphisms on Rocuronium Pharmacokinetics

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.

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Key information

Conditions

Sepsis Infections Inflammation Pathologic Processes Pathological Conditions, Signs and Symptoms Septic Shock Shock Shock, Septic Systemic Inflammatory Response Syndrome

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Universidade Estadual Paulista Júlio de Mesquita Filho

Araraquara, São Paulo, 14801902, Brazil

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Serial blood sampling

Procedure

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.

Train of four monitoring

Procedure

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).

Other names: TOF

Blood testing for liver and renal function

Procedure

Blood testing: urea, creatinine, aspartate aminotransferase, alanine aminotransferase, albumin, glycemia

General anesthesia

Drug

All patients were induced with individual intravenous doses of midazolam, rocuronium, fentanyl and propofol.

Other names: Midazolam, Rocuronium, Fentanyl, Propofol

Small to medium sized surgery under general anesthesia

Procedure

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 outcomes

  1. Determination of AUC/dose

    Time frame: Up to 6h after rocuronium administration

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

Secondary outcomes

  1. Determination of total clearance

    Time frame: Up to 6h after rocuronium administration

    Determination of total clearance of rocuronium will be estimated for pharmacokinetic analysis.

  2. Determination of volume of distribution

    Time frame: Up to 6h after rocuronium administration

    Determination of volume of distribution of rocuronium will be estimated for pharmacokinetic analysis.

  3. Determination of mean residence time

    Time frame: Up to 6h after rocuronium administration

    Determination of mean residence time of rocuronium will be estimated for pharmacokinetic analysis.

  4. OATP1A2 genotyping using Real Time-PCR

    Time frame: Up to 5 minutes before rocuronium administration

    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.

  5. Analysis of cytokine IL-1α in plasma

    Time frame: Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration

    Plasma cytokine Interleukin-1α (IL-1α) will be evaluated in each patient.

  6. Analysis of cytokine IL-1β in plasma

    Time frame: Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration

    Plasma cytokine IL-1β will be evaluated in each patient.

  7. Analysis of cytokine IL-6 in plasma

    Time frame: Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration

    Plasma cytokine IL-6 will be evaluated in each patient.

  8. Analysis of cytokine TNF-α in plasma

    Time frame: Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration

    Plasma cytokine Tumor Necrosis Factor-α (TNF-α) will be evaluated in each patient.

  9. Pharmacokinetic-Pharmacodynamic analysis: relationship between rocuronium plasma concentration and the neuromuscular blockade

    Time frame: Up to 6h after rocuronium administration

    The relationship between rocuronium plasma concentration and the neuromuscular blockade will be described by a sigmoid maximum effect model for each patient

Sponsors and collaborators

Lead sponsor

Universidade Estadual Paulista Júlio de Mesquita Filho

Other

Collaborators

  • University of Sao Paulo

Registry information

Official study title

Influence of Sepsis, Age and SLCO1A2 Genetic Polymorphisms on Rocuronium Pharmacokinetics-pharmacodynamics in ASA I-III Surgical Patients

Acronym: ROCSEPSIS

Important dates

Study start
2014
Primary completion
2015
Study completion
2015
First posted
Mar 26, 2015
Registry last updated
Jan 25, 2017

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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