Sepsis, Septic Shock, Systemic Inflammatory Response Syndrome
Conditions
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.
Interventions
PROCEDURESerial blood sampling
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.
PROCEDURETrain of four monitoring
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).
PROCEDUREBlood testing for liver and renal function
Blood testing: urea, creatinine, aspartate aminotransferase, alanine aminotransferase, albumin, glycemia
DRUGGeneral anesthesia
All patients were induced with individual intravenous doses of midazolam, rocuronium, fentanyl and propofol.
PROCEDURESmall to medium sized surgery under general anesthesia
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.
Sponsors
University of Sao Paulo
Universidade Estadual Paulista Júlio de Mesquita Filho
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determination of AUC/dose | 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
| Measure | Time frame | Description |
|---|---|---|
| Determination of volume of distribution | Up to 6h after rocuronium administration | Determination of volume of distribution of rocuronium will be estimated for pharmacokinetic analysis. |
| Determination of mean residence time | Up to 6h after rocuronium administration | Determination of mean residence time of rocuronium will be estimated for pharmacokinetic analysis. |
| OATP1A2 genotyping using Real Time-PCR | 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. |
| Analysis of cytokine IL-1α in plasma | 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. |
| Determination of total clearance | Up to 6h after rocuronium administration | Determination of total clearance of rocuronium will be estimated for pharmacokinetic analysis. |
| Analysis of cytokine IL-6 in plasma | Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration | Plasma cytokine IL-6 will be evaluated in each patient. |
| Analysis of cytokine TNF-α in plasma | 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. |
| Pharmacokinetic-Pharmacodynamic analysis: relationship between rocuronium plasma concentration and the neuromuscular blockade | 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 |
| Analysis of cytokine IL-1β in plasma | Up to 5 minutes before rocuronium administration; 30 and 360 minutes after rocuronium administration | Plasma cytokine IL-1β will be evaluated in each patient. |
Countries
Brazil
Outcome results
None listed