INFLUENCE OF POTENTIAL GENE POLYMORPHISMS
ON PROPOFOL DOSAGE REGIMEN IN PATIENTS
UNDERGOING ABDOMINAL HYSTERECTOMY
Ivanov E, Sterjev Z, Budic I, Nojkov J, Karadzova D, Sivevski A
*Corresponding Author: Emilija Ivanov, Prim. M.Med., University Clinic for Gynecology and Obstetrics,
University “Ss Cyril and Methodius” Medical Faculty, Mother Theresa, Skopje, Republic of North
Macedonia. Tel./Fax: +389-(0)-23-228-440. E-mail: emilijaivanov@gmail.com
page: 41
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MATERIALS AND METHODS
This was a prospective study, performed at the Clinic
for Gynecology and Obstetrics, University Ss. Cyril and
Methodius, and the Center for Biomolecular Pharmaceutical
Analysis, Faculty of Pharmacy, University Ss. Cyril and
Methodius, Skopje, Republic of North Macedonia, from
October 2016 to November 2017. The study complied
with the 2013 Declaration of Helsinki and the protocol
was approved by the Ethics Committee at the Medical
Faculty of Skopje, Ss. Cyril and Methodius University
[No. 03-242/1], and the Faculty of Pharmacy, Ss. Cyril
and Methodius University [No. 03-51/1]. Ninety patients,
scheduled for abdominal hysterectomy, were included in
this study. All of them signed informed consent before
being enrolled in the study.
Adult and older female patients (from 25 to 75 years),
with body weight not above and below 20.0% of the ideal,
and classification status I, II or III, according to the American
Society of Anesthesiologists Physical Status Classification
System (ASA), were included in the study. The
patients were aged 29 to 74 years; median age of 51.5 ±
8.8 years. The body weight varied between 48 and 131 kg;
median weight of 77.7 ± 16.6 kg. Regarding ethnicity, there
were 66 Macedonians (73.3%), 23 Albanians (25.6%) and
one patient of Turkish ethnicity (1.1%). According to the
ASA physical status classification: nine patients (10.0%)
belonged to the ASA I group, 70 patients (77.8%) belonged
to the ASA II classification group, and 11 patients (12.2%)
belonged to the ASA III group. Twelve patients (13.3%)
had a history of comorbidities (six with hypertension,
three with obesity and diabetes, two with obesity and one
with obesity and high blood pressure). Exclusion criteria
included: other anesthetics, soy or nut allergies, history
of alcohol or drug addiction, chronic diseases such as
psychiatric, hepatic or kidney disease.
The propofol was administered according to standard
protocol based on individual patients’ status and characteristics
and evidence-based medicine data obtained from
the Summary of Product Characteristics (0.1-0.15 mg/
kg/min. IV for 3-5 min.). The patients were appropriately
preoperatively prepared, and a peripheral intravenous line
was inserted before the anesthesia was started. Noninvasive
monitoring [arterial tension (TA), electrocardiography
(ECG), pulse, oxygen saturation (SpO2) and capnography]
was used to monitor the vital functions.
In this study, the side effects of propofol, nausea,
vomiting and level of sedation, were also analyzed. Recording
of side effects started after surgery and ended after
24 hours. The presence of vomiting was noted as number of
incidents, while nausea with a nausea score (0; no nausea;
1: mild degree; 2: moderate degree; 3: severe degree). The
sedation was scored according to the Ramsey sedation
score (0: awake; 1: anxious and agitated or restless or
both; 2: cooperative, oriented and tranquil; 3: responding
to commands only; 4: brisk response; 5: sluggish response;
6: no response to stimulus).
General endotracheal anesthesia was performed as
follows: introduction (0.1 mg/kg midazolam, 2 μg/kg
fentanyl, 2 mg/kg propofol, 0.4-0.6 mg/kg rocuronium bromide; maintenance: rocuronium 0.3 mg/kg, fentanyl 2
μg/kg and propofol 100 mcg/kg/min.). At the end of the
intervention, reversal of neuromuscular block was achieved
with 2.5 mg neostigmine and 1 mg atropine, after which
the patients were extubated and taken to a recovery room.
The depth of anesthesia was standardized by a method of
determining entropy [13]. This method also reduces the
incidence of consciousness during general anesthesia. The
entropy module is an integral part of the Datex-Ohmeda
anesthesia machine. The entropy parameters are: response
entropy (RE) values of 0-100 and state entropy (SE) values
of 0-91. Response entropy responds rapidly with activation
of the facial muscles, while SE is a stable parameter that
monitors the hypnotic effect of the applied anesthetic. The
SE values are always identical or slightly lower than the
RE values. To achieve a unified level of depth of general
anesthesia we have always strived to have these values
between 40-60 [14].
Genomic DNA was extracted from peripheral blood
according to the protocol provided by the manufacturer of
the Mag Core HF16 Plus automatic DNA extractor (RBC
Bioscience, New Taipei, Taiwan). The presence of CYP2B6
(c.516G>A) (rs3745274, assay ID C___7817765_ 60;
Thermo Fisher Scientific Co., Waltham, MA, USA; https://
www.thermofisher.com/order/genome-database/ details/
genotyping/), GABRA1 (c.1059+15G>A) (rs2279020,
assay ID___15966 883_10; Thermo Fisher Scientific
Co.) and ABCB1 (c.3435 T>C) (rs1045642, assay ID
C___7586657_20; Thermo Fisher Scientific Co.) polymorphisms
were analyzed using TaqMan SNP genotype
analysis on Stratagene MxPro 3005P real-time polymerase
chain reaction (qPCR), apparatus (Agilent Technologies,
Edinburgh, UK) using the protocol recommended by the
manufacturer.
The χ2 test was used to compare the observed vs. expected
genotype frequencies according to Hardy-Weinberg
equilibrium. The descriptive statistical analysis was done
using the Statistical Package for Social Sciences (SPSS)
software version 17 for Windows (www.ibm.com). For
the statistical analyses we also used Kolmogorov-Smirnov
and Shapiro-Wilk test, χ2 test, Fisher exact test, Student’s
t-test, one-way analysis of variance (ANOVA) (post-hoc
Bonferroni test).
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