Role of Preoperative Oral Pregabalin in Reducing Inhalational Anesthetic Requirements in Elective Abdominal Hysterectomy Under General Anesthesia: A Randomized Controlled Trial
Phase: PHASE3
Conditions: Hysterectomy
Sponsor: Nesrine El-Refai

Patients and methods
This randomized controlled study was conducted in kasr
-Alainy Hospi tal,
Faculty of Medicine. Cairo University. After obtaining approval form the
Ethics
and Research Committee, an informed written consent was taken from 50 female
patients, aged 18 -60 years, ASA physical status I or II, scheduled for elective
abdominal hysterectomy surgery under general anesthesia.
Patients younger than 18 or above 60 years old, patients with (ASA)
physical status ≥ III, patients with compromised cardiovascular, renal, hepatic or
neurological function and who were allergic to pregabalin were exclude
d. In
addition, patients recei ving calcium channel blockers,
anti-convulsant, oral
hypoglycemic agents or any analgesic or sedatives were excluded from the study.
Patients were randomly allocated to two study groups, 25 per group, using a
random computer allocation with numbered closed opaque envelopes.
Pregabalin group ( Gp): patients received oral pregabal in capsule single dose 150
mg 1h pre-operatively.
Control group ( Gc): Patients received oral placebo capsule single dose 1h pre
-
operative.
The night before surgery through history
-taking a nd clinical examination
were done.Laboratory tests were ordered and reviewed pre-operatively:

Complete blood picture.

Liver function tests.

Kidney function tests.

Bleeding profile.

Solid food was not allowed 6 hours before surgery, but clear fluids were given for
up to 4 hours pre-operatively.
The day of surgery patients atten ded at the pre-anesthesia room 2 hours before the
procedure. Standard monitoring (electrocardiography, pulse oximetry and non
-
invasive blood pressure monitoring) were applied to the p
atients and basal
hemodynamic measurements (oxygen saturation, systolic, diastolic and mean BP
and HR were measured and recorded. A 20 Gauge cannula was inserted
peripherally and all patients received
intravenous
Ranitidine 50 mg and
Metoclopramide 10 mg.
Patients were pre
-medicated orally 1h before surgery with the study
medication pregabalin capsule 150 mg (G P) or identical empty capsule as placebo
(GC) given with sips of water.
Randomization was done using a computer-generated random numbers. The
study drugs, were further packed and sealed in opaque plastic containers labeled
with randomized number, each consenting patient received a consecutive
randomization number.
The anesthesiologist administering drugs and
conducting anesthesia was
blinded to the drug administered.
Bi-Spectral Index monitor (COVIDIEN BIS Monitoring system P/N 185 -
0151) was applied by using commercially available disposable Bis
-Sensor strips
(Aspect Medical Systems). The strips used four electrodes, three active and one
ground. Plac ement on the forehead as
follows: sensor 1
in center of forehead,
approximately 2 inches (5cm) above the bridge of the nose, the 3rd sensor directly
above the eyebrow, the 2nd sensor between 1st and 3rd,  and the 4th  on temple
between corner of eye and ha
irline. The algorithm within the BIS monitor had

limits for electrode impedance and signal quality, and no BIS value was displayed
if the signal has too much noise or artifact. The anesthetic depth, with an objective
level of 40 –60 during the maintenance p hase and a level of 60 –70 during the last
10 minutes of surgery, was maintained.
The anesthetic protocol was standardized for all patients. Anesthesia was
induced with, fentanyl (1 mcg/kg), thiopental sodium (5
-7 mg/kg IV) (till
the
abolition of the eyelash reflex) and Atracurium (0.5 mg/kg). Laryngoscopy and
intubation were done a fter 3 minutes when the patient was at a sufficiently deep
level of anesthesia (BIS < 60) and hemodynamic parameters recorded.
After endotracheal intubation, a nesthesia was maintained usingIsoflurane in
a mixture of oxygen and air and
Atracurium (0.1mg/kg) every 15
minutes for
muscular relaxation. Intra -operative IPPV ventilation is used MAQUET Flow-I
anesthetic machine to maintain PaCO2 within normal range.
Isoflurane concentra
tion was adjusted to maintain intra
-operative
hemodynamic stability (blood pressure and heart rate ± 20% of baseline), BIS
value in the range 40 –60 during the operation and 60 –70 in the last 10 minutes of
surgery. Hemodynamic parameters were measured and r ecorded immediately after
intubation and after 3min, 5min, 10min and e
very 15min till extubation.
Hemodynamics parameter out of rang ±20% of baseline in the presence of normal
end tidal CO2 were treated with
additional doses of fentanyl (0.5mcg/kg).
The
response was checked after 10min non responders were managed by
the
incremental increase of Isoflurane till hemodynamic normalization. Intra -operative
consumption of Isoflurane was measured and recorded (ml/hr).

At the end of
surgery, residualNeuro -muscular paralysis was reversed with
neostigmine (0.04 -0.08mg/kg) and atropine (0.01 -0.02mg/kg) and surgical time
was checked and recorded.
Post-operatively hemodynamics checked and recorded immedi
ately after
extubation, at 3min and 10min. Post-operative pain was assessed using the Visual
Analogue Score (VAS) (0-10cm) (VAS; 0 = no pain and 10 = worst imaginable
pain). Visual analogue score (VAS) ≥ 6 was controlled using pethidine 1mg/kg IM.
(2)
The time to first rescue analgesia and total analgesic requirements were
recorded. Post -operative side effects, including nausea and vomiting, headache,
blurring vision, dizziness and sedation were checked and recorded in the recovery
room 1, 2, 4 and 6 h post -operatively. Over sedation was defined as a score ≤2 on
a 5-point scale (1):
Score 1 (barely arousable): Asleep, needs shaking or shouting to arise.
Score 2 (asleep): Eyes closed, arousable with soft voice or light touch.
Score 3 (sleepy): Eyes opened, less active, and responsive.
Score 4: Awake.
Score 5: Agitated.
Statistical analysis:
Sample size:
A Previous study showed that 1 h pre
-operative oral pregabalin versus
placebo reduced intra -operative i nhalational an esthesia by 0.9 versus 1.2
with
standard deviation ± 0.31 (1). The sample size was calculated using Student’s t
-

test. Taking a power of the study of 80% and alpha error of 0.05, a minimum
number of 20 patients will be needed for each group. T
his number will be
increased to 25patients per group to compensate for possible dropouts.
Statistical analysis:
Data were statistically described in terms of mean ± standard deviation (±
SD), and range, or frequencies (number of cases) and percentages when
appropriate. Comparison of numerical variables between the study groups was
done using the Student t test for independent samples. For comparing categorical
data, Chi-square (C2) test was performed. Exact test was used instead when the
expected frequency is less than 5. P
values less than 0.05
were considered
statistically significant. All statistical calculations were done using computer
program IBM SPSS (Statistical Package for the Social Science; IBM Corp,
Armonk, NY, USA) release 22 for Microsoft Windows.
1.
Gupta P, Saxena A and Chaudhary L. Effect of pregabalin premedication on
the requirement of anesthetic and a
nalgesic
drugs in laparoscopic
cholecystectomy: Randomized comparison of two doses. Anesthesia. 2016
October2017; 11(2);330-333.
2.
Mishriky BM, Waldron NH and Habib AS. Impact of pregabalin on acute
and persistent postoperative pain: a systematic review and meta
-analysis.
British journal of anesthesia. 2015 Jan; 114(1);10-31.