Effect of Alkalinisation of Lignocaine for Propofol Injection Pain: A Prospective, Randomised, Double-Blind Study

Abstract

The aim of this study was to determine whether pretreatment with alkalinised lignocaine reduced the incidence and severity of pain during propofol injection. This prospective, randomised, double-blind study included 300 adult, American Society of Anesthesiologists physcial status I to II patients undergoing elective surgery. Patients were randomly allocated to one of three groups: Group L received 0.05 ml/kg of 1% lignocaine (5 ml normal saline + 5 ml 2% lignocaine), Group A received 0.05 ml/kg alkalinised lignocaine (5 ml 2% lignocaine + 1 ml 8.4% NaHCO3 + 4 ml normal saline), and Group S, the control group, was given the same amount of normal saline (NaCl 0.9%). All drugs were given as a bolus over 20 seconds before propofol administration. A blinded researcher assessed the patient's pain level using a four-point scale. The pain score [median (range)] and the incidence of pain in Group A (6%) was significantly lower than in groups L (41%) and S (88%, P <0.001). In addition, the pain score and the incidence of pain were found to be significantly different between Group L and Group S (P <0.001). The incidence of moderate and severe pain were greater in Group S when compared with groups A and L (P <0.001). Intravenous pretreatment with alkalinised lignocaine appears to be effective in reducing the pain during propofol injection.

Full text

Anaesth Intensive Care 2013; 41: 501-504
Effect of alkalinisation of lignocaine for propofol injection
pain: a prospective, randomised, double-blind study
U. OZGUL*, Z. BEGEÇt, M. A. ERDOGANt, M. S. AYDOGANÍ, M. SANLIÍ, C. ÇOLAK§,
M. DURMUS**
Department of Anesthesiology and Reanimation, Inonu
University,
Malatya, Turkey
SUMMARY
The aim of this study was to determine whether pretreatment with alkalinised lignocaine reduced the incidence
and severity of pain during propofol injection. This prospective, randomised, double-blind study included
300 adult, American Society of Anesthesiologists physcial status I to II patients undergoing elective surgery.
Patients were randomly allocated to one of three groups: Group L received 0.05 ml/kg of 1% lignocaine (5 ml
normal saline
-1-
5 ml 2% lignocaine), Group A received 0.05 ml/kg alkalinised lignocaine (5 ml 2% lignocaine
-I-
1 ml 8.4% NaHCOj -I- 4 ml normal saline), and Group S, the control group, was given the same amount of
normal saline (NaCl 0.9%). All drugs were given as a bolus over 20 seconds before propofol administration.
A blinded researcher assessed the patient's pain level using a four-point scale. The pain score [median
(range)] and the incidence of pain in Group A (6%) was significantly lower than in groups L (41%) and S
(88%,
P <0.001). In addition, the pain score and the incidence of pain were found to be significantly different
between Group L and Group
S
(P <0.001). The incidence of moderate and severe pain were greater in Group S
when compared with groups A and L (P <0.001). Intravenous pretreatment with alkalinised lignocaine appears
to be effective in reducing the pain during propofol injection.
Key
Words:
lignocaine carbonate, lignocaine, propofol, pain
Approximately 70 to 90% of patients who receive
propofol for anaesthesia induction experience pain
during injection and this pain can be quite severe'^
Many factors influence the incidence of this pain
including the injection site, the size of the vein,
injection speed, propofol temperature, speed of
the intravenous carrier fluid and the use of local
anaesthetics and opioidsl Various methods have been
used to decrease propofol injection
pain;
these include
the addition of lignocaine to propofol, the application
of propofol at a different temperature or dilution,
along with the adjuvant use of lignocaine, alfentanil,
remifentanil, ondansetron, ephedrine, thiopentone
ketamine or paracetamol prior to injection''-'^
The most frequently used agent for propofol
injection pain is intravenous lignocaine and the
application of 0.5 mg/kg lignocaine via venous
occlusion has been one of the the most effective
methods''^ The use of lignocaine to decrease
* MD, Assistant Professor.
t MD, Associate Professor.
t MD, Assistant Professor.
§ MD, Associate Professor, Department of Biostatistics.
••MD,
Professor.
Address for correspondence: Dr U. Ozgul, Inonu University, Department
of Anesthesiology and Reanimation, Malatya, Turkey. Email: ulku.ozgul@
inonu.edu.tr
Accepted for publication on May 24, 2013.
Anaesthesia and Intensive
Care,
Vol.
41, No. 4, July 2013
propofol injection pain is based on its presumed
local anaesthetic effect on the vein\ However,
lignocaine does not prevent pain effectively in
approximately 40% of the patients treated in this
manner'.
The addition of sodium bicarbonate (NaHCOj) to
local anaesthetics accelerates both the intraneural
diffusion of local anaesthetics and their penetration
to the connective tissue around the nerve, thereby
reducing the onset time and improving block
quality'"".
We hypothesised that alkalinisation of lignocaine
would accelerate its local anaesthetic effect and thus
further reduce propofol injection pain when used
prior to the administration of propofol.
METHODS
The Ethics Committee of Inonu University Turgut
Ozal Medical Centre, Malatya, Turkey approved
this study (number 2011/A-207), and all patients
provided written informed consent. This prospective,
randomised, double-blind study (Clinical Trial
Number NCT01773044) included 300 American
Society of Anesthesiologists (ASA) physical status
I to II patients aged between 18 and 60 years for
whom elective surgery was planned with general

502
U. OZGUL, Z. BEGEÇ ET AL
anaesthesia. Exclusion criteria were communication
difficulties, a history of allergy to the study drugs, a
history of a suspicious or known difficult airway, and
the use of opioid or nonsteroidal anti-inflammatory
drugs within the past week.
Patients were assigned to one of three groups of
100 patients each by using computer-generated
numbers as a simple randomisation method. Group
L was injected with 0.05 ml/kg of 1% lignocaine
(Aritmal 2%, Osel Ilaç San. Tic. A.S, Istanbul,
Turkey), (5 ml normal saline + 5 ml 2% lignocaine),
Group A with 0.05 ml/kg alkalinised lignocaine (5 ml
2%
lignocaine + 1 ml 8.4% NaHC03 + 4 ml normal
saline) (NaHC03 8.4%, DROGSAN Ilaç San. ve Tic.
A.§,
Ankara, Turkey) and Group S with the same
amount of normal saline (NaCl 0.9%). A person who
did not participate in the study prepared the study
drugs in
10 ml
injectors, and the syringes were labelled
such that their contents could not be identified.
The pH values were measured with an NEL
890
pH
meter. The pH of 1% lignocaine was 6.20, whereas
the pH of lignocaine alkalinised
by
NaHCOj was 7.15.
Electrocardiogram, noninvasive arterial blood
pressure and peripheral oxygen saturation (SpO,)
measurements along with standard monitoring
techniques were used in the operating room. Patients
did not receive preoperative medication. A 20-gauge
intravenous cannula was placed on the dorsum of
the non-dominant hand. The running carrier
fluid
was
not started before the study drug was administered.
We explained to the patients prior to anaesthetic
induction that they might feel some pain in their arms
due to the application of the intravenous anaesthetic.
All drugs were prepared at room temperature just
before application. The anaesthetist
who
administered
the study drug was unaware of the identity of the
solution that was being administered to each patient.
To provide standardised venous occlusion, an
automated blood pressure cuff was placed on the
ipsilateral upper arm and programmed to inflate to
venous puncture mode (continual 50 mmHg). The
study drug was administered over a 20 second period
after venous occlusion. The tourniquet was opened
after 30 seconds.
Propofol (10 mg/ml ampoule, Fresenius, Turkey)
was used at 2.5 mg/kg for anaesthetic induction.
Patients received 25% of the calculated dose of
propofol over five seconds. Another anaesthetist
who did not know which study drug had been
administered graded the pain using the four-
point verbal rating scale published by McCrirrick
and Hunter^ The grading was as follows: 0 = no
pain (negative response to questioning); 1 = mild
pain (pain reported only in response to question
without any behavioural signs); 2 = moderate pain
(pain reported spontaneously, or in response to
question, accompanied by a behavioural sign); and
3 = severe pain (strong vocal response or response
accompanied by facial grimacing, arm withdrawal
or tears).
Fentanyl (1 Mg/kg) was applied after the propofol
injection pain was graded. Anaesthetic induction was
completed by the administration of the remaining
propofo!. Trachéal intubation was facilitated with
0.1 mg/kg vecuronium bromide. Anaesthesia was
continued with desflurane 6.0 to 8.0% and 60%
nitrous oxide in 40% O^.
An anaesthetist who was unaware of the patient's
study group checked for the presence of pain,
oedema, inflammation and allergic reactions at the
injection area within 24 hours.
When assuming a pain incidence of- 70%'^ after
intravenous propofol injection and a difference of
11%,
a power analysis with an alpha error of 0.05
and a beta error of 0.20 revealed that a minimum of
100 patients were required in each group (MedCalc
Version 12.4.0.0 for Windows, MedCalc Software,
Ostend, Belgium).
Statistical analyses were performed with SPSS
version 21.0 (SPSS Inc., Chicago, USA). The results
are expressed as the median values with min to max
and frequencies with percentages. The data were
tested using Kolmogorov Smirnov test. Categorical
variables were compared by using the Pearson chi-
square test among the groups. The scores related to
pain severity were compared by using the Kruskal-
Wallis H test. Grading of pain (0: no pain, 1:
mild pain, 2: moderate pain, 3: severe pain) was
compared among the groups using the Pearson chi-
square test. Multiple comparisons of the groups
were performed by Mann Whitney U test with
Bonferroni adjusted method. P values <0.05 were
considered statistically significant.
RESULTS
A total of 305 patients were included in the
study. Three patients in Group L, one in Group A
and one in Group S were excluded from the study
because of problems with difficult insertion of the
cannula in a dorsal vein, leaving 100 in Group L, 100
in Group A and 100 in Group S. The demographic
data of the patients were similar across the groups
(Table 1).
The incidence and severity (as determined by
pain scores) of pain during propofol injection in all
groups are shown in Table 2. The pain score [median
(range)] and the incidence of pain in Group A
(6%) was significantly lower than in groups L (41%)
Anaesthesia and Intensive
Care,
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41, No. 4, July 2013

PROPOFOL INJECTION PAIN AND ALKALINISED LIGNOCAINE
503
and
S (88%, P
<0.001).
In
addition, statistically
significant differences
for the
pain score
and the
incidence
of
pain were found between groups
L
and
S {P
<0.001).
The
incidence
of
moderate
and
severe pain were greater
in
Group S when compared
with groups
A and L {P
<0.001).
In
Group
A, the
incidence
of
mild pain
was
significantly lesser than
in groups
L and S (P
<0.001).
The
number
of
patients
who
experienced
no
pain were greater
in Group
A
than
in
groups
L and S (P
<0.001).
In
addition,
the
number
of
patients
who
experienced
no pain were greater
in
Group
L
than
in
Group
S
{P <0.001).
Oedema, pain, wheal
or
flare response were
not
observed
at the
injection site
or
reported
by any
patients during
the
24 hours after the operation.
DISCUSSION
In this study,
we
showed that alkalinised ligno-
caine
was
more effective than lignocaine alone
or
saline
in
reducing both
the
incidence
and
severity
of propofol injection pain.
To our
knowledge, this
is
the first study showing that NaHCOj added
to
Table
1
Demographical data (mean
± SD
or frequency)
Group
Age,
years
Height, cm
Weight, kg
Gender, M/F
ASA physical
status (I/II)
Group L
(n = 100)
32 ±10
166.9±9.9
69.4±13.5
34/66
88/12
Group A
(n=100)
33±11
164.5 ±12.8
70.5±16.1
32/68
83/17
Group S
(n = 100)
30±10
167.5±8.3
67.8±13.1
35/65
85/15
Group L=lignocaine group. Group A=alkalinised ligno-
caine group, Group S=normal saline group, M=tnale,
F=female, ASA=Àmerican Society of Anesthesiologists.
Table 2
The distribution of
observed
pain during injection of propofol
Group
No pain
Mild pain (A)
Moderate pain (B)
Severe pain (C)
Any pain
(A-l-B+C)
Pain score, median
(min-max)
Group L
(n = 100)
59-,b
32-
6"
3"
41^
0 (0-3)'''
Group A
(n = 100)
94'
5"
1"
0'
6"
0 (0-2)'
Group S
(n = 100)
12
23
27
38
88
2(0-3)
P value
<0.001*
<0.001*
<0.001*
<0.001*
<
0.001*
<0.001t
Dataarepresentedasmedian(min-max)or
incidence.
a=significantly
different from Group A. b=significantly different Group S.
*
Pearson chi-square test, f Kruskal Wallis test.
Anaesthesia
and
Intensive
Care,
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41, No.
4, July
2013
lignocaine decreases propofol injection pain.
We
hypothesise that
the
alkanisation
of
lignoeaine
accelerated local anaesthetic effect
on
the vein.
Propofol
is a
frequently used agent
for the
induction
and
maintenance
of
anaesthesia.
How-
ever,
the
pain that occurs during injection causes
discomfort
for the
patients Although
the
aetiology
of propofol injection pain
has not
been clarified,
two basic mechanisms have. been proposed
as the
cause
of
injection pain.
The
first mechanism
is the
direct irritation
of the
skin, mucous membranes
and venous intima
due to the
phenol groups
contained
in
propofol'.
The
second mechanism
is
due
to an
indirect effect
of
propofol
on the
endo-
thelium, whereby
the
kinin-kallikrein system
is
activated with
a
consequent increase
in
bradykinin
formation. Bradykinin increases
the
contact
of
propofol with nerve endings
of the
vein
and
consequently increases
the
pain related
to
propofol
injection'^".
The incidence
of
propofol injection pain
can increase
up to 90%
when
the
veins
on the
dorsum
of the
hand
are
used during anaesthetic
induction^ Similarly,
in our
study, propofol injection
pain
was
observed
in 88% in the
saline group
when the veins
on the
dorsum
of
the hand were used.
Different methods have been used
to
decrease
the incidence
and
severity
of the
pain caused
by
propofol injection.
The
most popular methods
used
to
prevent propofol injection pain
are the
addition
of
lignocaine
to
propofol
or
pretreatment
with lignocaine
via
bolus injection prior
to
propofol
injeetionl However, failure rates
of 32 and 42%
were reported even with these methods'"".
The mechanism
by
which lignocaine prevents
pain when applied prior
to
propofol injection
is
reported
to be its
local anaesthetic effect
on the
vein
and its
stabilisation
of the
kinin cascade'.
It
is thought that lignocaine forms
a
modified Bier
block
on the
proximal forearm after
its
application
via
a
tourniquet
and
this
is
thought
to be the
most
effective method
for
preventing propofol injection
pain'l
In our
study,
a
tourniquet
was
applied
for
a period
of 30
seconds
and the
pain ratio with
0.5 mg/kg
1%
lignocaine
was
41%. This ratio
is in
accordance with results from previous
studies'
I
Increasing
the pH of
local anaesthetics
by
adding NaHCOj increases their onset speed
and
effectiveness.
It has
been shown
in
some studies
that
the
alkalinisation
of
local anaesthetic with
NaHCOj increases
the
quality (spread
and
duration)
of
the
regional block
and
decreases onset time"'"'^
The pain-reducing effect
of
alkalinisation depends
on
the
influence
of the
higher
pH on the
amounts

504
U. OZGUL, Z. BEGEÇ ET AL
of ionised and non-ionised forms of lignocaine.
Because only the non-ionised form of lignocaine
can infiltrate nerve membranes and interstitial
tissues, the increase in the amount of the non-
ionised form with the addition of NaHC03
increases the effectiveness of the local anaesthetic'^
The greater diffusability of the non-ionised form
may result in rapid inhibition of pain transmission,
thereby preventing nociceptive impulses from being
fully appreciated'^ It has been reported that the
non-ionised form of lignocaine varies between
less than 1 and 11% according to pH levels of the
solution, when pH levels of solution vary between
six and seven respectively. In our study, the
incidence of propofol injection pain was 6% after
the alkalinisation of lignocaine.
There are some limitations in the present study.
First, we did not investigate the optimum dose of
bicarbonate and further studies are warranted in
this area. We used a ratio of one to ten since this
was used in other studies carried out with
lignocaine"*'^-^. Second, it would have been better
for the patients to report their own pain instead
of an observer. When the pain was evaluated by
the patient it could be more difficult to distinguish
between mild and moderate pain^'. The patient's
assessment of pain may require some subjective
scales (such as visual analog scale) and is not
practical for use in a clinical setting^^ so we used
verbal rating scale as did previous studies'^^. Third,
recalled percieved pain postoperatively was not
evaluated. Studies that have not used premedication
demonstrated that there were no differences in
the recall of propofol injection pain^-^. We did
not evaluate recall of propofol injection pain
postoperatively because we felt that recall may
not always be reliable.
In conclusion, intravenous pretreatment with
alkalinised lignocaine appears to be effective in
reducing both the incidence and severity of the pain
during propofol injection when compared to both
lignocaine alone and a saline placebo.
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