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UNIVERSITAS INDONESIA

EFFICACY OF SPINAL ADDITIVES NEOSTIGMINE AND


MAGNESIUM SULFATE ON CHARACTERISTICS OF
SUBARACHNOID BLOCK, HEMODYNAMIC STABILITY
AND POSTOPERATIVE PAIN RELIEF: A RANDOMIZED
CLINICAL TRIAL

Suchita Joshi-Khadke, V. V. Khadke, S. J. Patel, Y. M. Borse, K. V. Kelkar,


J. P. Dighe, R. D. Subhedar.
Anesthesia: Essays And Researches, Jan-Apr 2015: 9(1) 63-71

CRITICAL APPRAISAL

Ratna Widiyanti K
NPM 1206234300

Moderator
dr. Aldy Heriwardito, SpAn-KAKV

DEPARTMENT OF ANESTHESIOLOGY AND INTENSIVE CARE


FACULTY OF MEDICINE UNIVERSITAS INDONESIA
JAKARTA
MEI 2017
CRITICAL APPRAISAL

Journal Title:

Efficacy of spinal additives neostigmine and


magnesium sulfate on characteristics of subarachnoid
block, hemodynamic stability and postoperative pain
relief: A randomized clinical trial
Suchita Joshi-Khadke, V. V. Khadke, S. J. Patel, Y. M. Borse, K. V. Kelkar,
J. P. Dighe, R. D. Subhedar.
Anesthesia: Essays and Researches, Jan-Apr 2015: 9(1) 63-71

General
1. Is the clinical question clearly defined?
Yes.

2. What is the clinical question evaluating?


The clinical question evaluating the effect of neostigmine and MgSO4 on
characteristics of spinal anaesthesia (SA), hemodynamic stability and
postoperative analgesia when added to 0.5% hyperbaric bupivacaine for
spinal anaesthesia.

3. What was the study design?


Randomized, double-blind, prospective, and parallel group clinical trial.

4. Was there a clearly focused clinical question and primary hypothesis?


Yes.
The clinical question was clearly focused. The hypothesis was that intrathecal
neostigmine and MgSO4 when added to hyperbaric bupivacaine for spinal
anaesthesia, will improve hemodynamic stability and reduce postoperative

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pain and consumption of analgesic after lower abdominal surgery when
compared to saline control.

5. Are there any declared conflicts of interest that may bias the result of
the study?
No.

Methodology
Population
1. What was the sampling method?
It was a prospective, randomized, double-blind, parallel group clinical trial
conducted at Department of Anaesthesiology, Sri Bhausaheb Hire
Government Medical College during October 2011 to March 2013. The
patients were randomly assigned to one of three groups of 25 each using
computer generated randomization list using GraphPad QuickCalcs software.
.
2. Were the inclusion/exclusion criteria clearly defined?
Yes.
Inclusion criteria: patient cohort comprised of consecutive American
Society of Anaesthesiologist physical status I and II adult females of age 20-
60 years weighing 40-70 kg scheduled for elective gynecological surgery
under spinal anaesthesia.
Exclusion criteria: patients on chronic analgesic therapy or having
contraindications to spinal anaesthesia (coagulopathy, gross spinal deformity,
central and peripheral neuropathy, etc), morbid obesity, and sensitivity to
study drugs.

3. Did the sample include a representative spectrum of subject?


Yes.
A total of 88 patients was screened for the study. Eighty subjects satisfying
the inclusion criteria were enrolled in the study. In three patients, surgery was

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postponed after enrollment hence not included in the study. One case each
from Group C and Group M were excluded because GA was supplemented
for unexpected prolonged duration of surgery. Data from 75 subjects (25 in
each group) were analyzed.

4. How was the sample size determined?


The study was designed to enroll 75 patients (25 per group). The sample size
of 23 subjects in each group was required to detect a difference of 60 min in
the mean duration of analgesia, assuming a standard deviation (SD) of 62 min
based on pilot study, a power of 90% and a significance level of 5%. They
included 25 patients in each group to allow for dropout and protocol violation.

5. Do the authors explain how selection bias was minimized?


Yes. Selection bias was minimized by restricting in inclusion and exclusion
criteria. The patients were also randomized using GraphPad QuickCalcs
software. The researcher also explained about the equal intervention for all
groups. But in postoperative pain measurement, there was no clear
information about protocol regarding additional analgesic administration that
would be a bias factor.

6. Was allocation of subjects to intervention and control groups


concealed from the researchers?
Yes.
The study drug was prepared by anesthesiologist not involved in outcome
measurement. The patient, anesthesiologist who performed the spinal block,
and the observer collecting data about study parameters were blinded to group
allocation.

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Confounders
1. Were the intervention group and control group similar at the start of
the study?
Yes.
The researchers mention that the three groups were comparable in
demographic characters age, duration of surgery, and incision time (table 1).

2. Were the groups treated equally except for the receipt of intervention?
Yes.
All patients received tablet alprazolam 0.25 mg and tablet ranitidine 150 mg
orally night before surgery. They were kept fasting for 8 h for solid food. On
arrival in the operating room, standard monitoring was established.
Intravenous (IV) line was started with 18gauge canulla followed by
preloading with 10 ml/kg lactated ringers solution and maintenance infusion
610 ml/kg/h. IV ondansetron 4 mg and ranitidine 50 mg was given as
antiemetic prophylaxis. SA was carried out in the lateral position at lumbar
34 interspace using 23gauge disposable spinal needle. After clear and free
flow of cerebrospinal fluid (CSF), one of the study solutions was
administered intrathecally depending upon the group. All the study drugs
were preservative free and total volume of drug injected was 4 ml.

3. How were patient allocated to the treatment and control groups?


They were randomly assigned to one of the three groups of 25 each using
computer generated randomization list using GraphPad QuickCalcs
(GraphPad Software, Inc., 7825 Fay Avenue, Suite 230 La Jolla, CA 92037
USA). The assignment was sealed in opaque envelops along with code of the
group and opened just before entry into the study.

4. Were either the researchers or subjects blinded to the treatment?


Yes.

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The patient, anesthesiologist who performed the spinal block, and the
observer collecting data about study parameters were blinded to group
allocation.

5. Was the blinding process clearly explained?


Yes.
All the study drugs were preservative free and total volume of drug injected
was 4 ml. The study drug was prepared by anesthesiologist not involved in
outcome measurement.

6. Was an adequate placebo used in the controlled group?


Yes. The researchers used normal saline as a placebo.

7. Were the clinical endpoints measured clearly stated?


Yes.
Primary outcome: Intrathecal neostigmine and MgSO4 when added to
hyperbaric bupivacaine for SA, will improve hemodynamic stability and
reduce postoperative pain and consumption of analgesic after lower
abdominal surgery when compared to saline control.
It consists of:
a. Characteristics of spinal anesthesia: Time of onset of sensory block
and duration of sensory block. And time of onset of motor block and
duration for complete motor recovery
b. Hemodynamic stability: Variation in HR, MAP, hemoglobin oxygen
c. Analgesia characteristics: Postoperative pain score, duration of
analgesia, addition analgesia requirement
Secondary outcome:
a. Sedation score
b. Side effects

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8. How was the clinical endpoint measured?
Primary outcome:
a. Characteristics of spinal anesthesia: Unable to flex ankle. Time of onset
of sensory block to L1 level, onset of motor block to Bromage score 1,
maximum level of sensory block, time to achieve maximum sensory level,
duration of sensory block, that is, time for two segment regression of
sensory level, duration of motor block, that is, time for complete motor
recovery to Bromage score 0 or ability to move lower limbs. Sensory
block assessed using loss of sensation to pinprick (assessed every 2 min
interval for 15 min, then every 5 min until maximum sensory level) at
desired level surgery was started. Motor block to be assessed with
modified Bromage scale as 0 No paralysis, 1 Unable to raise extended
leg, 2 Unable to flex knee, 3
b. Hemodynamic stability: Variation in HR, MAP, hemoglobin oxygen was
every 5 min for 30 min, then every 10 min till end of surgery.
c. Analgesia characteristics: Postoperative pain score, duration of analgesia,
addition analgesia requirement. Postoperative assessment was carried out
at hourly interval until first analgesic dose followed by 6, 12, 24, 48 h,
and 7th day postoperatively. Postoperative pain score was measured using
Rupee Scale. Duration of analgesia was calculated from intrathecal
injection till demand of first analgesic dose. Analgesia requirement was
calculated by the use of intramuscular (IM) diclofenac sodium (mg), IV
tramadol (mg), and the total number of analgesic doses in 24 h.

Secondary outcome:
a. Sedation score: Sedation score was recorded every 15 min
intraoperatively and postoperatively for 6 h as described by Chernik et al:
0 no sedationWide awake, 1 Mild sedationsleeping comfortably, 2
Moderate sedationDeep sleep but arousable, and 3 Severe sedationDeep
sleep not arousable.

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b. Side effects: Hypotension was defined as the fall in MAP 30% below
baseline or <90 mmHg. Bradycardia was defined as the fall in pulse rate
< 60 beats/min. The patients were also observed for side effects like
postoperative nausea and vomiting (PONV), drowsiness, respiratory
depression (respiratory rate <10 breaths/min), shivering, nystagmus,
sweating, salivation, hallucinations, agitation bowel/bladder dysfunction,
itching, neurological deficit, headache etc., recorded as and when they
occur. They were free to report any problems although no direct questions
were asked.

Reliability and Validity


1. Was a valid measurement of the clinical endpoint made?
Yes.

2. Were the endpoints assessed using validated measuring


methods/instruments?
Yes.
Most of the measuring methods in this research assessed using validated
methods/ instruments. It was stated that one of the measuring method used
was The Rupee Scale that can be compared with visual rating scales as the
valid methods to measure the pain score. It also stated that the person who
assessed and collecting data about study parameters was the anaesthesiologist
who performed spinal block and trained staff nurse.

3. Is there evidence provided for the reliability of the measuring


instruments/methods used?
No
It was only stated that The Rupee scale is a technique for assessment of pain
and requirement of analgesics in a clinic setting of an Indian hospital where
level of literacy is variable.

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4. Was training and standardization used to improve the consistency of
the measurements made?
Yes.
It was not clearly described but the researcher stated that the person who
assessed and collecting data about study parameters was the anaesthesiologist
who performed spinal block and trained staff nurse.

5. Was follow up complete and of sufficient duration?


Yes.

6. Has an appropriate methods of statistical analysis been chosen?


Yes.
The statistical analysis was carried out using software GraphPad InStat 3
(www.graphpad.com), (GraphPad Software, Inc.7825 Fay Avenue, Suite 230
La Jolla, CA 92037 USA), Version 3.10 and online statistical calculator for
the Chisquare test (www.physics.csbsju.edu). The continuously distributed
variables (demographic data, duration of surgery, characteristics of SA,
hemodynamic parameters cumulative analgesic use and pain score) are
expressed as mean (SD) and analyzed using oneway analyses of variance
followed by Tukey Krame multiple comparisons test or KruskalWallis test
with Dunns multiple comparisons test as appropriate. Categorical data are
expressed as number (percentage) and analyzed using the Chisquare test. P
<0.05 was considered statistically significant.

7. How many groups were compared?


Three group were compared.
Group N: Neostigmine 25 g
Group M: MgSO4 50 mg
Group C: Control/ placebo with normal saline

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Results
1. Was the study analyzed using an intention to treat analysis?
Not stated

2. How precise was the estimate of the intervention effect?


Table 2 depicts the characteristics of spinal anaesthesia. The sensory block
was slightly prolonged with neostigmine and motor block with MgSO4 but it
was not statistically significant. The onset and duration of motor block were
similar in all the groups.
The analgesia characteristics are described in Table 3. The duration of
analgesia was more prolonged in the neostigmine group than in MgSO4 group
when compared to saline group. The time to first analgesic demand was
longest with neostigmine (5.1 h) followed by MgSO4 (4.2 h) and saline
control (3.8 h). Diclofenac sodium was first analgesic given on demand.
Further doses were given at fixed interval after first dose. Diclofenac
requirement was slightly less with neostigmine and MgSO4, but it was not
statistically significant. Furthermore, the total dose of tramadol was
significantly less with intrathecal neostigmine. The cumulative analgesic
requirement was indicated by the total number of analgesic doses required
during first 24 h after surgery. It was lowest in the neostigmine group than
MgSO4 and control groups. The analgesic consumption was not significantly
reduced with MgSO4.
The baseline hemodynamic variables were comparable among all the three
groups (Table 4). We observed the lowest incidence of hypotension in the
neostigmine group 48% compared to 64% in MgSO4 group and 84% in the
saline group. The incidence of bradycardia and atropine requirement was
reduced significantly by MgSO4.
The placebo group was more sedated after surgery than the active group (table
5). The incidence of PONV was significantly higher in group placebo
compared to Group Neostigmine and Group MgSO4. The mean antiemetic
use was comparable among three Groups. The three groups were comparable

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with respect to other side effects namely vomiting during surgery, pain on
traction, desaturation, shivering, other neurological symptoms, headache, etc.

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Applicability
1. Are your patients similar to target population?
Yes.

2. Was the entire relevant outcome measures considered?


Yes.

3. Will the intervention help your patient population?


No, my patient population mostly using Opioid (fentanyl) as a SA adjuvant. From the
conclusions of this study it was stated Neostigmine though it provides some protection
against SA-induced hypotension and has a significant effect to reduce postoperative
pain, but it also has a high incidence of nausea and vomiting. It also stated that this
study is not adequately powered to comment upon neurotoxicity clinical trials
performed to date have not reported any evidence of neurological complications
following intrathecal neostigmine and MgSO4. The reader considers that the use of
neostigmine and magnesium sulfate doesnt have a better result than opioid since this
research did not compare between them, and the safety of Neostigmine and Magnesium
Sulfate is not clear.

4. Are the benefits of the intervention worth the risks and costs?
No.

5. Have patient values and preferences been considered?


Yes. All patients signed an informed consent.

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