EL-MINIA MED. BULL. VOL. 20, NO. 2, JUNE, 2009
Asida
COMPARISON OF TWO DOSES OF NEOSTIGMINE FOR
REVERSAL OF RESIDUAL NEUROMUSCULAR
BLOCK OF ATTRACURIUM
By
Salah Mostafa Asida, M.D.
Department of Anesthesia, Qena Faculty of Medicine
ABSTRACT:
Background: Residual neuromuscular block is still occurring and represents a real
threat in the postanesthesia care unit ( PACU) I have examined the effect of two doses
of neostigmine that can change a Train of four (TOF) ratio of 0.6 to 0.9 or 1.0 after
general anesthesia using total intravenous anesthesia technique.
Study design: randomized controlled study
Methods: 75 patients assigned to 3 groups to receive neostigmine (15 ug/kg and 25
ug/kg and placebo ) for reversal of residual atracurium block to assess time to reach
TOF ratio from 0.6 to 0.9 and 1.0 and time to reach pre-induction tidal volume and
the total dose of neostigmine required for complete reversal of neuromuscular block
Results: time to reach TOF ratio of 0.9 or 1.0 and pre-induction tidal volume in the
PACU was shorter in the neostigmine groups (4.5-5 min) than the placebo group( 1011 min ), the difference between the two doses of neostigmine was not clinically or
statistically significant .
Conclusion: In total intravenous anesthesia ;reduced doses of neostigmine ( 15-25
ug/kg ) are effective in reversing the relaxant effect of residual atracurium doses
assuring safety of recovery of patients in the PACU.
KEYWORDS:
Neostigmine
Residual neuromuscular block
Atracurium
It was found recently that
residual paralysis is responsible for
postoperative respiratory complications
as the mean TOF ratio in the PACU
was found to be 0.62 and these low
degrees of block are not detected
clinically or even by simple nerve
stimulators.
this
led
to
the
recommendation that quantitative
nerve stimulator assessment with
continuous calibration and monitoring
until the TOF ratio more than 7.0 is
essential
for
assuring
patient's
complete recovery2
INTRODUCTION:
When giving atracurium to
patients under general anesthesia the
aim of giving neostigmine to these
patients at the end of operation is to
reverse the residual relaxant effect of
atracurium on the skeletal muscles
specially the respiratory muscles.
If the relaxant effect was not
completely reversed; residual block
may still be present and cause
hypoventilation in the PACU as a
result of possible interruption of
pharyngeal muscles power and airway
obstruction leading also to reduction of
the vital capacity and the hypoxic
ventilatory response1.
The side effects of neostigmine
are
dose-dependent
and
more
3
importantly the overdose or the dose
given at improper time4 are more
303
EL-MINIA MED. BULL. VOL. 20, NO. 2, JUNE, 2009
harmful as it was found to cause
accumulation of acetylcholine and
muscle weakness . This muscle
weakness affects the upper airway
dilator muscles5 causing partial or
complete obstruction of the airway in
an incompletely conscious patient after
general anesthesia. So , if the dose of
neostigmine
was
reduced
this
paradoxical effect of neostigmine
cannot occur .
Asida
monitor cables on the other hand and
arm.
The cables of the accelerograph
(TOF Watch SX®; Schering-Plough,
Swords, Co.) were applied as the
acceleration transducer was applied on
the volar side of the distal phalanx on a
small hand adaptor for recording the
muscle response to TOF stimulation .
surface stimulating electrodes were
applied on the ulnar nerve on the
medial side of the arm just proximal to
the wrist located by nerve stimulator of
the TOFwatch.
The dose of neostigmine
required to reverse low atracurium
blockade levels is not precisely known.
This study was done to detect the
efficacy and safety of two relatively
low doses of neostigmine in reversing
the residual neuromuscular block of
atracurium.
Induction
of
anesthesia
(without premedication) was done by 1
ug/kg fentanyl followed by 2mg/kg
propofol in 100% oxygen then
followed by an infusion of propofol
10-12 mg /kg/hour and intermittent
doses (0.5 ug/kg) of fentanyl as
required for maintenance of anesthesia
.
PATIENTS AND METHODS:
After obtaining the ethical
committee approval of Qena faculty of
medicine for the research protocol , a
written informed consent was taken
from 75 adult patients ASA I &II
enrolled for surgery under general
anesthesia (using total intravenous
anesthesia
technique)
in
Qena
university hospital – south valley
university excluding any patient with
deviation of ideal body weight more
than or equal to 25% , abnormal airway
anatomy, neuromuscular ,renal ,or
hepatic disease, pregnancy, any history
of allergy to the study drugs , burn or
deformity of the hand and forearm or
patients refusing to share in the study.
Before tracheal intubation with
the face mask tightly fit to the patient '
face the record of tidal volume
displayed on the screen of the
anesthesia machine during spontaneous
ventilation was recorded.
A TOF stimulation was started
(four pulses of 0.2 ms in duration, at a
frequency of 2 Hz, every 15 s).the
stimulating current was set at 60 mA
and the response was set to 100%. I
decreased the stimulating current by 5
mA until the recorded response drop
below 90% and then I added 10% to
the stimulating current value to get
supramaximal stimulus current.
On arrival to the operating
room patients were assigned to one of
the three groups, an I.V. line was
inserted in one hand or arm,
monitoring was established including:
5 leads ECG, pulse oximetry,
noninvasive blood pressure, capnography, and skin temperature leaving
one hand and arm free for the
accelerograph cables and applying the
Attracurium was then injected
IV 0.5mg/kg, manual bag –mask
ventilation with 100% oxygen until
TOF ratio of less than 0.1 and
orotracheal intubation was done. Bolus
304
EL-MINIA MED. BULL. VOL. 20, NO. 2, JUNE, 2009
doses of 0.1 mg/kg attracurium were
given intraoperatively as required.
Asida
Time (in minutes) to reach TOF
ratio of 0.9 and 1.0 were recorded and
the total dose of neostigmine (ug/kg)
given to achieve these ratios was
recorded. As well as time (in minutes)
to return tidal volume to pre operative
value.
Heart rate, oxygen saturation,
blood pressure, Et Co2, were recorded
every 5 minutes. (Data scope
Ohmeda)
Statistical Analysis:
Data were collected and analyzed using SPSS (version11 interface)
program. Patient's characteristics were
compared using the Mann-Whitney U
test. Type & time of operations were
compared with Chi-square test Comparison between neostigmine total
doses was made with student's t test.
Comparison of the time to reach TOF
of 0.9 and 1.0 between the two neostigmine groups was done by the
unpaired t test and between the three
groups with the kruskall Wallis test. P
value less than 0.05 was considered
significant.
Once the TOF ratio recovered
to 0.6 (at the end of surgery ) patients
assigned to group (A) [25 patients]
received
15 ug/kg neostigmine
preceded by atropine and patients
assigned to group (B) [25 patients]
received 25 ug/kg neostigmine
preceded by atropine and patients
assigned to group (C) [25 patients]
received saline (same volume of
solution as that of neostigmine syringe)
. Randomization of the patient's group
was done using computer-generated
allocation table.
Tidal volume recording was
done using the screen monitor of the
anesthesia machine (DateX Ohmeda
Aespire) showing the ventilator
parameters of tidal volume respiratory
rate, mean and peak airway pressures.
RESULTS:
No statistically significant
difference was found regarding
patient's characteristics type of operations or cumulative attracurium doses
and time of operations. (Table 1, 2)
Table (1): Patient's characteristics: (mean ± SD)
groupA Group B Group C P value
n=25
n=25
n=25
33 ±5
31±7
35±2
n.s
Age (years)
68±10
70±6
73±4
n.s
Weight (kg)
166±6
171±3
168±5
n.s
Height (cm)
13/12
19/6
n.s
Gender ( M/F) 15/10
n.s = not significant (Mann-Whitney U test )
305
EL-MINIA MED. BULL. VOL. 20, NO. 2, JUNE, 2009
Asida
Table (2): Type of operations & total attracurium dose
Group A Group B Group C P value
12
15
11
n.s
Cholecystectomy (open)
6
4
7
n.s
Umbilical hernia
7
6
7
n.s
Mastectomy
55±5
64±8
60±3
n.s
Total attracurium dose (mg)
79±10
75±6
82±2
n.s
Operative time (minutes)
n.s= not significant (Chi-square test)
Cardiorespiratory parameters were stable along the operative time in the three groups
All cases of the study reached a
TOF ratio of 0.9 or 1.0 and no decrease
in TOF ratio occurred after giving
neostigmine in the study doses.
The total dose of neostigmine
in group A did not exceed that of group
B as there was no significant difference
in mean weight of the patients in the
three study groups and this not affected
the time of full recovery to TOF ratio
of 1.0.
Time to reach 0.9 and 1.0
showed significant difference between
the neostigmine groups and placebo
group: Table (3) being shorter in the
neostigmine groups A & B (5 min in
group A and 4.6 min in group B) than
in the placebo group (9 min).
Time to return to pre induction
tidal volume was significantly shorter
in the two neostigmine groups than in
the placebo group (3.7min & 3.9min.
in group A&B respectively and 6.2min
in placebo group) table 3.
Table (3): Recovery time of TOF ratio, tidal volume and total neostigmine dose in the
three groups (mean±SD)
group A
n=25
Time to reach TOF ratio of 0.9 (min)
5±0.7
Time to reach TOF ratio of 1.0 (min)
6±1
Time to preinduction tidal volume recovery (min) 6±3
Total neostigmine dose (ug)
975±55
group B group C
P
n=25
n=25 value
4.5±0.6
9±3
***
5.4±0.4
11±3
***
5±4
10±2
***
1158±47 ----*
Comparing each two groups with unpaired t – test, between the three groups:
the kruskall Wallis test. P value between the two neastigmine groups and the placebo
group * mild significance ***high significance no significant difference between the
two neostigmine groups
especially if the patient was not
properly witnessed in the PACU.
DISCUSSION:
Investigation of the solution of
the problem of low or shallow degrees
of residual neuromuscular block was
my aim of this study as it represents a
problem in the postoperative time
Debaene et al. reported that
45% of patients arrived to the PACU
with a residual neuromuscular block
304
EL-MINIA MED. BULL. VOL. 20, NO. 2, JUNE, 2009
and a majority of them suffered low
level of residual paralysis with its
conesquences on the respiratory
muscles power6.
Asida
present study and that of Fuchs- Buder
though statistically different but clinically not. They reported that clinically
relevant consequences of residual
paralysis are efficiently reversed after
dose as small as 20 ug/kg.
This study tested antagonism of
low levels of neuromuscular block
under general anesthesia using total
intravenous anesthetics. Infact volatile
anesthetics potentiate the relaxant
effect of neuromuscular blocking drugs
increasing the dose of neostigmine
required for reversal and increasing
time to reach full recovery from the
effect of muscle relaxant7,8.
Trying dose range of 1525ug/kg gave shorter time for recovery
in this study and again no paradoxical
weakness has occurred in any patient
in the present study.
Kirke-gaard et al. gave 70
ug/kg neostigmine at reappearance of
1-4 TOF responses and they failed to
prove 0.9 reversal of TOF ratio within
20-30- minutes after its administration.
this may be because they depended on
the tactile response of the adductor
policis muscle to TOF stimulation and
on a mechanomyogrph both are old
and in accurate methods for monitoring
neuromuscular activity11 this means
that waiting until more and more time
should be allowed for the spontaneous
recovery before giving neostigmine
especially for attracurium and cisattracurium .
What is the proper dose of
neostigmine for the reversal of residual
block? Indeed this depends on the
detection of the precise level of
paralysis still present after the last dose
of neuromuscular blocking drug
administered to the patient intraoperatively. Unfortunately devices that
can measure the degree of block are
not always available in all hospitals.
The standard most routinely used dose
of 40-70 ug/kg when given in low level
of residual block can lead to a
paradoxical effect with more muscle
weakness rather than return of normal
muscle power9.
The most important result of
this study is that low dose of
neostigmine (15-25 ug/kg) is sufficient
to reverse residual block of attracurium
without causing paradoxical effect in
rather shorter time (4-5min) than if the
patient was left without reversal (911min).
Sacan et al. compared neostigmine with sugammadex and edrophonium for reversal of rocuronium relaxant effect, a dose of neostigmine of 70
ug/kg was given and a TOF ratio of 0.9
was only found in the neostigmine
group after 10-16 minutes, this may be
applied to rocuronium and they were
not trying to reverse residual block but
actually comparing the efficacy of the
three drugs.12
Fuchs-Buder et al.10 examined
three doses (10, 20, 30 ug/kg) of
neostigmine for reversal of a TOF ratio
from 0.4 or 0.6 to 0.9 and 1.0.
According to the results of their study
they found at least 20ug/kg should be
given to reach TOF ratio of 0.9 within
10 minutes. The difference between the
The present study confirmed
the full recovery from the effect of
attracurium by the measurement of the
tidal volume of spontaneous breathing
before attracurium administration and
after extubation as an indicator of the
recovery of the respiratory muscles,
time to return to preinduction tidal
305
EL-MINIA MED. BULL. VOL. 20, NO. 2, JUNE, 2009
volume was shorter in the neostigmine
groups co- incidenting with the recovery of TOF ratio this was agreed by
the study of Eriksson1 and Murphy2 as
they reported definitive effect of
residual paralysis on the hypoxic ventilatory drive leading to critical
respiretory events affecting respiratory
parameters.
Asida
gmine in anaesthetized man. B J
Anaesth 1980; 52:69 –76
4- Goldhill DR, Wainwright AP,
Stuart CS, Flynn P: Neostigmine after
spontaneous recovery from neuromuscular blockade. Effect of depth of
blockade monitored with train-of-four
and tetanic stimuli. Anaesthesia 1989;
44: 293–9
5- Eikermann M, Fassbender P,
Malhotra A, Takahashi M, Kubo S,
Jordan AS, Gautam S, White DP,
Chamberlin NL: Unwarranted administration of acetylcholinesterase inhibittors can impair genioglossus and
diaphragm muscle function. Anesthesiology 2007; 107:621–9
6- Debaene B, Plaud B, Dilly MP,
Donati F: Residual paralysis in the
PACU after a single intubating dose of
nondepolarizing muscle relaxant with
an intermediate duration of action.
Anesthesiology 2003; 98:1042– 8
7- Reid JE, Breslin DS, Mirakhur
RK, Hayes AH: Neostigmine antagonism of rocuronium block during
anesthesia with sevoflurane, isoflurane
or propofol. Can J Anaesth 2001;
48:351–5
8- Oris B, Crul JF, Vandermeersch
E, Van Aken H, Van Egmond J, Sabbe
MB. Muscle paralysis by rocuronium
during halothane, enflurane, isoflurane,
and total intravenous anesthesia.
Anesth Analg 1993; 77: 570–3.
9- Bartkowski RR: Incomplete
reversal of pancuronium neuromuscular blockade by neostigmine,
pyridostigmine, and edrophonium.
Anesth Analg 1987;66:594 – 8
10- Fuchs-Buder T, Meistelman C,
Alla F, Grandjean A, Wuthrich Y,
Donati F. Antagonism of low degrees
of attracurium- induced neuromusculsr
blockade, dose effect relationship for
neostigmine. Anesthesiology 2010;
112: 34-40
11- Kirkegaard H, Heier T,
Caldwell JE: Efficacy of tactileguided
reversal from cisatracurium-induced
This study was done using total
intravenous technique for general anesthesia which is not always the case, as
volatile anesthetics are more comm.only used and the dose of neostigmine
needed for reversal of residual block of
neuromuscular drugs was confined to
attracurium, so the dose of neostigmine
given during general anesthesia using
volatile anesthetics should be tested
and compared with that used during
total intravenous anesthesia technique
and for other neuromuscular blocking
drugs.
Finally, I found 15-25 ug/kg of
neostigmine as a safe and effective
dose for reversal of residual block of
attracurium within 5-6 minutes in the
postoperative period as confirmed by
accelerography and respiratory parmeters assuring patient's safe recovery
from general anesthesia in the PACU.
REFERENCES:
1- Eriksson LI, Sato M,
Severinghaus
JW:
Effect
of
vecuronium-induced partial neuromuscular block on hypoxic ventilatory
response.
Anesthesiology
1993;
78:693–9
2- Murphy GS, Szokol JW,
Marymont JH, Greenberg SB, Avram
MJ, Vender JS: Residual neuromuscular blockade and critical respiratory events in the postanesthesia care
unit. Anesth Analg 2008; 107:130 –7
3- Payne JP, Hughes R, Al Azawi
S: Neuromuscular blockade by neosti-
306
‫‪Asida‬‬
‫‪EL-MINIA MED. BULL. VOL. 20, NO. 2, JUNE, 2009‬‬
‫‪neuromuscular block. Anesthesiology‬‬
‫‪2002; 96:45–50‬‬
‫‪12- Sacan O, White PF,‬‬
‫‪Tufanogullari B, Klein K: Sugam‬‬‫‪madex reversal of rocuronium-induced‬‬
‫‪neuromuscular blockade: A compa‬‬‫‪rison with neostigmine-glycopyrrolate‬‬
‫‪and edrophonium-atropine. Anesth‬‬
‫‪Analg 2007; 104: 569–74‬‬
‫الملخص العربى‬
‫مقارنة جرعتين من النيوستجمين لمعادلة‬
‫بقايا التأثير العصبى العضلى لألتراكيوريوم‬
‫أجرى هذا البحث بمستشفى قنا الجاامىى ليا ‪ 75‬مارض ماا الباال ضا الاذضا أ اياس المستشافى‬
‫ألجراء لميضات جراحضة تحت ما ر كيى باستا ام البرسبسفسل ساألتراكضسرضاسم لتسايضل تركضا‬
‫األنبسبة الحنجرضة ‪.‬‬
‫ستاام تيسااضميم ال ‪ 3‬مجمسلااات متساااسضة سلن ا امفاقااة مااا التا ا ضر الكي ا بىيااار البرسبسفااسل‬
‫المستمر حتى نياضة الىميضة الجراحضة تم الطاء المجمسلة األسلى ‪ 15‬مضكرسجرام لكل كجام ماا‬
‫سزا المرض نضسستجمضا ‪ +‬أترسبضا‬
‫ستم الطاء المجمسلة الثانضة ‪ 25‬مضكرسجرام لكل كجم ما سزا المرض نضسستجمضا ‪ +‬أترسبضا‬
‫ستم الطاء المجمسلة الثالثة محيسل ميح س ذالك لن سصسل قراءة جياز المحفاز الىصابى الاى‬
‫‪ 0.6‬سذلك بي ف السصسل بيراءة الجياز الـ ‪ 0.9‬أس ‪ 1‬صحضح مىينا بذلك انياء التاثثضر المرااى‬
‫ليىضالت لىيار األتراكضسرضسم ‪0‬‬
‫سق سجا ت أا السقات الاالزم لمىا لاة تاثثضر األتراكضسرضاسم بىا حياا النضسساتجمضا بجرلاة ‪25‬‬
‫س‪ 15‬مضكرسجرام كاا بمتسسط ‪ 5-4‬قائق ليى الترتض بضنما كاا السقت أطسل ( ‪ 11-10‬قضية)‬
‫لن حيا محيسل الميح‬
‫لذا فإ ا حيا جرلات منافضة ما النضسستجمضا فاى نياضاة الىميضاات الجراحضاة ضىا سساضية فىالاة‬
‫لمىا لة تثثضر امتراكضسرضسم سمنع ح سث مضالفات تنفساضة ليمارض أثنااء األفاقاة ماا التاا ضر‬
‫الكيى‬
‫‪307‬‬