Abstract
Objective: To compare the impact of preinduction with Fentanyl, Ketamine
or Midazolam on the frequency and intensity of etomidate induced myoclonic muscle movements.
Methods: One hundred five adult, American
Society of Anesthesiology class I, of both genders, aged 31-49 years and assigned for elective
ENT, ophthalmology and general surgery at King Hussein
Medical Center,
during the period from July 2009 to Feb 2010 were included in this study.
Subjects who had been given analgesics or sedatives during the past 24 hours
were ruled out. The study was approved
by the local ethics committee of the Royal Medical Services Directorate of the
Jordanian Army and written informed consent was obtained from all participants. Patients
were divided into one of 3 groups according to the intravenous preinduction
agent received: group F, n=36, received Fentanyl 2 mcg/kg, group M, n=34, received
midazolam 0.015 mg/kg and group K, n=35,
received Ketamine 0.2 mg/kg, ninety seconds before the induction of general anesthesia
using intravenous etomidate 0.3 mg/kg. An Anesthesiologist recorded the etomidate
induced myoclonic muscle movements frequency and intensity based on a scale
from 0 to 3, where 0=none, 1= mild, 2=moderate, and 3=severe myoclonus.
Results: Two of the 36
subjects in the fentanyl group (5.6%) reported etomidate induced myoclonic
muscle movements, while four subjects (11.8%) in the Midazolam group and 22
subjects (62.9%) in the ketamine group had such movements(P<0.05).
Conclusion:
Intravenous Fentanyl 2 mcg/kg administration
preintravenous etomidate induction of general anesthesia decreases
significantly the frequency and severity of etomidate induced myoclonic muscle
movements.
Key words: Fentanyl,
Ketamine, Midazolam, Myoclonic muscle movements.
JRMS
September 2011; 18(3): 38-41
Introduction
Myoclonus
(myoclonic muscle movements) is a sudden, involuntary jerking of a single
muscle or a group of muscles. It occurs in a wide range of disorders and is
sometimes provoked by sudden stimuli such as loud noise.(1) Etomidate
induced myoclonic muscle movements are a frequent side effect during induction
of intravenous general anesthesia. Myoclonic muscle movements are mainly of
clinical significance in non fasting subjects (myoclonus might increase the
risk of regurgitation and aspiration(2)), in subjects with
open globe injury (myoclonus may increase the risk of vitreous prolapse due to
high intraocular pressure(3)) or in those who are cardiovascular
compromised.
Etomidate,
a carboxylated imidazole compound, is an anesthetic induction drug with a very favorable
hemodynamic character. Nevertheless, it has few undesirable side effects such
as electroencephalic activation and myoclonic muscle movements.(4) Etomidate induced myoclonic muscle movements
are seen in up to 90% of subjects if no supplemental opioids are administered.(5)
Despite
different agents including opioids or benzodiazepines have been chosen for
potentially inhibiting etomidate induced myoclonus, the mechanism by which this
effect is achieved is still unclear. An ideal myoclonus preventive preinduction
agent must be short acting without cardiorespiratory side effects and without
prolonging recovery from anesthesia. Opioids
can decrease myoclonic muscle movements.(5) Fentanyl is a phenylpiperidine opioid. The
potency of preinduction with a phencyclidine derivative such as ketamine to
prevent etomidate induced myoclonus has been investigated.(6)
Midazolam is an imidazobenzodiazepine derivative was also evaluated for such
preventive impact in other studies.(2) The problem of
etomidate induced preventive myoclonus and the drug of choice have yet to be
identified.
This
study was conducted to compare the potency of preinduction with midazolam, ketamine
or fentanyl on the frequency and intensity of etomidate induced myoclonic
muscle movements.
Methods
One
hundred five adult, American Society of Anesthesiology (ASA) class I, of both genders,
aged 31-49 years and assigned for elective ENT, ophthalmology and general
surgery at King Hussein Medical Center (KHMC), during the period from July 2009
to Feb 2010 were included in this study. Subjects who had been given analgesics
or sedatives during the past 24 hours were ruled out. The study was approved by the local ethics
committee of the Royal Medical Services Directorate of the Jordanian Army and
written informed consent was obtained from all participants. In the operating
room, an 18 gauge intravenous cannula was inserted. Subjects were allocated into
one of 3 groups according to the intravenous preinduction agent used. Fentanyl (fentanyl
citrate, 0.05 mg/ml, Janssen-cilag) 2 mcg/kg (group F, n=36), Midazolam (5
mg/ml, Hikma pharmaceutical - Jordan)
0.015 mg/kg (group M, n=34) and Ketamine (Tekam 10mg/ml, Hikma ph.- Jordan)
0.2 mg/kg (group K, n=35). Ninety seconds after administration of the
investigated agent, anesthesia was induced with Intravenous (I.V.) etomidate (hypnomidate
2mg/ml-Janssen-cilag ltd) 0.3 mg/kg. Sixty seconds after etomidate
administration, Atracurium 0.5 mg/kg was given to facilitate intubation. Fentanyl
2mcg/kg was given to all patients groups after they were put to sleep. Anesthesia
was maintained using halothane 0.5-1% in a mixture of 70% nitrous oxide in 30% oxygen.
Randomization
was performed using a non-random fashion with sealed envelopes. Neither the anesthesiologis performing the
induction nor the patients were aware of the preinduction agent groups. Heart rate,
oxygen saturation and noninvasive arterial blood pressure were monitored.
An
anesthesiologist blinded to group division inquired and recorded frequency of
etomidate induced myoclonic muscle movements during one minute after etomidate
administration and its severity on a scale from 0 to 3 where 0=no myoclonus, 1=mild
myoclonus (movement at the wrist only or mild fasciculation involving the face
and/or distal upper and/or lower extremities), 2=moderate myoclonus (movement
involving the arm only, elbow or shoulder or marked movement of the face and
/or limbs) and 3=severe myoclonus (generalized response ,movement in more
than one extremity or involving limbs
and trunk.(6)
Statistics
Chi
square test was used for categorical comparison. Student's t test was used for parametric comparison.
If t test was P<0.05, it was recorded as significant.
To
detect a 25% reduction in myoclonus after midazolam pretreatment, 32 patients
per treatment would be needed.
Results
Patient
characteristics were similar between the groups regarding gender, age, weight, ASA
class and type of operation (Table I).
Preinduction
with ketamine did not reduce significantly the incidence or intensity of
etomidate induced myoclonus compared to fentanyl or midazolam. Preinduction with
fentanyl or midazolam decreased the frequency and intensity of etomidate
induced myoclonus (P<0.05) .There were no significant differences between
the fentanyl and midazolam groups regarding
the frequency and intensity of etomidate induced myoclonus, but there were significant differences between fentanyl and ketamine groups (P<0.05) and between midazolam and ketamine groups (P<0.05) regarding the frequency and intensity of etomidate induced myoclonic muscle movements.
Table I. Patients demographics (number
or mean)
|
|
Group
F
|
Group
K
|
Group
M
|
|
Age (yr) 31-40
41-49
|
16
19
|
20
15
|
18
17
|
|
Weight(kg) 70-75
76-80
|
15
20
|
17
18
|
16
19
|
|
Gender F
M
|
14
21
|
15
20
|
15
20
|
|
ASA I
|
35
|
35
|
35
|
|
Type of surgery
General surgery
ENT
surgery
EYE
surgery
|
11
12
12
|
12
11
12
|
12
12
11
|
Table II. Etomidate induced myoclonus.
(number %)
|
|
Frequency
|
Intensity
|
|
None
|
Yes
|
Mild(1)
|
Moderate(2)
|
Severe(3)
|
|
Group F (n=36)
|
34
(94.6)
|
2 (5.6)
|
1 (50)
|
1 (50)
|
0 (0)
|
|
Group K (n=35)
|
13
(37.1)
|
22
(62.9)
|
12
(54.6)
|
5 (22.7)
|
5 (22.7)
|
|
Group M (n=34)
|
30
(88.2)
|
4 (11.8)
|
2 (50)
|
1 (25)
|
1 (25)
|
94.4%, 37.1% and 88.2% did not develop
etomidate induced myoclonic muscle movements in groups F, K and M respectively. Regarding mild myoclonus, it was evident in
50%, 54.6% and 50% respectively in groups F, K and M, while moderate myoclonus
was observed in 50%, 22.7% and 25% in the same groups. Severe myoclonus was
found to be in 0% in F group, 22.7% in K group and 25% in M group. (Table II)
Discussion
The
present data demonstrated that preinduction with I.V. fentanyl 2mcg/kg and
midazolam 0.015 mg/kg decreased the frequency and severity of etomidate induced
myoclonus. We found few reports about
fentanyl and myoclonus in literature, therefore we chose the dose of 2mcg/kg
that was effective.(7) Ketamine was used at a dose of
0.2mg/kg to prevent etomidate induced myoclonus where 64% of patients experienced myoclonic
movements,(6) whereas 62.9% developed myoclonus in our study.
We waited 90 seconds before etomidate administration to have enough time for the
investigated agents to act. We assessed myoclonus after etomidate in order to
distinguish between various actions of the preinduction agents on myoclonus.
Different
studies have demonstrated that preinduction with opioids decreased etomidate
induced myoclonus.(8) Preinduction with fentanyl 2 mcg/kg
decreased the frequency of myoclonus to 6.7%(7) whereas 5.6%
developed myoclonus in our investigation. Benzodiazepines preinduction has also
been studied to decrease etomidate associated myoclonus. Huter et al(2)
showed that the frequency of myoclonus was significantly less in subjects
preinduced with 0.015mg/kg midazolam(10%) compared with placebo (50%), whereas
11.8% treated with midazolam in our study had myoclonus. Ketamine 0.2mg/kg
preinduction was shown to decrease the incidence of etomidate induced myoclonus
to 64%.(6) Although
various agents have been tested to
reduce its frequency, the mechanism of
etomidate induced myoclonus is unknown. Doenicke et al(9)
proposed that myoclonus is due to subcortical disinhibition. Fassoulaki et
al(10) showed no effect on the myoclonic rate when giving
100mcg fentanyl before the induction of anesthesia with etomidate. There are conflicting data regarding the
effect of benzodiazepines on etomidate induced myoclonus. In a previous study with low dose midazolam
in premedicated subjects, myoclonus was
in the rate of 20%.(11)
It is vital that the preinduction for inhibiting myoclonus does not
affect recovery from anesthesia.
Etomidate
induced myoclonus may be clinically relevant. Electrocardiogram
(ECG) leads could be detached during myoclonus and a reduction of oxygen
saturation has been shown during myoclonic muscle movement.(12)
Although
opioids have been demonstrated to decrease myoclonus,(13) their
mechanism of action is still unclear. In a study by stockham et al(8)
using 3 different doses of fentanyl,it was demonstrated that apnea is
correlated with the decrease of myoclonus. In the group receiving 500mcg fentanyl,
no subject had myoclonus but they were apneic and in the group receiving 100
mcg fentanyl, the frequency of myoclonus was 33%. The mechanism of the effect
of ketamine is non competitive N-methyl-D-aspartate (NMDA) receptor antagonism,
which in turn can ameliorate withdrawal movements caused by different chemical
mediators by blocking NMDA receptor activation in the CNS (central nervous
system). However, we could find one
study in the literature about preinduction with ketamine before etomidate
induction.
Etomidate
interacts with gaba amino butyric acid type A (GABA) receptors suppressing the
central nervous reticular activating system. Another reason could be that the
inhibitory circuits are depressed earlier than excitatory neuronal circuits
after etomidate administration.(14) With interruption of GABA
neurons pathways associated with skeletal muscle control can become more
sensitive allowing spontaneous nerve transmission to occur. These can finally
lead to myoclonus.(15) Etomidate induced myoclonus is not
centrally mediated.(16) Probably, the different effects of benzodiazepines on the different
GABA receptors may explain the mechanism by which these drugs decrease the
frequency of myoclonus. Etomidate is contraindicated in porphyria and adrenal
failure.
Both midazolam and fentanyl
have demonstrated efficacy in terms of inhibiting etomidate induced myoclonus
and it is recommend that midazolam is to be given in less painful or painless operation
and fentanyl is to be given if postoperative analgesia is anticipated.
Conclusion
This
clinical investigation demonstrated that fentanyl 2mcg/kg or Midazolam 0.015
mg/kg, given before etomidate induction decreases myoclonic muscle movements.
Ketamine was not effective significantly in decreasing the myoclonus.
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