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336 Original article

Comparison between different atropine doses as an

antisialagogue for patients receiving ketamine-midazolam
undergoing gamma knife radiosurgery
Hesham M. Elazzazi, Adham A. Saleh

Department of Anesthesiology, Intensive Care, Objectives

and Pain Management, Faculty of Medicine,
Ain-Shams University, Cairo, Egypt
Correspondence to Adham A. Saleh, MD,
Department of Anesthesiology, Intensive Care,
and Pain Management, Faculty of Medicine,
Ain-Shams University, Cairo, Egypt
e-mail: dr.adhamsaleh@gmail.com
Received 21 May 2014
Accepted 20 June 2014
Ain-Shams Journal of Anesthesiology
2014, 07:336339
Comparing different atropine doses to detect the least effective dose as an antisialagogue, in
patients receiving ketamine-midazolam sedation for gamma knife radiosurgery.
Patients and methods
The study included 120 American Society of Anesthesiologists Physical Status I, II patients
(age range 1860 years) undergoing gamma knife radiosurgery. The patients were randomly
divided into three equal groups. Patients in group A received atropine 0.5 mg intravenously,
atropine 0.3 mg intravenously in group B, whereas patients in group C received 0.1 mg
atropine intravenously. All patients received intravenous ketamine 0.5 mg/kg, plus intravenous
midazolam 1 mg. Baseline heart rate and blood pressure, change in heart rate, and occurrence
of increased secretions were recorded.
Results
A total of 120 patients undergoing gamma knife radiosurgery were included in the study. Only
one patient in group A and two patients in group B showed increased secretions (2.5 and
5%, respectively), whereas in group C 15 patients experienced increased secretions (37.5%).
None of the patients who experienced increased secretions required suctioning of secretions.
With regard to the change in heart rate, group A patients had significant increase in heart rate,
whereas the changes in heart rate in group B and C were not significant.
Conclusion
The dose of 0.3 mg atropine used in group B showed the same efficacy as an antisialagogue
as the dose of 0.5 mg atropine that was used in group A, and was significantly more efficient
than the dose of 0.1 mg atropine used in group C patients, who experienced significant increase
of secretions. In addition, group B patients did not experience the significant increase in heart
rate that was experienced by group A patients.

Keywords:
gamma knife, ketamine, midazolam

Ain-Shams J Anesthesiol 07:336339

2014 Department of Anesthesiology, Intensive Care and Pain Managment,
Faculty of Medicine, Ain-Shams University, Cairo, Egypt
1687-7934

centers from perceiving visual, auditory, or painful

Introduction
Gamma knife radiosurgery is a very unique form
of therapeutic radiology performed using the
gamma knife, which is a noninvasive neurosurgical
tool, depending on gamma radiation. This type of
radiation therapy can shrink small brain tumors or
block abnormal blood vessels, for example, cavernous
hemangioma. Many beams of gamma radiation join
together just to focus on the lesion, providing a very
intense dose of radiation, without a surgical incision.
Procedural sedation and analgesia is a technique of
administering sedatives (e.g. midazolam, propofol) or
dissociative agents (e.g. ketamine), with or without
opioid analgesics (e.g. fentanyl), to help patients
tolerate procedures such as gamma knife radiosurgery,
without impairing cardiorespiratory function [1].
Ketamine is a phencyclidine derivative that dissociates
the cortex from the limbic system, preventing the higher
1687-7934 2014 Department of Anesthesiology, Intensive Care and Pain Management,
Faculty of Medicine, Ain-Shams University, Cairo, Egypt
stimuli. It is characterized by rapid onset of action and
profound sedation and analgesia. Fortunately, laryngeal
reflexes are maintained and respiratory depression is
rare. That is why ketamine has become a very popular
agent for procedural sedation and analgesia [2].
Side effects of ketamine include vomiting and
unpleasant emergence phenomenon. Ketamine also
leads to hypersalivation and increased tracheobronchial
secretions. The most feared complication of ketamine
sedation necessitating advanced airway management
is laryngospasm, which occurs more commonly in the
presence of increased secretions [3].
Therefore, antisialagogues have been recommended
as a routine adjunct, a view particularly favored by
anesthetists. Atropine with its antimuscarinic effects
is most commonly used, with glycopyrrolate being an
alternative drug [4].
DOI: 10.4103/1687-7934.139560
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Aim of the work
The aim of the study was to compare between
different atropine doses as an antisialagogue agent,
with the least effect on heart rate for patients
receiving ketamine-midazolam sedation for gamma
knife radiosurgery.
Patients and methods
This study was conducted at Gamma Knife Center,
Nasser Institute (Cairo, Egypt), in collaboration with
Ain Shams University. After getting an informed
patient consent, 120 patients of either sex, with
the American Society of Anesthesiologists (ASA)
IorII physical status classification, aged 1860 years,
scheduled for gamma knife treatment for brain tumors,
were randomly divided into three groups using simple
randomization tables and sealed envelopes: group A
included 40 patients who received 0.5 mg atropine
intravenously, group B patients received 0.3 mg
atropine intravenously, and patients of group C received
0.1 mg atropine intravenously. All patients received
intravenous ketamine 0.5 mg/kg plus intravenous
midazolam 1 mg.
Exclusion criteria for both groups included patients
with ASA III or IV physical status classification,
patients with compromised cardiac, respiratory, renal,
or hepatic disease, patients with increased ICT, or
patients with known hypersensitivity to ketamine or
midazolam.
Methods
Patients had fasted for at least 8 h before the
procedure. Baseline vital data were recorded (heart
rate, blood pressure, and respiratory rate). After
intravenous cannulation, patients of the three groups
received ketamine 0.5 mg/kg intravenously (Ketamine,
50 mg/ml; Sigma Pharmaceuticals, Egypt) plus
midazolam 1 mg intravenously (Midathetic, 5 mg/ml;
Amoun pharmaceuticals, Egypt). Group A patients
received atropine 0.5 mg intravenously (Atropine,
1 mg/ml; Misr Pharmaceuticals, Egypt), patients
of group B received atropine 0.3 mg intravenously,
and patients of group C received 0.1 mg atropine
intravenously.
The patients were observed visually during the
treatment inside the treatment room through a closed
audio video circuit. All patients were monitored
by pulse oximetry (Homedics Px-100 Deluxe) for
arterial oxygen saturation and pulse rate throughout
the treatment. The patients were observed for
hypersalivation manifested by drooping of secretions
Atropine in gamma knife radiosurgery Elazzazi and Saleh 337
from the nose or mouth, gargling sounds, the need for
suctioning, or stridor.
Demographic features (age, sex, body weight) and
duration of treatment were recorded. Heart rate was
recorded just before start of the injection of intravenous
ketamine and atropine, and 1, 5, 10, and 20 min after
injection. With regard to the occurrence of increased
secretions, the aforementioned events were considered
as increased secretions, if happened.
Statistical analysis
Sample size was calculated using Epilnfo version 6.0,
setting the type-1 error () at 0.05 and the power
(1-B) at 0.8. Calculation produced a minimal sample
size of 40 cases in each group.
Data were analyzed using statistical program for
social science (SPSS version 18.0; SPSS Inc., Chicago,
Illinois, USA). Quantitative data were expressed
as mean SD. Qualitative data were expressed as
frequency and percentage.
The following tests were conducted: a one-way analysis
of variance when comparing between more than two
means; and 2-test of significance was used to compare
proportions between two qualitative parameters.
P-value of less than 0.05 was considered significant,
P-value of 0.01 was considered as highly significant,
and P-value of more than 0.05 was considered
insignificant.
Results
The study included 120 patients (75 male and 45
female), who were randomly divided into three equal
groups according to the atropine dose (0.5, 0.3, and 0.1
mg, respectively). All patients underwent gamma knife
radiosurgery for brain tumors.
With regard to age, sex, body weight of patients,
baseline hemodynamic data, and duration of
treatment, no statistically significant differences
were found among the three groups (P > 0.05)
(Table 1).
Only one patient (2.5%) in group A (who received
atropine 0.5 mg), and two patients (5%) in group B
(who received atropine 0.3 mg), had increased
secretions, whereas 15 patients (37.5%) had increased
secretions in group C (who received atropine 0.1 mg).
Comparison between the three groups showed that
the incidence of increased secretions was significantly
lower in groups A and B than in group C (P < 0.05)
(Table 2) (Fig. 1).
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338 Ain-Shams Journal of Anesthesiology

Table 1 Patients age, sex, body weight, baseline heart rate, blood pressure, respiratory rate, and duration of treatment
Parameters Mean SD ANOVA
Group A Group B Group C F P-value
Age (years) 37.75 11.76 41.00 11.61 39.88 10.47 0.854 0.428
Sex [N (%)]
Female 19 (47.5) 14 (35) 12 (30) 2 = 2.772 0.250
Male 21 (52.5) 26 (65) 28 (70)
Body weight (kg) 76.50 11.56 80.13 9.90 79.38 13.12 1.088 0.340
Baseline HR/min 79.75 6.40 80.13 4.73 77.25 10.06 1.781 0.173
Systolic BP 126.38 7.76 129.88 13.28 125.63 11.78 1.646 0.197
Diastolic BP 75.00 6.41 78.13 6.86 76.75 9.37 1.673 0.192
Baseline RR/min 15.53 1.57 16.55 2.14 15.90 2.18 2.739 0.089
Duration of treatment (min) 34.83 8.75 39.10 7.78 37.28 7.64 2.825 0.073
ANOVA, analysis of variance; BP, blood pressure; HR, heart rate.

Table 2 Relation among groups with regard to the number Figure 1

of cases with increased secretions
Secretions N (%) A and A and B and
B C C
Group A Group B Group C
Yes 1 (2.50) 2 (5.00) 15 (37.50) >0.05 0.003 0.001
No 39 (97.50) 38 (95.00) 25 (62.50)
Total 40 (100.00) 40 (100.00) 40 (100.00)
2 23.922
P-value <0.01

After administration of the medications, group A

patients had significant increase in heart rate (P<0.05),
whereas patients of groups B and C had statistically
nonsignificant increase in heart rate (P > 0.05)
(Table3).
Relation among groups with regard to the number of cases with
increased secretions.

Discussion
Administration of atropine as an antisialagogue to
patients receiving ketamine sedation for gamma knife
radiosurgery was an effective technique to reduce
hypersalivation induced by ketamine. The doses of 0.5
and 0.3 mg of atropine showed nearly the same efficiency
in decreasing secretions, but the dose of 0.1mg atropine
did not prevent the increase in secretions in 15 patients
in group C (37.5% of patients). Atropine dose 0.3 mg
also caused significantly lower incidence of tachycardia
than the dose of 0.5 mg, which was used in group A
patients.
Heinz et al. [5] conducted a prospective, randomized,
double-blind study, including a total of 83 patients, aged
13 months14.5 years, who required ketamine procedural
sedation in a tertiary emergency department. Patients
were randomized to receive 0.01 mg/kg of atropine
or placebo. All received 4 mg/kg of intramuscular
ketamine. Hypersalivation occurred in 11.4% of
patients administered atropine compared with 30.8%
of patients administered placebo. They concluded that
ketamine sedation was successful and well tolerated
in all cases, and the use of atropine as an adjunct
for intramuscular ketamine sedation in children
significantly reduces hypersalivation.
Brown et al. [6] conducted a prospective observational
study over 3 years on 1090 pediatric patients who
received ketamine sedation in the emergency
department, and they used 100-mm visual analogue
scale to rate excessive salivation. Of the 1090
ketamine sedations, 947 were administered without
adjunctive atropine, and surprisingly, their results
showed that 92% of these subjects had salivation
score of 0 mm.
Green et al. [7] published a secondary analysis of an
observational database of 8282 ED ketamine sedations
assembled from 32 studies. They compared the relative
incidence of adverse events including airway adverse
events and laryngospasm (most probably owing
increased secretions) between children who received
atropine, glycopyrrolate, or no anticholinergic. Their
results showed that glycopyrrolate was associated
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Atropine in gamma knife radiosurgery Elazzazi and Saleh 339

Table 3 Comparison between three groups with regard to changes in heart rate
Groups Mean SD P-value
Baseline 1 min 5 min 10 min 20 min
Group A 79.75 6.40 86.72 11.40 94.63 14.18 86.11 10.36 80.60 7.86 <0.01
Group B 80.13 4.73 83.01 7.78 83.93 11.96 82.09 9.86 80.90 7.01 >0.05
Group C 77.25 10.06 81.00 11.86 79.11 9.92 80.63 7.06 78.30 5.61 >0.05
P-value of group A was highly significant with regard to the increase in heart rate and is indicated in bold.

with significantly more airway and respiratory adverse significantly less tachycardia. More studies are needed
events than either atropine or no anticholinergic. to confirm this finding.

Another clinical study was conducted by Islam

et al. [8] to evaluate the effect of different atropine
doses on heart rate during reversal of nondepolarizing
neuromuscular blockade. They divided the patients
into three groups (A, B, and C) according to the dose
of atropine administered (0.02, 0.015, and 0.01 mg/kg,
respectively). They recommended the use of atropine
0.015 mg/kg during reversal of neuromuscular
blockade, because group B patients who received this
dose had significantly less tachycardia than group A,
and less secretions than group C.
To the best of our knowledge, this is the first clinical
study on different atropine dose as an antisialagogue,
as adjunct to ketamine sedation in adults undergoing
gamma knife radiosurgery.
Conclusion
Atropine 0.3 mg was the least effective dose that
significantly reduced hypersalivation in patients
receiving ketamine sedation for gamma knife
radiosurgery. This dose was significantly much more
effective in decreasing secretions than the dose of 0.1
mg, and as efficient as the dose of 0.5 mg, but with
Acknowledgments
Conflicts of interest
None declared.
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