Research Report

Journal of International Medical Research

2016, Vol. 44(4) 817–823
Anticholinergic ! The Author(s) 2016
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premedication-induced fever sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/0300060515595649
in paediatric ambulatory imr.sagepub.com

ketamine anaesthesia
Kyung Woo Kim1, Won Joo Choe2,
Jun Hyun Kim2, Kyung-Tae Kim2,
Sang-Il Lee2, Jang Su Park2, Jung Won Kim2
and Min Hee Heo2

Abstract
Objective: A randomized, double-blind, prospective study to evaluate the effect of anticholinergic
drugs on thermoregulation in paediatric patients undergoing ambulatory anaesthesia with ketamine.
Methods: Patients were randomized to receive either 0.005 mg/kg glycopyrrolate or the
equivalent volume of normal saline (placebo) at 30 min before ketamine anaesthesia. Body
temperature was measured tympanically at baseline and at 0, 30, 60 and 90 min postoperatively.
The quantity of saliva prodiced during surgery and incidence of fever were recorded.
Results: Body temperature was significantly higher in the glycopyrrolate group (n ¼ 42) than the
placebo group (n ¼ 42) at 30, 60 and 90 min after surgery, and higher than baseline at 0, 30, 60 and
90 min after surgery. In the placebo group, body temperature was significantly higher than baseline
at 0 and 30 min after surgery. Saliva secretion was significantly lower in the glycopyrrolate group
than the placebo group.
Conclusion: Routine premedication with adjunctive anticholinergics should not be considered in
paediatric patients receiving ketamine sedation due to the increased risk of fever.

Trial registration number, Clinicaltrials.gov: NCT02430272

Keywords
Child, outpatient, adverse events, premedication, intravenous agents

Date received: 9 April 2015; accepted: 16 June 2015

1
Department of Anaesthesia and Pain Medicine, Inje Corresponding author:
University Seoul Paik Hospital, Seoul, Republic of Korea Won Joo Choe, Inje University Ilsan Paik Hospital, 2240
2
Department of Anaesthesia and Pain Medicine, Inje Daehwa-dong, Ilsan Seo-gu, Goyang-si, Gyeonggi-do,
University Ilsan Paik Hospital, Gyeonggi-do, Republic of Republic of Korea.
Korea Email: [email protected]

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818 Journal of International Medical Research 44(4)

Introduction medications used routinely in these patients

Ketamine has been widely used in minor (including Hartmann’s solution, normal
procedures for children for its quick sedative saline, adjunctive anticholinergics, ketamine
and analgesic effects with minimal impact on and anti-inflammatory analgesic drugs),
airway reflexes and respiratory depression.1 anticholinergics alone are reported to cause
However, adverse effects such as nausea, fever as an adverse effects.7,8 Ketamine
vomiting, rash, emergence reactions, has also been reported to cause fever, but
increased bronchial secretions and hypersa- this is not generally regarded as an
livation have also been related to ketamine adverse event.12 The other listed medica-
sedations.2,3 Increased bronchial and oral tions (fluid and anti-inflammatory drugs)
secretions hinder oral and bronchial-related are used to treat fever, and are not the
procedures, and the suction to remove cause.13
excessive mucosal secretions can result in The aim of this study was to evaluate the
laryngospasm.2,3 Therefore, adjunctive anti- fever-causing effects of adjunctive anti-
cholinergics, such as atropine or glycopyr- cholinergics in children under ambulatory
rolate, have been used prior to ketamine anaesthesia using ketamine.
administration. Anticholinergics are used as
a premedication in oral or bronchial pro- Patients and methods
cedures because they reduce mucosal
secretions and the resulting reflexive
Study population
bronchospasms, thereby preventing vagus- This randomized, double-blind, placebo-
induced bradycardia and improving surgical controlled, prospective study recruited
visibility.4–6 However, anticholinergics sequential paediatric outpatients aged
inhibit muscarinic acetylcholine receptors, 12 months – 8 years who were scheduled
exerting antimuscarinic actions such as dry for procedures requiring ketamine sedation
mouth and fever. Thermoregulation is more (including v-tube insertion, simple incision
dependent on sweating in children than in for cyst removal, and frenuloplasty of the
adults, and children may be more suscep- tongue) between May and December 2014
tible to higher body temperatures after at the Department of Anaesthesia and Pain
injection of anticholinergics.7–9 Medicine, Inje University Ilsan Paik
Delayed discharge of paediatric patients Hospital, Gyeonggi-do, Republic of Korea.
due to postsurgical fever is frequently Inclusion criteria were: (i) American Society
observed in patients anaesthetized with of Anaesthesiologists class I14; (ii) surgery
ketamine and adjunctive anticholinergics. performed between 08.00 and 09.00 (to
Fever accounts for 4.7% of complications minimize variation due to body temperature
in paediatric outpatients after surgery,10 and fluctuations and duration of preoperative
may be caused by underlying disease, fasting). Patients who required endotracheal
dehydration after preoperative fasting, or intubation due to respiratory failure during
medication. Surgery is usually postponed in the procedure and patients who received
paediatric patients with fever or cold symp- medications other than ketamine were
toms, reducing the likelihood that under- excluded.
lying conditions cause fever in this patient Written informed consent was obtained
group. Although dehydration after pre- from the parents or guardians of the patients,
operative fasting can cause fever,11 the fact and the study protocol was approved by the
that body temperature was normal before Institutional Review Board of Inje University
surgery suggests that fasting is unlikely to Ilsan Paik Hospital, Gyeonggi-do, Republic
be the cause of fever in these cases. Of the of Korea.
Kim et al. 819

Figure 1. Consort flow diagram for patient enrolment into a randomized controlled clinical trial to evaluate
the fever-causing effects of adjunctive anticholinergics in children under ambulatory anaesthesia using
ketamine.

Study design of the study. Oxygen was supplied via nasal

Patients were randomly assigned between cannula, blood pressure and oxygen satur-
two groups (using http://randomization. ation were monitored, and heart rate
com): glycopyrrolate- group (group G), was monitored via electrocardiogram. The
and saline (control) group (group N; second researcher (M.H.H.), who was
Figure 1). After randomization, a single blinded to the experimental grouping of
researcher (K.W.K.) prepared the study the subjects, measured body temperature at
drugs (0.005 mg/kg glycopyrrolate [Tabinul 0, 30, 60 and 90 minutes after surgery.
injection 0.2 mg/ml; Hana Pharm Co. Ltd., The quantity of oral secretion produced
Seoul, Republic of Korea], or the same during the procedure was recorded by a
volume of saline [placebo]) in a blinded third researcher (J.H.K.), using a Visual
manner. Another researcher (M.H.H.) mea- Analogue Scale (VAS) by indicating a pos-
sured the body temperature of the patient ition from 0 mm (no secretion) to 100 mm
prior to surgery using a tympanic thermom- (maximum secretion); the distance from 0
eter (Braun ThermoScan IRT 4520, Braun (in mm) was then measured by the first
GmbH, Germany) three times in each ear, researcher (K.W.K.). The fluid infusion rate
and recorded the highest value as the body was increased when the body temperature of
temperature for that patient. The second the patient exceeded 37.8 C, and antipyr-
researcher (M.H.H.) then administered the etics were administered when fever contin-
prepared study drugs. Ketamine (1 mg/kg ued after body temperature measurements
initial dose, 5–10 mg additional dose, intra- were completed. Fever was defined as body
venous bolus) was used for sedation, and no temperature >37.8 C at more than one
other drugs were administered until the end time point.
820 Journal of International Medical Research 44(4)

Table 1. Demographic and clinical data of paediatric patients undergoing ambulatory anaesthesia with
ketamine sedation and receiving either 0.005 mg/kg glycopyrrolate intravenously or the same volume of saline
preoperatively (control group).

Glycopyrrolate group Control group Statistical

Characteristic n ¼ 42 n ¼ 42 significancea

Sex, male/female 22/20 23/19 NS

Age, years 3.5  1.6 3.7  2.2 NS
Weight, kg 16.7  3.8 17.7  6.8 NS
Duration of surgery, min 6.7  3.1 7.6  4.0 NS
Ketamine dose, mg/kg 3.1  0.6 2.9  0.9 NS
Baseline temperature,  C 37.0  0.3 37.0  0.2 NS
Postoperative feverb 14 4 P ¼ 0.02
Total intravenous fluid, ml 97.4  44.1 76.1  32.6 P ¼ 0.03
Oral secretion volume, VAS 35.3  14.3 44.8  19.5 P ¼ 0.02

Data presented as n, or mean  SD.

NS, not statistically significant (P  0.05); VAS, visual analogue scale (mm).
a
Independent t-test.
b
Temperature  37.8 C at more than one time point.

Statistical analyses group N (23 males/19 females; mean age

A preliminary study with ten paediatric 3.7  2.2; age range 1 – 8 years). Demographic
patients indicated that around 30% of and clinical characteristics of the patients are
patients receiving anticholinergics devel- shown in Table 1. There were no significant
oped postoperative fever, compared with between group differences in age, gender,
4.7% of the control group. The incidence of weight, duration of surgery, ketamine dose
a type I error was 0.05 and a type II error or preoperative body temperature. The inci-
was 0.2. Based on these parameters, 42 dence of postoperative fever and total volume
patients were required in each group (84 of intravenous fluid administered were signifi-
patients in total). cantly higher, and the quantity of oral secre-
Data were presented as n or mean  SD. tions was significantly lower in group G than
Between group comparisons were made group N (P ¼ 0.02, P ¼ 0.03 and P ¼ 0.02,
using independent t-test, with repeated respectively; Table 1).
measures analysis of variance used to evalu- Data regarding mean postoperative body
ate between group differences in body tem- temperature are shown in Figure 2. Overall,
perature. All statistical analyses were mean body temperature was significantly
performed using MedcalcÕ version 14.8.1 higher in group G than group N (P ¼ 0.001).
for WindowsÕ (MedCalc Software, Ostend, In addition, mean body temperature was
Belgium). P-values < 0.05 were considered significantly higher in group G than group N
to be statistically significant. at 30, 60 and 90 min after surgery (P < 0.05
for each comparison, Figure 2). In group G,
mean body temperature was significantly
Results higher than baseline at all postoperative
The study recruited a total of 84 patients, time points (0, 30, 60 and 90 min; P < 0.05
who were randomized between group G for each comparison, Figure 2), In group N,
(n ¼ 42; 22 males/20 females; mean age mean body temperature was significantly
3.5  1.6 years; age range 1 – 7 years) and higher than baseline at postoperative 0 and
Kim et al. 821

Figure 2. Body temperature in paediatric patients undergoing ambulatory anaesthesia with ketamine
sedation and receiving either 0.005 mg/kg glycopyrrolate intravenously (group G, n ¼ 42) or the same volume
of saline preoperatively (group N, n ¼ 42). Body temperature was measured tympanically before surgery
(baseline), and at 0, 30, 60 and 90 minutes postsurgery. *P ¼ 0.001 between glycopyrrolate and placebo group;
y P < 0.05 vs control group at same time point; z P < 0.05 vs baseline in same group; repeated measures
analysis of variance.

30 min (P < 0.05 for each comparison, after surgery. Of clinical importance, how-
Figure 2), but not significantly different ever, was the significantly higher incidence of
from baseline at 60 and 90 min. fever in patients treated with anticholinergic
drugs than those in the placebo group.
The definition of fever used in the present
Discussion study was a tympanic temperature of 37.8 C.
Premedication with an anticholinergic drug Fever is generally defined as a rectal tempera-
resulted in increased postoperative body tem- ture of >38 C, but the routine use of a rectal
perature compared with placebo in the pre- thermometer is challenging and tympanic
sent study. This finding could be regarded as thermometers are preferred. Temperatures
clinically negligible because the overall mean measured using tympanic thermometers
body temperature of both groups was 37 C – have been reported to be 0.1–0.2 C lower
37.5 C, a small difference from the baseline than those measured using a rectal thermom-
body temperature (37.0 C), and requiring no eter.15,16 We used a declining body tempera-
treatment. Higher body temperatures per- ture <37.8 C as one of our discharge criteria
sisted until 90 min after surgery in patients in order to ensure the safety of our patients.
treated with anticholinergic drugs in the As expected, the quantity of oral secretions
current study, whereas temperatures in the was significantly lower in the anticholinergic-
placebo group returned to baseline by 60 min treated group than the placebo group,
822 Journal of International Medical Research 44(4)

although there were no secretion-associated be limited to procedures that require a high

complications observed in any patient. The level of secretion suppression.
increased amount of suction required to deal
with the greater volume of oral secretions in
the placebo group did not increase the dur- Declaration of conflicting interests
ation of the procedure. The total volume of The authors declare that there is no conflict of
administered fluid was higher in the antic- interest.
holinergic-treated group compared with the
placebo group, due to the increase in infusion
of fluids when fever was present. Funding
The effectiveness of adjunctive anticholin- This research received no specific grant from any
ergics prior to sedation is unclear, and rou- funding agency in the public, commercial, or not-
tine administration of anticholinergics in for-profit sectors.
procedures such as bronchoscopy has been
viewed skeptically.17,18 Some recommend the References
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