Download Clonidine Infusions

Pediatric Anesthesia 2008
18: 217–222
doi:10.1111/j.1460-9592.2008.02413.x
Intravenous clonidine infusion in infants after
cardiovascular surgery
A N J A P O H L- S C H IC K IN GE R M D * , JU L IA LE M M E R M D †,
M I C H A E L H Ü B L E R M D ‡, V L A D I M I R A L E X I - M E S K I S H V I L I
M D , P h D ‡, M A T T H I A S R E D L I N M D § , F EL I X BE R G ER M D , P h D –
A N D B R I G I T TE S T I L L E R M D , P h D #
*Department of Neonatology, University Hospital Charité, †Department of Congenital Heart
Disease, Deutsches Herzzentrum Berlin, ‡Department of Cardiothorathic and Vascular Surgery,
Deutsches Herzzentrum Berlin, §Department of Anesthesia, Deutsches Herzzentrum Berlin and
–Department of Congenital Heart Disease, Deutsches Herzzentrum Berlin and Charité,
University Children¢s Hospital, Berlin, Germany, #Department of Congenital Heart Disease,
Deutsches Herzzentrum Berlin and Childrens University Hospital, Freiburg, Germany
Summary
Background: The aim of this study was to investigate the hemodynamic profile and heart rhythm in infants who were given
intravenous clonidine infusion after prolonged analgesia ⁄ sedation
following cardiac surgery.
Methods: This is a single center retrospective review. A total of 542
cardiovascular surgical procedures in infants aged 0–24 months with
congenital heart disease were performed between 01 ⁄ 2003 and
12 ⁄ 2005 at the Deutsches Herzzentrum in Berlin. The majority
received no long-term analgesia ⁄ sedation, but 50 (9%) of these infants
received clonidine (dosed at 0.18–3.6 lgÆkg)1Æh)1) for sedation and to
reduce withdrawal symptoms such as CNS hyperactivation, hypertension, tachycardia, and fever. The hospital records of these infants
were studied.
Results: Fifty infants (median age 5.0 months, median body weight
5.3 kg, 32 males ⁄ 18 females) received prolonged analgesia ⁄ sedation to
ensure hemodynamic stability. Clonidine infusion started on day 5
(median) after surgery. During clonidine treatment we found an agerelated normalized profile of hemodynamic parameters with a
reduction of heart rate and mean arterial pressure from the upper
norm to the mean within 24 h (P < 0.001). In no case did clonidine
cause low blood pressure resulting in additional therapy to reach the
target blood pressure. There were no adverse effects on cardiac
rhythm, especially no onset of atrioventricular block. Midazolam,
fentanyl, and other opioids could be ended on day 4 of clonidine
treatment.
Conclusions: Although off-label, it is feasible to use clonidine infusions
in infants in the PICU setting after cardiac surgery without hemodynamic problems arising.
Keywords: cardiovascular surgery; clonidine; infants; withdrawal
Correspondence to: Anja Pohl-Schickinger, Department of Neonatology, Campus Virchow Klinikum, University Hospital Charité,
Augustenburger Platz 1, 13353 Berlin, Germany (email: [email protected]).
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Journal compilation 2008 Blackwell Publishing Ltd
217
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A . P O H L - S C H I C K I N G E R ET AL .
Introduction
Cardiac surgery has achieved major improvements
within the last decade. Nowadays, an increasing
number of severe congenital cardiac diseases can be
surgically corrected within the first year of life.
Concurrently, the majority of patients can be extubated early after surgery without the need for
prolonged analgesia ⁄ sedation.
However, when procedures are complicated by
longer duration of surgery, postoperative hemodynamic instability, pulmonary hypertensive crises,
primary elective open sternum, capillary leak syndrome, or junctional ectopic tachycardia, the need
for analgesia and sedation for several days to
guarantee hemdynamic stability may be inevitable.
Withdrawal is a common side-effect after prolonged
administration of benzodiazepines and opioids for
postoperative sedation and analgesia (1). Clonidine,
a partial a-2 adrenoreceptor agonist with antihypertensive, analgesic, and sedative properties (2),
decreases the dose requirements of sedatives and
facilitates opioid withdrawal (3). Several studies
describe the beneficial effects of clonidine for premedication in pediatric anesthesia (4), prolongation of
postoperative analgesia as a supplement to regional
anesthesia (5) and treatment of emergence delirium
(6,7). The safe use of oral clonidine for routine
sedation in the pediatric intensive care unit in
combination with morphine and lorazepam has
been reported in children with respiratory failure
(3).
The objective of this retrospective study was to
evaluate the efficacy of continuous intravenous (i.v.)
clonidine infusion in reducing benzodiazepine and
opioid withdrawal symptoms regarding hemodynamic safety in neonates and infants with congenital
heart defects early after cardiac surgery.
Methods
Between 2003 and 2005 a total of 542 cardiovascular
surgical procedures were performed in children
aged 0–24 months with congenital heart disease at
the Deutsches Herzzentrum in Berlin. While approximately 90% of these patients are extubated early
postoperatively, long-term sedation and analgesia
are occasionally unavoidable to ensure hemodynamic stability. Fifty of these children (32 males,
18 females) were treated with i.v. clonidine for
symptoms of withdrawal (including agitation, hypersalivation, tachycardia, hypertension, and fever)
after prolonged (>24 h) treatment with midazolam
and fentanyl.
Midazolam was used for premedication in all
cases. General anesthesia and relaxation were
induced with fentanyl, midazolam, and norcuronium. All patients were intubated and ventilated with
normal blood gases. All had a urinary bladder
catheter, a central venous catheter and a radial or a
femoral artery catheter. In patients who required
more complex monitoring, catheters were placed
surgically in the left atrium and ⁄ or the pulmonary
artery to enable continuous measurement for several
days.
The hospital records of these patients were
reviewed. The data collected included demographics, anatomic diagnosis, details of surgery,
and postoperative course. Means of heart rate, mean
arterial blood pressure (MAP), core temperature,
nutrition, infusion of midazolam, fentanyl and additional sedative or analgesic medication was
documented on the day before clonidine was
started, 2–4 h after the start of clonidine and daily
during clonidine treatment, for a maximum of
5 days. Minimal heart rate and cardiac rhythm were
documented for the whole time of clonidine usage.
Descriptive statistics are reported as medians with
25–75th interquartile ranges (IQR). Statistical analysis was performed using SPSS 12.0 (Chicago, IL, USA).
Nonparametric Friedman test was used to compare
several samplings. The nonparametric Wilcoxon test
was then applied to test for differences between the
parameters before and during clonidine treatment.
Significance was established at P < 0.05.
Results
Fifty infants and young children with a median age
of 5.0 months (IQR, 3.0–9.0) received clonidine for a
median of 3 days (IQR, 2–5). Clonidine treatment
was started 5 days (IQR, 2–6) after cardiac surgery.
At this time, 38 patients received midazolam with
a median dosage of 7.58 lgÆkg)1Æmin)1 (IQR, 1.26–
11.22) and 17 patients fentanyl (median 0.0 lgÆkg)1Æ
min)1, IQR, 0.0–0.1 lgÆkg)1Æmin)1). The highest infusion rate of midazolam was 16.9 lgÆkg)1Æmin)1 and
the highest fentanyl infusion rate 0.27 lgÆkg)1Æmin)1.
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd, Pediatric Anesthesia, 18, 217–222
I .V . C L O N I D I N E A F T E R C A R D I A C S U R G E R Y
Table 1 shows general patient data and the number
of patients receiving clonidine on each of the 5 days.
Diagnoses and surgical procedures are listed in
Table 2. There were six patients with Down syndrome, one with Williams-Beuren syndrome and six
former preterm infants. Clonidine was reduced
when symptoms of withdrawal such as agitation,
hypersalivation, vomiting, tachycardia, hypertension, and fever diminished. The shortest duration
of clonidine administration was 14 h. Six patients
received clonidine for longer than 5 days, the
longest duration of clonidine administration being
18 days. The reason for termination of clonidine was
improvement of withdrawal symptoms in nearly all
patients. In two patients clonidine was stopped after
reintubation and in one patient after sinus bradycardia (55 bpm) that resolved spontaneously within
seconds. Before clonidine was started, sinus rhythm
was present in 47 patients. Three patients had
external pacemaker treatment for slow atrioventricular node rhythm, atrioventricular dissociation, and
first-degree atrioventricular block, respectively.
There was no adverse effect of clonidine on the
cardiac rhythm, in particular no new onset of
atrioventricular block. The one patient with
atrioventricular dissociation regained sinus rhythm
during treatment with clonidine. In no case did
clonidine cause low blood pressure resulting in
additional inotropic need to reach the target blood
pressure.
219
Table 2
Diagnoses and surgical procedures
Cardiac diagnoses
d-TGA
CAVSD
TOF ⁄ DORV
TA
VSD ± ASD
Cc-TGA, AS, PS, VSD, ASD
CoA
CoA, ASD, VSD
HLHS, CoA
HLHS
ALCAPA
CAVSD, TGA, PS
AS, PS, PFO
Aortopulmonary window
PA
PA, VSD, TGA
DAA
Cardiomyopathy
MVR, TVR
Number
of patients
1
9
10
4
11
1
1
1
1
2
1
1
1
1
1
1
1
1
1
Surgical procedures
Arterial switch
Correction
Correction
Glenn ⁄ shunt
Closure
PABa
End-to-end repaira
End-to-end repair, closure
Aortic arch repair,
Damus-Kaye-Stansel
operation, A-P-shunt
Norwood I ⁄ II
Correction, Berlin Heart
Glenn
Correction
Correction
Correction
A-P-shunt
Correctiona
Berlin Heart
TR, MR
a
Operations without cardiopulmonary bypass.
d-TGA, d-transposition of great arteries; CAVSD, complete
atrioventricular septal defect; TOF, tetralogy of fallot; DORV,
double outlet right ventricle; TA, tricuspid atresia; VSD, ventricular septal defect; ASD, atrial septal defect; Cc-TGA, congenitally
corrected transposition of great arteries; AS, aortic stenosis; PS,
pulmonary stenosis; CoA, coarctation of the aorta; HLHS, hypoplastic left heart syndrome; A-P-shunt, aortopulmonary shunt;
ALCAPA, anomalous left coronary artery from pulmonary artery;
PFO, patent foramen ovale; PA, pulmonary atresia; DAA, doubled
aortic arch; MVR, mitral valve regurgitation; TVR, tricuspid valve
regurgitation; PAB, pulmonary arterial banding; AP, aortopulmonary; TR, tricuspid reconstruction; MR, mitral reconstruction.
Table 1
Description of the study group
Age (months), median (IQR)
Body weight (kg), median (IQR)
Body height (cm), median (IQR)
Sex (male ⁄ female)
Days on ventilation, median (IQR)
Days on ventilation with
clonidine, median (IQR)
Postoperative start of clonidine
treatment (day), median (IQR)
Duration of clonidine
treatment (days), median (IQR)
Number of patients on clonidine
2–4 h
Day 1
Day 2
Day 3
Day 4
Day 5
IQR, interquartile range.
5.0
5.3
61.0
32
7
2
(3.0–9.0)
(4.0–6.6)
(55.0–68.8)
⁄ 18
(5–9)
(1–3)
5 (2–6)
3 (2–5)
50
49
39
27
19
14
The effects of clonidine on MAP, heart rate, and
core temperature are shown in Table 3. Milk intake
rose from 22 mlÆkg)1 day)1 before clonidine treatment to 54 mlÆkg)1 day)1 on day 5 (P < 0.009 for
each day of treatment, data not shown).
Nineteen patients were extubated during clonidine treatment. Reintubation was necessary in four
of them. Seven patients received clonidine while
already breathing spontaneously.
There was a significant reduction in midazolam
(2–4 h after start of clonidine until day 2, Table 4),
fentanyl (2–4 h after start of clonidine until day 4,
P < 0.05) and other opioids (day 1 and day 2,
P < 0.05). The number of patients receiving midazolam infusion diminished from 38 before clonidine
treatment to 16 on day 1. In the further course, the
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd, Pediatric Anesthesia, 18, 217–222
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A . P O H L - S C H I C K I N G E R ET AL .
MAP
(mmHg)
Previous day
2–4 h
Day 1
Day 2
Day 3
Day 4
Day 5
60
53
55
55
55
59
55
(55–68)
(50–59)
(50–60)
(50–64)
(52–64)
(51–63)
(52–63)
Heart rate
(bÆmin)1)
P
138
124
120
120
120
120
125
0.000
0.000
0.005
0.291
0.080
0.221
(125–152)
(111–140)
(112–130)
(111–129)
(112–130)
(106–130)
(108–131)
P
0.000
0.000
0.000
0.000
0.007
0.054
Temperature (C)
37.3
37.1
37.1
37.2
37.2
37.2
37.5
(36.9–37.7)
(36.6–37.3)
(36.8–37.5)
(36.8–37.4)
(37.0–37.5)
(36.8–37.7)
(37.3–37.8)
P
Table 3
Parameters in the course of
clonidine treatment
0.004
0.001
0.013
0.579
0.527
0.482
The median and interquartile range of mean arterial blood pressure, heart rate (bÆmin)1) and
central temperature the day before and up to 5 days after the start of clonidine infusion are shown.
The P-values indicate the level of significance for a decrease between the day before infusion and
the given day.
Table 4
Doses of clonidine and midazolam in the course of clonidine
treatment
Clonidine
(lgÆkg)1Æh)1)
Previous day
2–4 h
Day 1
Day 2
Day 3
Day 4
Day 5
1.50
1.44
1.37
1.20
1.34
1.14
(1.20–1.80)
(0.63–1.80)
(0.71–1.80)
(0.81–1.80)
(0.63–2.33)
(0.69–2.19)
Midazolam
(lgÆkg)1Æmin)1)
7.58
3.01
0.00
0.00
0.00
0.00
0.00
(1.26–11.22)
(0.00–8.01)
(0.00–3,76)
(0.00–0.00)
(0.00–0.00)
(0.00–0.00)
(0.00–0.00)
P
0.000
0.000
0.000
0.000
0.000
0.003
The doses of clonidine and midazolam are shown as median and
interquartile range. The P-values indicate the level of significance
for a decrease of the midazolam dose between the day before
clonidine treatment and the given day.
number of patients receiving midazolam further
decreased and there was no patient with midazolam
treatment on day 5. Two patients still had fentanyl
infusion on day 1; there was no patient with fentanyl
infusion from day 3 to day 5. There was no influence
of clonidine on the administration of nonopioid
analgesics.
Discussion
Oral clonidine given as premedication causes
anxiolysis and sedation and provides perioperative
hemodynamic stability in adults. Nishina et al.
(8,9) reproduced these beneficial effects in children
aged 5 years and older. It was shown that oral
clonidine given in a dose of 4 lgÆkg)1 significantly
reduced the intraoperative instability of blood
pressure and heart rate. While the majority of
studies examined the use of clonidine as
coanalgesic prior to surgery (3), its use in children
as an i.v. sedative in the postoperative course has
not been sufficiently investigated. Ambrose et al.
(2) found that i.v. clonidine in combination with
midazolam can provide dose-dependent sedation
in ventilated critically ill children without adverse
effects on cardiovascular performance. Children
enrolled in their study were aged 10 years and
under. Our study confirms their findings in
younger children.
The onset of withdrawal symptoms with a median
of 5 days (IQR, 2–6) after surgery is comparable with
recently published data on current UK sedation
practice in pediatric intensive care units (10). This
study reports an incidence of withdrawal of between
5% (intubated patients after cardiac surgery, median
age 0.42 years, IQR: 0.06–3) and 15% (intubated
noncardiac patients, median age 1.5 years, IQR:
0.42–7). We observed an incidence of 9% in our
study group, which has a median age of 5 months
(IQR, 3–9).
The consensus guidelines on sedation and analgesia in critically ill children recommend a dose of
i.v. clonidine of 0.1–2 lgÆkg)1Æh)1 (11). Our findings
suggest that continuous i.v. clonidine in 0- to 24month-old postoperative cardiac surgical patients
may be safe and efficacious. It provides hemodynamic stability in this group of patients at high risk
for cardiac failure because of complex congenital
heart defects. We showed that i.v. clonidine facilitates a quick and significant reduction of midazolam, fentanyl, and other opioids, and can
significantly minimize symptoms of withdrawal by
normalizing MAP, heart rate, and core temperature.
As our patients suffer from cardiac disease, the body
temperature was lowered by antipyretics and
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd, Pediatric Anesthesia, 18, 217–222
I .V . C L O N I D I N E A F T E R C A R D I A C S U R G E R Y
mechanical cooling to prevent elevated oxygen
demand and higher cardiac index.
The appearance of atrioventricular block has been
repeatedly described as a side-effect of clonidine
(12,13). In our study, we did not experience any
serious adverse effects of clonidine in a dose of 0.18–
3.6 lgÆkg)1Æh)1 on cardiac rhythm and in particular
no higher degree of atrioventricular block. Only one
patient developed sinus bradycardia during clonidine treatment; this lasted only a few seconds and
resolved spontaneously. As clonidine elimination
half-time ranges from 6 to 24 h, a causal relationship
between clonidine and bradycardia seems unlikely
in this context.
The reduction of MAP and core temperature was
highly significant until the third day after the start of
clonidine, the decrease and normalization of the
heart rate until the fourth day. For patients with a
good response to clonidine the treatment usually
lasted <5 days. For later days the statistics do not
exhibit a significant decrease, because the number of
patients still receiving clonidine decreased from 50
to 19.
The respiratory depressant effect has been described in clonidine poisoning of children (12–15) but
clonidine does not potentiate opioid-induced respiratory depression (16). Although randomized studies have shown that clonidine administered via the
caudal route does not affect respiratory function (17–
20), there are several case reports describing apnea
in preterm infants, ex-preterm infants and neonates
in connection with caudal clonidine (21–24). In
adults, clonidine infusion has no statistically significant effect on cardiorespiratory variables (25). We
found no major respiratory depressant effect, as the
reintubation rate was not higher than that normally
found in this patient group.
Other drugs used for treating withdrawal in
pediatric intensive care units are morphine, chloral
hydrate, paracetamol or other NSAID, diazepam,
fentanyl with midazolam and odanstron with dexamethason, named in descending frequency (10).
Also there is growing interest in the use of dexmedetomidine, a complete a-2 adrenoreceptor agonist that has a shorter half-life (2–3 h) and limited
effects on hemodynamic and respiratory function
(26).
To summarize, we studied the use of i.v. clonidine
in 0- to 24-month-old children for the treatment of
221
withdrawal after cardiac surgery. Clonidine
decreased the symptoms of withdrawal by lowering
MAP, heart rate, and core temperature. There was a
significant effect in terms of reduction of opioid
analgesics and no side-effects on cardiac rhythm.
Therefore, we consider the use of continuous i.v.
clonidine for the treatment of withdrawal to be safe.
There are several limitations. As this study was
not conceived in prospective form, no validated
scores have been used to quantify withdrawal
symptoms. It lacks a placebo-matched control group,
which makes it impossible to discriminate the
natural process after surgery in these children.
Nevertheless, the hemodynamic profile of these
young and hemodynamically critical clonidinetreated infants may provide helpful information,
especially as clonidine, often used in pediatric
intensive care units, is still off-label. Prospective,
randomized studies are needed to corroborate our
conclusions.
Acknowledgement
We thank Ms. Anne Gale, medical editor, for
editorial assistance.
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Accepted 18 October 2007
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd, Pediatric Anesthesia, 18, 217–222