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Incidence of hypotension and bradycardia in dose-response intrathecal

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 Vol. 2 (1), pp. 029-033, June, 2015.
Global Journal of Anesthesiology and Plastic Surgery © Global Science Research Journals
http://www.globalscienceresearchjournals.org/

Full Length Research Paper

Incidence of hypotension and bradycardia in dose-

response intrathecal clonidine: A prospective study
Thiago Mamoru Sakae
UNISUL - Universidade do Sul de Santa Catarina, Campus Tubarão. Address: Av Marcolino Martins Cabral, sn, Centro,
Tubarão-SC, Brazil. Zip code: 88701-900

E-mail: thiagosakae@gmail.com

Accepted 2 June, 2015

Abstract

Background: The anesthesia provided by bupivacaine alone may be too short for the planned surgery.
The addition of clonidine 0.5 – 2ug/kg to bupivacaine provides a prolonged anesthetic action but may
be associated with hypotension. The objective of this study was to compare different doses of clonidine
in spinal block about hemodynamic effects, blockade duration and post operative analgesia.
Methods: Prospective cohort study, involving 262 spinal anesthetics.
Results: The mean time of achievement of motor block (Bromage 3) was significantly longer in the
clonidine (low and high doses)+morphine groups compared with just morphine group (p<0.001, p<0.01,
respectively). The motor block regression time was significantly longer in clonidine high dose group
(p<0.05). The postoperative analgesia was significantly longer in clonidine + morphine group compared
with morphine group (p<0.001). Requirement of additional analgesia was greater in just morphine group
(p<0.01) and was not significantly different between the two clonidine groups (p=0.431). Hypotension
had higher incidence in clonidine low dose group (p=0.003) and the ephedrine dose was lower in high
dose clonidine group (p=0.12). Bradycardia was associated with low dose clonidine and age (p=0.048).
Discussion: Intrathecal clonidine addition in high dose demonstrate lower incidence of hypotension but
not prolongs post operative analgesia. The dose used intrathecally demonstrate a correlation with
hypotension incidence.

Keywords: Anaesthesiology, spinal anesthesia, clonidine, hypotension, bradycardia, multivariate analysis,

linear regression

INTRODUCTION

Clonidine, an imidazoline derivative, is a partial agonist of are associated with many side effects such as pruritis,
α2-adrenergic receptors, interacts with local anesthetics nausea, vomiting, urinary retention, and especially late
in the neural axis. The analgesic effect of the drug is and unpredictable respiratory depression.(3-6) This has
quite evident, due to its action on spinal and supraspinal directed the research toward the use of newer and better
a2-adrenergic receptors (CNS), including activation of α2 local anesthetic additives for spinal anesthesia (SA) such
postsynaptic receptors from noradrenergic descending as neostigmine, ketamine, midazolam, and clonidine.(5,6)
pathways of cholinergic neurons and the release of nitric Intrathecal clonidine 0.5–2 mcg/kg (7,8) prolongs the
oxide.(1,2) sensory block achieved with bupivacaine. Previous
Opioids such as morphine, fentanyl, and sufentanil studies have described the use of clonidine in a wide
have been administered intrathecally as adjuncts to range (15-150mcg).(9-11) Some studies shown that low
increase the duration of postoperative analgesia. fixed doses of clonidine (15 to 50 mcg)(11-13) prolongs
Although they ensure superior quality of analgesia, they the sensory block and improves post operatory analgesia.
Glob. J. Anesthesiol. Plast. Surg. 030

Others papers recommended higher doses of clonidine bradycardia evaluated as heart rate below 50 beats per
(75 to 150mcg) (14,15) to not change cephalad spread minute (bpm). When heart rate was equal to or lower
and hemodynamic effects of spinal anesthesia and than 45 bpm or when there was hemodynamic instability,
improves post operatory analgesia. intravenous atropine (0.5 to 1.0mg) was administered.
No ideal clonidine dose has yet been found that can Motor block onset and intensity according to Bromage’s
produce optimum analgesia with minimum side effects. criteria(16) (grade 0: ability to raise lower limbs without
Therefore, the present study has been planned to bending the knees; grade 1: ability to raise lower limbs
investigate whether the addition of different dosages (15 bending the knees; grade 2: ability to bend feet only; and
to 150mcg) of intrathecal clonidine to hyperbaric grade 3: total lower limbs immobility.
bupivacaine increases the duration of post-operatory Postoperative pain intensity evaluated by the Pain
analgesia and its hemodynamic effects. Analog Visual Scale (0 = absence of pain; 10 = maximum
possible pain) when patients requested analgesic
medication for the first time. Analgesic medications
METHODOLOGY standard were tramadol 50 mg or nalbuphine 10mg.
Patients not requesting analgesics were submitted to the
The study was performed after obtaining approval from pain scale at Post-Anesthetic Recovery Unit (PACU)
the Medical Research Ethics Committee of the institution discharge.
(CEP number 023/2013). This was a single-blind, For statistical analysis, the software used was
observational, prospective, which consecutively included Statistical Package for Social Sciences (SPSS) 15.0
262 patients, both gender, physical status ASA 1 and 2, (Chicago, Illinois). Numerical variables were described by
undergoing elective to lower abdomen, plastic or lower mean and standard deviation (sd). Analysis of Variance
limbs surgery and receiving spinal anesthesia. Exclusion (ANOVA) was used to test numerical variables. For
criteria were: contraindications to spinal block, history of variables measured in ordinal scale to compare more
hypersensitivity to drugs used, previous administration of than two independent groups, ANOVA was followed by
opioids and/or other CNS depressants, body weight < 50 Post Hoc Dunnet C for multiple comparisons. Fisher’s
kilograms (kg), Body Mass Index (BMI) > 40kg/m2. Exact test or Chi-square test (X2) were used to compare
Patients were not premedicated. Venous puncture was proportions. Logistic Regression was used to analyze
performed in the operating room with a 18 or 20G multiple factor associated to hypotension and
catheter for 0.9% sodium chloride infusion (10 ml.kg- bradycardia. Linear regression was used to associate
1.h-1). Monitoring consisted of non-invasive blood numerical variables. Statistics were considered significant
pressure, ECG (5 lead) and also used for heart rate when p<0.05.
measurements, and pulse oximetry for hemoglobin
peripheral oxygen saturation. Before spinal puncture,
patients were medicated with midazolam 2-10mg and RESULTS
fentanyl 0.5-1.0mcg/kg endovenous (EV). Multimodal
analgesia was performed with tenoxicam 20-40mg or
ketoprofen 100mg. Spinal puncture was performed with The sample was compound by 262 spinal blocks, 42.4%
25 or 27G Quincke needle in L3-L4 interspace, with realized in male patients, mean age of 41.1 years old
patients in the sitting or lateral position. Bupivacaine (sd=14.4), mean weight of 73.9 kg (sd=14.5) and mean
0.5% hyperbaric was spinally administered combined to body mass index (BMI) of 26.2 kg/m2 (sd=4.6). There
morphine 0.5-1.0 ug/kg and clonidine in different doses were no differences among the groups about age, BMI,
(15-105mcg). Anesthesia records were consulted gender and type of surgeries (Table 1)
randomly after spinal block and all variables for the study The global incidence of hypotension was 33.6% and
were collected. Patients were classified in two groups bradycardia was 14.9%. The incidence of hypotension in
according to clonidine dose: low (15-60mcg) and high control group was 24.8%, in clonidine low dose group
(75-105mcg). After spinal anesthesia, patients returned to was 49.9%, and in clonidine high dose group was 24.2%
the supine position and the table was placed in 5º to 30º (p<0,001). Patients with hypotension used a lower dose
head-down position for the anesthetic block and the of clonidine (mean: 51.05mcg; sd: 23.43) compared to
highest level of dermatome was noted. that without hypotension (mean: 65.95mcg; sd: 25.19)
Intra and postoperative arterial hypotension, evaluated (p<0.001). In the same way, patients with lower dose of
as equal to or above 30% of initial systolic blood pressure clonidine need more ephedrine doses (mean: 20.87mg;
(SBP) or SBP lower than 90 mmHg. Arterial hypotension sd:10.18) compared to higher dose group (mean:
was initially treated by increasing lactated 16.18mg; sd:11.25) (p=0.12). The incidence of
Ringer’s/sodium chloride 0.9% solution and, when bradycardia in control group was 5.7%, in clonidine low
needed, with intravenous bolus of ephedrine (5 to 10 mg) dose group was 25.3%, and in clonidine high dose group
or metaraminol 0,250mg; Intra and postoperative was 14.5% (p<0,001).
 Sakae 031

Table 1: Demographic and clinical data

Variable Groups
Control Clonidine low dose Clonidine high dose
(N=105) (N=95) (N=62)
Age (years old) mean: 39.30 (sd:14.57) mean: 43.29 (sd:15.65) mean: 40.48 (sd:11.65)
Weight (kg) mean: 74.79 (sd:12.87) mean: 71.75 (sd:14.92) mean: 75.72 (sd:16.03)
Height (m) mean: 1.68 (sd:0.08) mean: 1.67 (sd:0.08) mean: 1.67 (sd:0.07)
2
Body Mass Index (kg/m ) mean: 26.42 (sd:4.03) mean: 25.52 (sd:4.67) mean: 27.01 (sd:5.03)
Gender
male 43.8% 47.4% 32.2%
female 56.2% 52.6% 67.7%
Surgeries*
orthopedic 27.6% 57.9% 38.7%
plastic 2.9% 18.9% 40.3%
general surgery 69.5% 23.2% 21.0%
ASA status*
I 73.3% 51.6% 33.9%
II 26.7% 41.4% 66.1%
Spinal anesthesia position
sitting 42.9% 33.7% 38.7%
left lateral 40.0% 44.2% 46.8%
right lateral 17.1% 22.1% 14.5%
Spinal anesthesia punction
median 33.3% 41.1% 27.4%
paramedian 66.7% 58.9% 72.6%
Bupivacaine dose mean: 10.56 (sd:2.63) mean: 13.06 (sd:2.18) mean: 13.40 (sd:2.03)
Morphine dose mean: 67.7 (sd:13.67) mean: 66.71 (sd:12.68) mean: 73.15 (sd:13.71)

*p<0.05

According to logistic regression, two variables were study, various clinical studies have shown that as the
associated independently to hypotension: male gender intrathecal dose of clonidine is increased, the incidence
and low dose clonidine group. In the same analysis, the of hypotension also increases.(10,17,18) Other studies
only factor associated to bradycardia was low dose (10,17), where the incidence of arterial hypotension was
clonidine group. (Table 2) significant when high-level spinal anesthesia was
When we analyze the linear regression, hypotension reached with the high clonidine dose (75 μg). With the
was independently associated to patient weight and low clonidine dose (45 μg) the incidence of arterial
surgery. Likewise, bradycardia was associated to age hypotension was intermediate, without significant
(Table 3). The surgery with high hypotension incidence differences as compared to control group or to clonidine
was general surgery (57.1%). 75ug group.(17) However, alpha2-agonist-induced
There have been significant differences among groups arterial hypotension is easily treated with α1-adrenergics
in pain intensity in the PACU (p<0.001) with lower values such as ephedrine, which show increased
for clonidine groups. Postoperative analgesia duration vasoconstriction response in the presence of such
was also significantly longer in clonidine groups (p<0.01). drugs.(18)
The number of patients needing postoperative analgesia A significant fall was observed in the arterial blood
was significantly lower in the groups receiving clonidine pressure after intrathecal clonidine administration in our
(Table 4). study. The fall in blood pressure occurred at 15–180 min
after spinal injection of clonidine. Other authors(11,19)
also recorded a significant decrease in MAP 15–240 min
DISCUSSION after spinal injection of clonidine and until 8 hours (20)
after intrathecal injection.
In this study, low/high clonidine dose increased Clonidine affects arterial blood pressure in a complex
postoperative analgesia, the spread and duration of manner because of opposing actions at multiple sites.
sensory block, duration of motor block, and time to first The α2-adrenergic agonists produce sympathicolysis and
analgesic request with higher incidence of hypotension reduce arterial blood pressure through effects at specific
and bradycardia as controllable side effects. brainstem nuclei and on sympathetic preganglionic
These results are consistent with a significant number neurons in the spinal cord, effects that are counteracted by
of previous studies.(7-9, 12, 13, 15) Different of our direct vasoconstriction resulting from the α2-adrenergic
Glob. J. Anesthesiol. Plast. Surg. 032

Table 2: Factors associated to Hypotension and Bradycardia by Logistic Regression

Variables Hypotension CI95% p
Adjusted Odds
Ratio (OR)
gender (male) 2.08 1.12 – 3.87 0.020*
age (years) 1.01 0.98 – 1.03 0.345
sitting position 1.62 0.69 – 3.79 0.268
paramedian puncture 0.83 0.44 – 1.56 0.568
bupivacaine dose (mg) 1.13 0.99 – 1.29 0.055
ASA I status 1.80 0.89 – 3.63 0.100
general surgery 1.65 0.81 – 3.34 0.162
clonidine low dose 3.22 1.48 – 7.05 0.003*
clonidine high dose 0.82 0.32 – 2.13 0.684

Variables Bradycardia CI95% p

Adjusted Odds
Ratio (OR)
gender (male) 0.48 0.21 – 1.09 0.078
age (years) 0.99 0.97 – 1.03 0.897
sitting position 0.49 0.17 – 1.42 0.193
paramedian puncture 0.92 0.41 – 2.08 0.841
bupivacaine dose (mg) 0.91 0.76 – 1.09 0.299
ASA I status 1.05 0.44 – 2.53 0.899
general surgery 0.59 0.22 – 1.58 0.298
clonidine low dose 4.99 1.63 – 15.29 0.005*
clonidine high dose 2.42 0.64 – 9.12 0.193
*p<0,05

Table 3: Linear regression of factors associated to hypotension and bradycardia

Hypotension
Variables Standardized Beta p
clonidine dose -0.173 0.044
bupivacaine dose 0.047 0.572
morphine dose 0.032 0.727
surgery -0.177 0.034*
weight -0.229 0.011*
age 0.146 0.085

Bradycardia
Variables Standardized Beta p
clonidine dose -0.077 0.394
bupivacaine dose 0.021 0.814
morphine dose 0.048 0.623
surgery -0.038 0.667
weight 0.010 0.919
age -0.178 0.048*
*p<0.05

agonists on the peripheral vasculature. Combining α2- bradycardia caused by such receptors’ agonists, one
adrenergic agonists with local anesthetic can potentially cannot exclude the participation of imidazoline I1
increase the degree of sympatholysis and the resulting receptors located in the reticular nucleus, the activation of which
hypotension. In spite of the evidences relating the caused by clonidine, which is an imidazoline derivative, may
activation of α2-adrenergic receptors to hypotension and determine bradycardia and arterial hypotension.(21)
 Sakae 033

Table 4: Duration of Analgesic and Motor Blocks

Groups
Control Clonidine low dose Clonidine high dose
(N=105) (N=95) (N=62)
Motor block duration (min)*
Grade 1 mean: 154.7 (sd: 50.2) †‡ mean: 193.3 (sd: 45.7) ‡ mean: 252.9 (sd: 54.8)
†‡ ‡
Grade 2 mean: 132.6 (sd: 37.4) mean: 188.4 (sd: 41.5) mean: 226.3 (sd: 50.7)
†‡ ‡
Grade 3 mean: 93.4 (sd: 38.2) mean: 126.8 (sd: 36.8) mean: 187.2 (sd: 43.4)
Pain Analog Visual Scale
†‡
in PACU (mean+sd) mean: 4.6 (sd: 3.4) mean: 2.4 (sd: 1.7) mean: 2.7 (sd: 3.1)
Need for additional 47.6%†‡ 33.6% 33.8%
analgesic
*Bromage scale
† p<0,05 to clonidine low dose
‡ p<0,05 to clonidine high dose

Our research has also shown that low/high clonidine to hyperbaric bupivacaine for spinal anesthesia increased
dose associated to hyperbaric bupivacaine for spinal the spread and duration of sensory block, duration of
anesthesia has not interfered with major advantages motor block, and time to first analgesic request with
obtained with this association, such as prolonged sensory minimum side effects. We observed that motor block
block and postoperative analgesia, with lower Pain regression was slower with increasing clonidine dose.
Analog Visual Scale scores and a lower number of Some studies evaluated peak sensory level and
patients needing additional analgesia in the PACU, as regression to T10 and found that it was comparable
compared to control group. among the groups. (11,15,17,20,23) Grandhe et al
Eisenach (3) found that clonidine associated to suggested that the dose of intrathecal clonidine (1
bupivacaine has also increased motor block level 3 mcg/kg) does not affect the peak sensory level. (20) This
duration, although shorter (32%) as compared to doses same clonidine dose prolonged the duration of sensory
above 75 μg (91%). It should be highlighted that motor block achieved with bupivacaine 0.2– 0.3 mg/kg by 30
block duration increase, which may be important in min, motor block by 60 min, and postoperative analgesia
surgeries needing good muscle relaxation, is always a by 120 min.(7)
factor of concern and discomfort in the postoperative Compared with morphine 100 mcg or clonidine 150
period. In addition, there has been no significant increase mcg alone, the combination of subarachnoid morphine
in motor blocks level 2 and 1 recovery time, with all 100 mcg and at least 60mcg of clonidine was found to
clonidine doses(3). This findings are similar to our study. increase the duration of postcesarean analgesia, reduce
Postoperative pain relief was better and prolonged in opioid requirement, and increase intraoperative
patients receiving intrathecal clonidine as compared to sedation.(24)
just morphine in our study. Although De Kock et al.
recommended a dose of 15–45 μg of clonidine as optimal
for supplementing spinal anesthesia. Other studies
CONCLUSION AND RECOMENDATION
(11,17,19,22) suggested that analgesia significantly
increases by 15 mcg of intrathecal clonidine, but In the conditions of this study, both doses of clonidine
increasing the dose further does not increase the associated to hyperbaric bupivacaine during spinal
duration of analgesia. Also, in neonates and adolescents, anesthesia have maintained their major association
some authors (7,8) describe that clonidine 1mcg/kg advantages which are: analgesic block duration and
seems to be the most appropriate dosage, because postoperative analgesia. However, the lowest clonidine
2mcg/kg of clonidine intrathecally was associated with a dose (<60 mcg) has significantly increased the incidence
frequent incidence of cardiovascular instability. of arterial hypotension and bradycardia.
Its analgesic effect is mediated spinally through
activation of post-synaptic α2 receptors in substantia
gelatinous of the spinal cord. It is known to increase both
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