|Year : 2016 | Volume
| Issue : 2 | Page : 195-200
Effect of intrathecal hyperbaric bupivacaine with small dose clonidine versus hyperbaric bupivacaine alone in lower abdominal surgeries: A comparative study
Amit Tyagi1, Shivani Rastogi1, Manoj Tripathi1, Rajlaxmi Bhandari2, Prateek Singh Bais1, Mahendra Singh1
1 Department of Anesthesia and Critical Care, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Anesthesia and Critical Care, VPIMS, Lucknow, Uttar Pradesh, India
|Date of Web Publication||26-Apr-2016|
G/A, Saubhagya Apartments, Sector-A, Mahanagar, Lucknow - 226 007, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Context: The continued success of regional anesthetic techniques can be credited due to improved local anesthetic drugs, with lower toxicities and longer duration of action, but still many efforts are being done to increase the duration of the block and postoperative analgesia. Therefore, use of adjuvant drugs for anesthesia is intended to prolong analgesia and preventing deleterious clinical effects of local anesthetics.
Aims: The present study is designed to evaluate effects of intrathecal hyperbaric bupivacaine versus hyperbaric bupivacaine with low dose clonidine on the onset and level of sensory and motor block, the intensity of motor blockade, and time of analgesia required in the postoperative period.
Settings and Design: Study area were our operation theater and postanesthesia care unit of Department of Anesthesiology, this was a prospective, randomized, placebo-controlled, and double-blind study for a period of 1 year comprising of 60 patients.
Materials and Methods: Patients were randomly allocated into two groups: Group 1 (S) (n = 30): Patients received intrathecal hyperbaric bupivacaine 12.5 mg with normal saline 0.5 ml and Group 2 (C) (n = 30): Patients received intrathecal hyperbaric bupivacaine 12.5 mg with 1 μg/kg clonidine (approximated to 0.5 ml with normal saline).
Statistical Analysis: Two groups were compared by Student's t-test, Chi-square test; ANOVA and significance of mean difference bet were done by Newman–Keuls test.
Results and Conclusion: Duration of analgesia was prolonged in Group C (363.07 ± 166.30 min) patients compared to Group S patients (226.95 ± 119 min) and they also required less top up analgesic in the postoperative period.
Keywords: Clonidine, α-agonist, hyperbaric bupivacaine, Wilson's sedation score
|How to cite this article:|
Tyagi A, Rastogi S, Tripathi M, Bhandari R, Bais PS, Singh M. Effect of intrathecal hyperbaric bupivacaine with small dose clonidine versus hyperbaric bupivacaine alone in lower abdominal surgeries: A comparative study. Anesth Essays Res 2016;10:195-200
|How to cite this URL:|
Tyagi A, Rastogi S, Tripathi M, Bhandari R, Bais PS, Singh M. Effect of intrathecal hyperbaric bupivacaine with small dose clonidine versus hyperbaric bupivacaine alone in lower abdominal surgeries: A comparative study. Anesth Essays Res [serial online] 2016 [cited 2020 Jul 6];10:195-200. Available from: http://www.aeronline.org/text.asp?2016/10/2/195/172723
| Introduction|| |
The word pain is derived from Greek term “poine” meaning “penalty.” Pain is also defined as a complex multidimensional human perception which is thought to be an emotion rather than a sensory modality. Melzack and Wall proposed the gate control theory of pain in 1965. The gate theory of pain has had considerable influence on anesthesiologist's management of pain by focusing attention on the unique pharmacology of dorsal horn of spinal cord. Anesthesiologist's have learnt to suppress nociceptive transmission at the first synaptic relay in the spinal cord by using intrathecal and epidural injections in lower abdominal surgeries. Use of adjuvant drugs for anesthesia is intended to improve the success of regional anesthesia by prolonging analgesia of local anesthetics and preventing deleterious clinical effects of their toxic doses. Since long time intrathecal opioids have been used extensively to treat pain, despite their universal ability to alleviate pain with less hemodynamic instability, spinal opioids have certain unpleasant side effects such as nausea, vomiting, pruritis, urinary retention, respiratory depression, and tolerance. Clinicians and investigators have been looking at opioids alternative, where α-2 adrenergic agonist are one of the most studied nonopioids, nonlocal anesthetics, pain modulatory systems in recent years. With the introduction of dexmedetomidine in recent times, a more potent α-2 agonist than clonidine, there is increased use of these drugs as adjuvants for spinal anesthesia. This study is designed to evaluate effects of intrathecal hyperbaric bupivacaine alone versus intrathecal low dose clonidine with hyperbaric bupivacaine in lower abdominal surgeries.,
| Materials and Methods|| |
“A comparative study of intrathecal hyperbaric bupivacaine with small dose clonidine versus hyperbaric bupivacaine alone in lower abdominal surgeries,” was a prospective, randomized, placebo-controlled double-blind study for a period of 1 year comprising of 60 patients, undertaken from May 2009 to May 2010 in our Institute of Medical Sciences, Lucknow, Uttar Pradesh, India. After approval of Ethical Committee, patients were explained regarding nature of the study and written informed consent was taken. Inclusion criteria: American Society of Anaesthesiologists (ASA) Grades I and II, age >_20–<_60 years, either sex, elective surgery, weight >45 kg and <75 kg. Exclusion criteria: Patients who are not willing to participate in study, patient of Classes III and IV, any contraindication to subarachnoid block such as blood disorders, anatomical abnormalities, allergy to drug under study, patient of age <20 years of age and >60 years, weight <45 and >75 kg, any emergency surgery, patients with severe psychiatric disorders, depression and dementia, on drugs, which could interfere with comprehension of the study. Patients were randomly allocated into two groups: Group S (n = 30): Patients received intrathecal hyperbaric bupivacaine 12.5 mg with normal saline 0.5 ml. Group C (n = 30): Patients received intrathecal hyperbaric bupivacaine 12.5 mg with 1 µg/kg clonidine (approximated to 0.5 ml with normal saline). All patients underwent thorough preanesthetic check-up including relevant history and systemic examination. On a day before surgery, vitals were examined, and investigation reports checked. All patients were thoroughly screened for any previous medication and drug therapy for concomitant medical problems, which was continued as deemed appropriate by an anesthesiologist. After shifting patient in the preoperation room, an intravenous (i.v.) cannula was inserted and patients were preloaded with crystalloid of choice (10–12 ml/kg) 15 min prior to the procedure. The monitoring of following parameters, noninvasive blood pressure (NIBP), heart rate (HR), electrocardiogram (ECG), oxygen saturation (SpO2), respiratory rate, was started after taking the patient into operation theater (baseline values were noted). NIBP was measured at 5 min interval for first 30 min thereafter every 30 min until completion of surgery. HR, SpO2, ECG, respiratory rate were monitored continuously. Under all aseptic precautions, lumbar puncture was performed at L3–4 intervertebral space in the midline, with the patient in sitting position, by using 25-gauge Whitacre needle. After free flow of cerebrospinal fluid, 3 ml of anesthetic solution was administered over 10 s. Time of onset, the upper level of sensory block and intensity of motor block (modified Bromage scale – [Table A]) was recorded at 2 min interval for first 20 min, and then every 5 min for next 30 min and 15 min thereafter until motor block was recovered.
Total duration of analgesia was assessed by time of administration of the first injection of analgesic in the postoperative period till need for analgesic injection was assessed by visual analog scale scoring system.
Hypotension (fall in >20% of baseline mean arterial pressure [MAP]) was treated with 3 mg increments of injection mephentermine mg i.v. Bradycardia (HR <50 beats/min) was treated with injection atropine 0.3–0.6 mg i.v. Respiratory depression was defined as rate of <8 breath/min and SpO2 <92% in room air. Intra- and post-operative pain were checked whenever patient complained of discomfort or pain, expressed on VAS. Intra- or post-operative hypotension, bradycardia, nausea, vomiting, shivering, urinary retention, postdural puncture headache were also recorded. To assess the level of sedation produced by clonidine, a modified Wilson sedation scale (MWSS), an observer based sedation scale was used. It is quick and easy to use, by defining clear sedation endpoints and can be used for determining sedation during regional anesthesia.
The sedation level of each patient was assessed twice during the case, first at a minimum of 15 min and secondly after 30 min and thereafter 1 hourly until patient is shifted to respective wards. The criteria to shift patient from postanesthesia care unit toward as per Aldrette's postoperative discharge scoring system.
| Observations and Results|| |
In our study, as in [Graph 1], there was no statistically significant difference between groups regarding mean age, weight, height, sex ratio, and ASA physical status. Thus, the groups were comparable in demographic parameters. No significant difference in HR between two groups was seen at any time interval (P > 0.05). No significant difference in systolic BP (SBP) of two groups was seen at any time interval except that at 10 min when mean SBP of the study group was found to be significantly lower as compared to control group. A significant difference in diastolic BP (DBP) of two groups was seen at 10 min, 30 min and 1 h with study group showing lower values as compared to control group (P < 0.05). As shown in [Table 1], no significant difference in MAP of two groups was seen at any time interval except at 10 min when mean MAP of the study group was found to be significantly lower as compared to control group (P = 0.012). The mean of MAP was at baseline (pre), it reached to its minimum at 10 min in the study group and at 30 min in control group thereafter it started showing a gradual increase. However, the MAP did not reach to its baseline status at the end of follow-up (2 h).
|Table 1: Comparison of mean arterial pressure in two groups at different time intervals|
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As shown in [Table 2], the mean MWSS at 15 min time interval in both groups was 1.0 ± 0.0, showing no statistically significant difference. At 30 min onward mean MWSS in study group started to increase while in the control group it remained stable. A statistically significant difference between two groups was seen from 30 min onward (P < 0.001). The patients were sedated to that extent where they could be woken up by calling their respective name or a gentle ear tug on the right side. As shown in [Table 3] and [Table 4], the mean modified Bromage scale score at 2 min in study group was 5.87 ± 0.35 while in control group it was 6.0 ± 0.0 showing a statistically significant difference between two groups (P = 0.040). The mean score in study group was found to be significantly lower as compared to study group up to 5 min time interval. From 10 min onwards both the groups had mean Bromage Scale of 1.0 ± 0. In our study, as in [Graph 2], 22 patients required analgesia after >5 h (55%), 12 patients between 3 and 5 h (30%), 5 patients in 2–3 h (12.5%), and 1 patient in <2 h (2.5%) in postoperative period in clonidine group. Twenty-one patients in Group S demanded for top up analgesia in 2–3 h, after the block was given (52.5%), 11 patients required top up analgesia between 3 and 5 h (27.5%) while 6 patients asked for analgesia 5 h (15%).
|Table 2: Comparison of modified Wilson sedation scale in two groups at different time intervals|
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|Table 4: Comparison of Bromage scale in two groups at different time intervals|
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| Discussion|| |
Recent trends for lower abdominal and orthopedic surgery show increased acceptance of regional anesthesia. General anesthesia is associated with higher morbidity and longer hospitalization in comparison to regional anesthesia; however regional anesthesia also needs careful selection of patients. However, side effects such as delayed respiratory depression have prompted further research to develop nonopioid analgesics. Intrathecal clonidine is being extensively evaluated as an alternative to neuraxial opioids for control of pain and has proven to be a potent analgesic, free of some of opioids related side effects., Local anesthetic bupivacaine acts mainly by blockage of voltage-gated Na + channels in axonal membrane. It also interferes with synaptic transmission by presynaptic inhibition of Ca ++ channels in addition to their effect on nerve conduction. On other hand, clonidine is a specific α-2 receptor agonist; α-2 receptors are present within both presynaptic and postsynaptic terminals of primary afferent nociceptive neurons within the dorsal horn of the spinal cord. Spinal α-2 receptors agonist alter pain transmission by binding presynaptically to nociceptive Aδ and C fiber terminals and reducing neurotransmitter release, and postsynaptically by hyperpolarizing second-order neurons within the dorsal horn. Therefore, a combination of these effects may explain the synergism between bupivacaine and clonidine found in our study.
In this study, there were not much significant changes in HR, SBP, or MAP as compared to the control group. Although there was a significant difference in the DBP between the two groups, but this parameter did not affect our study significantly because no active therapeutic intervention was needed during perioperative period. To support our result, the data obtained from Sethi et al. 2007 indicated that addition of 1 µg/kg of clonidine to 0.5% bupivacaine prolongs analgesia. Even though a statistically significant decrease in MAP and HR was noted in clonidine group compared to control group, none of the patients required any therapeutic intervention for either. Hemodynamic and analgesic profile after intrathecal clonidine in humans: A dose response study conducted by Filos et al. concluded that clonidine reduced MAP compared with baseline only in Group 1 (21% ± 13%, P < 0.05). Delayed hypotension or bradycardia was not encountered after any of the three dose studies (150 [Group 1], 300 [Group 2], or 450 [Group 3] µg clonidine). After 300 and 450 µg intrathecal clonidine a relative hemodynamic stability is observed, suggesting a presser effect at peripheral sites with larger doses.
Our results of onset time of sensory block showed that there was faster onset in clonidine group 3.73 ± 1.3 min compared to control group 5.60 ± 1.6 min. Our findings are in tandem with those of Van Tuijl et al. Their study came to a conclusion that 71% of the patients, who received low dose clonidine (15 µg) and hyperbaric bupivacaine for spinal anesthesia achieved optimal time of onset of analgesia, that is within 5 min of intrathecal injection, compared with only 54% in control group. They also found that increasing the clonidine dose to 30 µg did not increase time of onset. Kanazi et al. 2006 in their study concluded that combination of 12 mg of intrathecal bupivacaine with low dose of 3 µg of dexmedetomidine or 30 µg of clonidine significantly shortened the onset of motor block. Which is further supported by Fournier et al., that a slightly shorter onset of action was observed with the sufentanil (7.5 µg) + clonidine (30 µg) mixture when compared to sufentanil (7.5 µg) used alone in patients undergoing total hip replacement.
In this study, median, upper level of sensory block achieved was higher (T6) in clonidine group as compared to control group (T8) which is in support with Dobrydnjov et al., while comparing three groups; (i) Group B with low dose bupivacaine 0.5%; (ii) Group BC15 with bupivacaine 0.5% + clonidine 15 µg; and (iii) Group BC30 with bupivacaine 0.5% + clonidine 30 µg, during spinal anesthesia for inguinal herniorrhaphy, concluded in their study that cephalad spread of sensory block on dependent side was significantly higher (2–4 dermatomes) in Group BC15 (P < 0.05) and BC30 (P < 0.02) compared to Group B. The study also showed that patients who received intrathecal clonidine had more intensified motor blockade compared to control group. Eisenach et al. in their clinical review of clonidine (1984–1995) for regional anesthesia confirmed above finding that clonidine enhances both sensory and motor blockade from epidural and peripheral nerve block of local anesthetics. They also concluded that clonidine prolongs and intensifies anesthesia from epidural local anesthetic without increasing hypotension during surgical epidural anesthesia. Strebel et al. observed a significantly larger proportion of patients with intense motor blockade that resolved after 8–10 h in patients who received 150 µg intrathecal clonidine compared with control group in a dose response study for small dose intrathecal clonidine and isobaric bupivacaine for orthopedic surgery. The explanation for this could be that α-2 adrenoceptor agonist induce a cellular modification in ventral horn of spinal cord (motorneuron hyperpolarization) and facilitate local anesthetic action (Bonnet et al. 1990). Improved perioperative analgesia after co-administration of clonidine and bupivacaine can be explained by the synergistic inhibitory action of clonidine (α-2 adrenergic agonist) and bupivacaine (a local anesthetic) on Aδ and C-fiber conduction, presynaptic and postsynaptic, respectively. This suggests that clonidine does potentiates or prolong neuronal blockade effects of local anesthetic, by reducing vascular uptake and thereby maintaining a higher concentration of lidocaine near neuronal tissues for a longer period of time. Our results were supported by Van Tuijl et al., they demonstrated that addition of 75 µg clonidine to hyperbaric bupivacaine prolongs spinal analgesia and the motor block after cesarean section and improves analgesia. They also concluded that this effect was obtained without clinically relevant maternal or neonatal side effect (Van Tuijl et al.; 2006)., The results of Kaabachi et al. indicated that clonidine is an effective adjuvant to bupivacaine in spinal anesthesia in adolescents. At a dose of 1 µg/kg of body weight, clonidine prolonged the duration of sensory block achieved with bupivacaine 0.2–0.3 mg/kg by 30 min, motor block by 60 min, and postoperative analgesia by 120 min. These results were in tandem with their previous experience in younger children, where clonidine 2 µg/kg was used as an adjuvant to bupivacaine 5 mg/ml for spinal anesthesia. However, in adolescents, clonidine 1 µg/kg of body weight seems to be more appropriate dosage. In fact, a dose of 2 µg/kg clonidine added to bupivacaine seems to cause more frequent and severe bradycardia and hypotension than that observed in the present study. D'Angelo et al. studied effects of spinal clonidine administered with spinal sufentanil and bupivacaine on labor analgesia using combined spinal-epidural technique and conclude that clonidine significantly prolongs labor analgesia from spinal sufentanil and bupivacaine without producing serious adverse effects. In their study, clonidine 50 µg significantly prolonged labor analgesia from sufentanil 7.5 µg and bupivacaine 2.5 mg and they reported 197 min of labor analgesia in the study. This difference of postoperative regression of motor and sensory blockade in comparison to our study could be due to increased amount of bupivacaine 0.5% in our study.
Clonidine affects the electroencephalogram in a variety of ways: It increases slow-wave activity (delta) and attenuates the physiological alfa fluctuations.,, In a study by Hall et al. on a sedative, analgesic and cognitive effects of clonidine infusions in humans demonstrated significant sedation without analgesia and hypotension when using clonidine at lower doses. By and large good sedation was seen that was easily overcome by calling patients name in a normal or loud voice. The present study sedation results were supported by Sethi et al. in which the incidence of sedation as assessed by sedation score, was higher in clonidine group than in control group, even 3–6 h after injection which was statistically significant (P < 0.001).
| Results|| |
A prospective, double-blind, randomized study was done to compare and evaluate the effect of intrathecal hyperbaric bupivacaine with low dose (1 µg/kg) clonidine for lower abdominal and orthopedic surgeries. We found that both groups were comparable demographically with respect to age, weight and sex. We concluded that mean time of onset of sensory block was faster in patients who received intrathecal clonidine (3.73 ± 1.3 min) compared to control patients (5.9 ± 1.6 min) with maximum upper level of sensory block attained T6 in both groups. Thus mean value of the highest level of block was comparable in two groups. On other hand intensity of motor blockade was better in clonidine group patients compared to control patients. These all factors increased duration of analgesia in clonidine group (363.07 ± 166.30 min) compared to control group (226.95 ± 119 min) and they also required less top up analgesic in postoperative period. There was a significant fall in MAP in study group after 10 min of subarachnoid procedure as compared to control group. Sedation of different quality was observed during and after the surgery in study group without any respiratory depression or any decrease in SpO2. When interviewed regarding patients satisfaction in spinal anesthesia all patients in clonidine group were satisfied while in control group patients remained dissatisfied. The present study revealed that when clonidine in low doses 1 µg/kg was added to hyperbaric bupivacaine 12.5 mg, leads to faster onset and intense sensory and motor blockade. The duration of postoperative analgesia was also prolonged without any remarkable side effects such as severe hypotension, bradycardia, respiratory depression, shivering, xerostomia, nausea, vomiting, backache or a headache. Thus, overall combined effect of intrathecal clonidine-bupivacaine is far superior over bupivacaine alone.
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| References|| |
Miller RD. Miller's anesthesia. 6th ed. Vol. I, Ch.1, Sec. 1. Philadelphia: Elsevier Churchill Livingstone. 2005. p. 9-25.
Caplan RA, Ward RJ, Posner K, Cheney FW. Unexpected cardiac arrest during spinal anesthesia: A closed claims analysis of predisposing factors. Anesthesiology 1988;68:5-11.
Gustafsson LL, Friberg-Nielsen S, Garle M, Mohall A, Rane A, Schildt B, et al.
Extradural and parenteral morphine: Kinetics and effects in postoperative pain. A controlled clinical study. Br J Anaesth 1982;54:1167-74.
Eisenach JC, Marc KD, Klimscha W. Alpha sub 2-adrenergic agonists for regional anaesthesia: A clinical review of clonidine (1984-1995). J Am Soc Anesthesiol 1996;85:1-38.
Rathmell JP, Lair TR, Nauman B. The role of intrathecal drugs in the treatment of acute pain. Anesth Analg 2005;101 5 Suppl: S30-43.
Sethi BS, Sameul M, Sreevastava D. Efficacy of analgesic effect of low dose intrathecal clonidine as adjuvant to bupivacaine. Indian J Anesth 2007;51:415-9.
Chiari A, Lorber C, Eisenach JC, Wildling E, Krenn C, Zavrsky A, et al.
Analgesic and hemodynamic effects of intrathecal clonidine as the sole analgesic agent during first stage of labor: A dose-response study. Anesthesiology 1999;91:388-96.
Van Tuijl I, Giezeman MJ, Braithwaite SA, Hennis PJ, Kalkman CJ, van Klei WA. Intrathecal low-dose hyperbaric bupivacaine-clonidine combination in outpatient knee arthroscopy: A randomized controlled trial. Acta Anaesthesiol Scand 2008;52:343-9.
Kanazi GE, Aouad MT, Jabbour-Khoury SI, Al Jazzar MD, Alameddine MM, Al-Yaman R, et al.
Effect of low-dose dexmedetomidine or clonidine on the characteristics of bupivacaine spinal block. Acta Anaesthesiol Scand 2006;50:222-7.
Fournier R, Van Gessel E, Weber A, Gamulin Z. Epinephrine and clonidine do not improve intrathecal sufentanil analgesia after total hip replacement. Br J Anaesth 2002;89:562-6.
Dobrydnjov I, Axelsson K, Thörn SE, Matthiesen P, Klockhoff H, Holmström B, et al.
Clonidine combined with small-dose bupivacaine during spinal anesthesia for inguinal herniorrhaphy: A randomized double-blinded study. Anesth Analg 2003;96:1496-503.
Strebel S, Gurzeler JA, Schneider MC, Aeschbach A, Kindler CH. Small-dose intrathecal clonidine and isobaric bupivacaine for orthopedic surgery: A dose-response study. Anesth Analg 2004;99:1231-8.
Bonnet F, Boico O, Rostaing S, Loriferne JF, Saada M. Clonidine-induced analgesia in postoperative patients: Epidural versus intramuscular administration. Anesthesiology 1990;72:423-7.
Mensink FJ, Kozody R, Kehler CH, Wade JG. Dose-response relationship of clonidine in tetracaine spinal anesthesia. Anesthesiology 1987;67:717-21.
Van Tuijl I, van Klei WA, van der Werff DB, Kalkman CJ. The effect of addition of intrathecal clonidine to hyperbaric bupivacaine on postoperative pain and morphine requirements after Caesarean section: A randomized controlled trial. Br J Anaesth 2006;97:365-70.
Grandhe RP, Wig J, Yaddanapudi LN. Evaluation of bupivacaine-clonidine combination for unilateral spinal anaesthesia in lower limb orthopedic surgery. J Anaesthesiol Clin Pharmacol 2008;24:155-8.
Kaabachi O, Ben Rajeb A, Mebazaa M, Safi H, Jelel C, Ben Ghachem M, et al.
Spinal anesthesia in children: Comparative study of hyperbaric bupivacaine with or without clonidine. Ann Fr Anesth Reanim 2002;21:617-21.
Kaabachi O, Zarghouni A, Ouezini R, Abdelaziz AB, Chattaoui O, Kokki H. Clonidine 1 microg/kg is a safe and effective adjuvant to plain bupivacaine in spinal anesthesia in adolescents. Anesth Analg 2007;105:516-9.
D'Angelo R, Evans E, Dean LA, Gaver R, Eisenach JC. Spinal clonidine prolongs labor analgesia from spinal sufentanil and bupivacaine. Anesth Analg 1999;88:573-6.
Fehr SB, Zalunardo MP, Seifert B, Rentsch KM, Rohling RG, Pasch T, et al.
Clonidine decreases propofol requirements during anaesthesia: Effect on bispectral index. Br J Anaesth 2001;86:627-32.
Bischoff P, Plümer L, Scholz J, Drögemeier K, von Knobelsdorff G, Schulte Am Esch J. Effect of remifentanil on clinical and electroencephalographic parameters of depth of anesthesia in balanced anesthesia with propofol, enflurane or isoflurane. Anaesthesiol Reanim 1998;23:116-23.
Hall JE, Uhrich TD, Ebert TJ. Sedative, analgesic and cognitive effects of clonidine infusions in humans. Br J Anaesth 2001;86:5-11.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]