Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 9  |  Issue : 4  |  Page : 524-530

Intravenous low-dose ketamine injection versus dexmedetomidine infusion for prevention of intraoperative shivering during spinal anesthesia


Department of Anesthesia, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission02-Mar-2015
Date of Acceptance08-Sep-2015
Date of Web Publication12-Jan-2017

Correspondence Address:
Mostafa Mansour Houssein
5 Abdelazem Salama Street, Nasr City, Cairo, 11727
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-7934.198266

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  Abstract 

Background
Shivering is considered one of the most common adverse effects that occur during spinal anesthesia. Besides causing patient discomfort, shivering also interferes with patient monitoring and increases tissue oxygen demand. The present study was carried out to compare the effectiveness of intravenous low-dose ketamine (0.25 mg/kg) and dexmedetomidine intravenous infusion in prevention of shivering during spinal anesthesia.
Materials and methods
Sixty patients of both sexes were included in this prospective randomized-controlled study. Patients were divided randomly into two groups of 30 patients each. Group K (30 patients) received low-dose ketamine (0.25 mg/kg) and group D (30 patients) received dexmedetomidine infusion. The primary outcome measure of this study was intraoperative shivering. The secondary outcome measures were hemodynamic changes, sedation scores, and postoperative side effects.
Results
Patients in group D had a lower incidence of postspinal anesthesia shivering compared with patients in group K. In all, 13.33% of group K patients had grade 3 shivering in comparison with only 3.33% of patients in group D 10 min after the onset of spinal anesthesia (P=0.031). Deeper sedation was observed in group D patients as 36.67% of group D patients had grade 4 sedation compared with 23.33% of patients in group K after 10 min (P=0.048).
Conclusion
Dexmedetomidine infusion is more effective as an antishivering and sedating agent than low-dose ketamine injection in patients receiving spinal anesthesia.

Keywords: dexmedetomidine, ketamine, shivering, spinal anesthesia


How to cite this article:
Houssein MM, Ibrahim IM. Intravenous low-dose ketamine injection versus dexmedetomidine infusion for prevention of intraoperative shivering during spinal anesthesia. Ain-Shams J Anaesthesiol 2016;9:524-30

How to cite this URL:
Houssein MM, Ibrahim IM. Intravenous low-dose ketamine injection versus dexmedetomidine infusion for prevention of intraoperative shivering during spinal anesthesia. Ain-Shams J Anaesthesiol [serial online] 2016 [cited 2017 Dec 13];9:524-30. Available from: http://www.asja.eg.net/text.asp?2016/9/4/524/198266

The study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12614001246673).



  Introduction Top


Shivering is considered one of the common complications that occur during spinal anesthesia and its incidence has been reported to reach up to 56.7% [1],[2]. Shivering leads to patient inconvenience and also interferes with monitoring of ECG, blood pressure, and oxygen saturation. It increases oxygen consumption and carbon dioxide production, and may lead to lactic acidosis. It also increases intracranial and intraocular pressures [3],[4].

The normal human core temperature usually ranges from 36.5 to 37.5°C [5]. Thermoregulation (which is a part of the homeostatic mechanism) is performed at the level of the anterior hypothalamus. The anterior hypothalamus compares the peripheral inputs with a threshold value or the set point. If the temperature was lower than this set point, this will activate certain reflexes to warm the body, whereas if the temperature was higher than this set point, this will trigger a cooling response [6].

Both cooling and warming responses are decreased during regional anesthesia, suggesting an affection in central, rather than peripheral control [7]. Impairment of centrally mediated thermoregulation by the local anesthetics is usually caused by alteration in the afferent thermal inputs from legs. All thermal inputs from the blocked regions are interrupted by regional anesthesia, which is primarily cold sensation. This decrease in cold sensation is then interpreted by the brain as relative leg warming [8].

Various methods are available to control shivering during anesthesia. These methods are either pharmacological or nonpharmacological. Pharmacological methods use drugs that have antishivering properties such as clonidine, pethidine, nefopam, tramadol, ketanserin, doxapram, etc. This method is cost effective, simple, and easy to implement. The nonpharmacological methods using equipment to maintain normal temperature of the body are effective, but expensive, and lack practicality.

Recently, ketamine and dexmedetomidine have been used to prevent shivering during anesthesia, with good results. Ketamine (a competitive NMDA receptor antagonist) plays a role in thermoregulation at various levels. The NMDA receptor modulates serotonergic and noradrenergic neurons in the locus ceruleus. It is used as an antishivering agent at a dose of 0.25–0.75 mg/kg intravenously. However, even at these doses, it causes side effects (i.e. drowsiness, delirium, hallucination) [9],[10].

Dexmedetomidine is a highly selective α-2-adrenergic receptor agonist with potent effects on the central nervous system [11],[12]. Although dexmedetomidine is among several pharmacological agents used for the treatment of shivering, its effects as antishivering during central neuroaxial blockade have not been evaluated to date.


  Aim of the study Top


The aim of this study is to compare between an intravenous low dose of ketamine and an intravenous infusion of dexmedetomidine for prevention of intraoperative shivering during spinal anesthesia.


  Materials and methods Top


This prospective randomized-controlled study was carried out at Ain-Shams University Hospital in the period from February 2013 to January 2014 after obtaining the approval of the local ethical committee. The study design was a parallel one with an active control group. The study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12614001246673). The date of registration was 27 November 2014, registered by Mostafa Mansour Houssein.

Sixty patients of both sexes between 20 and 50 years old undergoing elective lower abdominal surgery and elective orthopedic lower limb surgery were included in the study. Patients selected were American Society of Anesthesiologists (ASA) I and II physical status. After approval of the local ethics committee, all patients provided written consent to participate. Patients with thyroid disease, Parkinson’s disease, dysautonomia, Raynaud’s syndrome, cardiopulmonary disease, a need for blood transfusion during surgery, a history of allergy to the agents to be used, an initial core temperature greater than 37.5°C or less than 36.5°C, a known history of alcohol use, use of sedative–hypnotic agents, use of vasodilators, or having contraindications to spinal anesthesia were excluded from the study. All operation theaters in which the operations were performed maintained a constant humidity of 70% and an ambient temperature of around 23°C. Irrigation and intravenous fluids were administered at room temperature and without inline warming. No other warming device was used. A core temperature below 36°C was considered to indicate hypothermia. Before performing spinal anesthesia, each patient received 10 ml/kg of lactated Ringer’s solution. Before beginning spinal anesthesia, standard monitoring of heart rate (HR), noninvasive blood pressure, oxygen saturation (SpO2), and body temperature (axillary) was recorded and then every 10 min. Subarachnoid anesthesia was administered at either the L3/L4 or the L4/L5 interspace with 3 ml of 0.5% hyperbaric bupivacaine (Marcaine Spinal Heavy 0.5%; AstraZeneca, Istanbul, Turkey) using a 25-G Quincke’s needle and blockade up to the T9–T10 dermatome was achieved. Motor block was assessed using a modified Bromage scale (0=no motor block, 1=can flex the knee, move the foot, but cannot raise the leg, 2=can move the foot only, 3=cannot move the foot or the knee) [13]. Sensory block was assessed by the pinprick test.

After administration of spinal anesthesia, group K received a prophylactic low dose of ketamine (0.25 mg/kg), whereas group D received a prophylaxis of dexmedetomidine (Precedex). Dexmedetomidine ampoule (200 μg/ml) was diluted to a volume of 50 ml (4 μg/ml). Patients received a dose of 1 μg/kg dexmedetomidine over 10 min by a syringe pump (Perfusor Compact®, Braun, Melsungen, Germany), followed by a continuous infusion of 0.4 μg/kg/h during the surgery, which was stopped at the completion of surgery. Supplemental oxygen (2 l/min) was delivered through a nasal cannula during the operation.

Grading of shivering was performed as follows [4]:

Grade 0: No shivering.

Grade 1: Peripheral vasoconstriction or piloerection or peripheral cyanosis without visible muscle activity.

Grade 2: Visible muscle activity confined to one muscle group.

Grade 3: Visible muscle activity in more than one muscle group.

Grade 4: Gross muscle activity involving the entire body.

If shivering grade was 3 or greater at 15 min after spinal anesthesia, the prophylaxis was considered ineffective and 25 mg pethidine was administered by the intravenous route.

Side effects such as nausea, vomiting, bradycardia (<60/min), hypotension (>20% decline below baseline), dizziness, and sedation were recorded.

The degree of sedation was assessed using a five-point scale [14]:

1=fully awake and oriented patient.

2=Drowsy.

3=eyes closed, arousable on command.

4=eyes closed, arousable to physical stimuli.

5=eyes closed, unarousable to physical stimuli.

If the patient’s HR decreased below 60 beats/min, 0.5 mg atropine was administered by the intravenous route. If the mean arterial pressure (MAP) decreased more than 20% from baseline, 10 mg ephedrine through an intravenous bolus was administered and further intravenous infusion of lactated Ringer’s solution was required. If the patients developed nausea and vomiting, 10 mg metoclopramide was administered through the intravenous route.

HR, MAP, temperature, and oxygen saturation (SpO2) were recorded as a baseline before the start of spinal anesthesia and then recorded every 10 min during the intraoperative period till the end of the operation.

The primary outcome measure was the intraoperative shivering score. The secondary outcome measures were hemodynamic parameters (HR, MAP, oxygen saturation, and temperature) measured at baseline and then every 10 min, in addition to sedation scores and postoperative side effects (e.g. nausea, vomiting, dizziness).

Statistical analysis

Sample size was calculated using PASS 11 (SPSS Inc., Chicago, IL., USA). On the basis of a pilot study, it was calculated that a sample size of 24 patients per group will achieve 80% power to detect a 10% decrease in the occurrence in shivering in the dexmedetomidine group compared with the ketamine group. The significance level of the test was set at 0.0500. Thirty patients per group were included to replace any dropouts.

Methods of randomization

Randomization of patients was performed using a computerized program (SPSS).

  1. Sealed envelopes were numbered according to the randomization tables.
  2. Packing, sealing, and numbering of the envelopes were performed by a neutral medical personnel (under the supervision of doctors from the Department of Anesthesiology).
  3. The number of cases included in this study was simple allocated randomly to two groups (30 patients in each group).


Data were analyzed using the Statistical Program for Social Science (SPSS) version 18.0. Quantitative data were expressed as mean±SD. Qualitative data were expressed as frequency and percentage.

The following tests were performed:

  1. A paired-sample t-test of significance was used when comparing between related samples.
  2. The χ2-test of significance was used to compare proportions between two qualitative parameters.
  3. Probability (P-value):
    1. P-value of 0.05 or less was considered significant.
    2. P-value of 0.01 was considered highly significant.



  Results Top


Comparison of the demographic data (age, sex, weight, height, ASA physical status, duration of surgery, type of surgery) showed no statistically significant difference between the two groups (P>0.05) ([Table 1]).
Table 1: Demographic data of patients in both groups

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[Table 2], [Table 3], and [Table 4] shows that there were statistically significant differences between the two groups in HR, MAP, and temperature. HR and MAP were lower in group D in comparison with group K, especially at 50 min, with a HR mean±SD of 68±6.4 beats/min and a MAP mean±SD of 69.3±15.8 mmHg, and also at 60 min, with a HR mean±SD of 67.1±9.8 beats/min and a MAP mean±SD of 65.3±14.8 mmHg.
Table 2: Heart rate changes

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Table 3: Mean arterial blood pressure changes

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Table 4: Temperature changes

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Body temperature was lower in group K than group D beginning from the first 10 min, with mean±SD of 36.6±0.2 at 10 min ([Table 4]). There was no statistically significant difference between the two groups in oxygen saturation (SpO2) ([Table 5]).
Table 5: SpO2 changes

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[Table 6] shows the relation between the two groups in shivering. Shivering was considered significant when the patient reaches at least grades 3 and 4 after 10 min of spinal anesthesia. After 10 min, four patients of the ketamine group had grade 3 shivering, with a percentage of 13.33%, whereas only one patient of the dexmedetomidine group had grade 3 shivering, with a percentage of 3.33%. After 20 min, two patients (6.67%) in the ketamine group had grade 3 shivering, whereas only one patient (3.33%) of the dexmedetomidine group had grade 3 shivering. Grade 4 shivering was not noted in any patient in either group.
Table 6: Shivering score

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[Table 6] shows that there was a statistically significant difference between the two groups in the shivering score after 10 min and after 20 min. Shivering was less in group D, especially after 10 and 20 min.

Patients in group D were more sedated than patients in group K. After 10 min, 11 patients (36.67%) in group D achieved grade 4 sedation, whereas only seven patients (23.33%) in group K achieved grade 4 sedation. After 20 min, 12 patients (40%) in group D achieved grade 4 sedation, whereas only seven patients (23.33%) in group K achieved grade 4 sedation. No patients in either group achieved grade 5 sedation ([Figure 1]).
Figure 1: Sedation scores in the two groups. After 10 min, 36.67% of patients in group D (11 patients) achieved grade 4 sedation, whereas only 23.33% of patients in group K (seven patients) achieved grade 4 sedation. After 20 min, 40% of patients in group D (12 patients) achieved grade 4 sedation, whereas only 23.33% of patients in group K (seven patients) achieved grade 4 sedation. In group D, from 30 to 60 min, 36.67% of patients (11 patients) achieved grade 4 sedation. In group K, after 30 min, 23.33% of patients (seven patients) achieved grade 4 sedation, whereas from 40 to 60 min, 20% (six patients) achieved grade 4 sedation. No patients in either group achieved grade 5 sedation. The overall percentage of patients reaching sedation score 4 is higher in the D group than in the K group.

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[Figure 1] shows that there was a statistically significant difference between the two groups in the sedation score after 10 min and after 20 min. Patients were more sedated in group D, especially after 10 and 20 min.

Four patients (13.33%) in group D had postoperative dizziness in comparison with three patients (10%) in group K. Three patients (10%) in group D experienced intraoperative nausea and vomiting in comparison with two patients (6.67%) in group K ([Table 7]).
Table 7: Relation between two groups in nausea and vomiting, and dizziness

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[Table 7] shows that there was no statistically significant difference between the two groups in nausea and vomiting, and dizziness.


  Discussion Top


The present study showed that a loading dose of dexmedetomidine of 1 μg/kg, followed by a continuous administration at an infusion rate of 0.4 μg/kg/h led to a potent antishivering effect with adequate level of sedation. However, there was a tendency for the incidence of hypotension and bradycardia compared with low-dose ketamine.

Dexmedetomidine, which is an α-2-adrenoceptor agonist (it has eight times higher affinity for the α-2-adrenoceptor than clonidine), produces its sedative and anxiolytic action through binding to α-2-adrenoceptors in the locus ceruleus, resulting in a decrease in the release of norepinephrine with inhibition of sympathetic activity, thus decreasing HR and blood pressure [15]. Hypotension and bradycardia in the dexmedetomidine group is augmented by the addition of the hypotensive and bradycardic effects of spinal anesthesia after reaching maximum sensory block levels. Bradycardia with a dexmedetomidine infusion was increased only in cases with a loading dose.

The motor shivering center exists close to the posterior hypothalamus, which receives impulses from cold receptors. Upon activation of this shivering center by the cold impulses, it sends bilateral impulses to anterior horn cells in the spinal cord, resulting in an increase in the tone of the skeletal muscles over the entire body. Shivering is observed when muscle tone is increased above a certain level [16].

The etiology of postspinal shivering is inadequately understood. Meperidine (pethidine), which binds to both κ-opioid and μ-receptors, is usually recommended for the treatment of postoperative shivering and the antishivering action of meperidine has been attributed previously to its action on κ-opioid receptors [17].

Shivering is a thermoregulatory response to cold and can complicate both general and neuroaxial anesthesia. General anesthesia causes an impairment in the thermoregulatory mechanism characterized by a decrease in the cold response threshold from 0.4 to 4°C and an increase in the warm response threshold. Some of the causative factors of this type of shivering may be common to both general and neuroaxial anesthesia, but some are particular to neuroaxial anesthesia [18]. Shivering may have beneficial thermoregulatory effects; however, it places the body under increased physiological stress. This physiological stress includes an increase in oxygen consumption and carbon dioxide production, and increased cardiac work. Therefore, prevention of shivering is more important than its treatment [18].

We found that not all patients who develop shivering are hypothermic and postspinal shivering is not necessarily associated with core hypothermia. Shivering can occur in patients who are normothermic.

Our results are consistent with the study carried out by Elvan et al. (2008) [12], who reported that dexmedetomidine infusion during surgery was effective in the prevention of postanesthetic shivering in patients undergoing an elective abdominal hysterectomy.

Another study carried out by Bicer et al. (2006) [19] found that the incidence of shivering was 15% with dexmedetomidine and 55% with placebo following general anesthesia. Also, Coskuner et al. [20] did not observe shivering with the same dose used in our study.

Bicer et al. [19] reported that intraoperative intravenous dexmedetomidine of 1.0 μg/kg reduces postanesthetic shivering with effects comparable with those of meperidine 0.5 mg/kg.

Many studies were carried out to detect the effect of ketamine on the incidence and severity of anesthesia-related shivering. Dal et al. [21] showed that ketamine 0.5 mg/kg was effective in preventing postanesthetic shivering in patients receiving general anesthesia. Sagir et al. [10] showed that 0.5 mg/kg of ketamine was also effective in preventing shivering during spinal anesthesia. In our study, 0.25 mg/kg of ketamine was also as effective as 0.5 mg/kg of ketamine. Shivering was observed in 13.33% of group K patients, who developed grade 3 shivering, in comparison with only 3.33% of patients in group D 10 min after onset of spinal anesthesia (P=0.031).

Nausea and vomiting are also one of the adverse effects of dexmedetomidine and occur more frequent than in patients receiving ketamine. However, there are some studies showing no difference of dexmedetomidine compared with placebo for nausea [12].


  Conclusion Top


Dexmedetomidine infusion exerts a beneficial dual effect as an antishivering and sedating agent during spinal anesthesia without any major adverse reactions. Therefore, we concluded that dexmedetomidine infusion is a good choice and better than low-dose ketamine during spinal anesthesia when shivering is considered a problem.


  Acknowledgements Top


Mostafa Mansour Houssein: contributed in the conduct of the study, study design and manuscript preparation. He also reviewed the original study data and attested the final manuscript.

Ibrahim Mohamed Ibrahim: contributed in data collection, data analysis and statistics. He also attested to the integrity of the original data and the analysis reported in the manuscript and also attested to be the archival author.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Chan AM, Ng KF, Tong EW, Jan GS. Control of shivering under regional anesthesia in obstetric patients with tramadol. Can J Anaesth 1999; 46:253–258.  Back to cited text no. 1
    
2.
Jeon YT, Jeon YS, Kim YC, Bahk JH, Do SH, Lim YJ. Intrathecal clonidine does not reduce post-spinal shivering. Acta Anaesthesiol Scand 2005; 49:1509–1513.  Back to cited text no. 2
    
3.
Macintyre PE, Pavlin EG, Dwersteg JF. Effect of meperidine on oxygen consumption, carbon dioxide production, and respiratory gas exchange in postanesthesia shivering. Anesth Analg 1987; 66:751–755.  Back to cited text no. 3
    
4.
Tsai YC, Chu KS. A comparison of tramadol, amitriptyline, and meperidine for postepidural anesthetic shivering in parturients. Anesth Analg 2001; 93:1288–1292.  Back to cited text no. 4
    
5.
Sellden E, Lindahl S. Aminoacid-induced thermogenesis reduces hypothermia during anaesthesia and shortens hospital stay. Anesth Analg 1999; 89:1551–1556.  Back to cited text no. 5
    
6.
Berti M, Fanelli G, Casati A, Aldegheri G, Lugani D, Torri G. Hypothermia prevention and treatment. Anaesthesia 1998; 53:46–47.  Back to cited text no. 6
    
7.
Joris J, Ozaki M, Sessler DI, Hardy AF, Lamy M, McGuire J et al. Epidural anesthesia impairs both central and peripheral thermoregulatory control during general anesthesia. Anesthesiology 1994; 80:268–277.  Back to cited text no. 7
    
8.
Frank SM, El-Rahmany HK, Cattaneo CG, Barns RA. Predictors of hypothermia during spinal anesthesia. Anesthesiology 2000; 92:1330–1334.  Back to cited text no. 8
    
9.
Dal D, Kose A, Honca M, Akinci B, Basgul E, Aypar U. Efficacy of prophylactic ketamine in preventing postoperative shivering. Br J Anaesth 2005; 95:189–192.  Back to cited text no. 9
    
10.
Sagir O, Gulhas N, Toprak H, Yucel A, Begec Z, Ersoy O. Control of shivering during regional anaesthesia: prophylactic ketamine and granisetron. Acta Anaesthesiol Scand 2007; 51:44–49.  Back to cited text no. 10
    
11.
Doze VA, Chen BX, Maze M. Dexmedetomidine produces a hypnotic-anesthetic action in rats via activation of central alpha-2 adrenoceptors. Anesthesiology 1989; 71:75–79.  Back to cited text no. 11
    
12.
Elvan EG, Oç B, Uzun S, Karabulut E, Coşkun F, Aypar U. Dexmedetomidine and postoperative shivering in patients undergoing elective abdominal hysterectomy. Eur J Anaesthesiol 2008; 255:357–364.  Back to cited text no. 12
    
13.
Bromage PR. A comparison of the hydrochloride and carbon dioxide salt of lidocaine and prilocaine in epidural analgesia. Acta Anaesthesiol Scand 1965; 16:55–69.  Back to cited text no. 13
    
14.
Wilson E, David A, MacKenzie N, Grant IS. Sedation during spinal anaesthesia: comparison of propofol and midazolam. Br J Anaesth 1990; 64:48–52.  Back to cited text no. 14
    
15.
Jorm CM, Stamford JA. Actions of the hypnotic anesthetic, dexmedetomidine, on noradrenaline release and cell firing in rat locus coeruleus slices. Br J Anaesth 1993; 71:447–449.  Back to cited text no. 15
    
16.
Guyton AC. Body temperature, temperature regulation and fever. In: Guyton AC, Hall JE, editors. Text book of medical physiology. 9th ed. Philadelphia: W.B. Saunders; 1996: 911–922.  Back to cited text no. 16
    
17.
Takada K, Clark DJ, Davies MF, Tonner PH, Krause TK, Bertaccini E et al. Meperidine exerts agonist activity at the α2 B-adrenoceptor subtype. Anesthesiology 2002; 96:1420–1426.  Back to cited text no. 17
    
18.
Horn EP, Sessler DI, Standl T, Schroeder F, Bartz HJ, Beyer JC, Schulte am Esch J et al. Nonthermoregulatory shivering in patients recovering from isoflurane or desflurane anesthesia. Anesthesiology 1998; 89:878–886.  Back to cited text no. 18
    
19.
Bicer C, Esmaoglu A, Akin A, Boyaci A. Dexmedetomidine and meperidine prevent postanaesthetic shivering. Eur J Anaesthesiol 2006; 232:149–153.  Back to cited text no. 19
    
20.
Coskuner I, Tekin M, Kati I, Yagmur C, Elcicek K. Effects of dexmedetomidine on the duration of anaesthesia and wakefulness in bupivacaine epidural block. Eur J Anaesthesiol 2007; 24:535–540.  Back to cited text no. 20
    
21.
Dal D, Kose A, Honca M, Akinci SB, Basgul E, Aypar U. Efficacy of prophylactic ketamine in preventing postoperative shivering. Br J Anaesth 2005; 95:189–192.  Back to cited text no. 21
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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