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Tanta University Faculty of Medicine Anesthesiology Department

COMPARISON OF MIDAZOLAM, MIDAZOLAM PLUS KETAMINE, TRAMADOL, AND TRAMADOL PLUS KETAMINE FOR PREVENTION OF POST-SPINAL SHIVERING

A Thesis Submitted for the partial fulfillment of the requirements of master degree in

Anesthesiology By Mohammad Ibrahim El-Kolaly M.B.B.Ch

Supervisors Prof. Badrya Abdel Haleem El-Kastawy Professor of Anesthesiology and Critical care Faculty of Medicine Tanta University

Prof. Salama Ibrahim El-Hawary Professor of Anesthesiology and Critical care Faculty of Medicine Tanta University

Dr. Reda Sobhi Salama Abdel Rahman Lecturer of Anesthesiology and Critical care Faculty of Medicine Tanta University

Faculty of Medicine Tanta University 2010




 

 

 

  


Acknowledgment First of all I can not give a word to fulfill my deepest thanks to "Allah" the most gracious and the most merciful for lighting me the way not only throughout this work but also throughout my whole life. I

would

like

to

express

my

deep

thanks,

and

everlasting gratitude to Prof. Badrya Abdel Haleem ElKastawy Professor of Anesthesiology & critical Care Tanta University, for here kind support, and supervision throughout the entire work which gave me the valuable opportunity to benefit from this contrast help and faithful guidance. I would also like to thank and express my extreme indebtedness to Prof. Salama Ibrahim El-Hawary Professor of Anesthesiology & critical Care - Tanta University, for his constructive criticism, constant help, expert guidance and very generous cooperation. I sincerely thank him for revising the whole work, so that the final presentation of this piece of work was achieved. Also, I wish to express my gratitude and most sincere thank to Dr. Reda Sobhi Salama Abdel Rahman Lecturer of Anesthesiology & critical Care - Tanta University for his support, help and encouragement. In addition, I wish to thank every and each member in the Department of Anesthesiology at the Faculty of Medicine Tanta University who taught me and always working

to

create

new

generations

of

competent

anesthetists. Last but not least, I thank all my colleagues, the nursing, and all who gave me hand while working on this thesis.


Dedication This work is dedicated to those who gave meaning to my life To my Father and Mother who gave me every thing and took nothing To my wife for her patience throughout this work. To LEEN, my beloved daughter, for being in my life. To my brother and my sister who occupy an important space inside my heart.

Mohammad El-Kolaly 6/1/2011


Abstract Background: Post-spinal shivering is very distressing for patients and may induce a variety of complications. In this prospective randomized, comparative, placebo controlled study, the efficacy of each of midazolam, midazolam plus ketamine, tramadol, and tramadol plus ketamine for prophylaxis of post-spinal shivering was evaluated and compared to each other. Methods: one hundred ASA status I and II patients between the ages of 21- 60 years, who were undergoing elective orthopedic surgery under spinal anesthesia, were randomly assigned to one of five groups; Group C (n=20) received saline as a control. Group M (n=20) received Midazolam 75 Âľg/kg. Group MK (n=20) received Midazolam 37.5 Âľg/kg plus Ketamine 0.25 mg/kg. Group T (n=20) received Tramadol 0.5 mg/kg. Group TK (n=20) received Tramadol 0.25 mg/kg plus Ketamine 0.25 mg/kg. All of these drugs were diluted to volume of 5 ml and was given as an I.V. bolus immediately after intrathecal injection. Results: The incidences of shivering in Groups C, M, MK, T and TK were 55%, 45%, 5%, 30% and 15% respectively (P-value was 0.003). The differences between Group MK and Groups C, M, and T were statistically significant (P-value was < 0.001, 0.004 and 0.046 respectively) while the difference between Group MK and Group TK was not significant (P-value was 0.302). Group TK also showed a statistically significant lower incidence of shivering when compared to Groups C and M (P-value was 0.009 and 0.041 respectively) but when compared with Group T, the difference was not statistically significant (P-value was 0.225). The incidence of shivering in Group T was less than its incidence in Groups C and M but this was not statistically significant (P-value was 0.100 and 0.257 respectively). The difference between Groups C and M was not statistically significant (P-value was 0.376). Conclusion: I.V. midazolam plus ketamine or Tramadol plus Ketamine is better than Midazolam or Tramadol for prophylaxis of postspinal shivering. Whereas the midazolam plus ketamine is superior to tramadol plus ketamine.


List of Abbreviations 5-HT

5-hyroxytryptamine

ASA

American Society of Anesthesiology

CBF

Cerebral blood flow

CMRO2

Cerebral metabolic rate for oxygen

CNS

Central nervous system

CSF

Cerebrospinal fluid

CVS

Cardiovascular system

ECG

Electrocardiogram

GABA

Îł-amino-butyric acid

HR

Heart rate

ICP

Intracranial pressure

IOP

Intraocular pressure

MAP

Mean arterial blood pressure

NMDA

N-methyl-D-aspartate

PDPH

Post-dural puncture headache

RR

Respiratory rate

SD

Standard Deviation

SpO2

Peripheral O2 saturation

Temp

Tympanic membrane temperature

i


List of Tables Table

Title

Page

1

Dermatomal levels of spinal anesthesia for common surgical procedures

11

2

Drug selection for hyperbaric spinal Anesthesia

17

3

Factors That May Increase the Incidence of PDPH

20

4

Factors Not Increasing the Incidence of PDPH

20

5

Doses of Ketamine

57

6

Patients' demographic data, ASA status and duration of surgery

72

7

Changes of heart rate in Group C

73

8

Changes of heart rate in Group M

75

9

Changes of heart rate in Group MK

77

10

Changes of heart rate in Group T

79

11

Changes of heart rate in Group TK

81

12

Changes of the mean heart rate in the five groups

83

13

Changes of MAP in Group C

85

14

Changes of MAP in Group M

87

15

Changes of MAP in Group MK

89

16

Changes of MAP in Group T

91

17

Changes of MAP in Group TK

93

ii


18

Changes of the MAP in the five groups

95

19

Changes of reparatory rate in Group C

97

20

Changes of reparatory rate in Group M

99

21

Changes of reparatory rate in Group MK

101

22

Changes of reparatory rate in Group T

103

23

Changes of reparatory rate in Group TK

105

24

Changes of the respiratory rate in the five groups

107

25

Changes of SpO2 in Group C

109

26

Changes of SpO2 in Group M

111

27

Changes of SpO2 in Group MK

113

28

Changes of SpO2 in Group T

115

29

Changes of SpO2 in Group TK

117

30

Changes of the SpO2 in the five groups

119

31

Changes of tympanic membrane temperature in Group C

121

32

Changes of tympanic membrane temperature in Group M

123

33

Changes of tympanic membrane temperature in Group MK

125

34

Changes of tympanic membrane temperature in Group T

127

35

Changes of tympanic membrane temperature in Group TK

129

36

Changes of tympanic membrane temperature in the five groups

131

iii


37

Overall incidence of shivering in the five groups

134

38

Shivering score of all patients in the five groups

136

39

Incidence of severe shivering (score â&#x2030;Ľ 3) in the five groups

138

40

Incidence of complications in the five groups

140

41

Sedation score of all patients in the five groups

142

iv


List of Figures Figure

Title

Page

1

Sagittal section through lumbar vertebrae

4

2

Arterial supply to the spinal cord [Cross-sectional view]

7

3

Spinal needles

13

4

Lateral decubitus position

13

5

Sitting position

14

6

Unintentional hypothermia during general anesthesia

25

7

Schematic diagram of the shivering pathway

26

8

Chemical structure of bupivacaine

40

9

Chemical structure of midazolam

45

10

Chemical structure of ketamine

51

11

Simulated time course of plasma levels of ketamine after an induction dose of 2 mg/kg

52

12

Chemical structure of tramadol

60

13

Changes of heart rate in Group C

74

14

Changes of heart rate in Group M

76

15

Changes of heart rate in Group MK

78

16

Changes of heart rate in Group T

80

17

Changes of heart rate in Group TK

82

18

Changes of the mean heart rate in the five groups

84

v


19

Changes of MAP in Group C

86

20

Changes of MAP in Group M

88

21

Changes of MAP in Group MK

90

22

Changes of MAP in Group T

92

23

Changes of MAP in Group TK

94

24

Changes of the MAP in the five groups

96

25

Changes of reparatory rate in Group C

98

26

Changes of reparatory rate in Group M

100

27

Changes of reparatory rate in Group MK

102

28

Changes of reparatory rate in Group T

104

29

Changes of reparatory rate in Group TK

106

30

Changes of the respiratory rate in the five groups

108

31

Changes of SpO2 in Group C

110

32

Changes of SpO2 in Group M

112

33

Changes of SpO2 in Group MK

114

34

Changes of SpO2 in Group T

116

35

Changes of SpO2 in Group TK

118

36

Changes of the SpO2 in the five groups

120

37

Changes of tympanic membrane temperature in Group C

122

vi


38

Changes of tympanic membrane temperature in Group M

124

39

Changes of tympanic membrane temperature in Group MK

126

40

Changes of tympanic membrane temperature in Group T

128

41

Changes of tympanic membrane temperature in Group TK

130

42

Changes of tympanic membrane temperature in the five groups

132

43

Overall incidence of shivering in the five groups

134

44

Shivering score of all patients in the five groups

136

45

Incidence of severe shivering (score â&#x2030;Ľ 3) in the five groups

138

46

Incidence of complications in the five groups

140

47

Sedation score of all patients in the five groups

142

vii


Table of Contents Title

Page

Introduction

……………………………………. 1

Review of literature

……………………………………. 3

Aim of the work

……………………………………. 65

Patients and methods.

……………………………………. 67

Results.

……………………………………. 71

Discussion

……………………………………. 145

Summary and conclusion

……………………………………. 155

References

……………………………………. 159

Arabic summary

viii


Introduction

2010


Introduction

Introduction Post-anesthetic shivering is spontaneous, involuntary, rhythmic, oscillating, tremor-like muscle hyperactivity

(1)

that increases metabolic

heat production up to 600% after general or regional anesthesia(2). Regional anesthesia is associated with post-anesthetic shivering in up to 60% of patients

(3)

. Shivering may be normal thermoregulatory

mechanism in response to core hypothermia due to redistribution of heat from core to periphery

(4)

. However, non- thermoregulatory shivering

also occurs in normothermic patients (5). Post-anesthetic shivering may cause major discomfort to patients(6), and aggravate wound pain by stretching incisions and increase intracranial

(7)

and intraocular pressure (8). Shivering may increase tissue

oxygen demand by as much as 500% and accompanied by increases in minute ventilation and cardiac output to maintain aerobic metabolism. This may be deleterious in patients with impaired cardiovascular reserve or a limited respiratory capacity(9). Shivering also may interfere with the monitoring of patients by causing artifacts of the ECG, blood pressure, and pulse oximetry recording (10). Various opioid and non-opioid agents were used to prevent and treat shivering, but they are not without side effects like hemodynamic instability, respiratory depression, nausea and vomiting etc. A variety of physical agents (radiant heat, space blanket, etc.) were also used to prevent post-anesthetic shivering, but those were cumbersome and with limited success (11).

1


Introduction

DJ J MWT R L RJL N VJ T T aJ LR VPJ VJ T P NR LM P R h-opioid agonist effect has been found effective in prevention and treatment of shivering

R T N

R M NN O O N L

J V W N h-opioid agonists

(5, 7)

.

Midazolam is one of the benzodiazepines. It was found that it may decrease the incidence of shivering

(3)

. Ketamine which is a competitive

N-Methyl-D-Aspartate (NMDA) receptors antagonist, has been found to be effective in preventing and treating post-anesthetic shivering via central effects or via its effect on the hemodynamics of the cardiovascular system (12, 13).

2


Review of literature

2010


Review of literature

Spinal Anesthesia Spinal, caudal, and epidural blocks were first used for surgical procedures at the turn of the twentieth century. These central blocks were widely used prior to the 1940s until increasing reports of permanent neurological injury appeared. However, a large-scale epidemiological study conducted in the 1950s indicated that complications were rare when these blocks were performed skillfully with attention to asepsis and when newer, safer local anesthetics were used. A resurgence in the use of central blocks ensued, and today they are once again widely used in clinical practice. (14)

Functional Anatomy: I) The vertebral column: The vertebral column consists of 33 vertebrae: 7 cervical (C), 12 thoracic (T), 5 lumbar (L), 5 sacral (S), and 4 coccygeal (Co) vertebrae. All of the vertebrae have the same basic shape, which is subject to certain variations in the individual sections of the spine. The basic shape consists of an anterior body and a dorsal vertebral arch, which consists of pedicles and laminae. The laminae of the vertebral arch join dorsally to form the spinous process. A transverse process branches off on each side of the vertebral arch, as well as a superior and an inferior articular process. The vertebral column usually contains three curves. The cervical and lumbar curves are convex anteriorly, and the thoracic curve is convex posteriorly. The vertebral canal (which provides excellent protection for the spinal cord) and the spinal cord, with its meningeal covering, extend throughout the whole length of the spine terminating in the cauda equina. The spinal vessels and nerves emerge laterally through

3


Review of literature

openings at the upper and lower margins of the roots of the arches of the adjoining vertebrae (the intervertebral foramina) (15) II) The ligaments of the spinal column: (figure 1) The anterior longitudinal ligament is attached at the anterior edge of the vertebral bodies and intervertebral disks. The posterior longitudinal ligament lies behind the vertebral bodies in the medullary canal. The supraspinous ligaments extend from C7 to the sacrum along the tips of the spinous processes, with which they are connected, and they become thicker from cranial to caudal. The interspinous ligaments connect the roots and tips of the spinous processes. The intertransverse ligaments Serve to connect the transverse processes. The ligamentum flavum connects the neighboring laminae. It is at its thinnest in the midline, and its thickness increases laterally. The size and shape of the ligamentum flavum vary at the various levels of the spine. (15)

Figure 1 : Sagittal section through lumbar vertebrae

4

(14)


Review of literature

III)The spinal cord: Spinal cord is continuous cephalad with the brainstem through the foramen magnum and terminates caudally in the conus medullaris.This caudal termination, because of differential growth rates between the bony vertebral canal and the central nervous system (CNS), varies from L3 in infants to the lower border of L1 in adults (14). IV) The spinal cord coverings: (figure 1): a) The dura mater is the outermost layer. It is a randomly organized fibroelastic membrane which is a direct extension of the cranial dura mater and extends as the spinal dura mater from the foramen magnum to S2, where the filum terminale (an extension of the pia mater beginning at the conus medullaris) blends with the periosteum on the coccyx. There is a potential space between the dura mater and the arachnoid, the subdural space that contains only small amounts of serous fluid and thus allows the dura and arachnoid to move over each other. Surrounding the dura mater is the epidural space which contains the nerve roots that traverse it from foramina to peripheral locations, as well as fat, areolar tissue, lymphatics, and blood vessels. This space is the target when performing epidural anesthesia or analgesia(14). b) The arachnoid mater is the middle layer, and it is a delicate, nonvascular membrane closely attached to the dura and ends also at S2. It functions as the principal barrier to drugs crossing in and out of the cerebrospinal fluid (CSF) and is estimated to account for 90% of the resistance to drug migration(16). c) The pia mater is a highly vascular membrane that closely invests the spinal cord. It is continuous cranially with the pia of the brain 5


Review of literature

and caudally ends in the filum terminale, which helps to hold the spinal cord to the sacrum. The space between the arachnoid and pia mater is known as the subarachnoid space in which are the CSF, spinal nerves, a trabecular network between the two membranes, and blood vessels that supply the spinal cord and lateral extensions of the pia mater and dentate ligaments, which provide lateral support from the spinal cord to the dura. This space is the target when performing spinal anesthesia. Although the spinal cord ends at the lower border of L1 in adults, the subarachnoid space continues to S2(14). V) The spinal cord Blood Supply: a) Arterial supply: (figure 2) The two posterolateral arteries arise from the vertebral arteries and supply the posterior 1/3 of the cord. The anterior spinal artery arises from the vertebral arteries and supplies the anterior 2/3 of the cord. The radicular arteries enter every intervertebral foramen and supply the spinal nerve roots The radiculospinal branches arise from the vertebral arteries and the aorta. Of these, the largest is the artery of Adamkiewicz. It supplies much of blood flow to anterior spinal artery(14).

6


Review of literature

Figure 2: Arterial supply to the spinal cord [Cross-sectional view]

(14)

b) Venous drainage: The venous drainage comprises a plexus of anterior and posterior spinal veins that drain along the nerve roots through the intervertebral foramina into the segmental veins; the vertebral veins in the neck, the azygos veins in the thorax, lumbar veins in the abdomen and lateral sacral veins in the pelvis. At the foramen magnum, they communicate with the medullary veins (17).

Physiology of spinal anesthesia: The principal site of action for neuraxial blockade is the nerve root. Local anesthetic is injected into CSF and bathes the nerve root in the subarachnoid space. Blockade of neural transmission in the posterior nerve root fibers interrupts somatic and visceral sensation, whereas blockade of anterior nerve root fibers prevents efferent motor and autonomic outflow (14). I) Somatic Blockade: By interrupting the transmission of painful stimuli and abolishing skeletal muscle tone, neuraxial blocks can provide excellent operating conditions. Sensory blockade interrupts both somatic and visceral painful 7


Review of literature

stimuli, whereas motor blockade produces skeletal muscle relaxation. Spinal nerve roots contain varying mixtures of nerve fiber types. Smaller (in diameter) and myelinated fibers are generally more easily blocked than larger and unmyelinated ones. This, and the fact that the concentration of local anesthetic decreases with increasing distance from the level of injection, explains the phenomenon of differential blockade. Differential blockade typically results in sympathetic blockade that may be two segments higher than the sensory block, which in turn is usually two segments higher than the motor blockade

(14)

.

II) Autonomic Blockade: a) Cardiovascular Effects of Spinal Anesthesia: The sympathetic blockade produced by spinal anesthesia induces hemodynamic changes. The block height determines the extent of sympathetic blockade, which determines the amount of change in cardiovascular parameters. However, this relationship cannot be predicted. Hypotension

occurs

in

about

33%of

the

non-obstetric

population(18). Arterial and venodilatation both occur in spinal anesthesia and combine to produce hypotension. Arterial vasodilatation is not maximal after spinal blockade as the vascular smooth muscle continues to retain some autonomic tone after sympathetic denervation. Due to retention of autonomic tone, total peripheral vascular resistance decreases only by 15% to 18%, thus mean arterial pressure (MAP) decreases by 15% to 18% if cardiac output is not decreased. In patients with coronary artery disease, systemic vascular resistance can be decreased by up to 33% after spinal anesthesia(19).

8


Review of literature

However, after spinal anesthesia, venodilatation will be maximal. Venous return to the heart, or preload, therefore depends on patient positioning during spinal anesthesia. Because preload determines cardiac output and patient positioning is a major factor in determining preload, as long as a euvolemic patient is positioned with the legs elevated above the heart, there should be no significant changes in cardiac output after spinal anesthesia. The reverse Trendelenburg position, however, leads to large decreases in preload and thus large decreases in cardiac output(20). Most patients do not experience a severe change in heart rate after spinal anesthesia. The incidence of bradycardia in the non-obstetric population is about 13%(18).The sympathetic cardiac accelerator fibers emerge from the T1 to T4 spinal segments, and blockade of these fibers is proposed as the cause of bradycardia. Another cause of bradycardia may be the fall in right atrial filling, which decreases outflow from intrinsic stretch receptors located in the right atrium and great veins(21). Even though both of these mechanisms are proposed to cause bradycardia, other undetermined factors may contribute to the bradycardia seen with spinal anesthesia(22). Even though bradycardia is usually well tolerated, asystole and second- and third-degree heart block can occur, so it is wise to be vigilant when monitoring a patient after spinal anesthesia and treat promptly and aggressively(23). b) Respiratory Effects of Spinal Anesthesia: Alterations in pulmonary variables in healthy patients during neuraxial block are usually of little clinical consequence. Tidal volume remains unchanged during high spinal anesthesia, and vital capacity decreases a small amount. This is a result of a decrease in expiratory 9


Review of literature

reserve volume related to paralysis of the abdominal muscles necessary for forced exhalation rather than a decrease in phrenic or diaphragmatic function(24). c) Gastrointestinal Effects of Spinal Anesthesia: The sympathetic innervation to the abdominal organs arises from T6 to L2. Sympathetic blockade and unopposed vagal activity cause increased peristalsis of the gastrointestinal tract, which leads to nausea. Accordingly, atropine is useful for treating nausea after high spinal blockade

(25)

. Nausea and vomiting occur after spinal anesthesia

approximately 20% of the time, and risk factors include blocks higher than T5, hypotension, opioid administration, and a history of motion sickness(18). There is no auto-regulation of hepatic blood flow, thus, hepatic blood flow correlates to arterial blood flow

(26)

. So if mean arterial

pressure (MAP) is maintained after placing a spinal anesthetic, hepatic blood flow will be maintained. d) Urological Effects of Spinal Anesthesia: Neuraxial blocks are a frequent cause of urinary retention, which delays discharge of outpatients and necessitates bladder catheterization in inpatients. However, some studies do not support this belief.(27) Renal blood flow is auto-regulated. The kidneys remain perfused when the MAP remains above 50mmHg. Transient decreases in renal blood flow may occur when MAP is less than 50 mm Hg, but even after long decreases in MAP, renal function returns to normal when blood

10


Review of literature

pressure returns to normal. In other words, renal perfusion changed very little after spinal anesthesia(28).

Indications of spinal anesthesia: :m N N WMWOLWR L NW OJ VN NR JO WJ Va

PR L J T WL N MN

at or below the level of T4 (table 1) requiring sensory loss with or without motor blockade and not requiring a secured airway or mechanical ventilation like cesarean section

(14)

.

Table 1: Dermatomal levels of spinal anesthesia for common surgical procedures (29) Procedure Upper abdominal surgery

Dermatomal Level T4

Intestinal, gynecologic, and urologic surgery

T6

Transurethral resection of the prostate Vaginal delivery of a fetus, and hip surgery T10 Thigh surgery and lower leg amputations

L1

Foot and ankle surgery

L2

Perineal and anal surgery

S2 to S5 (saddle block)

Contraindications of spinal anesthesia:(14) I)

Absolute contraindications to spinal anesthesia:

Infection at the site of injection, patient refusal, coagulopathy or other bleeding diathesis, severe hypovolemia, increased intracranial pressure, severe aortic stenosis or severe mitral stenosis. II) Relative contraindications: Sepsis, uncooperative patient, pre-existing neurological deficits e.g. demyelinating lesions, stenotic valvular heart lesions or severe spinal deformity.

11


Review of literature

III) Controversial contraindications: Prior back surgery at the site of injection, inability to communicate with patient or complicated surgery as in case of prolonged operation, major blood loss or maneuvers that compromise respiration.

Technique of spinal anesthesia: I) Spinal needles: Spinal needles are commercially available in an array of sizes, lengths, and bevel and tip designs (figure 3). All should have a tightly fitting removable stylet that completely occludes the lumen to avoid tracking epithelial cells into the subarachnoid space. Broadly, they can be divided into either sharp-tipped or blunt-tipped needles. The Quincke needle is a cutting needle with end injection. The Whitacre and other pencil-point needles have rounded points and side injection. The Sprotte is a side-injection needle with a long opening. It has the advantage of more vigorous CSF flow compared with similar gauge needles. However, this can lead to a failed block if the distal part of the opening is in the subarachnoid (with free flow CSF), the proximal part is not past the dura, and the full dose of medication is not delivered(14). The introduction of blunt-tipped (pencil-point) needles has markedly decreased the incidence of postdural puncture headache. Also, the one type of needles is provided in different sizes; in general the smaller the gauge of the needle the lower the incidence of headache.

12


Review of literature

Figure 3: Spinal needles

(14)

II) Patient's Position (14): a) Lateral Decubitus: Patient lies on his side with his knees flexed and pulled high against the abdomen or chest, assuming a "fetal position." An assistant can help the patient assume and hold this position. (figure 4)

Figure 4: Lateral decubitus position

13

(14)


Review of literature

b) Sitting Position: The anatomic midline is often easier to appreciate when the patient is sitting than when the patient is in the lateral decubitus position especially if the patient is very obese. The patient sits with his elbows resting on his thigh or a bedside table or he can hug a pillow. Flexion of the spine (arching the back "like a mad cat") maximizes the "target" area between adjacent spinous processes and brings the spine closer to the skin surface. (figure 5)

Figure 5: Sitting position

(14)

c) Prone Position: This position may be used for anorectal procedures utilizing a hypobaric anesthetic solution. The advantage is that the block is done in the same position as the operative procedure (jackknife) so that the patient does not have to be moved following the block. The disadvantage is that CSF will not freely flow through the needle, so that correct subarachnoid needle tip placement will need to be confirmed by CSF aspiration. The prone position is also used whenever fluoroscopic guidance is required. 14


Review of literature

III) Approaches: a) Median Approach: The most common approach, the needle or introducer is placed midline, perpendicular to spinous processes, aiming slightly cephalad. When spinal needle goes through the dura mater, a "pop" is often appreciated. Once this pop is felt the stylet should be removed from the introducer to check for flow of CSF. When performing a spinal anesthetic using the midline approach, the layers of anatomy that are traversed (from posterior to anterior) are: Skin, subcutaneous

fat, supraspinous

ligament, interspinous

ligament,

ligamentum flavum, dura mater, subdural space, arachnoid mater and subarachnoid space (14). b) Paramedian Approach: Indicated in patients who cannot adequately flex because of pain or whose ligaments are ossified. The injection site is located 1-1.5 cm lateral and caudal to the lower edge of the spinous process. The puncture is carried out in a craniomedial direction, at an angle of about 10-15 . When performing a spinal anesthetic using the paramedian approach, the supraspinous and interspinous ligaments are avoided, so that the ligamentum flavum is the primary target on the way to the subarachnoid space (15). c) Taylor or Lumbosacral Approach: This approach is useful in patients with calcified or fusion of higher intervertebral spaces. This approach is a paramedian injection via the intervertebral space of L5 and S1, the largest interlaminar space in the spinal region. The injection site is located about 1 cm medial and about 1 cm caudal to the posterior superior iliac crest. The injection needle is advanced in a craniomedial direction and at an angle of about 60d(15).

15


Review of literature

IV) Procedure (15): 1. Anatomic landmarks for the desired interspace of spinal column are first identified. The iliac crests usually mark the interspace between the L4-L5 vertebrae, and a line can be drawn between them to help locate this interspace. 2. A sterile field is established with povidone-iodine applied with three basic sponges, the solution is applied starting from the injection site moving outward in a circular fashion. 3. A fenestrated drape is applied, and using sterile gauze, wipe the iodine from the injection site to avoid initiation into the subarachnoid space. 4. A skin wheal is raised with 2 ml of 1% lidocaine using a 25G needle to the selected space. 5. A 17G introducer is passed through the skin wheal, angled slightly cephalad through the epidermis, dermis, subcutaneous tissue, supraspinous ligament, interspinous ligament, stopping in the ligamentum flavum. 6. A small gauge spinal needle is inserted into the introducer, passing through the epidural space, dura, and arachnoid to the subarachnoid space stopping when the presence of CSF is determined. The local anesthetic dose is slowly injected 7. The dose of the local anesthetic is injected according to the level of the dermatome needed and the duration of surgery

16


Review of literature

(table 1 and table 2). Then all needles are removed intact and the patient is positioned. Table 2: Drug selection for hyperbaric spinal anesthesia(29) Dose (mg) *

Duration (min)

Local Anesthetic Mixture to T10

to T4

Plain

Epinephrine, 0.2 mg

Lidocaine (5% in 7.5% dextrose)

50-60

75-100

60

75-100

Tetracaine (0.5% in 5% dextrose)

6-8

10-16

70-90

100-150

Bupivacaine (0.75% in 8.5% dextrose)

8-10

12-20

90-120

100-150

Ropivacaine (0.5% in dextrose)

12-18

18-25

80-110

Levobupivacaine

8-10

12-20

90-120

100-150

* Doses are for use in a 70-kg adult male of average height

V)

Factors affecting level of spinal block (29): a) Patient characteristics: Age, height, weight, gender, intraabdominal pressure, anatomic configuration of the spinal column and position. b) Technique of injection: Site of injection, direction of injection (needle), direction of bevel, use of barbotage and rate of injection. c) Characteristics of spinal fluid: Volume, pressure (cough, strain, Valsalva maneuver) and density (iso-, hypo- or hyperbaric). d) Characteristics of the anesthetic solution: Density, amount (mass),

concentration,

vasoconstrictors. 17

temperature,

volume

and


Review of literature

Complications of spinal anesthesia: I) Early complications: a) Failed Anesthesia: Spinal block is blind techniques that rely on indirect signs of correct needle placement. It is associated with a small but significant failure rate that is usually inversely proportional to the clinician's experience. Failure may still occur even when CSF is obtained during spinal anesthesia. Movement of the needle during injection, incomplete entry of the needle opening into the subarachnoid space, subdural injection, or loss of potency of the local anesthetic solution may be responsible (14). b) Intravascular Injection: Inadvertent intravascular injection of the local anesthetic can produce very high serum levels leading to systemic toxicity. this complication is seen primarily with epidural and caudal blocks because the dosage of medication for spinal anesthesia is relatively small (14). c) High or total spinal anesthesia: High or Total spinal anesthesia occurs when local anesthetic spreads high enough to block the most or the entire spinal cord and occasionally

the

brainstem during

spinal

anesthesia.

Profound

hypotension and bradycardia are common secondary to complete sympathetic blockade. Respiratory arrest may occur as a result of respiratory muscle paralysis or dysfunction of brainstem respiratory control centers(30).

18


Review of literature

d) Severe hemodynamic changes: Some cases of sudden cardiac arrest in healthy patients receiving spinal anesthesia were identified.(22) Because these cases seemed to appear suddenly after stable hemodynamic status, it was concluded that a poorly understood potential exists for sudden cardiac arrest in healthy patients. Also cases of severe bradycardia after spinal anesthesia had been recognized for many years.(31, 32) e) Shivering: Will be discussed later in details.

II) Late complications: a) Postdural puncture headache (PDPH): This PDPH is not exclusively related to spinal anesthesia; it also occurs after myelography and diagnostic lumbar puncture. PDPH is believed to result from leakage of CSF from a dural defect and decreased intracranial pressure. Loss of CSF at a rate faster than it can be produced causes traction on structures supporting the brain, particularly the dura and tentorium. Increased traction on blood vessels also likely contributes to the pain. Traction on the cranial nerves may occasionally cause diplopia (usually the sixth cranial nerve) and tinnitus

(14)

. Definitive

treatment is Epidural blood patching therapy; its safety and efficacy have been well documented, and contemporary practice has validated that epidural blood patch continues to have a greater than 90% improvement rate.(33) Factors increasing the incidence of post-spinal puncture headache or unrelated to its development are listed in table 3 and table 4:

19


Review of literature

(34)

Table 3:Factors That May Increase the Incidence of PDPH Age

Younger more frequent

Gender

Females more than males

Needle size

Larger more than smaller

Needle bevel

- Less when the needle bevel is placed in the long axis of the neuraxis - Non-cutting needle tip designs have a lower frequency of PDPH than cutting needle tip designs do.

Pregnancy

More when pregnant

Dural punctures number

More with multiple punctures

(34)

Table 4:Factors Not Increasing the Incidence of PDPH Continuous spinals Timing of ambulation

An arbitrary period of recumbency after spinal anesthesia has not been found to decrease the incidence of PDPH, and some data indicate that early ambulation may actually decrease its incidence.

b) Backache: As a needle passes through skin, subcutaneous tissues, muscle, and ligaments it causes varying degrees of tissue trauma (14). A localized inflammatory response with or without reflex muscle spasm may be responsible for postoperative backache. Data from Brown and Elman(35) demonstrate that approximately 25% of all surgical patients undergoing anesthesia, regardless of anesthetic technique, experience backache. Backache after neuraxial block should not immediately be attributed to k VN N MT R VP lWO NKJ L S(14).

20


Review of literature

c) Spinal hematoma: Needle or catheter trauma to epidural veins often causes minor bleeding in the spinal canal although this is usually benign and selflimiting. A clinically significant Spinal hematoma is a rare but potentially devastating complication of spinal and epidural anesthesia,. Patients most commonly present with numbness or lower extremity weakness. Early detection is critical because a delay of more than 8 hours in decompressing the spine reduces the odds of good recovery. It can occur following spinal or epidural anesthesia, particularly in the presence of abnormal coagulation or bleeding disorder. A mass effect causes direct pressure injury and ischemia to the spinal cord and nerves(14). d) Neurologic injury after spinal anesthesia: Serious neurologic injury is a rare but widely feared complication of spinal anesthesia. Multiple large studies of spinal and epidural anesthesia report that neurologic injury occurs in approximately 0.03 to 0.1% of all central neuraxial blocks, although in most of these studies the block was not clearly proven to be causative

(36)

. Persistent paresthesias

and limited motor weakness are the most common injuries, although paraplegia and diffuse injury to cauda equina roots (cauda equina syndrome) do occur rarely. Injury may result from direct needle trauma to the spinal cord or spinal nerves, from spinal cord ischemia, from accidental injection of neurotoxic drugs or chemicals, from introduction of bacteria into the subarachnoid or epidural space, or very rarely from epidural hematoma

(36)

. It should be noted that not all neurological

deficits occurring after a regional anesthetic are the result of the block(14).

21


Review of literature

e) Transient Neurological Symptoms (TNS): TNS are characterized by back pain radiating to the legs without sensory or motor deficits, occurring after the resolution of spinal block and resolving spontaneously within several days. It is most commonly associated with hyperbaric lidocaine, but has also been reported with other anesthetics like bupivacaine

(37)

. The pathogenesis of TNS is

believed to represent concentration-dependent neurotoxicity of local anesthetics (14). f) Urine retention: Local anesthetic block of S2i S4 root fibers decreases urinary bladder tone and inhibits the voiding reflex. These effects are most pronounced in male patients. Urinary bladder catheterization should be used for all but the shortest acting blocks. If a catheter is not present postoperatively, close observation for voiding is necessary. Persistent bladder dysfunction can also be a manifestation of serious neural injury occurred (14). g) Infection: Infection of the subarachnoid space can follow neuraxial blocks as the result of contamination of the equipment or injected solutions, or as a result of organisms tracked in from the skin. Indwelling catheters may become colonized with organisms that then track deep, causing infection. Fortunately, these are rare occurrences (14).

22


Review of literature

Shivering Post-anesthetic shivering is spontaneous, involuntary, rhythmic, oscillating, tremor-like muscle hyperactivity

(1)

that increases metabolic

heat production up to 600% after general or regional anesthesia(2). Regional anesthesia is associated with post-anesthetic shivering in up to 60% of patients (3).

Consequences: Although shivering may have beneficial thermoregulatory effects it may causes major discomfort to patients and aggravate wound pain by stretching incisions(6)

and increase intracranial(7) and intraocular

pressure.(8) Also it may increase tissue oxygen demand by as much as 500% and accompanied by increases in minute ventilation and cardiac output to maintain aerobic metabolism. This may be deleterious in patients with impaired cardiovascular reserve or a limited respiratory capacity.(9) Shivering also may interfere with the monitoring of patients by causing artifacts of the ECG, blood pressure, and pulse oximetry recording.(10)

Grading: Grading of shivering is important to allow meaningful comparisons of interventions in this area. In this study the presence of shivering is observed and graded by using a scale similar to that validated by Tsai and Chu(38) where:

23


Review of literature

0 = No shivering. 1 = Piloerection or peripheral vasoconstriction but no visible shivering. 2 = Muscular activity in only one muscle group. 3 = Muscular activity in more than one muscle group but not generalized. 4 = Shivering all over the body.

Pathophysiology The etiology of shivering still remains poorly understood. The obvious etiology is said to be normal thermoregulatory mechanism in response to core hypothermia (4). The way in which core hypothermia occurs in the post-anesthesia period is known and consistent with a combination of competitive inhibition of thermoregulatory responses by the anesthetics, with a decrease in metabolism, and exposure to a cold environment.(39) Schematically, the drop in core temperature during general anesthesia occurs in three phases (figure 6): 1. Phase I (Redistribution): is immediately after anesthesia induction and consists in an internal transfer of core heat to the periphery, known as internal redistribution. The temperature decrease takes place without heat loss. 2. Phase II (Heat loss): is a drop in core temperature as a result of heat losses (via the cutaneous route, by the exposure of viscera or by the perfusion of cold solutions) being higher than heat gains. 24


Review of literature

3. Phase III (Equilibrium): after a decrease in body temperature that varies depending on the anesthetic products

and

concentrations

used,

cutaneous

vasoconstriction occurs. During this period, the core temperature is almost stable.

(40)

Figure 6: Unintentional hypothermia during general anesthesia

At recovery and the waning of the effect of the anesthetic drugs, thermoregulation is no longer inhibited and other physiological responses to cold such as shivering appear. Therefore, prevention of post-anesthesia hypothermia will automatically reduce the incidence of post-anesthesia shivering. (40) However

non

thermoregulatory

shivering

may

occur

in

normothermic patients. The mechanism is unknown but may be related to the postoperative pain, direct effect of certain anesthetics, hypoxia hypercapnia or respiratory alkalosis, the existence of pyogens, early recovery of spinal reflex activity, sympathetic overactivity and/or adrenal suppression (5).

25


Review of literature

Thermoregulation: Similar

to

other

physiological

systems,

the

thermoregulatory system is often divided into 3 components

(41)

human :

1. Thermo receptors and afferent neural pathways. 2. A center for integration of this input. 3. Effector pathways. A simplified schematic representation of the shivering pathway is illustrated in figure 7

Figure 7: Schematic diagram of the shivering pathway

26

(41)


Review of literature

1. Afferent input: Afferent thermal input is generated by peripheral (skin & mucous membranes) and visceral thermoreceptors (deep abdominal and thoracic tissues in addition to spinal cord, hypothalamus and other brain tissues). Cold thermoreceptors are anatomically and physiologically distinct from those of warmth. Cold signals are transmitted via A nerve fibers while warmth signals via unmyelinated C fibers, although there is some overlap(41).The mean skin temperature represents 20% of the total thermoregulatory input.(11) 2. The center for integration of the afferent input: That afferent thermal input is projected by the lateral spinothalamic tract to the hypothalamic thermoregulatory centers and to nuclei within the reticular formation in the pons. This input is modulated by spinal cord and brain stem especially the nucleus raphe magnus which facilitates transmission of thermal information to the hypothalamus and has an inhibitory role in shivering and the locus subcoeruleus which has a predominantly excitatory role in shivering. The preoptic area of the anterior hypothalamus appears to be the central integrator that compares the integrated afferent thermal inputs with the threshold temperatures for each thermoregulatory response(41). 3. Efferent responses: The efferent shivering pathway starts at an area between the anterior and posterior hypothalamus and makes multiple connections within the reticular formation before it ends at the motor neurons.

27


Review of literature

A reference temperature (set point), most probably generated by a network of thermal insensitive neurons in the pre-optic area is compared with feedback from the skin and core thermoreceptors. An error signal, proportional to the difference between the set point and feedback signal, is generated which activates thermoeffector pathways that control heat production and heat loss(41). In humans, core temperature is normally maintained within a tight J V PN

) d 4i

)d 4 S VW V J

Nk R VN N W T M J V PN lW

k N WVN J Tb W VNl4WN N NJ N J KWNW K N T W

R J VP N

trigger thermoregulatory responses such as vasoconstriction and shivering with lower and vasodilatation and sweating with higher core temperatures. The core temperature triggering each thermoregulatory response is known as the threshold (i.e. each thermoregulatory response has its threshold). How the body determines these thresholds is unknown but the mechanism appears to be mediated by norepinephrine, acetylcholine, dopamine, 5-hydroxytryptamine (5-HT), prostaglandin E, and neuropeptides.(11) The normal response to hypothermia involves thermoregulatory vasoconstriction to decrease cutaneous heat loss, and maintain heat within the core. Maximal vasoconstriction usually occurs before thermoregulatory shivering occurs. When the core temperature decreases to a certain point, known as the shivering threshold, thermoregulatory shivering then occurs. The threshold temperature at which shivering occurs may be lower in males relative to females(42), and may also decrease with age.(43) Also, it can be altered by many factors like exercise, food intake, infection, thyroid dysfunction, and drugs (including anesthetics, alcohol, sedatives, and nicotine) (41). 28


Review of literature

Thermoregulation and Neuraxial anesthesia: Core temperature during neuraxial anesthesia decreases in the same pattern as in during general anesthesia. During the first hour of neuraxial anesthesia core hypothermia results from redistribution of core body heat to the peripheral tissues (phase I). Then it continue to decrease as a result of the accompanying thermoregulatory impairment that allows continued heat loss (phase II). This impairment appears to be due to an altered perception of temperature in the blocked dermatomes by the hypothalamus as opposed to a central drug effect as seen with general anesthetics. But vasoconstriction is impaired below the level of the block which results in more cutaneous heat loss, the heat content of limbs continues to fall aggravating the hypothermia (phase III). (44) Thus Thermoregulation is impaired during neuraxial anesthesia and the result typically is core hypothermia which usually is not perceived by the patient resulting in a frequent clinical paradox, a shivering patient who denies feeling cold (41). For the first 30 minutes of anesthesia, core temperature decreased significantly faster in patients given spinal block when compared with those given epidural block. After 30 minutes, core temperatures decreased at identical rates during epidural and spinal anesthesia, with the end

result

being

lower

core temperature in

the

spinal

group(45).Though the intensity of shivering with epidural anesthesia may be higher than that with spinal anesthesia. This may be due to the greater intensity of the motor block with spinal block compared with that in epidural block, such that patients are actually unable to shiver during spinal block. Also it has long been known that the spinal cord has 29


Review of literature

thermoreceptors and is involved in thermoregulation. Administration of cold fluids into the epidural space may result in cooling of large epidural veins, which in turn communicate with the basal sinuses. This might also provide an explanation for the difference in shivering intensity for epidural and spinal anesthesia(41). A decrease in core temperature (measured at the tympanic N KJ VN W O )d 4R O O R L R N V WR V ML N RNR VPR VV WV-pregnant volunteers undergoing epidural anesthesia(46).

Prevention and Management I) Non-pharmacological measures As core hypothermia is responsible for post-anesthetic shivering in most patients, prevention of its occurrence decreases the incidence of shivering. Core hypothermia prevention during anesthesia entails limiting the effects of internal redistribution (Phase I), and reducing and making up for the heat losses (Phase II). i.

Preoperative skin surface rewarming efficiently limits the effects of internal redistribution. Covering the patient with forced-air warmer systems for 30 minutes before the induction of anesthesia is enough to eliminate the phenomenon of internal redistribution(47). If shivering already occurred they can reduce the frequency of the shivering and was found in all patients to reduce the duration (48).

ii.

Another method entails increasing the heat content of the patient by generating endogenous production. Providing the patient amino-acid solution resulted in values close to normothermia after hysterectomy(49). 30


Review of literature

iii.

Covering the patient as much as possible with the surgical drapes, which are excellent insulators, is sufficient to significantly reduce the loss of heat from the skin(50).

iv.

As patients mainly lose calories through radiation and convection on the skin surface, it also helps to raise the WNJR VP WW

N NJ N 1&d 4

J MR J V N J aN

applied in the recovery and operating rooms are efficient ways of preventing post-anesthetic shivering or rapidly inhibiting it when it occurs. This method is especially useful when the patient is uncovered (i.e. at the beginning and end of the operation). Also when the surgical field is very large or if a large amount of viscera is exposed, room temperature remains an important factor to limit heat loss. (50) v.

When a perfusion of a large volume of fluids or cold blood products are needed, intravenous solution rewarming prevents the patient from cooling down. (50)

II) Pharmacological measures: Multiple pharmacologic strategies to combat shivering have been evaluated. A majority of these have been applied in the peri-operative setting due to the potentially deleterious effects of hypothermia and shivering in postoperative recovery a) Opioids: Numerous peptides participate in central thermoregulatory control. Opioid peptides can also affect changes in body temperature. Possible sites of action include the preoptic anterior hypothalamus, dorsal raphe nucleus, raphe magnus and the spinal cord(11). 31


Review of literature

1. Meperidine is unique among opioids due to its special antishivering effect

(38)

, likely exerted predominantly via its

t-receptor activity although inhibitions of biogenic amine reuptake,

NMDA

receptor

antagonism

J VM p2

adrenoreceptor stimulation are all additional potential mechanisms (11). 2. Morphine(51) and fentanyl

(52)

are only moderately effective

in high doses. b)

2

agonists

D Np2 agonists hyperpolarize neurons, possibly by increasing potassium conductance, which in turn suppresses neuronal firing that is linked to thermo-sensitivity. The hypothalamus and other parts in the brain stem L WVJ R VJ R P M N VRa WOp2-adrenoceptors, which can influence firing of serotonergic neurons in the dorsal raphe nucleus and J LRJNp2-J MN V WL NW R V N R VJ TL WM : VJ N L J Tp2-adrenergic J P WV R

JNKN N V WVW N T N JNMa VW R V Jt-agonist) and to

stimulate norepinephrine and acetylcholine release. Depressor effects of these neurotransmitters at the dorsal horn may modulate the cutaneous thermal input (11). 1. Clonidine

was found effective in preventing shivering

when compared with Meperidine(53) 2. Similar

to

clonidine,

premedication

with

IM

dexmedetomidine reduces the incidence of postoperative shivering compared with midazolam(54).

32


Review of literature

c) 5-HT uptake inhibitors 5-HT impacts thermoregulatory responses through its action on different sites in the hypothalamus, midbrain and medulla. It is likely that the balance between the modulatory 5-HT and norepinephrine inputs is important for short and long term thermoregulatory control of the shivering threshold (11). 1. Tramadol is a centrally acting analgesic with multiple potential mechanisms by which it affects thermoregulation. Several randomized studies have indicated that tramadol is effective for prevention (7) and treatment of shivering (5). 2. Nefopam, is a potent inhibitor of 5-HT uptake with an analgesic with anti-shivering properties (55). d) 5-HT agonists/antagonists: 1. Buspirone, a 5-HT1A partial agonist, acts synergistically with meperidine and it has been used as such in several protocols of induced hypothermia(56). 2. Ondansetron, one of 5-HT3 antagonists, has a potential antishivering effect(57). e) N-Methyl-d-Aspartate (NMDA) antagonists: NMDA receptors modulate noradrenergic and serotonergic neurons in the brain stem although these and other potential mechanisms in thermoregulation remain unproven.

33


Review of literature

1. Magnesium sulfate is a competitive NMDA receptor antagonist which has been shown effective in postanesthetic shivering control(58). 2. Ketamine, another competitive NMDA receptor antagonist has been shown effective in preventing (12) and inhibiting (13) post-anesthetic shivering. f) Others Many other individual pharmaceutical agents have been found having properties like Physostigmine a nonselective, centrally acting cholinesterase

inhibitor

(53)

,the

analeptic

Dexamethasone (60)

34

Doxapram

(59)

and


Review of literature

Local anesthetics Local anesthetics are compounds with the ability to interrupt the transmission of the action potential in excitable membranes. They bind to specific receptors in the Na+ channels and their action at clinically recommended doses is reversible.

Chemical structure of local anesthetics: A typical local anesthetic is composed of two moieties, one a benzene ring (lipid soluble, hydrophobic) and the other an ionizable amine group (water soluble, hydrophilic), linked by a chemical chain. This chemical chain can be either of the ester or amide types defining two different groups of local anesthetics, aminoester or aminoamide compounds (61).

Physicochemical properties-activity relationship: I) Lipid solubility (Lipophilicity): k RW R T R L Ra lN N N NN V MN V L aWOJL W WV M WJ WL R JN with membrane lipids

(61)

. It determines both the potency and the

duration of action of local anesthetics by facilitating their transfer through membranes and binding the drug close to the site of action and thereby decreasing the rate of metabolism by plasma esterase and liver enzymes(62). II) Protein binding: Local anesthetics are bound in large part to plasma and tissue proteins. The bound portion is not pharmacologically active. The most 35


Review of literature

R WJ V KR VM R VP

WN R V R V T J J JN J T K R V J V M p1-acid

glycoprotein (AAG). Although albumin has a greater binding capacity than AAG, the latter has a greater affinity for drugs with pKa higher than 8 like most local anesthetics. However changes in protein binding are only clinically important for drugs highly protein bound such as bupivacaine, which is 96%, bound

(63)

. The fraction of drug bound to

protein in plasma correlates with the duration of action of local anesthetics: the greater the protein binding, the longer the duration of action (bupivacaine = ropivacaine > tetracaine > mepivacaine > lidocaine > procaine) (61). III) pKa: By definition the pKa is the pH at which 50% of the drug is ionized and 50% is present as a base. It determines the ratio between the ionized (cationic) and the uncharged (base) forms of the drug. The pKa generally correlates with the speed of onset of most local anesthetics. The closer the pKa is to the physiologic pH the faster the onset (e.g., lidocaine with a pKa of 7.7 is 25% non-ionized at pH 7.4 and has a more rapid onset of action than bupivacaine with a pKa of 8.1 which is only 15% nonionized). Increasing the pH of the drug solution will increase the fraction of the nonionized form, resulting in a faster onset. Most local anesthetic solutions are prepared commercially as a water-soluble HCL salt (pH 6 -7) (62).

Mechanism of local anesthetic action: Local anesthetics produce conduction blockade of neural impulses by preventing the passage of sodium ions through ion selective sodium channels in nerve membrane. It is likely that local anesthetics stabilize 36


Review of literature

and maintain sodium channels in the inactivated closed state by binding to specific receptors located in the inner portion of sodium channels. Local anesthetics may prevent the change in sodium permeability by obstructing sodium channels near their external openings. Failure of permeability to sodium ions slows the rate of depolarization so the threshold potential is not reached and an action potential is not propagated along the nerve membrane. The ion gradient and resting membrane potential are unchanged(62).

Pharmacokinetics: Systemic absorption: It depends on blood flow, which is determined by the following factors: 1. The vascularity at the Site of Injection: The rate of systemic absorption is proportionate to the vascularity of the site of injection: intravenous > tracheal > intercostal > caudal > paracervical

> epidural

> brachial plexus > sciatic >

subcutaneous(61). 2. Dose of the anesthetic agent: For a given site of injection, the rate of systemic absorption and the peak plasma level are directly proportional to the dose of local anesthetic deposited(61). 3. The type of the anesthetic agent: The rate of systemic absorption differs with individual local anesthetics. In general, more potent, lipid-soluble agents are associated with a slower rate of absorption than less lipid-soluble compounds. Sequestration into lipid-rich compartments may not be the only explanation. Local anesthetics exert direct effects on vascular smooth muscles in a concentration37


Review of literature

dependent manner. At low concentrations, more potent agents appear to cause more vasoconstriction than less potent agents, thereby decreasing the rate of vascular absorption. At high concentrations, vasodilator effects seem to predominate for most local anesthetics (61). 4. Presence of Vasoconstrictors: The addition of epinephrine or less commonly phenylephrine causes vasoconstriction at the site of administration. The consequent decreased absorption increases neuronal uptake, enhances the quality of analgesia, prolongs the duration of action, and limits toxic side effects. The effects of vasoconstrictors are more pronounced with shorter-acting agents(62). Distribution: Distribution depends on organ uptake, which is determined by the following factors: 1. Tissue Perfusion: The systemic distribution of local anesthetics can be described sufficiently by a two-compartment model. The highly perfused organs (brain, lung, liver, kidney, and heart) are responsible for the initiJ T JR M

J S N p

O WT T WN M Ka J T WN N MR R KR W V r

JN

R L R

JN W WMNJN T a

perfused tissues (muscle and gut) (64). 2. Protien binding and lipophilicity: Strong plasma protein binding tends to retain anesthetic in the blood, whereas high lipid solubility facilitates tissue uptake (62). 3. Tissue Mass: Muscle provides the greatest reservoir for local anesthetic agents because of its large mass(62). 38


Review of literature

Metabolism and Excretion: Esters: Ester local anesthetics are predominantly metabolized by pseudocholinesterase. Ester hydrolysis is very rapid, and the watersoluble metabolites are excreted in the urine. Procaine and benzocaine are metabolized to P-aminobenzoic acid (PABA), which has been associated with allergic reactions. Patients with genetically abnormal pseudocholinesterase are at increased risk for toxic side effects, as metabolism is slower. Cerebrospinal fluid lacks esterase enzymes, so the termination of action of intrathecally injected ester local anesthetics, eg, tetracaine, depends on their absorption into the bloodstream. In contrast to other ester anesthetics, cocaine is partially metabolized (Nmethylation and ester hydrolysis) in the liver and partially excreted unchanged in the urine (62). Amides: Amide local anesthetics are metabolized (N-dealkylation and hydroxylation) by microsomal P-450 enzymes in the liver. The rate of

amide

metabolism

depends

on

the

specific

agent

(prilocaine > lidocaine > mepivacaine > ropivacaine > bupivacaine), but overall is much slower than ester hydrolysis. Decreases in hepatic function (eg, cirrhosis of the liver) or liver blood flow (eg, congestive heart failure, vasopressors, or H2-receptor blockers) will reduce the metabolic rate and predispose patients to systemic toxicity. Very little drug is excreted unchanged by the kidneys, although the metabolites are dependent on renal clearance (62).

39


Review of literature

Bupivacaine

Figure 8: Chemical structure of bupivacaine

(61)

Physiochemical characteristics: Bupivacaine is an amide long acting local anesthetic agent that is chemically related to mepivacaine and differs only in having a butyl side chain in place of a methyl group. Both drugs have potency and toxicity approximately four times greater than those of lignocaine

(65)

. Its

molecular weight is 325, pH is 4.5-5.5 (at commercial preparations), pKa is 8.1, and plasma protein binding is 95% (66).

Pharmacokinetics The systemic absorption of bupivacaine as a local anesthetics is determined by: the site of injection, dosage, addition of a vasoconstrictor agent, and the pharmacologic profile of the agent itself (61). The systemic distribution of bupivacaine can be described sufficiently by a two-compartment model. The rapid disappearance JN p

JN R KN T R NN M W KN N T JN M W ptake by rapidly

40


Review of literature

equilibrating tissues (i.e., tissues that have high vascular perfusion). Then a T WN

JNr JNWOM RJ N JJ VL NOW KT W W M(64).

The physicochemical properties which influence anesthetic activity are lipid solubility, pKa and protein binding. Lipid solubility appears to be the primary determinant of intrinsic anesthetic potency. The duration of anesthesia is primary related to the degree of protein binding of the various local anesthetics. Physiologic or pathologic conditions that alter either protein content or protein structure will influence the amount of free local anesthetic. Bupivacaine is the first local anesthetics that combine the properties of an acceptable onset (20-30 min), profound conduction blockade, significant separation of sensory anesthesia and motor blockade and long duration of action (the average duration of surgical analgesia varies 90 to 200 minutes when used for spinal anesthesia) (61). Bupivacaine like other local anesthetics with an amide structure is detoxified in the liver by conjugation with glucuronic acid. Most of the drug is metabolized partly by N-dealkylation. Decreased hepatic function will reduce the metabolic rate and lead to systemic toxicity (61). About 10% of the drug is excreted unchanged by the kidney. A glucuronide conjugate is also excreted(61)

Mechanism of action(62): Bupivacaine (like other local anesthetics) produces conduction blockade of neural impulses by preventing the passage of sodium ions

41


Review of literature

Pharmacodynamics I) Local anesthetic action: Bupivacaine is used in a concentration of 0.125%, 0.25%, 0.5% and 0.75% for various regional anesthetic procedures including infiltration, peripheral nerve block, extradural and spinal anesthesia. It is widely used as a spinal anesthetic, either as a hyperbaric solution with 8.25% dextrose or by using the nearly isobaric 0.5% solution. Bupivacaine bolus doses at a concentration of 0.125% produce adequate analgesia in many clinical settings with only mild motor deficits(67). Continuous epidural infusions of Bupivacaine as dilute as 0.0625% to 0.1% are useful for labor epidural analgesia, especially when administered in combination with opioids and other additives. Bupivacaine 0.25% may be used for more intense analgesia (particularly during combined epidural) with moderate degrees of motor block. Bupivacaine at concentrations of 0.5% to 0.75% is associated with a more profound degree of motor block, which makes these solutions most suitable for major surgical procedures, particularly when epidural anesthesia is not combined with general anesthesia(61). II) Central nervous system: Bupivacaine has a central excitatory effects (restlessness, agitation, nervousness and paranoia) followed by depression (slurred speech, drowsiness and unconsciousness) (61).

42


Review of literature

III) Cardiovascular system: Bupivacaine depresses myocardial automaticity and reduces the duration of refractory period. At higher concentrations, myocardial contractility and conduction velocity are also depressed (61). IV) Respiratory system: Bupivacaine has no marked effect in usual dose on respiration but toxic doses depress hypoxic drive and decrease the tidal volume due to medullary depression (61).

Dosage: For spinal anesthesia, a concentration of 0.5% is usually used. The dose for perineal and lower limb surgery is 4-6 mg, while for lower abdominal surgery is 8-10 mg and for blockade up to T4 level, it is 12-20 mg (table 2). For epidural blockade a dose of 1-2 ml of 0.25-0.5% for each spinal segment to be anaesthetized is given. The maximum dose is 3mg/Kg(68).

Adverse effects: (toxicity): Toxic effects of local anesthetics are dose related and dependent on systemic absorption which is related to the amount of the drug used, the rate of injection, the vascularity of the area injected, any vasoactive properties of the drug, the toxicity of the drug and its rate of deactivation and excretion(68).

43


Review of literature

I) Cardio vascular system (CVS) toxicity: Fall of the blood pressure is usually the first sign of a systemic affection of CVS(68). Cardiodepression, Ventricular arrhythmias, Cardiac arrest and death may occur with local Anesthetics toxicity (Bupivacaine in particular)(69, 70). II) Central nervous system (CNS) toxicity: Initial symptoms such as visual or hearing disturbances, numbness of the tongue and mouth, dizziness, tingling and parasthesia are seen. Dysarthria, muscular rigidity and muscular twitching are more serious and may precede the onset of grand mal convulsions that may last from seconds to several minutes. Coma may follow (71).

44


Review of literature

Midazolam

Figure 9: Chemical structure of midazolam

(61)

Physiochemical properties: Midazolam is a benzodiazepine derivative having imidazole ring fused in positions 1, 2 with a diazepam ring. This imidazole ring accounts for the basicity, stability and rapid metabolism of the midazolam aqueous solution. When the environmental pH falls below 4, the imidazole ring opens between the 4 and 5 positions producing a polar water soluble primary amine derivative. At physiological pH, the drug is present in the closed ring form and lipid solubility is increased

(72)

. The

high lipophilicity has a number of clinical consequences including rapid absorption of midazolam from the gastrointestinal tract and rapid entry into brain tissue after IV administration midazolam is 362 while its pKa is 6.15 96% (75).

45

(73)

(74)

. The molecular weight of

and its protein binding is 94-


Review of literature

Pharmacokinetics Midazolam is absorbed very rapidly from the gastrointestinal tract after oral administration

(76)

. Midazolam undergoes extensive hepatic

first phase metabolism resulting in a systemic availability of approximately 40-50% of the orally administered dose in its non metabolized forms. Therefore, the oral dose of midazolam must be approximately twice as high as intravenous dose to achieve comparable clinical effect

(73)

. After intramuscular injection, midazolam is 80% to

100% absorbed. A physiological pH maintains the closed ring and enhances the lipid solubility of midazolam which contributes to the speed of onset of activity after intravenous administration

(77)

.

Midazolam is rapidly absorbed by the rectal route via the superior hemorrhoidal veins that lead to the portal circulation so the drug undergoes

first

administration

(78)

phase

hepatic

extraction

following

rectal

.

Although Midazolam is water, soluble at low pH, its imidazole ring closes at physiological PH, causing an increase in its lipid solubility which leads to rapid entry of midazolam into brain tissue after intravenous administration and redistribution is fairly rapid

(79)

.

Midazolam is extensively bound to plasma proteins (94-96%) with only about 4% being unbound(80). Albumin appears to be the major sources of binding, decrease in plasma protein concentration or reduction in the extent of binding, increase the fraction of free drug (81). Midazolam is hydroxylated by hepatic microsomal oxidative mechanisms. The resultant metabolites (mainly l-hydroxy-midazolam)

46


Review of literature

are excreted in urine in the form of glucuronide conjugates. Very little amount of the drug excreted unchanged in urine (79).

Mechanism of action Midazolam has a relatively high affinity for the benzodiazepine receptor, approximately two times that of diazepam(82). It reduces s amino-butyric acid (GABA) reuptake from synaptic clefts, thereby causing accumulation of GABA with increased stimulation of the GABA receptors thus inducing a conformational changes which triggers the opening of the chloride channels (83). The opening of the channel and the concomitant influx of chloride ions into the postsynaptic cell hyperpolarize its cell membrane delaying the propagation of the action potential and potentiate the synaptic inhibition

(84)

. That explains why

there was a reduction in the repetitive firing in response to depolarizing pulses in spinal cord neurons (85).

Pharmacodynamics: I) Central nervous system (CNS) effects: Clinically, Midazolam is 3 to 4 times as potent as diazepam because of its increased affinity for the benzodiazepine receptor (86). The maximum clinical effect of Midazolam is reached in about 3 minutes after IV injection

(87)

, 5 min after IM injection and 15-45 min after oral

administration (88). Midazolam causes sedation and hypnosis amnesia(89) and anticonvulsant action

(90)

(87)

, anterograde

.In a dose related manner

midazolam reduces cerebral blood flow (C.B.F) and cerebral metabolic rate for oxygen (CMRO2), so Midazolam can protect against cerebral 47


Review of literature

hypoxia and can be useful for patients who have increased intracranial pressure(91). II) Cardiovascular effects: Midazolam produces minimal haemodynamic changes including small reduction in the blood pressure and small increase in the heart rate(89). However, marked decrease in blood pressure can be observed in hypovolaemic patients (92)

activity

because midazolam depresses baroreflex

which is increased to compensate for this hypovolaemia. This

effect is especially important in the elderly and in those who have extensive major sympathetic blockade during regional anesthesia(93). III) Respiratory effects: In healthy humans IV Midazolam produces a 32-40% decrease in the tidal volume associated with an increase in the respiratory rate so the minute volume remains constant.Midazolam neither reduces the functional residual capacity nor residual lung volume and it does not cause bronchoconstriction(94). IV) Other: Midazolam significantly decreases intraocular pressure (IOP) within 3 minutes of its injection. The mechanism by which Midazolam decreases IOP involves a relaxation of the extraocular muscles, a moderate reduction in arterial blood pressure and an increase in the outflow of aqueous humor(95). Midazolam reduces the autonomic and hormonal responses to emotional or surgical stresses. Catecholamines levels are reduced after Midazolam treatment (96).

48


Review of literature

Adverse reactions: Midazolam can cause respiratory depression

(98)

, ventricular irritability

(99)

(97)

, and cardiovascular

and a change in the baroreflex

control of heart rate. Respiratory obstruction may occur if deep sedation occurs

(97)

. In addition, cardio-respiratory depression and death have

been reported (99). After Midazolam induction, the incidence of nausea and vomiting ranges from none to 15% (100). Although midazolam has a short half-life; it influences psychomotor function for several hours after its administration. Thus, patients should not drive or operate machinery for 8 hrs after receiving the drug

(101)

. A paradoxical reaction is a serious side effect of all

benzodiazepines, including midazolam, although it is rare and as yet not fully understood. The subjects become confused and aggressive and can harm themselves. Flumazenil 0.1 mg/Kg is very effective in treating and calming these patients (102). Other uncommon postoperative side effects following midazolam administration include dizziness, diplopia, hiccough and bad taste (79).

Clinical uses and dosage: I) Premedication: It is generally safe to premedicate with a Midazolam dose of 0.05 mg/kg IV with a maximal dose of 2.5 mg. In elderly patients, the initial dose should be no higher than 1-1.5 mg

49

(103)

. In children, midazolam is


Review of literature

an effective oral premedication. No marked side effects have been observed after doses of 0.4 - 0.5mg/kg (104). II) Intravenous sedation: Midazolam is a useful IV adjuvant to local or regional anesthesia for a variety of therapeutic and diagnostic procedures. The short-term anterograde amnesia allows endoscopy or injection of a local anesthetic without recall (105). Midazolam, in an initial IV dose of 0.08 mg/Kg with incremental doses of 0.04 mg/kg at 3 minutes interval until the desired effect has been reached, produces excellent sedation in patients receiving regional anesthesia and provides a much greater degree of amnesia than diazepam (106). III) Induction of anesthesia: As an induction agent, Midazolam produces sleep and amnesia but it does not have a great analgesic effect

(73)

. The induction dose of

Midazolam ranges from 0.1-0.4 mg/Kg (89). Midazolam is less commonly used as an induction agent for outpatients because of concerns regarding delayed recovery and residual amnesia

(107)

and therefore the risk of forgetting important postoperative

instructions. IV) Treatment of seizures: Midazolam at a dose of 0.1 mg/Kg IV it produces excellent sedation and abolishes seizure activity within 20-30 seconds (108).

50


Review of literature

Ketamine

Figure 10: Chemical structure of ketamine (79)

Physiochemical properties of ketamine: Ketamine hydrochloride is a non-barbiturate non barbiturate anesthetic that belongs to the phencyclidine group of drugs. Ketamine has a molecular weight of 238, is partially water soluble, and forms a white crystalline salt with a pKa of 7.5

(109)

. It has

lipid solubility 5 to 10 times that of thiopental (110). It is formulated as a slightly acid (pH 3.5 to 5.5) sterile solution for intravenous or intramuscular injection in concentrations of 10 10-, 50-, and 100-mg mg ketamine base per milliliter. Ketamine consists of two stereoisomers, S(+) and R(-). R( The S(+) is moree potent and is associated with fewer psychomimetic effects (111).

Pharmacokinetics of ketamine: Ketamine is administered intravenously or intramuscularly.

51


Review of literature

The anesthetic action is terminated by a combination of redistribution from the CNS to slower equilibrating peripheral tissues and by hepatic metabolism. Ketamine has a low degree of protein binding (12%). Because ketamine has a low molecular weight, a pKa near the physiologic pH, and relatively high lipid solubility, it crosses the blood-brain barrier rapidly and has an onset of action within 30 to 60 seconds of administration. The maximal effect occurs in about 1 minute. The duration of ketamine anesthesia after a single IV administration of a general anesthetic dose (2 mg/kg) is 10 to 15 minutes. The ketamine plasma concentration has an initial slope lasting about 45 minutes with a half-life of 10 to 15 minutes where full orientation to person, place, and time occurs. This slope corresponds clinically to the anesthetic effect of the drug (figure 11). (111)

Figure 11: Simulated time course of plasma levels of ketamine after an induction dose of 2 mg/kg (111)

52


Review of literature

Ketamine is metabolized by hepatic microsomal enzymes. The major pathway involves N-demethylation to form norketamine (metabolite I), which is then hydroxylated to hydroxynorketamine. These products are conjugated to water-soluble glucuronide derivatives and are excreted in the urine (109). Norketamine has 20% to 30% of the activity of the parent compound and may contribute in prolonging the analgesia provided by either a bolus or infusion of ketamine (112).

Mechanism of action of ketamine: Ketamine has been demonstrated to be an N-Methyl-D-Aspartate (NMDA) receptor antagonist. Ketamine has multiple effects throughout the central nervous system, including blocking polysynaptic reflexes in the spinal cord and inhibiting excitatory neurotransmitter effects in selected areas of the brain. In contrast to the depression of the reticular activating system induced by the barbiturates, ketamine functionally "dissociates" the thalamus which relays sensory impulses from the reticular activating system to the cerebral cortex, from the limbic cortex which is involved with the awareness of sensation (dissociative amnesia). Although some brain neurons are inhibited, others are topically

excited(79).

Additionally,

ketamine

has

many

other

pharmacological properties such as blocking amine uptake in the descending inhibitory monoaminergic pain pathways, interacting with L JR V R LN L NW

JR VPJT WL J TJ VN NR LJ LR WV J V MKN R V PJt-

opioid agonist.(113, 114)

53


Review of literature

Pharmacodynamics of ketamine: I) Central nervous system effects: Ketamine produces dose-related unconsciousness and analgesia. Patients anesthetized with ketamine have profound analgesia, but keep their eyes open and maintain many reflexes (dissociative anesthesia). Corneal, cough, and swallow reflexes all may be present, but should not be assumed to be protective(115). After ketamine administration, pupils dilate moderately, and nystagmus occurs. Lacrimation and salivation are common, as is increased skeletal muscle tone, often with coordinated but seemingly purposeless movements of the arms, legs, trunk, and head. (111) The duration of ketamine anesthesia is determined by the dose; larger doses produce more prolonged anesthesia, and the concurrent use of other anesthetics prolongs the time of emergence. Concomitant administration of benzodiazepines, a common practice, may prolong the effect of ketamine (116). Analgesia occurs at considerably lower blood levels than loss of L W VL R W VN

hP TW Peater). This means there is a considerable

period of postoperative analgesia after ketamine general anesthesia, and subanesthetic doses can be used to produce analgesia. (111) Ketamine increases CBF, which appears higher than the increase in CMRO2 would mandate. With the increase in CBF and the generalized increase in sympathetic nervous system response, there is an increase in ICP after ketamine (117).

54


Review of literature

II) Cardiovascular effects: Ketamine stimulates the cardiovascular system and is usually associated with increases in blood pressure, heart rate, and cardiac output and this is associated with increased work and myocardial oxygen consumption. The healthy heart is able to increase oxygen supply by increased cardiac output and decreased coronary vascular resistance, so that coronary blood flow is appropriate for the increased oxygen consumption. These hemodynamic changes are not dose-related. The mechanism by which ketamine stimulates the circulatory system remains enigmatic. It seems not to be a peripheral mechanism such as baroreflex inhibition, but rather to be central. There is some evidence that ketamine attenuates baroreceptor function via an effect on NMDA receptors nucleus tractus solitaries. Ketamine also causes the sympathoneuronal release of norepinephrine, which can be detected in venous blood. Blockade of this effect is possible with barbiturates, benzodiazepines, and droperidol. (111) III) Respiratory effects: Ketamine has minimal effects on the central respiratory drive as reflected by an unaltered response to carbon dioxide. There can be a transient (1 to 3 minutes) decrease in minute ventilation after the bolus administration of an induction dose of Ketamine. Rarely large doses can produce apnea. Ketamine is a bronchial smooth muscle relaxant. When it is given to patients with reactive airway disease and bronchospasm, pulmonary compliance is improved. (111)

55


Review of literature

Clinical uses of ketamine: I) Induction and Maintenance of Anesthesia: Most candidates for ketamine induction are poor-risk patients (ASA class IV) with respiratory and cardiovascular system disorders (excluding ischemic heart disease). e.g. patients with reactive airway disease, healthy trauma victims whose blood loss is extensive patients with septic shock

(119)

(118)

,

and patients with cardiac tamponade and

restrictive pericarditis(120) II) Pain Management: Ketamine administered in small doses decreases postoperative analgesic consumption. Side effects, especially psychotomimetic effects, were minimal, especially if a benzodiazepine also was administered (121). III) Sedation: Ketamine is particularly suitable for sedation of pediatric patients as pediatric patients have fewer adverse emergence reactions than adults(122). Ketamine can be used as a supplement or an adjunct to regional anesthesia, extending the usefulness of the primary (local anesthetic) form of anesthesia (123). Ketamine also may be considered for sedation of patients in a critical care unit because of its combined sedative and analgesic properties and favorable effects on hemodynamics (111).

56


Review of literature

Dosage of ketamine: (table 5) Table 5: Doses of Ketamine Induction of general anesthesia

(111)

0.5-2 mg/kg IV 4-6 mg/kg IM

Maintenance of general anesthesia

0.5-1 mg/kg IV with N2O 50% in O2 15-45 hPSP R V: F R 2O 50-70% in O2 30-90 hPSP R V: F R W 2O

Sedation and analgesia

0.2-0.8 mg/kg IV over 2-3 min 2-4 mg/kg IM

Preemptive/preventive analgesia 0.15-0.25 mg/kg IV

Contraindications of ketamine (111): Patients with increased ICP and with intracranial mass lesions because it can increase ICP . Patients with an open eye injury or other ophthalmologic disorders because it can increase IOP. As ketamine causes hypertension and tachycardia, with a commensurate increase in myocardial oxygen consumption, it is contraindicated as the sole anesthetic in patients with ischemic heart disease. Also it is unwise to give ketamine to patients with vascular aneurysms because of the possible sudden change in arterial pressure. Psychiatric disease, such as schizophrenia History of adverse reaction to ketamine or one of its congeners.

57


Review of literature

When there is a possibility of postoperative delirium from other causes (e.g., delirium tremens, possibility of head trauma), and a ketamine-induced psychomimetic effect would confuse the differential diagnosis.

Adverse reactions of ketamine: Ketamine produces undesirable psychological reactions, which occur during awakening from ketamine anesthesia and are termed emergence reactions. The common manifestations of these reactions, which vary in severity and classification, are vivid dreaming, extracorporeal experiences (sense of floating out of body), hallucinations and

illusions

experience)

(124)

(misinterpretation

of

a

real,

external

sensory

.

These incidents of dreaming and illusion are often associated with excitement, confusion, euphoria, and fear. They occur in the first hour of emergence and usually disappeared within one to several hours. It has been postulated that the psychic emergence reactions occur secondary to ketamine-induced depression of auditory and visual relay nuclei, leading to misperception or misinterpretation of auditory and visual stimuli (109). A clinically relevant range is probably 10% to 30% of adult patients who receive ketamine as a sole or major part of the anesthetic technique (111). Another potential problem is the increased salivation which may produce upper airway obstruction. Also it may contribute to or may complicate further laryngospasm. In addition, although swallow, cough, sneeze, and gag reflexes are relatively intact after ketamine

58


Review of literature

administration, there is evidence that silent aspiration can occur during Ketamine anesthesia(111).

59


Review of literature

Tramadol

Figure 12: 12 Chemical structure of tramadol

(111)

Physiochemical characters of tramadol: Tramadol is a centrally acting analgesic that acts at multiple sites, providing moderate pain relief with low risk of respiratory depression, tolerance and dependence. Tramadol is a synthetic 4-phenyl 4 phenyl-piperidine analog of codeine (figure igure 12). 12) Itt is administered as a racemic mixture of two enantiomers.

Pharmacokinetics of tramadol: Tramadol is rapidly and extensively absorbed after oral administration, appearing in the plasma 15 to 45 minutes after administration, with peak levels occurring after 2 h(125). Tramadol has a high oral bioavailability (70i (70 80%) that can increase to 90i 100% with repeated dosage. Tramadol has a high tissue affinity and is 20% bound to plasma proteins (126).

60


Review of literature

25-30% of the oral dose of tramadol is excreted unchanged in urine. The main metabolic pathways of tramadol are N- and Odemethylation then conjugation of the O-demethylated metabolites. This is done by hepatic cytochrome P450 system(127). 90% of tramadol and its metabolites are excreted in urine and the remainder in faeces

(128)

. Both tramadol and its metabolites cumulate in

chronic renal disease and hepatic failure, and dose requirements may be reduced by 50%. Conversely, the concurrent use of enzyme-inducing agents (e.g. carbamazepine) may considerably reduce its plasma concentration and analgesic efficacy (126).

Mechanism of action of tramadol: Tramadol exerts its analgesic effect by a multi modal mechanism. Tramadol possesses only a modest affinity for h-receptor and no affinity (129)

for q - J VM t-opioid receptors

. The (+)-O-desmethyltramadol

metabolite (M1) is an opioid J P W VR receptors than the parent compound

(126)

R J R PN J O O R V Ra O W h-

.

In addition to its opioid actions, tramadol inhibits the neuronal reuptake of norepinephrine and serotonin (5-HT). These monoamine neurotransmitters are involved in the anti-nociceptive effects of descending inhibitory pathways in the central nervous system(127).

Pharmacodynamics of tramadol: Tramadol is a potent analgesic that is found effective in providing analgesia superior to that of placebo when administered in its oral or parentral forms (127).

61


Review of literature

Analgesic doses of tramadol produce no respiratory depression, in part because of its non-opioid receptor-mediated actions(130), and have minimal effects on gastrointestinal motor function(131).

Side effects of tramadol: Tramadol is generally well tolerated; however, gastrointestinal and nervous system side effects, in particular, lead to 19 to 30% of patients discontinuing therapy(132). Dizziness (26-33%), headache (18-32%), sedation (16-25%), nausea (24-40%), vomiting (9-17%) and constipation (24-46%) are the most common side-effects(125). Side effects appear to be route- as well as dose-dependent, with parenteral administration associated with more complications

(125)

. Some

authors suggested that side-effects can be decreased by beginning with a low dose that is incremented to the target dose i.e. true rate effect, rather than simply dosage related (133).

Dosage and methods of administration Oral, parenteral and rectal formulations are available. Optimal dosage

regimens

are

currently

undecided.

The

manufacturer

recommends 50 mg every 4 to 6 hours as needed for moderate pain. For severe pain 100 mg is advocated, followed by 50 to100 mg every 6 hours to a maximum of 400 mg in 24 h (300 mg/24 h in the elderly). Epidural administration of preservative-free tramadol appears to be safe and effective (134).

62


Review of literature

Tramadol may be an advantageous adjunct to regional anaesthesia. Tramadol 100 mg added to mepivacaine 1% was shown to prolong the duration of brachial plexus block by 54% compared with patients receiving mepivacaine alone (135). Tramadol 25-50 mg has a local anaesthetic effect after intradermal injection (136), and significantly reduces the pain of propofol injection to a similar degree to lignocaine 1% (137).

Usage and indications Intravenously administered Tramadol is effective for post operative pain relief

(138)

. Also Tramadol is effective in the treatment of

chronic pain syndromes, both those caused by malignancy and other chronic inflammatory conditions e.g. low back pain syndromes, joint pain, neuropathic pain and pain from osteitis deformans(139,

140)

. So

tramadol can contributes to the reduction in the dosage and thus side effects of NSAID as well as drugs with a high dependency or tolerance profile.

63


Aim of the work

2010


Aim of the work

Aim of the Work This is a prospective randomized, comparative, placebo controlled study in which the efficacy of each of midazolam, midazolam plus ketamine, tramadol, and tramadol plus ketamine, for prophylaxis of postspinal shivering is evaluated and compared to each other.

65


Patients and methods

2010


Patients and methods

Patients and Methods After obtaining institutional approval and written consent from all patients, this prospective, randomized, comparative and placebo controlled study was carried out in Tanta University Hospital from November 2009 to July 2010 on one hundred ASA status I and II patients between the ages of 21- 60 years who were undergoing elective orthopedic surgery under spinal anesthesia. Exclusion criteria: Patients

with

thyroid

diseases,

cardiopulmonary

diseases,

neuromuscular diseases or psychological disorders were excluded from the study. Also patients on narcotics, sedatives, opioids, vasodilators, antipyretics or any medication likely to alter thermoregulation, or with a known history of drug abuse were excluded. Also we excluded patients in a need for blood transfusion during surgery, patients with an initial KWMa N NJ N1 ,)d 4W 0 d 4 JR N V

R N L N V RWaWO

febrile illness, and patients with history of malignant hyperthermia. Preoperative investigation: Routine preoperative investigations including complete blood picture, renal function tests, liver function tests and coagulation profile were done for preoperative evaluation. Anesthetic technique: All patients didn't receive any pre-medication. On arrival to the operating theatre, all patients had a venous cannula inserted. I.V fluids in

67


Patients and methods

NO W

WOT J LJN M R VPNm WT R WV NNR VO N MJ J JNWO

ml/kg/h over 30 minutes before spinal anesthesia then the rate was reduced to 6 ml/kg/h. I.V. fluids were not warmed. The ambient temperature was maintained at 22-&(d 4 All patients had spinal anesthesia where 15 mg hyperbaric Bupivacaine 0.5% was instituted at either L3/L4 or L4/L5 using a 22 G Quincke spinal needle under complete aseptic conditions. The patients were allocated randomly to one of five groups: Group C (n=20):

Received saline as a control.

Group M (n=20):

Received mR MJ b WT J )hPSP.

MJ b WT J Group MK (n=20): Received mR

)hPSP T ketamine

0.25 mg/kg. Group T (n=20):

Received tramadol 0.5 mg/kg.

Group TK (n=20):

Received tramadol 0.25 mg/kg plus ketamine 0.25 mg/kg.

All of these drugs were diluted to volume of 5 ml and was given as an I.V. bolus immediately after intrathecal injection. Supplemental oxygen was given via a face mask at a rate of 5 L/min during the operation. All patients were covered with one layer of surgical drapes over the chest, thighs and calves during the operation and one cotton blanket over the entire body after the operation. After intrathecal injection the sensory and motor block were assessed with a pinprick test every 5 minutes. When spinal anesthesia was established the presence of shivering was observed and graded by using a scale similar to that validated by Tsai and Chu (38) where:

68


Patients and methods

0 = No shivering. 1 = Piloerection or peripheral vasoconstriction but no visible shivering. 2 = Muscular activity in only one muscle group. 3 = Muscular activity in more than one muscle group but not generalized. 4 = Shivering all over the body. This score was evaluated during surgery. If shivering occurred, it was graded and recorded and if the grade was 3 or 4 after 15 minute from the administration of the tested prophylactic drug, it was considered severe shivering and rescue treatment in the form of I.V. 25 mg of pethidine was given. Heart rate, respiratory rate, mean arterial blood pressure, peripheral oxygen saturation (SpO2) and tympanic membrane temperature were recorded using standard noninvasive monitors at 10 minutes intervals during the pre- and the post-anesthesia period. The degree of sedation was assessed according to a five-point scale where: 1 = Fully awake and oriented. 2 = Drowsy. 3 = Eye closed but responds to commands. 4 = Eye closed but responds to mild physical stimulation. 5 = Eye closed and not responding to mild physical stimulation. Any other side effect was recorded and properly treated e.g. hypotension, nausea, vomiting and hallucination. 69


Patients and methods

Statistical Analysis All data was recorded, summarized, tabulated and statistically J VJ T a b N M R VP CACC CJRR L

WPJ

FN R WV

/CACC : VL

Chicago, IL, USA). Statistical presentation and analysis of this study was conducted, using the mean, standard deviation (SD), analysis of variance (ANOVA) test and Chi-

JN u & N WNJ R VNMR O O NN VL NJ WVP NO RN

groups as regard the parametric variables. Categorial variables were analyzed using 5o2 Chi-

JN Mu &

test to determine the difference among the five groups, followed by a series of 2o2 Fisher's exact test, Chi-

JN u &N

VNGJ a2

F2

test or Mann-Whitney test when appropriate for the intergroup differences. P-value < 0.05 was considered significant.

70


Results

2010


Results

Results This study was conducted after patient approval and consent on 100 patients presented for orthopedic surgery using spinal anesthesia. Part of the research was during anesthesia and surgery including clinical data such as the heart rate, mean arterial blood pressure, peripheral O2 saturation, respiratory rate and core temperature. The other part of the research was a trial to evaluate the prophylactic use of Midazolam, Midazolam plus Ketamine, Tramadol and Tramadol plus Ketamine on the incidence of post-spinal shivering, where the patients were closely observed for detection of shivering and its grade. Also the patients were closely monitored for detection of any side effect. Our results were recorded in the following tables:

71


Results

Demographic data: Table 6 : Patients' demographic data, ASA status and duration of surgery Group C

Group M

Group MK

Group T

Group TK

P-value

(n=20)

(n=20)

(n=20)

(n=20)

(n=20)

ANOVA

Age (years)*

( (( e(

Weight (kg)*

)e

)

(2)*

( &( ( e(

) e

( ,e (&

) e

() e

( e

29.64e(& ,

28.61e7.46

28.89e5.73

( e &) ,

)& e (

,

&

27.67e6.70

(

e

0.126

( e &,

0.951

30.28e5.84

0.710

Duration of surgery

e ) , ) e

), & e(

0.096

(minutes)*

ChiSex (male/female)

g

10/10

12/8

13/7

11/9

12/8

squared 0.899

g

ASA (I/II)

19/1

20/0

20/0

18/2

20/0

* FJ TN JNN N N MJ N J VeC5 )BMI = Body Mass Index gValues are expressed as number of patients

Table 6 shows patients' demographic data, duration of surgery and ASA status: The comparison of patients' demographic data showed that the differences among the five groups were not statistically significant as regard age (P-value was 0.126), weight (P-value was 0.951), BMI (Pvalue was 0.710) and sex (P-value was 0.899). Also there were no statistically significant differences between the groups as regard ASA status (P-value was 0.240) and duration of surgery (P-value was 0.096). 72

0.240


Results

Heart rate (HR): Table 7 : Changes of heart rate (beats/minute) in Group C Post anesthesia period n = 20

Base value

1

94

73

79

80

91

89

85

2

99

69

76

79

93

88

89

3

91

66

69

78

93

87

93

4

95

71

75

83

92

90

89

5

81

65

67

73

84

84

83

6

84

76

81

82

90

88

90

7

99

78

81

90

99

96

93

8

92

70

77

73

82

85

89

9

97

81

77

86

97

97

99

10

83

69

66

78

87

91

91

11

82

78

72

82

91

88

83

12

87

70

67

74

83

88

87

13

101

76

79

80

94

91

85

14

91

66

69

76

85

90

101

15

99

74

77

80

91

96

103

16

86

66

65

69

82

86

97

17

85

69

69

78

91

93

93

18

90

68

72

78

94

97

93

19

95

73

77

71

85

92

88

20

104

74

77

77

91

92

83

Min.

81

65

65

69

82

84

83

Max.

104

81

81

90

99

97

103

Mean

91.75

71.60

73.60

78.35

89.75

90.40

90.70

SD

6.882

4.593

5.236

5.008

4.919

3.899

5.895

Paired t-test

t

13.696

15.537

8.445

1.451

0.987

0.545

P-value

< 0.001*

< 0.001*

< 0.001*

0.163

0.336

0.592

10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

* statistically significant when compared with base value (P-value < 0.05)

73


Results

100 90 80 70 60 50 Base

10

20

30

40

50

60

Time in minutes

Figure 13: Changes of heart rate in Group C

Table 7 which is represented in figure 13 shows changes of heart rate in Group C: The base value of mean heart rate in Group C before spinal J VN NR J J

)e ,, &

J VN NR J NR WM W

R L R P V R O R L J VT a MN LN JN MR V W-

e()

e)& J V M , )e) ,J ON

10, 20 and 30 minutes respectively (P-values was < 0.001 at the three R N 2ON ( ) J V M (e , J V M

R VN

N N J V

e),) N N LRN T a

R L

NN, )e( NNR VR P V R O R L J VT a

different from the base (P-value was 0.163, 0.336 and 0.592 respectively).

74


Results

Table 8: Changes of heart rate (beats/minute) in Group M Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

96

74

83

85

92

91

87

2

97

67

72

78

88

86

88

3

104

72

83

79

84

93

84

4

91

68

72

70

97

88

94

5

94

71

75

85

87

101

97

6

86

60

63

76

97

82

85

7

101

76

80

72

88

96

95

8

82

65

67

77

87

85

84

9

82

73

78

83

84

86

88

10

91

68

75

75

94

84

88

11

95

78

74

87

92

95

96

12

85

70

67

83

94

93

97

13

86

81

75

89

85

92

87

14

86

68

65

76

95

87

86

15

103

77

80

85

97

93

87

16

98

72

75

82

84

95

96

17

91

70

72

82

92

98

94

18

102

71

74

78

85

90

81

19

96

75

77

75

90

93

89

20

96

70

76

72

86

89

85

Min.

82

60

63

70

84

82

81

Max.

104

81

83

89

97

101

97

Mean

93.10

71.30

74.15

79.45

89.90

90.85

89.40

SD

6.897

4.824

5.518

5.395

4.678

4.966

5.020

Paired t-test

t

14.203

16.001

6.744

1.592

1.551

1.915

P-value

< 0.001*

< 0.001*

< 0.001*

0.128

0.137

0.071

* statistically significant when compared with base value (P-value < 0.05)

75


Results

100 90 80 70 60 50 Base

10

20

30

40

50

60

Time in minutes

Figure 14: Changes of heart rate in Group M

Table 8 which is represented in figure 14 shows changes of heart rate in Group M: The base value of mean heart rate in Group M before spinal J VN NR J J

e,

J VN NR J NR WM W

R L R P VR O R L J VT aMN LN JN MR V Nposte(,& ( () e)),J V M

()e) )J ON

10, 20 and 30 minutes respectively (P-values was < 0.001 at the three R N 2ON ( ) J V M ,)e(

R VN

N N J V

J V M, (e) & N N LRN T a

R L

NN,

e( ,

N re insignificantly

different from the base (P-value was 0.128, 0.137 and 0.071 respectively).

76


Results

Table 9 : Changes of heart rate (beats/minute) in Group MK Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

90

66

75

81

82

94

82

2

97

70

71

82

88

83

93

3

86

69

67

81

89

94

89

4

94

70

85

80

92

98

94

5

90

65

64

73

88

90

89

6

88

66

72

80

94

94

92

7

89

70

71

85

90

91

88

8

93

69

65

81

86

96

97

9

97

73

76

81

96

94

93

10

90

67

65

76

93

91

90

11

96

70

73

79

94

102

94

12

94

74

81

83

97

99

97

13

91

75

73

86

97

90

89

14

83

65

63

84

88

89

90

15

100

77

82

89

87

89

94

16

95

69

68

80

89

96

95

17

96

64

72

80

87

89

86

18

91

71

76

82

89

89

86

19

97

70

68

82

89

96

91

20

102

74

80

79

95

97

96

Min.

83

64

63

73

82

83

82

Max.

102

77

85

89

97

102

97

Mean

92.95

69.70

72.35

81.20

90.50

93.05

91.25

SD

4.740

3.585

6.310

3.412

4.059

4.466

3.985

Paired t-test

t

25.835 < 0.001*

16.927 < 0.001*

9.322 < 0.001*

1.926 0.069

-0.076

1.700 0.106

P-value

* statistically significant when compared with base value (P-value < 0.05)

77

0.940


Results

100 90 80 70 60 50 Base

10

20

30

40

50

60

Time in minutes

Figure 15: Changes of heart rate in Group MK

Table 9 which is represented in figure 15 shows changes of heart rate in Group MK: The base value of mean heart rate in Group MK before spinal J VN NR J J &) e( ( J VN NR J NR WM W

R L R P VR O R L J VT aMN LN JN MR V N W-

e ), ) &) e

J V M, &e (&J ON

10, 20 and 30 minutes respectively (P-values was < 0.001 at the three times). After 40, 50 and 60 minute )e(( J V M

N N J V

&)e , )NN LRN T a

R L

NN

)e( )

NNR VR P V R O R L J VT a

different from the base (P-value was 0.069, 0.940 and 0.106 respectively).

78


Results

Table 10 : Changes of heart rate (beats/minute) in Group T Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

99

74

78

84

95

93

91

2

96

69

73

81

81

95

102

3

89

67

70

79

92

98

93

4

100

69

70

78

86

90

88

5

94

72

75

74

90

93

89

6

94

67

74

71

86

89

85

7

94

71

81

84

92

91

87

8

95

64

70

77

88

86

89

9

102

69

79

78

84

93

82

10

89

65

70

69

90

88

84

11

92

68

73

84

87

99

97

12

84

62

64

75

96

86

88

13

99

73

78

71

88

96

95

14

80

62

65

76

87

85

84

15

80

70

76

82

84

86

88

16

89

65

73

74

94

84

88

17

95

77

74

89

94

97

97

18

83

67

65

82

94

93

97

19

84

78

73

85

85

92

89

20

84

65

63

75

95

87

86

Min.

80

62

63

69

81

84

82

Max.

102

78

81

89

96

99

102

Mean

91.10

68.70

72.20

78.40

89.40

91.05

89.95

SD

6.805

4.485

5.116

5.384

4.418

4.571

5.286

Paired t-test

t

15.032

15.600

6.546

0.864

0.036

0.643

P-value

< 0.001*

< 0.001*

< 0.001*

0.398

0.972

0.528

* statistically significant when compared with base value (P-value < 0.05)

79


Results

100 90 80 70 60 50 Base

10

20

30

40

50

60

Time in minutes

Figure 16: Changes of heart rate in Group T

Table 10 which is represented in figure 16 shows changes of heart rate in Group T: The base value of mean heart rate in Group T before spinal J VN NR J J

e ,)

R L R P VR O R L J VT aMN LN JN MR V N W-

J VN NR J NR WM W , e((, ) &&e)

J V M ,(e) , (J ON

10, 20 and 30 minutes respectively (P-values was < 0.001 at the three R N 2ON ( ) J V M

R VN

N N J V

)e() J V M, )e)& , NN LRN T a

R L

NN, (e((, NNR VR P V R O R L J VT a

different from the base (P-value was 0.398, 0.972 and 0.528 respectively).

80


Results

Table 11 : Changes of heart rate (beats/minute) in Group TK Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

82

68

76

83

95

98

92

2

92

70

74

72

91

93

93

3

91

64

72

83

94

97

98

4

87

68

65

72

89

92

97

5

100

70

80

78

93

97

98

6

82

73

78

84

90

93

91

7

96

63

73

83

84

90

87

8

93

70

67

85

92

92

89

9

102

72

74

88

96

98

94

10

84

64

68

78

86

96

91

11

104

68

69

80

94

93

96

12

94

72

67

82

91

98

97

13

93

71

81

87

93

98

99

14

97

72

76

85

94

91

90

15

92

67

79

82

99

94

94

16

103

77

71

83

92

95

95

17

89

76

81

81

88

88

89

18

84

68

70

80

84

92

83

19

94

69

72

78

81

91

86

20

92

67

68

78

86

85

93

Min.

82

63

65

72

81

85

83

Max.

104

77

81

88

99

98

99

Mean

92.55

69.45

73.05

81.10

90.60

93.55

92.60

SD

6.637

3.677

5.000

4.254

4.593

3.620

4.382

Paired t-test

t

15.339 < 0.001*

10.490 < 0.001*

7.230 < 0.001*

1.268 0.220

-0.612

-0.034

0. 548

0.973

P-value

* statistically significant when compared with base value (P-value < 0.05)

81


Results

100 90 80 70 60 50 Base

10

20

30

40

50

60

Time in minutes

Figure 17: Changes of heart rate in Group TK

Table 11 which is represented in figure 17 shows changes of heart rate in Group TK:

The base value of mean heart rate in Group TK before spinal J VN NR J J &) )e J VN NR J NR WM W

R L R PV R O R L J VT aMN LN JN MR V Npos()e

) e)

J V M,

e(&) (J ON

10, 20 and 30 minutes respectively (P-values was < 0.001 at the three R N 2ON ( ) J V M

R VN

N N J V

))e & J V M & e( , &NN LRN T a

R L

NN

e()

Ne insignificantly

different from the base (P-value was 0.220, 0.548 and 0.973 respectively).

82


Results

Table 12 : Changes of the mean heart rate in the five groups Heart Rate (HR)

ANOVA

Group C Group M Group MK Group T Group TK Mean

91.75

93.10

92.95

91.10

92.55

SD

6.882

6.897

4.740

6.805

6.637

Mean

71.60

71.30

69.70

68.70

69.45

SD

4.593

4.824

3.585

4.485

3.677

Mean

73.60

74.15

72.35

72.20

73.05

SD

5.236

5.518

6.310

5.116

5.000

Mean

78.35

79.45

81.20

78.40

81.10

SD

5.008

5.395

3.412

5.384

4.254

Mean

89.75

89.90

90.50

89.40

90.60

SD

4.919

4.678

4.059

4.418

4.593

Mean

90.40

90.85

93.05

91.05

93.55

SD

3.899

4.966

4.466

4.571

3.620

Mean

90.70

89.40

91.25

89.95

92.60

SD

5.895

5.02

3.985

5.286

4.382

Base

10 minutes

20 minutes

30 minutes

40 minutes

50 minutes

60 minutes

Values are expressed as means and SD

83

F

P-value

0.345

0.847

1.712

0.154

0.457

0.767

1.724

0.151

0.252

0.908

2.145

0.081

1.247

0.297


Results

Group C

Group M

Group MK

Group T

Group TK

100 90 80 70 60 50 Base

10

20

30

40

50

60

Time in minutes

Figure 18: Changes of the mean heart rate in the five groups

Table 12 which is represented in figure 18 shows Changes of the mean heart rate in the five groups: There were no statistically significant differences among the five groups as regard the mean heart rate value at each time interval from the base value (P-value was 0.847) to 10, 20, 30, 40, 50 and 60 in the postanesthesia period (P-value was 0.154, 0.767, 0.151, 0.908, 0.081 and 0.297 respectively)

84


Results

Mean arterial blood pressure (MAP): Table 13 : Changes of MAP (mmHg) in Group C Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

97

75

79

83

94

92

88

2

102

71

76

82

96

91

92

3

94

68

69

81

96

90

96

4

98

73

75

86

95

93

92

5

84

67

67

76

87

87

86

6

87

78

81

85

93

91

93

7

102

80

81

93

102

99

96

8

95

72

77

76

85

88

92

9

100

83

77

89

100

100

102

10

86

71

66

81

90

94

94

11

85

80

72

85

94

91

86

12

90

72

67

77

86

91

90

13

104

78

79

83

97

94

88

14

94

68

69

79

88

93

104

15

102

76

77

83

94

99

106

16

89

68

65

72

85

89

100

17

88

71

69

81

94

96

96

18

93

70

72

81

97

100

96

19

98

75

77

74

88

95

91

20

107

76

77

80

94

95

86

Min.

84

67

65

72

85

87

86

Max.

107

83

81

93

102

100

106

Mean

94.750

73.600

73.600

81.350

92.750

93.400

93.700

SD

6.882

4.593

5.236

5.008

4.919

3.899

5.895

Paired t-test

t

14.375

18.105

8.445

1.451

0.987

0.545

P-value

< 0.001*

< 0.001*

< 0.001*

0.163

0.336

0.592

* statistically significant when compared with base value (P-value < 0.05)

85


Results

110 100 90 80 70 60 Base

10

20

30

40

50

60

Time in minutes

Figure 19: Changes of MAP in Group C

Table 13 which is represented in figure 19 shows changes of MAP in Group C: The base value of mean MAP in Group C before spinal anesthesia J ( )e ,, & NR W MW

R L R P VR O R L J VT aMN LN JN MR V NAW -anesthesia

e()

e)& J VM, )e) ,J ON

&

and 30 minutes respectively (P-values was < 0.001 at the three times). 2ON (

) J V M

( e, J V M

R VN

N

N J V

e),) N N LRN T a

NN & )e(

R L NNR VR P VR O R L J VT a

different from the base (P-value was 0.163, 0.336 and 0.592 respectively).

86


Results

Table 14 : Changes of MAP (mmHg) in Group M Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

108

88

93

96

105

103

107

2

106

86

89

94

104

102

105

3

93

78

79

86

97

91

95

4

101

92

70

80

96

98

97

5

101

87

90

95

102

105

101

6

83

68

68

73

87

89

93

7

88

70

75

75

89

87

89

8

110

87

74

73

100

103

106

9

91

75

77

83

94

92

89

10

93

74

79

82

91

93

95

11

82

64

65

73

84

86

89

12

87

65

73

77

85

89

86

13

92

79

80

87

95

94

95

14

104

88

68

72

91

89

88

15

108

84

88

91

104

102

105

16

85

65

71

75

87

89

86

17

95

79

82

90

99

97

93

18

104

88

89

93

97

101

95

19

101

78

87

84

96

99

93

20

87

62

71

66

81

85

82

Min.

82

62

65

66

81

85

82

Max.

110

92

93

96

105

105

107

Mean

95.950

77.850

78.400

82.250

94.200

94.700

94.450

SD

9.058

9.566

8.562

9.020

7.120

6.522

7.251

Paired t-test

t

19.730

10.406

7.194

1.598

1.152

1.193

P-value

< 0.001*

< 0.001*

< 0.001*

0.127

0.264

0.248

* statistically significant when compared with base value (P-value < 0.05)

87


Results

110 100 90 80 70 60 Base

10

20

30

40

50

60

Time in minutes

Figure 20: Changes of MAP in Group M

Table 14 which is represented in figure 20 shows changes of MAP in Group M: The base value of mean MAP in Group M before spinal anesthesia was 95 )e ) , period W

R L R P VR O R L J VT aMN LN JN MR V N W -anesthesia

, )e )

,( e,)&J VM, &&)e & J ON

&

and 30 minutes respectively (P-values was < 0.001 at the three times). 2ON ( (

) J V M

R VN

N

N J V

e) & &J V M (()e & ) NN LRN T a

NN (& e &

R L NNR VR P VR O R L J Vly

different from the base (P-value was 0.127, 0.264 and 0.248 respectively).

88


Results

Table 15 : Changes of MAP (mmHg) in Group MK Post anesthesia period n = 20

Base value

1

106

83

90

88

99

101

100

2

92

75

75

80

93

95

91

3

82

67

67

73

84

86

89

4

99

83

84

91

98

96

99

5

91

78

76

83

94

94

93

6

95

81

80

87

100

99

102

7

101

65

71

75

87

96

95

8

90

79

77

82

91

95

93

9

110

91

92

95

107

103

106

10

101

89

87

94

105

107

105

11

93

79

74

82

93

91

94

12

108

90

91

96

106

103

101

13

81

62

67

69

81

84

86

14

97

73

82

81

93

91

94

15

104

90

82

85

97

87

102

16

83

71

68

76

87

91

90

17

102

83

83

89

101

104

99

18

103

82

86

86

97

99

101

19

97

79

81

85

96

93

96

20

79

67

64

73

86

89

91

Min.

79

62

64

69

81

84

86

Max.

110

91

92

96

107

107

106

Mean

95.700

78.350

78.850

83.500

94.750

95.200

96.350

SD

9.217

8.671

8.468

7.647

7.304

6.396

5.603

Paired t-test

t

13.448

20.119

10.731

0.859

0.350

-0.565

P-value

< 0.001*

< 0.001*

< 0.001*

0.401

0.730

0.579

10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

* statistically significant when compared with base value (P-value < 0.05)

89


Results

110 100 90 80 70 60 Base

10

20

30

40

50

60

Time in minutes

Figure 21: Changes of MAP in Group MK

Table 15 which is represented in figure 21 shows changes of MAP in Group MK: The base value of mean MAP in Group MK before spinal J VN NR J J )

e&

R L R P V R O R L J VT aMN LN JN MR V N W-

J VN NR J NR W M W , )e,

,, )e,(, J V M, ) e (

after 10, 20 and 30 minutes respectively (P-values was < 0.001 at the three times). After 40, 50 and 60 minutes the means )& e

J V M

)e)

NN LRN T a

NN ( )e

(

R L NNR VR P VR O R L J VT a

different from the base (P-value was 0.401, 0.730 and 0.579 respectively).

90


Results

Table 16 : Changes of MAP (mmHg) in Group T Post anesthesia period n = 20

Base value

1

105

89

94

97

106

104

108

2

103

103

85

83

95

101

100

3

94

79

80

87

98

92

96

4

93

73

72

80

91

98

93

5

102

88

91

96

103

106

102

6

97

73

67

82

92

96

99

7

89

71

76

76

90

88

90

8

98

83

85

91

96

98

95

9

92

76

78

84

95

93

90

10

92

73

78

81

90

92

94

11

88

65

66

74

85

87

90

12

86

64

72

76

84

88

85

13

93

80

81

88

96

95

96

14

95

75

80

81

92

94

91

15

92

64

71

85

95

96

93

16

84

64

70

74

86

88

85

17

96

80

83

91

100

98

94

18

103

87

88

92

96

100

94

19

102

79

88

85

97

100

94

20

86

61

70

65

80

84

81

Min.

84

61

66

65

80

84

81

Max.

105

103

94

97

106

106

108

Mean

94.500

76.350

78.750

83.400

93.350

94.900

93.500

SD

6.237

10.489

8.181

8.022

6.418

5.946

6.134

Paired t-test

t

13.745

15.280

10.511

1.358

-0.734

1.285

P-value

< 0.001*

< 0.001*

< 0.001*

0.190

0.472

0.214

10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

* statistically significant when compared with base value (P-value < 0.05)

91


Results

110 100 90 80 70 60 Base

10

20

30

40

50

60

Time in minutes

Figure 22: Changes of MAP in Group T

Table 16 which is represented in figure 22 shows changes of MAP in Group T: The base value of mean MAP in Group T before spinal anesthesia J () e & NR W MW

R L R P VR O R L J VT aMN LN JN MR V N W -anesthesia

)e (,

, )e, , J VM, ( e, & &J ON

&

and 30 minutes respectively (P-values was < 0.001 at the three times). 2ON ( (

) J V M

e) ( J V M

) e

R VN

N

N J V

(N N LRN T a

NN

)e (,

R L NNR VR P VR O R L J VT a

different from the base (P-value was 0. 190, 0.472 and 0.214 respectively).

92


Results

Table 17 : Changes of MAP (mmHg) in Group TK Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

107

84

91

89

100

102

101

2

91

74

74

79

92

94

90

3

83

68

68

74

85

87

90

4

98

82

83

90

97

95

98

5

92

79

77

84

95

95

94

6

94

80

79

86

99

98

101

7

102

87

85

94

104

99

102

8

90

78

76

81

90

94

92

9

104

92

93

96

108

104

107

10

107

96

75

88

93

103

101

11

94

80

75

83

94

92

95

12

107

89

90

95

105

102

100

13

90

76

66

72

89

91

87

14

96

72

81

80

92

90

93

15

105

84

91

91

104

102

104

16

87

70

67

75

86

90

89

17

103

84

84

90

102

105

101

18

102

81

85

85

96

98

100

19

98

80

82

86

97

94

97

20

78

66

63

72

85

88

90

Min.

78

66

63

72

85

87

87

Max.

107

96

93

96

108

105

107

Mean

96.400

80.100

79.250

84.500

95.650

96.150

96.600

SD

8.363

7.759

8.855

7.437

6.831

5.575

5.707

Paired t-test

t

19.119

17.367

13.353

0.728

0.263

-0.192

P-value

< 0.001*

< 0.001*

< 0.001*

0.476

0.795

0.850

* statistically significant when compared with base value (P-value < 0.05)

93


Results

110 100 90 80 70 60 Base

10

20

30

40

50

60

Time in minutes

Figure 23: Changes of MAP in Group TK

Table 17 which is represented in figure 23 shows changes of MAP in Group TK: The base value of mean MAP in Group TK before spinal J VN NR J J anesthesia

( e,

NR W M W,

R L R P V R O R L J VT aMN LN JN MR V N We )

& )e,, ) )J V M, () e (

after 10, 20 and 30 minutes respectively (P-values was < 0.001 at the N NR N 2ON ( ) J VM )e)))J V M

e)

R VN N N J V NN ) )e , NN LRN T a

R L NNR VR P VR ficantly

different from the base (P-value was 0.476, 0.795 and 0.850 respectively).

94


Results

Table 18 : Changes of the MAP rate in the five groups

Mean arterial blood pressure

ANOVA

Group C Group M Group MK Group T Group TK Mean

94.75

95.95

95.7

94.5

96.4

SD

6.882

9.058

9.217

6.237

8.363

Mean

73.6

77.85

78.35

76.35

80.1

SD

4.593

9.566

8.671

10.489

7.759

Mean

73.6

78.4

78.85

78.75

79.25

SD

5.236

8.562

8.468

8.181

8.855

Mean

81.35

82.25

83.5

83.4

84.5

SD

5.008

9.02

7.647

8.022

7.437

Mean

92.75

94.2

94.75

93.35

95.65

SD

4.919

7.12

7.304

6.418

6.831

Mean

93.4

94.7

95.2

94.9

96.15

SD

3.899

6.522

6.396

5.946

5.575

Mean

93.7

94.45

96.35

93.5

96.6

SD

5.895

7.251

5.603

6.134

5.707

Base

10 minutes

20 minutes

30 minutes

40 minutes

50 minutes

60 minutes

Values are expressed as means and SD

95

F

P-value

0.202

0.937

1.664

0.165

1.739

0.148

0.522

0.720

0.603

0.661

0.596

0.666

1.137

0.344


Results

Group C

Group M

Group MK

Group T

Group TK

110 100 90 80 70 60 Base

10

20

30

40

50

60

Time in minutes

Figure 24: Changes of the MAP in the five groups

Table 18 which is represented in figure 24 shows Changes of the MAP in the five groups: There were no statistically significant differences among the five groups as regard the mean MAP value at each time interval from the base value (P-value was 0.937) to 10, 20, 30, 40, 50 and 60 of the postanesthesia period (P-value was 0.165, 0.148, 0.720, 0.661, 0.66 and 0.344 respectively).

96


Results

Respiratory Rate (RR): Table 19 : Changes of respiratory rate (cycles/minute) in Group C Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

14

13

13

16

15

14

14

2

15

13

16

16

15

14

15

3

15

14

16

14

13

17

15

4

15

11

17

16

12

14

16

5

14

15

13

15

15

13

14

6

16

16

18

15

14

16

12

7

16

16

16

15

15

17

15

8

14

13

15

15

14

15

16

9

15

13

12

12

15

15

14

10

13

14

14

12

14

13

14

11

12

12

14

15

12

13

15

12

15

18

12

15

14

14

16

13

15

16

16

14

13

13

17

14

14

12

15

16

13

15

15

15

17

15

14

16

13

17

16

16

15

14

13

13

17

12

13

17

13

15

13

13

14

14

14

18

14

15

14

15

13

11

16

19

13

16

14

17

15

12

13

20

16

12

14

16

14

14

17

Min.

12

11

12

12

12

11

12

Max.

17

18

18

17

17

17

17

Mean

14.550

14.150

14.450

14.800

14.000

14.150

14.850

SD

1.234

1.785

1.638

1.399

1.214

1.694

1.348

Paired t-test

t

0.902

0.261

-0.653

1.502

1.285

-0.842

P-value

0.379

0.797

0.522

0.150

0.214

0.410

97


Results

16

14

12

10 Base

10

20

30

40

50

60

Time in minutes

Figure 25: Changes of respiratory rate in Group C

Table 19 which is represented in figure 25 shows Changes of respiratory rate in Group C: The base value of mean respiratory rate in Group C before spinal J VN NR J

J

( )e , ) ( )e

())e &( which insignificantly changed to (( )e

,

(, e

(J VM (,)e (,J ON

&

(

e &(

( )J VM

R VN

of the post-anesthesia period respectively (P-value was 0.379, 0.797, 0.522, 0.150, 0.214 and 0.410 respectively).

98


Results

Table 20 : Changes of respiratory rate (cycles/minute) in Group M Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

14

11

13

16

11

14

16

2

15

13

14

14

16

14

15

3

12

15

14

16

12

13

14

4

14

14

14

13

15

15

14

5

12

15

15

14

13

15

12

6

17

16

15

17

13

15

17

7

13

13

14

15

16

14

14

8

13

11

15

15

14

17

14

9

16

16

13

15

13

13

13

10

15

15

15

15

12

13

14

11

15

14

12

14

16

12

15

12

18

13

13

13

11

14

14

13

14

14

14

13

14

15

14

14

15

14

13

17

15

14

13

15

17

14

17

15

12

13

16

16

11

15

13

16

13

14

16

17

13

12

15

15

15

12

15

18

15

12

17

14

14

12

15

19

17

14

16

12

13

15

15

20

15

14

15

16

15

14

15

Min.

11

11

12

12

11

12

12

Max.

18

16

17

17

16

17

17

Mean

14.550

13.750

14.350

14.750

13.650

13.900

14.550

SD

1.877

1.446

1.348

1.372

1.599

1.252

1.191

t

1.598

0.427

-0.348

1.484

1.239

0.000

P-value

0.126

0.674

0.731

0.154

0.230

1.000

Paired t-test

99


Results

16

14

12

10 Base

10

20

30

40

50

60

Time in minutes

Figure 26: Changes of respiratory rate in Group M

Table 20 which is represented in figure 26 shows Changes of respiratory rate in Group M: The base value of mean respiratory rate in Group M before spinal J VN NR J )e ( (

J

())e ,

R L R VR P VR O R L J VT a LJ V PN M W

( )e ( ,

e& ) &J VM ())e

( )e

J ON

&

& ( )J VM

)e1.599, R VN

of the post-anesthesia period respectively (P-value was 0.126, 0.674, 0.731, 0.154, 0.230 and 1.000 respectively).

100


Results

Table 21 : Changes of respiratory rate (cycles/minute) in Group MK Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

16

16

14

15

16

14

16

2

15

15

13

16

14

15

13

3

15

15

14

14

14

14

15

4

14

14

13

14

14

14

14

5

13

15

13

13

14

16

16

6

12

12

13

17

12

17

17

7

14

16

14

13

16

15

16

8

13

13

15

16

13

12

16

9

14

12

15

14

13

14

12

10

17

17

17

12

17

11

16

11

15

14

15

12

15

19

13

12

15

15

15

16

15

13

16

13

17

17

18

14

17

15

16

14

14

14

15

17

14

12

11

15

16

16

17

15

11

14

17

16

16

16

16

15

15

11

13

17

16

16

13

13

15

16

13

18

14

14

13

19

12

15

17

19

14

14

16

14

15

13

15

20

16

16

16

11

14

15

15

Min.

12

12

13

11

11

11

11

Max.

17

17

18

19

17

19

17

Mean

14.800

14.850

14.750

14.500

14.300

14.250

14.850

SD

1.361

1.461

1.552

1.960

1.593

1.970

1.785

t

-0.271

0.170

0.477

1.561

0.937

-0.097

P-value

0.789

0.867

0.639

0.135

0.361

0.924

Paired t-test

101


Results

16

14

12

10 Base

10

20

30

40

50

60

Time in minutes

Figure 27: Changes of respiratory rate in Group MK

Table 21 which is represented in figure 27 shows Changes of respiratory rate in Group MK: The base value of mean respiratory rate in Group MK before R VJ TJ VN NR J J (, e (,)e ( (&)e

R L R VR P VR O R L J VT aLJ V PN MW

( )e )) &

() e

J VM (,)e ,)J ON

&

( ( )J VM

e) R VN

of the post-anesthesia period respectively (P-value was 0.789, 0.867, 0.639, 0.135, 0.361 and 0.924 respectively).

102


Results

Table 22 : Changes of respiratory rate (cycles/minute) in Group T Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

15

15

14

14

16

15

15

2

13

13

14

13

13

14

13

3

17

16

14

14

15

16

14

4

13

13

14

15

14

13

12

5

15

15

16

14

13

14

15

6

14

13

13

14

14

13

13

7

13

14

15

15

16

13

15

8

13

12

14

15

14

13

14

9

17

14

15

13

14

16

15

10

13

13

14

14

14

14

14

11

13

14

13

14

13

14

14

12

13

14

14

13

14

13

13

13

14

15

15

14

14

15

14

14

14

15

14

13

14

14

13

15

16

16

15

15

15

16

14

16

17

15

14

15

14

15

15

17

14

14

13

12

13

13

14

18

13

15

14

14

14

13

14

19

17

15

14

14

16

15

15

20

14

14

13

15

14

13

12

Min.

13

12

13

12

13

13

12

Max.

17

16

16

15

16

16

15

Mean

14.400

14.250

14.100

14.000

14.200

14.100

13.900

SD

1.569

1.070

0.788

0.858

0.951

1.119

0.968

Paired t-test

t

0.547

0.860

1.017

0.593

1.453

1.648

P-value

0.591

0.400

0.322

0.560

0.163

0.116

103


Results

16

14

12

10 Base

10

20

30

40

50

60

Time in minutes

Figure 28: Changes of respiratory rate in Group T

Table 22 which is represented in figure 28 shows Changes of respiratory rate in Group T: The base value of mean respiratory rate in Group T before spinal J VN NR J

J

(&)e (

e

(( e ) (

J VM

R L R VR P VR O R L J VT a LJ V PN M W

e , , e

(

,J ON

&

e, ),

(& e )

( )J VM

R VN

of the post-anesthesia period respectively (P-value was 0.591, 0.400, 0.322, 0.560, 0.163 and 0.116 respectively).

104


Results

Table 23 : Changes of respiratory rate (cycles/minute) in Group TK Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

16

17

15

14

14

15

15

2

13

11

12

15

13

14

12

3

16

15

14

15

14

15

16

4

13

13

12

13

14

13

13

5

14

15

14

13

12

16

15

6

11

11

12

12

13

15

14

7

13

14

15

14

13

15

16

8

12

13

14

14

12

11

15

9

14

15

16

15

12

15

13

10

15

15

14

12

15

13

15

11

15

16

16

13

15

15

14

12

14

13

14

13

13

12

15

13

17

16

15

15

16

16

17

14

13

13

14

14

13

11

12

15

17

16

16

16

15

15

16

16

15

15

15

14

14

13

12

17

13

14

14

14

16

15

15

18

13

14

13

16

15

14

15

19

15

16

17

15

14

14

15

20

15

14

15

12

14

14

13

Min.

11

11

12

12

12

11

12

Max.

17

17

17

16

16

16

17

Mean

14.200

14.300

14.350

13.950

13.850

14.050

14.400

SD

1.609

1.625

1.387

1.234

1.226

1.468

1.465

Paired t-test

t

- 0.462

- 0.513

0.653

1.071

0.389

- 0.525

P-value

0.649

0.614

0.522

0.297

0.702

0.606

105


Results

16

14

12

10 Base

10

20

30

40

50

60

Time in minutes

Figure 29: Changes of respiratory rate in Group TK

Table 23 which is represented in figure 29 shows Changes of respiratory rate in Group TK: The base value of mean respiratory rate in group TK before spinal anesthesia was (

(& e

R L R VR P VR O R L J VT a LJ V PN M W

e & ) ( )e ,

and 14 ( e ()J ON

&

)e &(

, )e & &

( )J V M

( )e (,

R V N WO N W -

anesthesia period respectively (P-value was 0.649, 0.614, 0.522, 0.297, 0.702 and 0.606 respectively).

106


Results

Table 24 : Changes of respiratory rate in the five groups Respiratory Rate (RR)

ANOVA

Group C Group M Group MK Group T Group TK Mean

14.550

14.550

14.800

14.400

14.200

SD

1.234

1.877

1.361

1.569

1.609

Mean

14.150

13.7500

14.850

14.250

14.300

SD

1.785

1.446

1.461

1.070

1.625

Mean

14.450

14.350

14.750

14.100

14.350

SD

1.638

1.348

1.552

0.788

1.387

Mean

14.800

14.750

14.500

14.000

13.950

SD

1.399

1.372

1.96

0.858

1.234

Mean

14.000

13.650

14.300

14.200

13.850

SD

1.214

1.599

1.593

0.951

1.226

Mean

14.150

13.900

14.250

14.100

14.050

SD

1.694

1.252

1.97

1.119

1.468

Mean

14.850

14.550

14.850

13.900

14.400

SD

1.348

1.191

1.785

0.968

1.465

Base

10 minutes

20 minutes

30 minutes

40 minutes

50 minutes

60 minutes

Values are expressed as means and SD

107

F

P-value

0.408

0.802

1.389

0.244

0.582

0.677

1.647

0.169

0.766

0.550

0.143

0.966

1.623

0.175


Results

Group C

Group M

Group MK

Group T

Group TK

16 15 14 13 12 11 10 Base

10

20

30

40

50

60

Time in minutes

Figure 30: Changes of the respiratory rate in the five groups

Table 24 which is represented in figure 30 shows Changes of the respiratory rate in the five groups: There were no statistically significant differences among the five groups as regard the mean respiratory rate value at each time interval from the base value (P-value was 0.802) to 10, 20, 30, 40, 50 and 60 of the post-anesthesia period (P-value was 0.244, 0.677, 0.169, 0.550, 0.966 and 0.175 respectively).

108


Results

Peripheral O2 saturation (SpO2): Table 25 : Changes of SpO2 (%) in Group C Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

99

98

96

99

97

99

96

2

99

99

98

98

100

98

96

3

96

97

97

97

98

96

96

4

96

99

96

98

97

98

96

5

98

96

97

97

97

96

98

6

97

98

97

99

97

97

97

7

96

96

96

99

97

97

97

8

99

97

98

97

97

98

96

9

98

96

98

99

98

98

98

10

96

97

97

98

97

96

97

11

98

97

99

96

97

96

98

12

96

97

96

99

97

97

98

13

99

97

97

98

97

97

99

14

98

97

96

99

98

98

96

15

98

98

97

97

96

98

98

16

96

96

97

97

98

98

97

17

96

97

96

97

99

98

96

18

98

96

98

99

98

96

97

19

96

95

96

99

97

97

98

20

98

96

98

97

98

97

96

Min.

96

95

96

96

96

96

96

Max.

99

99

99

99

100

99

99

Mean

97.35

96.95

97.00

97.95

97.50

97.25

97.00

SD

1.226

1.050

0.918

0.999

0.889

0.910

0.973

Paired t-test

t

1.252

1.437

-1.641

-0.459

0.335

1.022

P-value

0.226

0.167

0.117

0.651

0.741

0.320

109


Results

100 99 98 97 96 95 Base

10

20

30

40

50

60

Time in minutes

Figure 31: Changes of SpO2 in Group C

Table 25 which is represented in figure 31 shows Changes of SpO2 in Group C: The base value of mean SpO2 in Group C before spinal anesthesia J

)e && e

,

)e

R L R VR P V R O R L J VT a LJ VP N M W )e , ,

&)e

J V M

)e ) e

after 10, 20, 30, 40, 50 and 60 minutes of the post-anesthesia period respectively (P-value was 0.226, 0.167, 0.117, 0.651, 0.741 and 0.320 respectively).

110


Results

Table 26 : Changes of SpO2 (%) in Group M Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

98

97

99

98

98

98

98

2

97

96

96

99

98

97

98

3

97

97

97

98

97

96

96

4

97

97

96

96

99

97

98

5

97

97

97

98

96

96

99

6

96

96

97

96

98

98

98

7

98

96

96

98

96

97

99

8

98

96

96

98

96

97

97

9

96

97

98

97

97

96

98

10

97

99

97

98

97

99

99

11

98

96

97

99

97

98

96

12

97

96

96

98

99

97

98

13

97

97

96

96

96

96

98

14

98

96

97

98

96

96

98

15

99

99

99

98

98

98

97

16

98

97

99

98

99

100

97

17

97

98

96

99

96

99

97

18

98

97

98

98

97

98

97

19

98

97

98

97

99

99

97

20

96

97

96

96

97

96

97

Min.

96

96

96

96

96

96

96

Max.

99

99

99

99

99

100

99

Mean

97.35

96.90

97.05

97.65

97.30

97.40

97.60

SD

0.813

0.912

1.099

0.988

1.129

1.231

0.883

Paired t-test

t

1.756

1.301

-1.453

0.165

-0.188

-0.839

P-value

0.095

0.209

0.163

0.871

0.853

0.412

111


Results

100 99 98 97 96 95 Base

10

20

30

40

50

60

Time in minutes

Figure 32: Changes of SpO2 in Group M

Table 26 which is represented in figure 32 shows Changes of SpO2 in Group M: The base value of mean SpO2 in Group M before spinal anesthesia J

)e , )e

R L R VR P V R O R L J VT a LJ VP N M W )e ,,

e &

(e & J V M

e

&

e0.883

after 10, 20, 30, 40, 50 and 60 minutes of the post-anesthesia period respectively (P-value was 0.095, 0.209, 0.163, 0.871, 0.853 and 0.412 respectively).

112


Results

Table 27 : Changes of SpO2 (%) in Group MK Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

97

97

97

98

99

100

96

2

96

96

96

98

98

97

99

3

97

97

96

97

97

99

97

4

98

99

96

98

99

97

97

5

96

96

97

98

97

95

98

6

98

98

96

97

98

98

98

7

99

99

99

96

97

97

98

8

98

98

98

99

96

97

99

9

98

98

98

96

98

98

97

10

98

98

98

100

98

99

98

11

97

97

97

96

98

100

99

12

96

97

97

98

97

97

97

13

97

97

97

98

98

98

98

14

96

97

96

96

98

97

99

15

97

97

97

98

98

98

97

16

98

96

98

96

97

96

98

17

97

97

97

97

98

97

98

18

98

99

98

98

97

96

97

19

98

97

97

96

98

96

98

20

96

96

97

98

100

97

97

Min.

96

96

96

96

96

95

96

Max.

99

99

99

100

100

100

99

Mean

97.20

97.30

97.10

97.40

97.80

97.45

97.75

SD

1.361

1.565

1.281

1.142

0.894

1.317

0.850

Paired t-test

t

-0.326

0.825

-0.459

-1.718

-0.567

-1.751

P-value

0.748

0.419

0.673

0.102

0.577

0.096

113


Results

100 99 98 97 96 95 Base

10

20

30

40

50

60

Time in minutes

Figure 33: Changes of SpO2 in Group MK

Table 27 which is represented in figure 33 shows Changes of SpO2 in Group MK: The base value of mean SpO2 in Group MK before spinal J VN NR J

J

e )) )e ,) J ON

&e e& , &

R L R VR P VR O R L J VT a LJ V PN M W (e (&

,e ,(

( ) J V M

()e

J V M

R VN W O N W-

anesthesia period respectively (P-value was 0.748, 0.419, 0.673, 0.102, 0.577 and 0.096 respectively).

114


Results

Table 28 : Changes of SpO2 (%) in Group T Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

98

98

98

99

99

99

99

2

96

96

96

98

97

96

97

3

98

98

98

97

96

97

96

4

97

96

96

96

98

96

97

5

98

98

98

98

98

97

100

6

96

94

96

98

97

97

97

7

99

97

97

99

97

98

100

8

97

96

97

97

96

96

96

9

97

98

99

100

98

97

99

10

96

98

96

99

99

98

98

11

99

97

98

97

98

99

97

12

97

96

97

98

98

96

97

13

98

98

97

97

97

97

99

14

97

97

96

97

97

96

97

15

100

100

100

99

99

99

98

16

97

96

98

97

98

99

96

17

96

99

96

99

97

100

98

18

97

96

97

99

96

97

96

19

98

98

99

98

100

100

98

20

96

96

96

95

96

96

96

Min.

96

94

96

95

96

96

96

Max.

100

100

100

100

100

100

100

Mean

97.35

97.10

97.25

97.85

97.55

97.50

97.55

SD

1.137

1.373

2.209

1.226

1.146

1.395

1.317

Paired t-test

t

0.893

0.525

-1.453

-0.677

-0.471

-0.657

P-value

0.383

0.606

0.163

0.507

0.643

0.519

115


Results

100 99 98 97 96 95 Base

10

20

30

40

50

60

Time in minutes

Figure 34: Changes of SpO2 in Group T

Table 28 which is represented in figure 34 shows Changes of SpO2 in Group T: The base value of mean SpO2 in Group T before spinal anesthesia J

)e

&)e&&

R L R VR P V R O R L J VT a LJ VP N M W ,)e & &

) )e (

)e

)J V M

e ))e

after 10, 20, 30, 40, 50 and 60 minutes of the post-anesthesia period respectively (P-value was 0.383, 0.606, 0.163, 0.507, 0.643 and 0.519 respectively).

116


Results

Table 29 : Changes of SpO2 (%) in Group TK Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

98

96

98

99

99

98

97

2

96

97

96

97

97

96

98

3

98

98

97

98

98

99

98

4

98

98

96

97

98

96

98

5

96

96

98

99

98

96

99

6

97

97

95

96

97

97

97

7

100

99

100

97

98

98

99

8

97

97

97

98

96

96

98

9

99

98

99

97

98

99

98

10

97

97

97

99

97

98

97

11

97

98

98

97

99

99

100

12

96

96

96

97

96

96

96

13

97

98

98

99

99

99

99

14

96

96

96

96

97

96

98

15

98

98

98

99

99

98

98

16

97

97

97

96

97

96

97

17

98

97

98

98

99

98

99

18

98

98

97

97

96

97

96

19

98

97

98

97

99

97

99

20

96

96

97

97

99

96

96

Min.

96

96

95

96

96

96

96

Max.

100

99

100

99

99

99

100

Mean

97.35

97.20

97.30

97.50

97.80

97.25

97.85

SD

1.089

0.894

1.174

1.051

1.105

1.209

1.137

Paired t-test

t

0.900

0.237

-0.459

-1.528

0.418

-1.648

P-value

0.379

0.815

0.651

0.143

0.681

0.116

117


Results

100 99 98 97 96 95 Base

10

20

30

40

50

60

Time in minutes

Figure 35: Changes of SpO2 in Group TK

Table 29 which is represented in figure 35 shows Changes of SpO2 in Group TK: The base value of mean SpO2 in Group TK before spinal J VN NR J

J

&e ,( ,)e

)e , e1 (

J ON

&

R L R VR P VR O R L J VT a LJ V PN M W

)e )

,e

( ) J V M

)

&)e & J V M

R VN W O N W-

anesthesia period respectively (P-value was 0.379, 0.815, 0.651, 0.143, 0.681 and 0.116 respectively).

118


Results

Table 30 : Changes of the SpO2 in the five groups Peripheral O2 saturation (SpO2)

ANOVA

Group C Group M Group MK Group T Group TK Mean

97.35

97.35

97.2

97.35

97.35

SD

1.226

0.813

1.361

1.137

1.089

Mean

96.95

96.9

97.3

97.1

97.2

SD

1.05

0.912

1.565

1.373

0.894

Mean

97

97.05

97.1

97.25

97.3

SD

0.918

1.099

1.281

2.209

1.174

Mean

97.95

97.65

97.4

97.85

97.5

SD

0.999

0.988

1.142

1.226

1.051

Mean

97.5

97.3

97.8

97.55

97.8

SD

0.889

1.129

0.894

1.146

1.105

Mean

97.25

97.4

97.45

97.5

97.25

SD

0.91

1.231

1.317

1.395

1.209

Mean

97

97.6

97.75

97.55

97.85

SD

0.973

0.883

0.85

1.317

1.137

Base

10 minutes

20 minutes

30 minutes

40 minutes

50 minutes

60 minutes

Values are expressed as means and SD

119

F

P-value

0.0693

0.991

0.396

0.811

0.168

0.954

0.905

0.465

0.843

0.501

0.177

0.950

1.986

0.103


Results

Group C

Group M

Group MK

Group T

Group TK

98 97.5 97 96.5 96 95.5 95 Base

10

20

30

40

50

60

Time in minutes

Figure 36: Changes of the SpO2 in the five groups

Table 30 which is represented in figure 36 shows changes of the SpO2 in the five groups: There were no statistically significant differences among the five groups as regard the mean SpO2 value at each time interval from the base value (P-value was 0.991) to 10, 20, 30, 40, 50 and 60 of the postanesthesia period (P-value was 0.811, 0.954, 0.465, 0.501, 0.950 and 0.103 respectively)

120


Results

Tympanic membrane temperature (Temp): Table 31 .4 J V P NW Oa J V R L N KJ V NN NJ Nd 4R V8 W 4 Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

36.2

36.1

35.7

35.9

36.6

36.6

36.7

2

36.2

36.1

36

35.8

35.6

36.1

36.1

3

36.3

35.8

35.3

35.7

35

36.4

36

4

37.4

35.6

35.6

35.8

35.8

37.2

36.3

5

37.5

34.5

35.5

35.8

36.1

35.9

35.8

6

36.4

35.9

35.6

36

36.6

36.6

36.7

7

36.9

36.1

35.8

36.5

36

36.7

36.4

8

36.6

36.3

35.6

36

36.4

36.5

36.3

9

37

35.3

35.8

35.9

36

36.2

35.8

10

36.9

36.2

35.7

36.1

36.1

36

35.8

11

36.6

35.2

35.8

35.8

36.4

36.2

36.3

12

36.4

36.2

35.8

35.7

36.2

36

35.9

13

36.4

35.8

35.6

36.4

36.6

36.3

36.3

14

36.8

35.2

35.7

36.2

35.9

36.5

36.4

15

36.3

35.1

35.6

36.2

36.6

36.5

36.3

16

37.2

35.7

35.6

36.3

36.5

36.3

35.8

17

36.9

36.1

35.5

35.7

36.5

36.3

36.9

18

36.8

36.1

36.2

36.3

36.5

36

36

19

36.6

36.4

35.7

35.7

36.2

36.6

36.4

20

36.7

36.4

35.8

35.8

35.4

35.8

36.5

Min.

36.2

34.5

35.3

35.7

35

35.8

35.8

Max.

37.5

36.4

36.2

36.5

36.6

37.2

36.9

Mean

36.705

35.805

35.695

35.980

36.150

36.335

36.235

SD

0.379

0.510

0.190

0.257

0.443

0.331

0.328

Paired t-test

t

5.404

10.238

7.350

4.177

3.340

3.650

P-value

< 0.001*

< 0.001*

< 0.001*

0.001*

0.003*

0.002*

* statistically significant when compared with base value (P-value < 0.05)

121


Results

37.5 37 36.5 36 35.5 35 34.5 Base

10

20

30

40

50

60

Time in minutes

Figure 37: Changes of tympanic membrane temperature in Group C

Table 31 which is represented in figure 37 shows changes of tympanic membrane temperature in Group C: The base value of mean tympanic membrane temperature in 8 W 4KN O WN R V J TJ VN NR J J

)e

MN LN JN M W ),)e )

) ,e &)

)e

J VM

) )e

&)e &,J ON

&

R L R P VR O R L J VT a ( )J VM

)e ( minutes

of the post-anesthesia period respectively (P-value was < 0.001, < 0.001, < 0.001, 0.001, 0.003 and 0.002 respectively).

122


Results

Table 32 .4 J V P NW Oa J V R L N KJ V NN NJ Nd 4R V8 W > Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

36.9

35.9

35.5

35.9

36.3

36.1

35.9

2

36.1

36.1

36

36.4

36

36.2

36.3

3

36.6

35.8

35.3

36

36.9

36.9

36.4

4

36.7

35.6

36.2

36.7

36.3

36.6

36.3

5

36.6

34.5

35.8

36.1

36.4

36.2

36.4

6

37.3

35.8

35.8

36.1

36.3

36.7

36.6

7

37.2

36.1

35.6

35.7

36.1

36.6

36.4

8

36.9

36.2

36.1

36.4

36.1

36.2

36

9

36.8

35.3

35.9

35.9

36.4

36.5

36.5

10

36.8

36.1

35.7

36.1

36.8

36.7

36.2

11

36.5

35.2

35.5

35.8

36.5

36.5

36.6

12

36.8

36.2

35.7

36.2

36.2

36.9

36.2

13

36.8

35.8

35.9

36.4

36.2

36.5

36.1

14

36.4

35.2

35.2

36.1

36.2

36.3

36

15

36.7

35

35.3

36.1

35.9

36.1

36.4

16

36.9

35.7

35.7

36.3

36.5

36.3

36.2

17

36.7

36

36.1

36.5

36.5

36.6

36.5

18

37

36.1

36.3

35.9

35.9

36

36

19

36.4

36.4

36.3

36.6

36.2

36.3

36.2

20

37.2

36.4

35.5

36.2

35.8

36.7

36.3

Min.

36.1

34.5

35.2

35.7

35.8

36

35.9

Max.

37.3

36.4

36.3

36.7

36.9

36.9

36.6

Mean

36.765

35.770

35.770

36.170

36.275

36.445

36.275

SD

0.292

0.502

0.331

0.270

0.283

0.268

0.205

Paired t-test

t

8.754

9.912

5.822

4.981

4.138

6.220

P-value

< 0.001*

< 0.001*

< 0.001*

< 0.001*

0.001*

< 0.001*

* statistically significant when compared with base value (P-value < 0.05)

123


Results

37.5 37 36.5 36 35.5 35 34.5 Base

10

20

30

40

50

60

Time in minutes

Figure 38: Changes of tympanic membrane temperature in Group M

Table 32 which is represented in figure 38 shows changes of tympanic membrane temperature in Group M: The base value of mean tympanic membrane temperature in 8W > K N O WN R V J TJ VN NR J J MN LN JN MW ) (( )e &,J VM

e )& )

)e && R L R P VR O R L J VT a

e

&)e &)J ON

e& &

&)e &,

( )J VM

R VN

of the post-spinal anesthesia respectively (P-value was < 0.001, < 0.001, < 0.001, < 0.001, 0.001 and < 0.001 respectively).

124


Results

Table 33 : Changes of tym J V R L N KJ V NN NJ Nd 4R V8 W >< Post anesthesia period n = 20

Base value 10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

1

37.3

35.5

36.5

36

37.1

36.8

36.5

2

37.2

36.6

36.6

37.1

36.6

36.8

36.2

3

36.4

36.5

36.7

36.8

36.9

37.1

36.9

4

36.9

36.6

36.8

36.4

36.7

36.9

36.1

5

36.4

36.6

36.6

36.7

36.8

36.8

37.2

6

37.5

36.7

36.4

36.2

36.7

36.8

36.6

7

36.5

36.7

36.6

36.2

36.7

36.7

37.3

8

37.1

35.8

36.9

37

36.6

36.8

37.2

9

37.3

37.3

36.7

36.8

36.8

36.8

36.5

10

36.8

36.2

36.3

36.5

36.5

36.7

36.4

11

36.7

36.4

36.7

36.7

36.8

37

36.9

12

37.2

36.9

37.1

37.3

37

37.1

36.7

13

36.5

35.8

36.6

37.1

36.9

36.8

36.7

14

36.9

36.3

37

37

37.2

36.8

36.9

15

36.4

37

37

36.9

36.9

36.8

37.3

16

36.7

36.7

36.4

36.8

36.7

36.8

37

17

37.3

36.9

36.4

36.7

37.2

36.8

37.3

18

36.4

37.5

36.4

36.3

36.8

36.8

36.7

19

36.5

37

36.9

37.1

37

36.8

36.4

20

36.9

36.4

36.6

36.8

36.8

36.9

36.7

Min.

36.4

35.5

36.3

36

36.5

36.7

36.1

Max.

37.5

37.5

37.1

37.3

37.2

37.1

37.3

Mean

36.845

36.570

36.660

36.720

36.835

36.840

36.775

SD

0.385

0.497

0.230

0.353

0.193

0.110

0.367

Paired t-test

t

1.820

1.771

1.017

0.106

0.056

0.513

P-value

0.085

0.093

0.322

0.916

0.956

0.614

125


Results

37.5 37 36.5 36 35.5 35 34.5 Base

10

20

30

40

50

60

Time in minutes

Figure 39: Changes of tympanic membrane temperature in Group MK

Table 33 which is represented in figure 39 shows changes of tympanic membrane temperature in Group MK: The base value of mean tympanic membrane temperature in 8W

>< KN O WN

R VJ TJ V N NR J

R VR P VR O R L J VT aMN LN JN MW ,)e

, (e

) e( J VM

J

,( )e , ) e&

)e ) J ON

R L

&e ) &

( )

and 60 minutes of the post-anesthesia period respectively (P-value = 0.085, 0.093, 0.322, 0.916, 0.956 and 0.614 respectively).

126


Results

Table 34 .4 J V P NW Oa J V R L N KJ V NN NJ Nd 4R V8 W D Post anesthesia period n = 20

Base value

1

36.6

35.6

35.8

36

35.9

36.2

36.2

2

36.3

35.5

36.3

36.9

37.1

36.9

36.5

3

36.1

36

35.5

36.3

36.2

36.2

36

4

37.2

36.1

36.3

36.9

37.1

36.3

36.4

5

36.6

35.9

35.5

36.7

35.7

36.2

36.1

6

36.1

35.3

36

36.5

36.9

37.1

36.7

7

37

35.6

36.5

35.8

36

36.4

36.3

8

36.4

36.2

36.4

35.9

35.7

35.4

36.1

9

36.2

35.7

35.9

36.3

36.9

36.9

36.7

10

36.5

36.4

35.3

36.7

36.5

36.4

36.5

11

36.7

36.4

36

36.7

36.7

36.7

36.9

12

37.2

36

36.2

36.7

36

35.9

35.8

13

36.3

36.5

36.3

36.5

36.3

36.3

36.6

14

36.7

36.9

35.4

35.8

36.5

36.8

36.5

15

36.3

35.7

36.2

36.4

37

36.1

36.3

16

36.7

35.8

36

36

36.4

36.1

36.2

17

36.5

36.4

36.6

36.6

36.3

37.3

36.9

18

36.3

36.3

35.4

35.1

36.6

36.3

36.6

19

36.8

36.4

35.5

35.5

36.1

37

36.3

20

36.4

35.9

35.4

36.7

36.3

36.6

36.5

Min.

36.1

35.3

35.3

35.1

35.7

35.4

35.8

Max.

37.2

36.9

36.6

36.9

37.1

37.3

36.9

Mean

36.545

36.030

35.925

36.300

36.410

36.455

36.405

SD

0.325

0.405

0.422

0.493

0.441

0.457

0.291

Paired t-test

t

4.931

5.820

1.889

1.001

0.662

1.247

P-value

< 0.001*

< 0.001*

0.074

0.329

0.516

0.227

10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

* statistically significant when compared with base value (P-value < 0.05)

127


Results

37.5 37 36.5 36 35.5 35 34.5 Base

10

20

30

40

50

60

Time in minutes

Figure 40: Changes of tympanic membrane temperature in Group T

Table 34 which is represented in figure 40 shows changes of tympanic membrane temperature in Group T: The base value of mean tympanic membrane temperature in 8 W DKN O WN R V J TJ VN NR J J MN LN JN MW

)( )e &)

e ()J V M ) &)e (& &J ON

R L R P VR O R L J VT a J VM&

R V N Wf

the post-anesthesia period (P-value was < 0.001 at both times) then the N NJ N J R VR PV R O R L J VT aLJ V PN MW () )e ) (J V M

()e & J ON

e(

( )J V M

( e( ( R V N WO N

post-anesthesia period respectively (P-value = 0.074, 0.329, 0.516 and 0.227 respectively).

128


Results

Table 35 .4 J V P NW Oa J V R L N KJ V NN NJ Nd 4R V8 W D< Post anesthesia period n = 20

Base value

1

36.2

36.2

36.4

37

36.9

36.8

36.8

2

36.1

37.2

36.9

36.7

36.8

36.9

36.4

3

37.1

36.3

36.6

36.5

36.5

36.7

36.8

4

37.3

37.2

36.7

36.5

37.2

37.4

37.3

5

36.3

35.9

35.7

36.6

36.8

36.6

36.5

6

36.8

36.6

36.2

36.4

36

36.6

36.8

7

36.7

36.3

36

36.2

36.4

36.6

36.7

8

36.7

36.3

36.6

36.2

36.4

36.7

36.7

9

36.8

36.3

36.7

36.5

36.7

36.6

36.8

10

37

36.8

36

35.9

36.3

36.2

36

11

36.5

36.2

36.5

36.7

36.5

36.9

36.5

12

36.3

36.1

36.5

37

36.6

36.2

36.3

13

36.5

35.8

36.9

37.1

36.8

36.7

36.5

14

36.7

36.3

36.2

36.7

36.5

36.8

36.7

15

36

36.9

37

36.9

36.6

37.2

37

16

36.9

36.7

36.7

36.3

36.3

36.5

36.9

17

36.5

36.2

36.8

36.7

36.2

36.4

36.7

18

36.6

36.8

36.6

36.5

36.7

36.5

36.6

19

36.9

36

36

36.2

36.1

36.3

36.7

20

36.7

36.4

35.9

36.3

36.3

36.9

37

Min.

36

35.8

35.7

35.9

36

36.2

36

Max.

37.3

37.2

37

37.1

37.2

37.4

37.3

Mean

36.630

36.425

36.445

36.545

36.530

36.675

36.685

SD

0.337

0.397

0.376

0.314

0.294

0.302

0.280

Paired t-test

t

1.886

1.489

0.642

0.913

-0.429

-0.654

P-value

0.075

0.153

0.529

0.373

0.673

0.521

10 minutes 20 minutes 30 minutes 40 minutes 50 minutes 60 minutes

129


Results

37.5 37 36.5 36 35.5 35 34.5 Base

10

20

30

40

50

60

Time in minutes

Figure 41: Changes of tympanic membrane temperature in Group TK

Table 35 which is represented in figure 41 shows changes of tympanic membrane temperature in Group TK: The base value of mean tympanic membrane temperature in 8W

D< KN O WN

R VJ TJ VN NR J

R VR P VR O R L J VT aLJ V P N MW ) e &(

)e

( &)e

&J VM

J

e

(( )e ,)e & ,J ON

R L )( )e

&

(

( )

and 60 minutes of the post-anesthesia period respectively (P-value was 0.075, 0.153, 0.529, 0.373, 0.673 and 0.521 respectively).

130


Results

Table 36 : Changes of tympanic membrane temperature in the five groups Tympanic membrane temperature

ANOVA

Group C Group M Group MK Group T Group TK Mean

36.705

36.765

36.845

36.545

36.630

SD

0.379

0.292

0.385

0.325

0.337

Mean

35.805

35.770

36.570

36.030

36.425

SD

0.510

0.502

0.497

0.405

0.397

Mean

35.695

35.770

36.660

35.925

36.445

SD

0.190

0.331

0.230

0.422

0.376

Mean

35.980

36.170

36.720

36.300

36.545

SD

0.257

0.270

0.353

0.493

0.314

Mean

36.150

36.275

36.835

36.410

36.530

SD

0.443

0.283

0.193

0.441

0.294

Mean

36.335

36.445

36.840

36.455

36.675

SD

0.331

0.268

0.110

0.457

0.302

Mean

36.235

36.275

36.775

36.537

36.685

SD

0.328

0.205

0.367

0.191

0.280

Base

10 minutes

20 minutes

30 minutes

40 minutes

50 minutes

60 minutes

Values are expressed as mean and SD

131

F

P-value

2.270

0.067

12.141

< 0.001

35.513

< 0.001

14.317

< 0.001

11.624

< 0.001

8.397

0.001

13.229

< 0.001


Results

Group C

Group M

Group MK

Group T

Group TK

37.5 37 36.5 36 35.5 35 Base

10

20

30

40

50

60

Time in minutes

Figure 42: Changes of tympanic membrane temperature in the five groups

Table 36 which is represented in figure 42 shows changes of the tympanic membrane temperature in the five groups: There were statistically insignificant differences among the five groups as regard the mean tympanic membrane temperature base value (P-value = 0.067) while there were statistically significant differences J WVP NO RNPW

JJ T T NR NR VN J T/ 0, 20, 30, 40, 50 and 60

of post-anesthesia period (P-value was < 0.001, < 0.001, < 0.001, < 0.001, 0.001 and < 0.001 respectively). CW

TRT N&o& V NGJ a2

F2 N

JM WVNKN N N VN J L

two groups at each time interval. The test revealed that: The change in the mean tympanic membrane temperature in Group MK was statistically significant (P-value was < 0.05) when compared with Group C, Group M and Group T at all time intervals.

132


Results

However that change in temperature was not statistically significant (Pvalue was > 0.05) when compared with Group TK at any time. The change in the mean tympanic membrane temperature in Group TK was statistically significant (P-value was < 0.05) when compared with group C and group M at all time intervals. However that change in temperature was statistically significant (P-value was < 0.05) when compared with Group T till 20 minutes of the post-anesthesia period, then at 30, 40, 50 and 60 minutes the change in temperature was statistically insignificant (P-value was > 0.05). The change in the mean tympanic membrane temperature in group T was not statistically significant when compared with group C and group M at any time of the post-anesthesia period (P-value was > 0.05). The change in the mean temperature in Group M was not statistically significant (P-value > 0.05) when compared with Group C at any time.

133


Results

Shivering: Table 37 : Overall incidence of shivering in the five groups Group C (n=20)

Group

Group

M

MK

(n=20)

(n=20)

Group T

Group TK

(n=20)

(n=20)

11 (55)

9 (45)

1 (5)*

6 (30)

3 (15)

Non-Shiverers

9 (45)

11 (55)

19 (95)

14 (70)

17 (85)

Values are expressed as number of patients (%) * Significant in comparison with group C, group M and group T (P-value < 0.05). gSignificant in comparison with group C and group M (P-value < 0.05).

Group M

Group MK

Group T

Group TK

20 18 16 14 12 10 8 6 4 2 0 Shiverers

Non-Shiverers

Figure 43: Overall incidence of shivering in the five groups

134

P

g

Shiverers

Group C

Chi-square

16.190

0.003


Results

In table 37 which is represented in figure 43 the incidence of shivering in the post-anesthesia period in the five studied groups is compared: There was significant difference among the five Groups (P-value J

CW

TRT N& o&7R N NJ LN

NNMW VN WL W JN

each two groups. Group MK showed significant low incidence of shivering (5%) when compared with Group C (55%), Group M (45%) and Group T (30%) (P-value was < 0.001, 0.004 and 0.046 respectively) that incidence is less than that occurred in Group TK (15%) but it was not statistically significant (P-value was 0.302). Group TK also showed a statistically significant lower incidence of shivering when compared to Group C and Group M (P-value was 0.009 and 0.041 respectively) but when compared with Group T, that less incidence of shivering was not statistically significant (P-value was 0.225). The incidence of shivering was less in the Group T than Group C and Group M but was not statistically significant (P-value was 0.100 and 0.257 respectively). There was no statistically significant difference between the group C and group M (P = 0.376).

135


Results

Table 38 : Shivering score of all patients in the five groups Group

Group

Group

Group

Group

C

M

MK

T

TK

(n=20)

(n=20)

(n=20)

(n=20)

(n=20)

0

9 (45)

11 (55)

19 (95)

14 (70)

17 (85)

16.190

0.003

1

3 (15)

4 (20)

0 (0)

1 (5)

0 (0)

8.967

0.062

2

2 (10)

3 (15)

1 (5)

4 (20)

2 (10)

2.462

0.651

3

5 (25)

2 (10)

0 (0)

1 (5)

1 (5)

9.035

0.060

4

1 (5)

0 (0)

0 (0)

0 (0)

0 (0)

4.040

0.401

Shivering Score

Chi-square P

Values are expressed as number of patients (%)

Group C

Group M

Group MK

Group T

Group TK

Score 2

Score 3

Score 4

20 18 16 14 12 10 8 6 4 2 0 Score 0

Score 1

Figure 44: : Shivering score of all patients in the five groups

136


Results

In the table 38 which is represented in figure 44 the number of patients suffered from each grade of shivering was compared: No statistically significant differences were found among the groups as regard the grade of shivering.

137


Results

Table 39 : Incidence of severe shivering (score

Shivering score

3) in the five groups

Group

Group

Group

Group

M

MK

T

TK

(n=20)

(n=20)

(n=20)

(n=20)

6 (30)

2 (10)

0 (0)*

1 (5)*

1 (5)*

14 (70)

18 (90)

20 (100)

19 (95)

19 (95)

Group C (n=20)

Chi-square P

12.222 0.016

<3

Values are expressed as number of patients (%) * Significant in comparison with group C (P-value < 0.05).

Group C

Group M

Group MK

Group T

Group TK

20 18 16 14 12 10 8 6 4 2 0 3

Score < 3

Figure 45: Incidence of severe shivering (score

3) in the five groups

The table 39 which is represented in figure 45 shows incidence of severe shivering (score f3): There was significant difference among the groups (P-value was CW

TRT N&o&7R N NJ LN

two groups.

138

NNMW VN WL W JNN J L


Results

No patients showed severe shivering in Group MK that was statistically significant when compared with Group C where 6 patients (30%) suffered from severe shivering (P-value was 0.010). When comparing Group MK with Group M (10%), Group T (5%) and Group TK (5%), no statistically significant differences were found (P-value was 0.243, 0.500 and 0.500 respectively). The incidence of severe shivering in Group T was equal with that of Group TK and low when compared with group C that was statistically significant (P-value was 0.045 for each group). The differences between Group C and Group M was not statistically significant (P-value was 0.117) in spite of the lower incidence in group M. Also the differences between group M and each of group T and group TK were not statistically significant (P-value was 0.500 for each group).

139


Results

Complications: Table 40 : Incidence of complications in the five groups Group C

Group M

Group MK

Group T

Group TK

(n=20)

(n=20)

(n=20)

(n=20)

(n=20)

Hypotension

4 (20)

3 (15)

1 (5)

3 (15)

2 (10)

2.299

0.681

Hallucinations

0 (0)

0 (0)

1 (5)

0 (0)

2 (10)

5.498

0.240

Nausea

3 (15)

4 (20)

5 (25)

6 (30)

5 (25)

1.468

0.832

Vomiting

1 (5)

0 (0)

0 (0)

2 (10)

1 (5)

3.646

0.456

Complication

Chi-square P

Values are expressed as number of patients (%)

Group C

Group M

Group MK

Group T

Group TK

8 7 6 5 4 3 2 1 0 Hypotension

Hallucinations

Nausea

Figure 46: Incidence of complications in the five groups

140

Vomiting


Results

In the table 40 which is represented in figure 46 the numbers of patients suffered from complications are enlisted: Statistical analysis showed that no significant differences among the groups as regard the incidence of hypotension, hallucinations, nausea and vomiting (P-value was0.681, 0.240, 0.832 and 0.456 respectively).

141


Results

Sedation: Table 41 : Sedation score of all patients in the five groups Group

Sedation Score

Group C

Group M Group MK Group T

(n=20)

(n=20)

(n=20)

(n=20)

1

20 (100)

3 (15)

7 (35)

14 (70)

10 (50)

34.380

< 0.001

2

0 (0)

4 (20)

7 (35)

6 (30)

8 (40)

10.667

0.031

3

0 (0)

9 (45)

5 (25)

0 (0)

2 (10)

21.875

< 0.001

4

0 (0)

4 (20)

1 (5)

0 (0)

0 (0)

12.632

0.013

5

0 (0)

0 (0)

0 (0)

0 (0)

0 (0)

Median (range)

1 (1-1)

3 (2-3)*

2 (1-3)

1 (1-2)

1.5 (1-2)

g

TK

Chi-square P

(n=20)

Not tested

Values are expressed as number of patients and percent (%) * Statistically significant when compared with other groups (P-value < 0.05) gCJRR L J T T aR P V R O R L J V N VL W JN M R 8 W 4 8 W D A-value < 0.05)

Group C

Group M

Group MK

Group T

Score 3

Score 4

Group TK

20 18 16 14 12 10 8 6 4 2 0 Score 1

Score 2

Figure 47: Sedation score of all patients in the five groups

142

Score 5


Results

In table 41 which is represented in figure 47 the numbers (and percent) of patients suffered from each grade of sedation were compared: Statistically significant differences were found among the groups as regard each sedation grade except for grade 5 where no test was done as there were no patients found to have grade 5 sedation. So further testing was done using Mann-Whitney Test to compare the median sedation score between each two groups. The median sedation score was significantly higher in Group M (3) than Group C (1), Group MK (2), Group T (1) and Group TK (1.5) where P-value was < 0.001, 0.027, 0.001 and 0.001 respectively. Group MK showed statistically significant higher median sedation score than Group C and Group T (P-value was < 0.001 and 0.009 respectively) but not statistically different when compared with group TK (P-value was 0.167) No statistically significant difference was found between group T and group TK though the higher median sedation score in group TK as P-value was 0.153.

143


Discussion

2010


Discussion

Discussion Post-anesthetic shivering is a common complication of regional anesthesia affecting up to 60% of patients

(3)

. It may cause major

(6)

discomfort to patients , aggravate wound pain by stretching incisions and increase intracranial

(7)

and intraocular pressure (8). Shivering may

increase tissue oxygen demand by as much as 500%. This may be deleterious in patients with impaired cardiovascular reserve or a limited respiratory capacity(9). Shivering also may interfere with the monitoring of patients by causing artifacts of the ECG, blood pressure, and pulse oximetry recording (10). Various opioid and non-opioid agents were used to prevent and treat shivering, but they are not without side effects like hypotension, hypertension, respiratory depression, nausea etc. Also a variety of physical agents (radiant heat, space blanket etc) were also used to prevent perioperative shivering, but those were cumbersome and with limited success (11) . The aim of this prospective, randomized, comparative, placebo controlled study is to evaluate the efficacy of each of midazolam, midazolam plus ketamine, tramadol, and tramadol plus ketamine, for prophylaxis of post-spinal shivering. In the present study post-spinal shivering incidence was 55% of the patients (11/20) in the control group (Group C) this is similar to the incidence of shivering in the control group of previous studies by Honarmand, et al(3) and Sagir, et al (12).

145


Discussion

Honarmand, et al compared the prophylactic use of midazolam, ketamine, ketamine plus midazolam and placebo for prevention of shivering during regional anesthesia, and found that the shivering incidence was 60% in the control group(3). Also, Sagir, et al compared placebo, ketamine, granisetron, and a combination of ketamine and granisetron for the prevention of shivering caused by regional anesthesia, and found that the incidence of shivering was 55% in the control group(12). This high incidence of shivering observed in the control group of the present study was consistent with the significant decrease of the core temperature observed in the patient of this group during the postanesthesia period. Core hypothermia during regional anesthesia is common

(141)

and

can be nearly as severe as that observed during general anesthesia(142). There are three principal reasons for hypothermia under spinal anesthesia. First, spinal anesthesia leads to an internal redistribution of heat from the core to the peripheral compartment(44). Secondly, with loss of thermoregulatory vasoconstriction below the level of the spinal block, there is increased heat loss from body surfaces. Lastly, there is altered thermoregulation under spinal anesthesia charactNR b N M Ka J )d 4 decrease in vasoconstriction and shivering thresholds(143). However, in the study of Kelsaka, et al who compared the efficacy of ondansetron and meperidine in the prevention of shivering after spinal anesthesia, they reported that shivering incidence was 36% of the control group (144). This lower incidence of shivering was probably due to a number of reasons: first, in contrast to the present study, all 146


Discussion

patients in Kelsaka's study received 10 mg diazepam orally as NN MR L JR W V( ) R V N KN O WN PNa CN L W VM T aR V<N TJ S J m

Ma

shivering was evaluated by observing the pectoralis major muscles for fasciculations for more than 10 s. In the current study, shivering was graded using a scale which considered piloerection or peripheral vasoconstriction, but no visible shivering as Grade 1. GABA receptors have been demonstrated in the spinal cord. GABAergic neurones mediate presynaptic inhibition, suppressing signals from

muscle

and

cutaneous

receptors.

Midazolam and

other

benzodiazepines, which decrease GABA reuptake from synaptic clefts, have been found to reduce repetitive firing in response to depolarizing pulses in spinal cord neurons

(85)

. Such inhibitory functions of

benzodiazepines in the spinal cord may be responsible for inhibiting the conduction of afferent impulses from cold receptors to the higher centers, thereby suppressing shivering (3). However, in the midazolam group (Group M) of the current study shivering occurred in 45% of patients (9/20) which was lower but, statistically insignificant, when compared with the control group (Group C). Also, the incidence of severe shivering (score f

J VW

significantly different than the control group (Group C). This incidence is similar with that found by Honarmand, et al where the shivering incidence was 50% of the midazolam group (3). Kurz, et al studied the effect of midazolam on thermoregulation and found that reduction in heat production after administration of midazolam is less than that after induction of anesthesia with clinical

147


Discussion

doses of volatile anesthetics, propofol, and opioids. Also, they reported that midazolam, even in plasma concentrations far exceeding those used routinely, produces minimal impairment of thermoregulatory control(145). This explains the lower incidence of shivering observed in our patients receiving midazolam. However, in another study by Grover, et al, they showed that administration of midazolam towards the end of the anesthetic procedure doesn't prevent shivering but it subsides earlier in the postoperative period (146). This incidence was consistent with the failure of midazolam to prevent or minimize the core hypothermia as the decrease in the core temperature in Group M during the post-anesthesia period was insignificantly different from that occurred in the control group. This can be explained by its action of inhibiting the tonic thermoregulatory vasoconstriction.(146) The incidence of shivering in the tramadol group (Group T) of the present study was 30% of the patients (6/20) which was significantly lower than that of the control group (Group C). In addition, tramadol significantly lowered the incidence of severe shivering when compared with Group C. This incidence coincides with previous studies like that of Atashkhoyi, et al who investigated the effect of tramadol for prevention of shivering after spinal anesthesia for cesarean section and they reported that shivering occurred in 28.57% of the patients in the tramadol group(7). Also, Bilotta, et al who investigated the effect of nefopam and tramadol on shivering during neuraxial anesthesia, had similar incidence

148


Discussion

of shivering in the Tramadol group (24%)

(147)

. On the other hand,

Talakoub, et al who used tramadol for prevention of shivering following spinal anesthesia, reported that the incidence of shivering was only 3% in the tramadol group

(5)

but this much lower incidence may be because

they recorded only shivering grade f3. Similar to its analgesic effect, the anti-shivering effect of tramadol is most likely mediated by multimodal mechanism. Tramadol possesses only a modest affinity for h-receptor and no affinity for q -J VMt-opioid receptors

(129)

. In addition to its opioid actions, tramadol inhibits the

neuronal reuptake of norepinephrine and serotonin (5-HT). These monoamine neurotransmitters are involved in the anti-shivering effects of descending inhibitory pathways in the spinal cord(127). In the midazolam plus ketamine group (Group MK) the incidence of shivering was 5% (1/20) of the patients. This incidence was not only lower than Group C, but also was lower than other groups including the Group M. This notice coincides with the findings by Honarmand, et al where the incidence of shivering in their midazolam ketamine group was 3.3% (3). Similarly in the tramadol plus ketamine group (Group TK) the incidence of shivering was 15%

(3/20) of patients which was

significantly lower than each of Group C and Group T. Searching the famous scientific databases of medical journals like PubMed and ScienceDirect didn't reveal a study in which this combination was used for prevention or treatment of shivering. So further studies on this combination should be performed to confirm or deny the results of the current study. 149


Discussion

These findings confirm the reported anti-shivering effect of ketamine by Honarmand, et al

(3)

and Sagir, et al

(12)

where ketamine

significantly decreased the incidence of shivering whenever it was used in their studies. Also, Sharma, et al(148) reported that ketamine has been shown to prevent shivering in patients undergoing regional anesthesia. This was consistent with the observation that there were no significant changes in core temperature in Group MK and Group TK of the current study. This coincides with the findings by Kinoshita, et al who showed that during spinal anesthesia, infusion of low-dose ketamine prevents decreases in the body temperature of patients sedated with propofol(149). Ketamine

probably

controls

shivering

by

N WPN VNR N R N Ka J LR W VW V N aW J T J

non-shivering W Ka N r-

adrenergic effect of norepinephrine(148). Thus, ketamine causes sympathetic stimulation and vasoconstriction in patients at risk of hypothermia. This effect of ketamine is in contrast to that of midazolam which reduces core temperature by inhibiting tonic thermoregulatory vasoconstriction (146). It is clear from the present study that adding ketamine to midazolam or tramadol enhanced their anti-shivering effect. This suggests that ketamine has a synergistic anti-shivering effect when combined with any of the two drugs. So, further studies are needed to find out the exact mechanism of interaction. During spinal and local anesthesia, intravenous sedation and hypnotic drugs are often administered to increase patient comfort, to

150


Discussion

maintain cardio respiratory stability, to improve surgical condition and to prevent recall of unpleasant events during surgery (150). The median sedation score was significantly higher in Group M than Group C, Group MK, Group T and Group TK. Group MK showed statistically significant higher median sedation score than Group C and Group T but not statistically different when compared with group TK. No statistically significant difference was found between group T and group TK. In this connection, the patients of Group M and Group MK have more preoperative comfort than other groups. The sympathetic blockade produced by spinal anesthesia induces hemodynamic changes. Hypotension and bradycardia are the most common side effects seen with spinal anesthesia

(151, 152)

. Carpenter , et

al reported an incidence of hypotension of 33% of the

patients

undergoing surgery under spinal anesthesia (18). In the present study the incidence of hypotension was 20% of the patients in the control group. This lower incidence than that of Carpenter , et al may be due to the difference in the patient group where the present study was restricted to patients scheduled for elective orthopedic surgery excluding any patient needing special fluid management or blood transfusion. This is supported by the similar incidence of hypotension in the control group in the study of Honarmand, et al (23.3%) which was conducted on a patients group similar to that in the present study (3). Sympathetic blockade and unopposed vagal activity cause increased peristalsis of the gastrointestinal tract, which leads to nausea. Accordingly, atropine is useful for treating nausea after high spinal blockade

(25, 147)

. Nausea and vomiting occur after spinal anesthesia 151


Discussion

approximately 20% of the time (18) which is consistent with the incidence of nausea and vomiting in the control group of the present study (15% and 5% respectively). In the groups where midazolam was used (Group M and Group MK), no significant difference between each of them and the control group as regard the hypotension, nausea and vomiting incidence. This coincides with the findings of Honarmand, et al(3) and support the previous findings of Forster, et al

(89)

that midazolam produces minimal

hemodynamic changes. Similarly, in the groups where tramadol was used (Group T and Group TK), no significant difference between each of them and the control group as regard the hypotension, nausea and vomiting incidence. This coincides with the findings of previous studies by Atashkhoyi, et al(7) and Bilotta, et al (147). No significant difference between the control group and each of the ketamine groups (Group MK and group TK) as regard the hypotension, nausea and vomiting incidence. This coincides with the findings of previous studies by Honarmand, et al (3), Sagir, et al (12) . Ketamine produces undesirable psychological reactions termed emergence reactions. The common manifestations are vivid dreaming, extracorporeal experiences (sense of floating out of body), hallucinations and

illusions

(misinterpretation

of

a

real,

external

sensory

experience)(124). However in the current study the incidence of hallucinations in patients receiving ketamine was very low (10% in Group TK and 5% in Group MK) that was not significant when

152


Discussion

compared to the control group. This can be explained by the use of low dose of ketamine in the present study (0.25 mg/kg). This is supported by previous studies by Honarmand, et al(3), Sagir, et al

(12)

where similar

dose of ketamine was used with no incidence of hallucinations. From all the observation in the present study it can be inferred that I.V. mR MJ b W T J

)hPS P T ketamine (0.25mg/kg) or tramadol

(0.25mg/kg) plus ketamine (0.25mg/kg) is better than midazolam )hPS P alone or tramadol (0.5mg/kg) alone for prophylaxis of postspinal shivering, whereas the midazolam plus ketamine combination is superior to tramadol plus ketamine combination as the former provides higher median sedation score.

153


Summary and conclusion

2010


Summary & conclusion

Summary and conclusion Post-anesthetic shivering is spontaneous, involuntary, rhythmic, oscillating, tremor-like muscle hyperactivity that increases metabolic heat production up to 600% after general or regional anesthesia. Regional anesthesia is associated with post-anesthetic shivering in up to 60% of patients. Post-anesthetic shivering may cause major discomfort to patients, and aggravate wound pain by stretching incisions and increase intracranial and intraocular pressure. Also it may increase tissue oxygen demand by as much as 500% and accompanied by increases in minute ventilation and cardiac output to maintain aerobic metabolism. This may be deleterious in patients with impaired cardiovascular reserve or a limited respiratory capacity. Shivering also may interfere with the monitoring of patients by causing artifacts of the ECG, blood pressure, and pulse oximetry recording. Shivering may be normal thermoregulatory mechanism in response to core hypothermia. Core Hypothermia during regional anesthesia is common and can be nearly as severe as that observed during general anesthesia. There are three principal reasons for hypothermia under spinal anesthesia. First, spinal anesthesia leads to an internal redistribution of heat from the core to the peripheral compartment. Secondly, with loss of thermoregulatory vasoconstriction below the level of the spinal block, there is increased heat loss from body surfaces. Lastly, there is altered thermoregulation under spinal anesthesia chJJ LNR b N MKaJ )d 4 MN LN JNR V JWL WV R LR W VJ V M

155


Summary & conclusion

shivering thresholds. However, non- thermoregulatory shivering also occurs in normothermic patients. Various opioid and non-opioid agents were used to prevent and treat shivering, but they are not without side effects like hypotension, hypertension, respiratory depression, nausea etc. A variety of physical agents (radiant heat, space blanket etc) were also used to prevent perioperative shivering, but those were cumbersome and with limited success. In this prospective, randomized, comparative, placebo controlled study, the efficacy of each of Midazolam, Midazolam plus Ketamine, Tramadol, and Tramadol plus Ketamine, for prophylaxis of post-spinal shivering was evaluated and compared to each other 100 ASA I and II patients between the ages of 21- 60 years who were undergoing elective orthopedic surgery under spinal anesthesia were allocated randomly to one of five groups: Group C (n=20):

Received saline as a control.

Group M (n=20):

Received midazolam 75 hPSP.

MJ b WT J Group MK (n=20): Received mR

)hPSP T ketamine

0.25 mg/kg. Group T (n=20):

Received tramadol 0.5 mg/kg.

Group TK (n=20):

Received tramadol 0.25 mg/kg plus ketamine 0.25 mg/kg.

All of these drugs were diluted to volume of 5 ml and was given as an I.V. bolus immediately after intrathecal injection.

156


Summary & conclusion

Shivering was observed and graded by using the following scale: 0

=

No shivering.

1

=

Piloerection or peripheral vasoconstriction but no visible shivering.

2

=

Muscular activity in only one muscle group.

3

=

Muscular activity in more than one muscle group but not generalized.

4

=

Shivering all over the body.

In the present study, post-spinal shivering occurred in 55% of patients of Group C. This high incidence of shivering was consistent with the significant decrease of the core temperature observed in the patient of this group. In Group M shivering occurred in 45% of patients which was lower (although, statistically insignificant) when compared with the Group C. Also the incidence of severe shivering (score f

J VW

significantly different in both groups. This incidence was consistent with the failure of midazolam to prevent or minimize the core hypothermia as the change in the core temperature in Group M was insignificant when compared with the Group C. The incidence of shivering in Group T was 30% of patients which was significantly lower than that of the control Group C. However, the change in the core temperature wasn't significantly different from that of Group C. In addition, Tramadol significantly lowered the incidence of sever shivering when compared with Group C

157


Summary & conclusion

Adding low dose ketamine to midazolam or tramadol enhanced their anti-shivering effect. When low dose ketamine was added to midazolam even with half of its dose of in group M the incidence is lowered to 5% in Group MK. Similarly when low dose ketamine was added to tramadol even with half of its dose of in group T the incidence is lowered to 15% of patients in Group TK. This was consistent with the observation that there were no significant changes in core temperature in each of Group MK and Group TK. No statistically significant differences were found among the five groups as regard the incidence of complications i.e. hypotension, hallucinations, nausea and vomiting.

Conclusion: I.V. midazolam plus ketamine or tramadol plus ketamine is better than midazolam or tramadol for prophylaxis of post-spinal shivering, whereas the midazolam plus ketamine combination is superior to tramadol plus ketamine combination.

158


References

2010


References

References 1.

<J VS NA 6K NJ 9 WN N DJ c > AW WNJRN Shivering in Children: A Review on Pharmacologic Prevention and DN J N V AN M R JR L5 P & / ) . -83.

2.

De Witte J, Sessler DI. Perioperative shivering: physiology and J J L WT W Pa2VN NR WT W Pa& &7N K / &. ( -84.

3.

Honarmand A, Safavi MR. Comparison of prophylactic use of midazolam, ketamine, and ketamine plus midazolam for prevention of shivering during regional anaesthesia: a randomized double-blind T J L N KWL W VW T T N MR J T3 2V J N & , L/ (. ))-62.

4.

Jeon YT, Jeon YS, Kim YC, Bahk JH, Do SH, Lim YJ. Intrathecal clonidine does not reduce post-spinal shivering. Acta Anaesthesiol CL J V M& ) W/ ( .) -13.

5.

Talakoub R, Meshkati SN. Tramadol versus meperidine in the treatment of shivering during spinal anesthesia in cesarean section. W VJ TWO NN JL R V>N MR L J TCL R N VL N & / .)-5.

6.

Jenkins K, Grady D, Wong J, Correa R, Armanious S, Chung F. Post-operative recovery: day surgery patients' preferences. Br J 2VJ N & 7N K/ , &. &&-4.

7.

Atashkhoyi S, Negargar S. Effect of Tramadol for Prevention of Shivering after Spinal Anesthesia for Cesarean Section. Research W VJ TWO3R W T WP R L J TCL R N VL N& , / &. )-9.

8.

Mahajan RP, Grover VK, Sharma SL, Singh H. Intraocular pressure changes during muscular hyperactivity after general anesthesia. 2VN NR WT WPa , >J/ . ( -21.

9.

Piper SN, Suttner SW, Schmidt CC, Maleck WH, Kumle B, Boldt J. Nefopam and clonidine in the prevention of postanaesthetic RNR V P2VJ N NR J T / ) ( .) -9.

159


References

10. Barker SJ, Shah NK. Effects of motion on the performance of pulse WR NN R VW TVN N 2VN NR WT W Pa L/ ,)(. (-81. 11. Mahmood MA, Zweifler RM. Progress in shivering control. J NW TCL R& L ) / & -2):47-54. 12. Sagir O, Gulhas N, Toprak H, Yucel A, Begec Z, Ersoy O. Control of shivering during regional anaesthesia: prophylactic ketamine and PJ VRN W V2LJ2V J N NR W TCL J V M& J V / ) . ( (-9. 13. Kose EA, Dal D, Akinci SB, Saricaoglu F, Aypar U. The efficacy of ketamine for the treatment of postoperative shivering. Anesth 2VJ T P& , J V / .&-2, table of contents. 14. Kleinman W, Mikhail MS. Chapter 16. Spinal, Epidural, & Caudal Blocks In: Morgan GE, Mikhail MS, Murray MJ, editors. Clinical Anesthesiology. 4th ed. New York: Lange Medical Books/McGraw 9R T T>N M R L J TA K5RRR W V/& & ,-323. 15. Jankovic D. Neuraxial anesthesia. In: Jankovic D, editor. Regional Nerve Blocks and Infiltration Therapy Textbook and Color AtlasOxford - E<.3T J L SN T TA K T RR V P M/& ( & - 396. 16. Bernards CM, Hill HF. Morphine and alfentanil permeability through the spinal dura, arachnoid, and pia mater of dogs and WVSN a 2VN NR W T W Pa 5N L / .&(-9. 17. Ellis H, Feldman SA, Harrop-Griffiths W. Part 3:The Vertebral Canal and its Contents. In: Ellis H, Feldman SA, Harrop-Griffiths W, editors. Anatomy for anaesthetists. 8th ed. Malden, Mass.: 3T J L SN T TCL R N VL N /& ( )-136. 18. Carpenter RL, Caplan RA, Brown DL, Stephenson C, Wu R. Incidence and risk factors for side effects of spinal anesthesia. 2VN NR WT WPa & V/ . -16.

160


References

19. Rooke GA, Freund PR, Jacobson AF. Hemodynamic response and change in organ blood volume during spinal anesthesia in elderly N V RL JMR J LM RN JN2VN 2V J T P T / , ) . -105. 20. Anzai Y, Nishikawa T. Heart rate responses to body tilt during R VJ TJ VN NR J2V N 2V J T P L/ (.,) -90. 21. Greene NM. Physiology of spinal anesthesia. 3d ed. Baltimore: GR T T R J GR T SR V/ , 22. Caplan RA, Ward RJ, Posner K, Cheney FW. Unexpected cardiac arrest during spinal anesthesia: a closed claims analysis of N MR WR V PO J LW 2VN NR WT WPa ,, J V /, . ) -11. 23. Bernards CM, Hymas NJ. Progression of first degree heart block to high-grade second degree block during spinal anaesthesia. Can J 2VJ N &7N K/ &. -5. 24. Greene NM. Perspectives in Spinal Anesthesia. Regional 2VN NR JJ VMAJ R V>N M R L R VN , &/ &. ))-62. 25. Ramaioli F, De Amici D. Central antiemetic effect of atropine: our personal experience. Can J Anaesth. 1996 Oct/ ( . 26. Nakayama M, Kanaya N, Fujita S, Namiki A. Effects of ephedrine on indocyanine green clearance during spinal anesthesia: evaluation Ka NO R VP N R N L N NW M2VN 2VJ T P W/ ).(-9. 27. Walts LF, Kaufman RD, Moreland JR, Weiskopf M. Total hip arthroplasty. An investigation of factors related to postoperative urinary retention. Clin Orthop Relat Res. 1985 Apr(194):280-2. 28. Runciman WB, Mather LE, Ilsley AH, Carapetis RJ, Upton RN. A sheep preparation for studying interactions between blood flow and drug disposition. III: Effects of general and spinal anaesthesia on regional blood flow and oxygen tensions. Br J Anaesth. 1984 W/ ) .& (-58.

161


References

29. Brown DL. Chapter 43 - Spinal, Epidural, and Caudal Anesthesia. In: Miller RD, editor. Miller's Anesthesia. 6th ed. Philadelphia, PA: 4 LR T T RR V P WV N6TNR N/& ) )-84. 30. Bernards CM. Chapter 37 - Epidural and Spinal Anesthesia. In: Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC, editors. Clinical anesthesia. 6th ed. Philadelphia: Wolters <T N R R VL W GR T T R J GR T S R V/& &-54. 31. Geffin B, Shapiro L. Sinus bradycardia and asystole during spinal and epidural anesthesia: a report of 13 cases. J Clin Anesth. 1998 V / (. &,-85. 32. Wetstone DL, Wong KC. Sinus bradycardia and asystole during R VJ TJ VN NR J2V N NR W T W Pa ( T / ( . ,-9. 33. Safa-Tisseront V, Thormann F, Malassine P, Henry M, Riou B, Coriat P, et al. Effectiveness of epidural blood patch in the management of post-dural puncture headache. Anesthesiology. & 2 P/)&. (-9. 34. Denny N, Masters R, Pearson D, Read J, Sihota M, Selander D. Postdural puncture headache after continuous spinal anesthesia. 2VN 2VJ T P ,2P / ,. -4. 35. Brown EM, Elman DS. Postoperative backache. Anesth Analg. 1961 Nov-5N L / (.,-5. 36. Kane RE. Neurologic deficits following epidural or spinal J VN NR J2VN 2VJ T P , >J/ .)-61. 37. Hiller A, Rosenberg PH. Transient neurological symptoms after spinal anaesthesia with 4% mepivacaine and 0.5% bupivacaine. Br 2VJ N CN/ . -5. 38. Tsai YC, Chu KS. A comparison of tramadol, amitriptyline, and meperidine for postepidural anesthetic shivering in parturients. 2VN 2VJ T P& W/ ).&, ,-92. 162


References

39. Sessler DI. Mild perioperative hypothermia. N Engl J Med. 1997 V& / & (. -7. 40. Morgan GE, Mikhail MS, Murray MJ. Chapter 6. Patient Monitors. In: Morgan GE, Mikhail MS, Murray MJ, editors. Clinical Anesthesiology. 4th ed. New York: Lange Medical Books/McGraw 9R T T>N M R L J TA K5RRR W V/& (-50. 41. Crowley LJ, Buggy DJ. Shivering and Neuraxial Anesthesia. N P R W VJ T2VN NR JJ V MAJ R V>N MR L R VN& , / . & (-52. 42. Lopez M, Sessler DI, Walter K, Emerick T, Ozaki M. Rate and gender dependence of the sweating, vasoconstriction, and shivering N WT MR V J V 2VN NR W T WPa (2 / , (.,-8. 43. Vassilieff N, Rosencher N, Sessler DI, Conseiller C. Shivering threshold during spinal anesthesia is reduced in elderly patients. Anesthesiology. 199)5N L / , . &-6. 44. Matsukawa T, Sessler DI, Christensen R, Ozaki M, Schroeder M. Heat flow and distribution during epidural anesthesia. 2VN NR WT WPa ) W/ , ). -7. 45. Saito T, Sessler DI, Fujita K, Ooi Y, Jeffrey R. Thermoregulatory effects of spinal and epidural anesthesia during cesarean delivery. Reg Anesth Pain Med. 1998 Jul-2 P/ & (. (,-23. 46. Sessler DI, Ponte J. Shivering during epidural anesthesia. 2VN NR WT WPa >J a /&). , -21. 47. Sessler DI, Schroeder M, Merrifield B, Matsukawa T, Cheng C. Optimal duration and temperature of prewarming. Anesthesiology. )>J/ , & . (-81. 48. Smith I, Newson CD, White PF. Use of forced-air warming during and after outpatient arthroscopic surgery. Anesth Analg. 1994 >J a /,). , -41.

163


References

49. Sellden E, Branstrom R, Brundin T. Preoperative infusion of amino acids prevents postoperative hypothermia. Br J Anaesth. 1996 7N K / &. & &-34. 50. Alfonsi P. Postanaesthetic shivering: epidemiology, pathophysiology, and approaches to prevention and management. 5 P & / ). & -205. 51. Rodriguez JL, Weissman C, Damask MC, Askanazi J, Hyman AI, Kinney JM. Morphine and postoperative rewarming in critically ill JR N V 4RLT JR W V , 5N L /, .&, -46. 52. Alfonsi P, Hongnat JM, Lebrault C, Chauvin M. The effects of pethidine, fentanyl and lignocaine on postanaesthetic shivering. 2VJ N NR J )>J/ ) . &(-7. 53. Horn EP, Standl T, Sessler DI, von Knobelsdorff G, Buchs C, Schulte am Esch J. Physostigmine prevents postanesthetic shivering as does meperidine or clonidine. Anesthesiology. 1998 J V / ,, . ,-13. 54. Erkola O, Korttila K, Aho M, Haasio J, Aantaa R, Kallio A. Comparison of intramuscular dexmedetomidine and midazolam premedication for elective abdominal hysterectomy. Anesth Analg. ( L/ (.(-53. 55. Rosa G, Pinto G, Orsi P, de Blasi RA, Conti G, Sanita R, et al. Control of post anaesthetic shivering with nefopam hydrochloride in mildly hypothermic patients after neurosurgery. Acta 2VJ N NR WTCL J V M )J V / . -5. 56. Zweifler RM, Voorhees ME, Mahmood MA, Parnell M. Rectal temperature reflects tympanic temperature during mild induced hypothermia in nonintubated subjects. J Neurosurg Anesthesiol. & ( T / . &&-5.

164


References

57. Powell RM, Buggy DJ. Ondansetron given before induction of anesthesia reduces shivering after general anesthesia. Anesth Analg. & V / .( &-7. 58. Kizilirmak S, Karakas SE, Akca O, Ozkan T, Yavru A, Pembeci K, et al. Magnesium sulfate stops postanesthetic shivering. Ann N Y Acad Sci. 1997 Mar 15/ , . -806. 59. Sarma V, Fry EN. Doxapram after general anaesthesia. Its role in stopping shivering during recovery. Anaesthesia. 1991 V / ( . ( -1. 60. Yared JP, Starr NJ, Hoffmann-Hogg L, Bashour CA, Insler SR, O'Connor M, et al. Dexamethasone decreases the incidence of shivering after cardiac surgery: a randomized, double-blind, placebo-L W VW T T N M Ma2VN 2V J T P , L/ , (. )-9. 61. Strichartz GR, Berde CB. Chapter 14 - Local Anesthetics. In: Miller RD, editor. Miller's Anesthesia. 6th ed. Philadelphia, PA: Churchill RR V P WV N6TNR N/& ) ) -604. 62. Morgan GE, Mikhail MS, Murray MJ. Chapter 14. Local Anesthetics In: Morgan GE, Mikhail MS, Murray MJ, editors. Clinical Anesthesiology. 4th ed. New York: Lange Medical Books/McG J 9R T T>N M R L J TA K5RRR W V/& & -75. 63. Booker PD, Taylor C, Saba G. Perioperative changes in alpha 1acid glycoprotein concentrations in infants undergoing major PNa3 2VJ N >J/ . ) -8. 64. Tucker GT, Mather LE. Pharmacology of local anaesthetic agents. Pharmacokinetics of local anaesthetic agents. Br J Anaesth. 1975 7N K / ( T . & -24. 65. Vickers MD, Morgan M, Spencer PSJ. Drugs in Anaesthetic Practice. 7th ed. Oxford,London: Butterworth-9N R VN J VV/

165


References

66. Henn F, Brattsand R. Some pharmacological and toxicological properties of a new long-acting local analgesic, LAC-43 (marcaine), in comparison with mepivacaine and tetracaine. Acta Anaesthesiol CL J V MC T / &.-30. 67. Cohen SE, Yeh JY, Riley ET, Vogel TM. Walking with labor epidural analgesia: the impact of bupivacaine concentration and a lidocaine-epinephrine test dose. Anesthesiology. 2000 7N K /&&.,-92. 68. Donald D, Denson H, Mazoit JM. Physiology, pharmacology and toxicity of local anesthetics. In: Prithvira P, editor. Clinical practice WON PR W VJ TJ V N NR J N HWS .4 LR T T RR VP W VN / 73-195. 69. Reiz S, Nath S. Cardiotoxicity of local anaesthetic agents. Br J 2VJ N , T / ) , . -46. 70. Moir DD. Local anaesthetic techniques in obstetrics. Br J Anaesth. , T / ), .(-59. 71. Englesson S, Matousek M. Central nervous system effects of local J VJ N NR LJ P N V 3 2VJ N )7N K / ( T . &(-6. 72. Gerecke M. Chemical structure and properties of midazolam compared with other benzodiazepines. Br J Clin Pharmacol. ,/ C T. C-6S. 73. Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ. Midazolam: J J L WT W PaJ VM N 2VN NR W T W Pa , )>J/& . -24. 74. Pieri L. Preclinical pharmacology of midazolam. Br J Clin PharmacWT ,/ C T. C-27S. 75. Greenblatt DJ, Abernethy DR, Locniskar A, Harmatz JS, Limjuco RA, Shader RI. Effect of age, gender, and obesity on midazolam SR VNR L 2VN NR W T WPa ,( T / . &-35.

166


References

76. Smith MT, Eadie MJ, Brophy TO. The pharmacokinetics of R MJ b WT J R V J V6 4T R VA J J L WT , >J/ (. & -8. 77. Dundee JW. New i.v. anaesthetics. Br J Anaesth. 1979 T / ) .(-8. 78. Clausen TG, Wolff J, Hansen PB, Larsen F, Rasmussen SN, Dixon JS, et al. Pharmacokinetics of midazolam and alpha-hydroxymidazolam following rectal and intravenous administration. Br J 4T R VA J J L WT ,,2 / &)(. ( )-63. 79. Morgan GE, Mikhail MS, Murray MJ. Chapter 8. Nonvolatile Anesthetic Agents. Clinical Anesthesiology. 4th ed. New York: Lange Medical BW WS >L 8 J 9R T T>N M R L J TA K 5RRR W V /& p. 179-204. 80. Allonen H, Ziegler G, Klotz U. Midazolam kinetics. Clin AJ J L WTD N , W/ ).)-61. 81. Trouvin JH, Farinotti R, Haberer JP, Servin F, Chauvin M, Duvaldestin P. Pharmacokinetics of midazolam in anaesthetized L R WR L JR N V 3 2VJ N ,, V / . &-7. 82. Mohler H, Okada T. Benzodiazepine receptor: demonstration in the L N VJ TVN W a N CL R N VL N W& )/ ,( . ,(-51. 83. Richards JG, Mohler H. Benzodiazepine NW J J L WT WPa , (7N K / & &3. & -42.

receptors.

84. Cheng SC, Brunner EA. Inhibition of GABA metabolism in rat brain synaptosomes by midazolam (RO-21-3981). Anesthesiology. , T / )) . (-5. 85. Adams RD, Victor M, Ropper AH. Motor paralysis. In: Adams RD, Victor M, Ropper AH, editors. Principles of neurology 6th ed. New York: McGraw-9R T T9N J T AWO NR WV 5RRR WV / ( )-63.

167


References

86. Lauven PM, Kulka PJ. Anaesthesia techniques for midazolam and flumazenil--an overview. Acta Anaesthesiol Scand Suppl. /&. ,( - /M RL R W V 87. Amrein R, Hetzel W. Pharmacology of Dormicum (midazolam) and 2VNJN O T J b N VR T 2LJ2VJ N NR W TCL J V MC T /&.) /M RL R W V( 88. Wilton NC, Leigh J, Rosen DR, Pandit UA. Preanesthetic sedation of preschool children using intranasal midazolam. Anesthesiology. , ,5N L / . &-5. 89. Forster A, Gardaz JP, Suter PM, Gemperle M. I.V. midazolam as an induction agent for anaesthesia: a study in volunteers. Br J Anaesth. , CN/ )& . -11. 90. Pieri L, Schaffner R, Scherschlicht R, Polc P, Sepinwall J, Davidson A, et al. Pharmacology of midazolam. 2b VN R RN T O WL V P ,/ & J. &,-201. 91. Nugent M, Artru AA, Michenfelder JD. Cerebral metabolic, vascular and protective effects of midazolam maleate: comparison WMR J b NJ 2VN NR WT W Pa , &>J/ ) . &-6. 92. Adams P, Gelman S, Reves JG, Greenblatt DJ, Alvis JM, Bradley E. Midazolam pharmacodynamics and pharmacokinetics during J L N aWWT NR J2VN NR WT WPa ,)2 P/ &.(-6. 93. Thomson D, Geller E, Lauven P, Whitwam J. Midazolam and flumazenil: the agonist-antagonist concept for sedation and J VJ N NR J2LJ2V J N NR W TCL J V MC T /& . ,-9. 94. SOUTHORN P, REHDER K, DIDIER EP. Midazolam sedation and respiratory mechanics in J V2VN NR W T W Pa ,/ ) ). 2 95. White PF, Eng MR. Chapter 18 - Intravenous Anesthetics. In: Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC,

168


References

editors. Clinical anesthesia. 6th ed. Philadelphia: Wolters <T N R R VL W GR T T R J GR T S R V/& 009. p. 445-64. 96. Nilsson A. Autonomic and hormonal responses after the use of midazolam and flumazenil. Acta Anaesthesiol Scand Suppl. /&. )-( /M RL R W V, 97. Forster A, Gardaz JP, Suter PM, Gemperle M. Respiratory depression by midazolam and diazepam. Anesthesiology. 1980 5N L / ) . ((-7. 98. Massaut J, d'Hollander A, Barvais L, Dubois-Primo J. Haemodynamic effects of midazolam in the anaesthetized patient with coronary artery disease. Acta Anaesthesiol Scand. 1983 2P / & (. & -302. 99. Arcos GJ. Midazolam-induced 2VN NR WT WPa , L/ (. &

ventricular

irritability.

100. Whitwam JG, Al-Khudhairi D, McCloy RF. Comparison of midazolam and diazepam in doses of comparable potency during PJ WL Wa3 2VJ N ,2P / )),. -7. 101. Dundee JW, Halliday NJ, Harper KW, Brogden RN. Midazolam. A review of its pharmacological properties and therapeutic use. Drugs. , (5N L / & , . ) -43. 102. Ricou B, Forster A, Bruckner A, Chastonay P, Gemperle M. Clinical evaluation of a specific benzodiazepine antagonist (RO 151788). Studies in elderly patients after regional anaesthesia under KN Vb W M R J b NR VN N MJR W V3 2VJ N , CN/ ) , . )-11. 103. Lindahl SG. The use of midazolam in premedication. Acta 2VJ N NR WTCL J V MC T /&. -8 /MRL R W V 104. Saarnivaara L, Lindgren L, Klemola UM. Comparison of chloral hydrate and midazolam by mouth as premedicants in children

169


References

undergoing otolaryngological surgery. Br J Anaesth. 1988 L/ (. -6. 105. Whitwam JG. The use of midazolam and flumazenil in diagnostic and short surgical procedures. Acta Anaesthesiol Scand Suppl. /&. -&/M RL R W V( 106. Dixon J, Power SJ, Grundy EM, Lumley J, Morgan M. Sedation for local anaesthesia. Comparison of intravenous midazolam and diazepam 2VJ N NR J , (2 / (. &-6. 107. Berggren L, Eriksson I. Midazolam for induction of anaesthesia in outpatients: a comparison with thiopentone. Acta Anaesthesiol CL J V M , 5N L / & ) . (& -6. 108. Tabaddor K, Frost EAM. Management of head injury. In: Frost EAM, editor. Clinical anesthesia in neurosurgery. 2nd ed. Boston: 3 N W / ( -38. 109. White PF, Way WL, Trevor AJ. Ketamine--its pharmacology and NJN R L N 2VN NR WT W Pa , &7N K/ ) &. -36. 110. Cohen ML, Trevor AJ. On the cerebral accumulation of ketamine and the relationship between metabolism of the drug and its pharmacological effects. J Pharmacol Exp Ther. 1974 >J a /, &.)-8. 111. Reves JG, Glass PSA, Lubarsky DA, McEvoy MD. Chapter 10 Intravenous Nonopioid Anesthetics. In: Miller RD, editor. Miller's anesthesia. 6th ed. Philadelphia, PA: Churchill RR V P WV N6TNR N/& ) -78. 112. Herd DW, Anderson BJ, Holford NH. Modeling the norketamine metabolite in children and the implications for analgesia. Paediatr 2VJ N & CN/ . , -40.

170


References

113. Dal D, Kose A, Honca M, Akinci SB, Basgul E, Aypar U. Efficacy of prophylactic ketamine in preventing postoperative shivering. Br J 2VJ N & )2 P/)&.,-92. 114. Gangopadhyay S, Gupta K, Acharjee S, Nayak SK, Dawn S, Piplai G. Ketamine, Tramadol and Pethedine in prophylaxis of shivering MR VP R V J TJ VN NR J 2V J N 4T R VA J J L WT& / & . )63. 115. Taylor PA, Towey RM, Rappoport AS. Further work on the depression of laryngeal reflexes during ketamine anaesthesia using a standard challenge technique. Br J Anaesth. 1972 W/ ( ( . -8. 116. Okamoto GU, Duperon DF, Jedrychowski JR. Clinical evaluation of the effects of ketamine sedation on pediatric dental patients. J Clin Pediatr Dent. 1992 Summer/ (. & )-7. 117. Gardner AE, Dannemiller FJ, Dean D. Intracranial cerebrospinal fluid pressure in man during ketamine anesthesia. Anesth Analg. 1972 Sep- L/ ) ).(-5. 118. Corssen G, Reves JG, Carter JR. Neuroleptanesthesia, dissociative anesthesia, and hemorrhage. Int Anesthesiol Clin. 1974 CR V P/& .()-61. 119. Van der Linden P, Gilbart E, Engelman E, Schmartz D, de Rood M, Vincent JL. Comparison of halothane, isoflurane, alfentanil, and ketamine in experimental septic shock. Anesth Analg. 1990 J V / . ,-17. 120. Kingston HG, Bretherton KW, Holloway AM, Downing JW. A comparison between ketamine and diazepam as induction agents for NR L JMR N LW a2VJ N : VN VRN4JN ,7N K/ . -70. 121. Elia N, Tramer MR. Ketamine and postoperative pain--a quantitative systematic review of randomised trials. Pain. 2005 J V / -2):61-70. 171


References

122. Sussman DR. A comparative evaluation of ketamine anesthesia in LR T MN VJ V MJ MT 2VN NR WT WPa (>J a / ( ). ( )-64. 123. Korttila K, Levanen J. Untoward effects of ketamine combined with diazepam for supplementing conduction anaesthesia in young and middle-J PN MJ MT 2LJ2VJ N NR W TCL J V M ,/ & & .(-8. 124. Garfield JM, Garfield FB, Stone JG, Hopkins D, Johns LA. A comparison of psychologic responses to ketamine and thiopental-nitrous oxide--halothane anesthesia. Anesthesiology. 1972 2 / (.&-38. 125. Gaynes BI, Barkin RL. Analgesics in ophthalmic practice: a review of the oral non-narcotic agent tramadol. Optom Vis Sci. 1999 T / . ( ))-61. 126. Calvey TN, Williams NE. Chapter 11: Analgesic Drugs. In: Calvey TN, Williams NE, editors. Principles and practice of pharmacology O WJ VJ N NR ) N M >J T MN V >J .3T J L SN T TA K/& , 195-226. 127. Stefan G, Armin S. Clinical Pharmacology of Tramadol. Clinical AJ J L WS R V NR L& ( / ( . , -923. 128. Dayer P, Desmeules J, Collart L. Pharmacology of tramadol. Drugs. / ) C T&., -24. 129. Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic. AJ J L WT6 D N &J V/ & . &)-85. 130. Vickers MD, O'Flaherty D, Szekely SM, Read M, Yoshizumi J. Tramadol: pain relief by an opioid without depression of N RJR W V2VJ N NR J &2 / ( (. & -6.

172


References

131. Wilder-Smith CH, Bettiga A. The analgesic tramadol has minimal effect on gastrointestinal motor function. Br J Clin Pharmacol. 1997 J V / ( . -5. 132. Rauck RL, Ruoff GE, McMillen JI. Comparison of tramadol and acetaminophen with codeine for long-term pain management in elderly patients. Current Therapeutic Research. 1994 december (/ ) ) &.( -31. 133. Ruoff GE. Slowing the initial titration rate of tramadol improves tolerability. PharmaL W NJa J V / . , ,-93. 134. Wilder-Smith CH, Wilder-Smith OH, Farschtschian M, Naji P. Preoperative adjuvant epidural tramadol: the effect of different doses on postoperative analgesia and pain processing. Acta 2VJ N NR WTCL J V M ,>J/ ( & . 299-305. 135. Kapral S, Gollmann G, Waltl B, Likar R, Sladen RN, Weinstabl C, et al. Tramadol added to mepivacaine prolongs the duration of an axillary brachial plexus blockade. Anesth Analg. 1999 2 / ,,(. ,)-6. 136. Pang WW, Mok MS, Chang DP, Huang MH. Local anesthetic effect of tramadol, metoclopramide, and lidocaine following intradermal injection. Reg Anesth Pain Med. 1998 Nov5N L / & . ) ,-3. 137. Pang WW, Huang PY, Chang DP, Huang MH. The peripheral analgesic effect of tramadol in reducing propofol injection pain: a comparison with lidocaine. Reg Anesth Pain Med. 1999 MayV / & ( . & (-9. 138. James MF, Heijke SA, Gordon PC. Intravenous tramadol versus epidural morphine for postthoracotomy pain relief: a placebocontrolled double-blind trial. Anesth 2VJ T P T / , . ,-91. 139. Sindrup SH, Andersen G, Madsen C, Smith T, Brosen K, Jensen TS. Tramadol relieves pain and allodynia in polyneuropathy: a 173


References

randomised, double-K T R VML WV WT T N MR J TAJ R V 90.

L/ ,

. ,)-

140. Sindrup SH, Madsen C, Brosen K, Jensen TS. The effect of tramadol in painful polyneuropathy in relation to serum drug and NJ K WT RNT NN T 4T R VA J J L WTD N 5N L / . -41. 141. Hendolin H, Lansimies E. Skin and central temperatures during continuous epidural analgesia and general anaesthesia in patients subjected to open prostatectomy. Ann Clin Res. 1982 2P /((.,-6. 142. Frank SM, Beattie C, Christopherson R, Norris EJ, Rock P, Parker S, et al. Epidural versus general anesthesia, ambient operating room temperature, and patient age as predictors of inadvertent aW N R J2VN NR W T W Pa &2 P/ &. & )&-7. 143. Ozaki M, Kurz A, Sessler DI, Lenhardt R, Schroeder M, Moayeri A, et al. Thermoregulatory thresholds during epidural and spinal anesthesia. AnesthesioloPa (2 P / , &. & ,& -8. 144. Kelsaka E, Baris S, Karakaya D, Sarihasan B. Comparison of ondansetron and meperidine for prevention of shivering in patients undergoing spinal anesthesia. Reg Anesth Pain Med. 2006 Jan7N K / . (-5. 145. Kurz A, Sessler DI, Annadata R, Dechert M, Christensen R, Bjorksten AR. Midazolam minimally impairs thermoregulatory L W VW T2VN 2VJ T P )2 P/ , &. -8. 146. Grover VK, Mahajan R, Yaddanapudi LN, Sudarshana HG, Gill KD. Efficacy of midazolam in preventing postoperative shivering. : V 4T R VA J J L WTD N & & W/ ( . )( -6. 147. Bilotta F, Pietropaoli P, Sanita R, Liberatori G, Rosa G. Nefopam and tramadol for the prevention of shivering during neuraxial anesthesia. Reg Anesth Pain Med. 2002 Jul-2 P/ & (.,-4.

174


References

148. Sharma DR, Thakur JR. Ketamine and shivering. Anaesthesia. 1990 >J/ ( ) . &) &-3. 149. Kinoshita T, Suzuki M, Shimada Y, Ogawa R. Effect of low-dose ketamine on redistribution hypothermia during spinal anesthesia sedated by propofol. J Nippon Med Sch & (2 / &.&-8. 150. Nishiyama T, Yokoyama T, Hanaoka K. Sedation guidelines for midazolam infusion during combined spinal and epidural J VN NR J 4T R V2V N & (5N L / ,. ),-72. 151. Bigler D, Hjortso NC, Edstrom H, Christensen NJ, Kehlet H. Comparative effects of intrathecal bupivacaine and tetracaine on analgesia, cardiovascular function and plasma catecholamines. Acta 2VJ N NR WTCL J V M , 2 / . -203. 152. Hartmann B, Junger A, Klasen J, Benson M, Jost A, Banzhaf A, et al. The incidence and risk factors for hypotension after spinal anesthesia induction: an analysis with automated data collection. 2VN 2VJ T P& & V /( .) &-9, table of contents.

175


Arabic summary

2010


‫اﻟﻣﻠﺧص اﻟﻌرﺑﻲ‬

‫أﻣﺎ ﻓﻲ اﻟﻤﺠﻤﻮﻋﺔ اﻟﺮاﺑﻌﺔ ﺣﯿﺚ ﺗﻢ ﺣﻘﻦ اﻟﺘﺮاﻣﺎدول ﻓﻘﻂ ﻟﻮﺣﻆ اﻧﺨﻔﺎض ﻧﺴﺒﺔ‬ ‫ﺣﺪوث اﻟﺮﻋﺸﺔ اﻟﻰ ‪ %٣٠‬ﻋﻠﻰ اﻟﺮﻏﻢ ﻣﻦ ﻓﺸﻞ اﻟﺘﺮاﻣﺎدول ﻓﻲ ﻣﻨﻊ اﻧﺨﻔﺎض درﺟﺔ‬ ‫ﺣﺮارة اﻟﺠﺴﻢ اﻟﺪاﺧﻠﯿﺔ‪.‬‬ ‫وﻋﻨﺪ إﺿﺎﻓﺔ اﻟﻜﯿﺘﺎﻣﯿﻦ ﻟﻜﻞ ﻣﻦ اﻟﻤﯿﺪازوﻻم واﻟﺘﺮاﻣﺎدول ﻓﻲ اﻟﻤﺠﻤﻮﻋﺘﯿﻦ اﻟﺜﺎﻟﺜﺔ‬ ‫واﻟﺨﺎﻣﺴﺔ ﻟﻮﺣﻆ اﻧﺨﻔﺎض ﻧﺴﺒﺔ ﺣﺪوث اﻟﺮﻋﺸﺔ اﻟﻰ ‪ %٥‬و‪ %١٥‬ﻋﻠﻰ اﻟﺘﺮﺗﯿﺐ ﻋﻠﻰ‬ ‫اﻟﺮﻏﻢ ﻣﻦ أن ﺟﺮﻋﺘﯿﮭﻤﺎ ﻛﺎﻧﺖ ﻧﺼﻒ ﻣﺎ ﻛﺎﻧﺖ ﻋﻠﯿﮫ ﻓﻲ اﻟﻤﺠﻤﻮﻋﺘﯿﻦ اﻟﺜﺎﻧﯿﺔ واﻟﺮاﺑﻌﺔ‪.‬‬ ‫و ﯾﺘﻨﺎﺳﺐ ذﻟﻚ ﻣﻊ ﻋﺪم اﻧﺨﻔﺎض درﺟﺔ ﺣﺮارة اﻟﺠﺴﻢ اﻟﺪاﺧﻠﯿﺔ‪.‬‬ ‫ﻛﺬﻟﻚ ﻟﻮﺣﻆ ﻋﺪم وﺟﻮد ﻓﺮق ﺑﯿﻦ اﻟﻤﺠﻤﻮﻋﺎت ﻓﯿﻤﺎ ﯾﺘﻌﻠﻖ ﺑﻨﺴﺐ ﺣﺪوث‬ ‫اﻷﻋﺮاض اﻟﺠﺎﻧﺒﯿﺔ ﻣﺜﻞ ھﺒﻮط ﺿﻐﻂ اﻟﺪم و اﻟﻐﺜﯿﺎن واﻟﻘﻲء واﻟﮭﻠﻮﺳﺔ‪.‬‬ ‫ﻟﺬﻟﻠﻚ ﯾﻤﻜﻦ اﺳﺘﻨﺘﺎج أن ﻛﻼً ﻣﻦ اﻟﻤﯿﺪازوﻻم ﺑﺎﻹﺿﺎﻓﺔ ﻟﻠﻜﯿﺘﺎﻣﯿﻦ أو اﻟﺘﺮاﻣﺎدول‬ ‫ﺑﺎﻹﺿﺎﻓﺔ ﻟﻠﻜﯿﺘﺎﻣﯿﻦ أﻓﻀﻞ ﻣﻦ ﻛﻞ ﻣﻦ اﻟﻤﯿﺪازوﻻم أو اﻟﺘﺮاﻣﺎدول ﻓﻲ ﻣﻨﻊ اﻟﺮﻋﺸﺔ ﺑﻌﺪ‬ ‫اﻟﺘﺨﺪﯾﺮ اﻟﻨﺼﻔﻲ‪ .‬ﻣﻊ وﺟﻮد أﻓﻀﻠﯿﺔ أﻛﺒﺮ ﻟﻠﻤﯿﺪازوﻻم ﺑﺎﻹﺿﺎﻓﺔ ﻟﻠﻜﯿﺘﺎﻣﯿﻦ ﺣﯿﺚ ﯾﻮﻓﺮ‬ ‫ﻧﺴﺒﺔ أﻋﻠﻰ ﻣﻦ اﻟﺘﮭﺪﺋﺔ ﻟﻠﻤﺮﯾﺾ اﺛﻨﺎء اﻟﻌﻤﻠﯿﺔ اﻟﺠﺮاﺣﯿﺔ‪.‬‬

‫‪٣‬‬


‫اﻟﻣﻠﺧص اﻟﻌرﺑﻲ‬

‫ﺗﻢ ﺗﻮزﯾﻊ اﻟﻤﺮﺿﻲ ﻋﺸﻮاﺋﯿﺎ ﻋﻠﻰ ﺧﻤﺲ ﻣﺠﻤﻮﻋﺎت ﻛﻞ ﻣﻨﮭﺎ ‪ ٢٠‬ﻣﺮﯾﻀﺎ ً ﺣﺴﺐ ﻧﻮع‬ ‫اﻟﻌﻘﺎر اﻟﻤﺴﺘﺨﺪم ‪:‬‬ ‫‪‬‬

‫اﻟﻤﺠﻤﻮﻋﺔ اﻷوﻟﻰ‪ :‬ﺗﻢ اﺳﺘﺨﺪام ﻣﺤﻠﻮل ﻣﻠﺢ ﻟﻠﻤﻘﺎرﻧﺔ‪.‬‬

‫‪‬‬

‫اﻟﻤﺠﻤﻮﻋﺔ اﻟﺜﺎﻧﯿﺔ‪ :‬ﺗﻢ اﺳﺘﺨﺪام ﻣﯿﺪازوﻻم ‪ ٧٥‬ﻣﯿﻜﺠﻢ‪/‬ﻛﺠﻢ ‪.‬‬

‫‪‬‬

‫اﻟﻤﺠﻤﻮﻋﺔ اﻟﺜﺎﻟﺜﺔ‪ :‬ﺗﻢ اﺳﺘﺨﺪام ﻣﯿﺪازوﻻم ‪٣٧.٥‬ﻣﯿﻜﺠﻢ‪/‬ﻛﺠﻢ ﺑﺎﻹﺿﺎﻓﺔ‬ ‫إﻟﻰ ﻛﯿﺘﺎﻣﯿﻦ ‪٠.٢٥‬ﻣﻠﺠﻢ‪/‬ﻛﺠﻢ‪.‬‬

‫‪‬‬

‫اﻟﻤﺠﻤﻮﻋﺔ اﻟﺮاﺑﻌﺔ‪ :‬ﺗﻢ اﺳﺘﺨﺪام ﺗﺮاﻣﺎدول ‪٠.٥‬ﻣﻠﺠﻢ‪/‬ﻛﺠﻢ ‪.‬‬

‫‪‬‬

‫اﻟﻤﺠﻤﻮﻋﺔ اﻟﺨﺎﻣﺴﺔ‪ :‬ﺗﻢ اﺳﺘﺨﺪام ﺗﺮاﻣﺎدول ‪٠.٢٥‬ﻣﻠﺠﻢ‪/‬ﻛﺠﻢ ﺑﺎﻻﺿﺎﻓﺔ‬ ‫إﻟﻰ ﻛﯿﺘﺎﻣﯿﻦ ‪٠.٢٥‬ﻣﻠﺠﻢ‪/‬ﻛﺠﻢ‪.‬‬

‫وﺗﻢ ﺗﺨﻔﯿﻒ ھﺬه اﻟﻌﻘﺎﻗﯿﺮ اﻟﻰ ‪ ٥‬ﻣﻞ وﺗﻢ ﺣﻘﻨﮭﻢ ﺑﺎﻟﻮرﯾﺪ ﻟﻠﻤﺮﺿﻰ ﻣﺒﺎﺷﺮةً ﺑﻌﺪ‬ ‫اﻟﺘﺨﺪﯾﺮ اﻟﻨﺼﻔﻲ اﻟﺬي ﺗﻢ ﺑﻨﻔﺲ اﻟﻄﺮﯾﻘﺔ ﻓﻲ ﻛﻞ اﻟﻤﺮﺿﻲ وﺗﻢ ﻣﻼﺣﻈﺔ اﻟﻤﺮﺿﻰ‬ ‫طﻮال ﻓﺘﺮة ﻣﺎ ﺑﻌﺪ اﻟﺘﺨﺪﯾﺮاﻟﻨﺼﻔﻲ‪.‬‬ ‫ﻟﻮﺣﻆ ﺣﺪوث اﻟﺮﻋﺸﺔ ﻓﻲ ‪ %٥٥‬ﻣﻦ اﻟﻤﺮﺿﻲ ﻓﻲ اﻟﻤﺠﻤﻮﻋﺔ اﻷوﻟﻰ اﻟﺘﻲ ﺗﻢ‬ ‫ﺣﻘﻨﮭﺎ ﺑﻤﺤﻠﻮل ﻣﻠﺢ وھﻮ ﻣﺎ ﯾﺘﻨﺎﺳﺐ ﻣﻊ اﻧﺨﻔﺎض درﺟﺔ ﺣﺮارة اﻟﺠﺴﻢ اﻟﺪاﺧﻠﯿﺔ ﻓﻲ‬ ‫ﻓﺘﺮة ﻣﺎ ﺑﻌﺪ اﻟﺘﺨﺪﯾﺮاﻟﻨﺼﻔﻲ ﻋﻦ ﻣﻌﺪﻟﮭﺎ ﻓﻲ ﻓﺘﺮة ﻣﺎ ﻗﺒﻠﮫ‪.‬‬ ‫أﻣﺎ ﻓﻲ اﻟﻤﺠﻤﻮﻋﺔ اﻟﺜﺎﻧﯿﺔ اﻟﺘﻲ ﺗﻢ ﺣﻘﻨﮭﺎ ﺑﺎﻟﻤﯿﺪازوﻻم ﻓﻘﻂ ﻛﺎﻧﺖ ﻧﺴﺒﺔ ﺣﺪوث‬ ‫اﻟﺮﻋﺸﺔ ‪ %٤٥‬وھﻲ ﻧﺴﺒﺔ ﻗﺮﯾﺒﺔ ﺟﺪاً ﻣﻦ اﻟﻤﺠﻤﻮﻋﺔ اﻷوﻟﻰ وﯾﺘﻨﺎﺳﺐ ذﻟﻚ ﻣﻊ ﻓﺸﻞ‬ ‫اﻟﻤﯿﺪازوﻻم ﻓﻲ ﻣﻨﻊ اﻧﺨﻔﺎض درﺟﺔ ﺣﺮارة اﻟﺠﺴﻢ اﻟﺪاﺧﻠﯿﺔ ﻛﻤﺎ ﺣﺪث ﻓﻲ اﻟﻤﺠﻤﻮﻋﺔ‬ ‫اﻷوﻟﻲ‪.‬‬

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‫اﻟﻣﻠﺧص اﻟﻌرﺑﻲ‬

‫‪‬‬ ‫ﺗﻌﺘﺒﺮ ﻣﺸﻜﻠﺔ اﻟﺮﻋﺸﺔ اﻟﺘﻲ ﺗﻈﮭﺮ ﻓﻲ ﺑﻌﺾ اﻟﻤﺮﺿﻰ ﺑﻌﺪ اﻟﺘﺨﺪﯾﺮ اﻟﻨﺼﻔﻲ‬ ‫ﻣﺸﻜﻠﺔ ﺷﺎﺋﻌﺔ ﺗﺼﻞ ﻧﺴﺒﺔ ﺣﺪوﺛﮭﺎ اﻟﻲ ‪ .%٦٠‬وﻓﯿﮫ ﺗﻈﮭﺮ ﻋﻠﻲ اﻟﻤﺮﯾﺾ ﺣﺮﻛﺎت‬ ‫اھﺘﺰازﯾﺔ ﻻ إرادﯾﺔ ﻏﺎﻟﺒﺎ ﺑﻤﻨﻄﻘﺔ اﻟﻄﺮﻓﯿﻦ اﻟﻌﻠﻮﯾﯿﻦ واﻟﺮﻗﺒﺔ واﻟﻔﻚ ﻣﻤﺎ ﯾﺆﺛﺮ ﺳﻠﺒﺎ ً ﻋﻠﻲ‬ ‫اﻟﻤﺮﯾﺾ ﺣﯿﺚ ﺗﺠﻌﻠﮫ ﯾﺸﻌﺮ ﺑﻌﺪم راﺣﺔ ﻛﻤﺎ ﺗﺰﯾﺪ ﻣﻦ اﺣﺴﺎﺳﮫ ﺑﺎﻷﻟﻢ اﻟﻨﺎﺗﺞ ﻋﻦ‬ ‫اﻟﺠﺮاﺣﺔ‪ .‬وﻛﻞ ذﻟﻚ ﯾﻀﺎف اﻟﻲ ﺗﺄﺛﯿﺮھﺎ اﻟﻔﺴﯿﻮﻟﻮﺟﻲ ﻣﻦ ﺣﯿﺚ زﯾﺎدة اﻟﻤﺠﮭﻮد اﻟﺬي‬ ‫ﯾﺒﺬﻟﮫ اﻟﺠﺴﻢ ﺑﻤﺎ ﯾﺸﻜﻠﮫ ﻣﻦ أﻋﺒﺎء ﻋﻠﻲ اﻟﻘﻠﺐ واﻟﺮﺋﺘﯿﻦ ﺣﯿﺚ ﯾﺰﯾﺪ ﻣﺎ ﯾﺤﺘﺎﺟﮫ اﻟﺠﺴﻢ‬ ‫ﻣﻦ اﻻﻛﺴﺠﯿﻦ اﻟﻲ ﺧﻤﺴﺔ أﺿﻌﺎف ﻣﺎ ﯾﺤﺘﺎﺟﮫ ﻋﺎدةً وھﻮ ﻣﺎ ﻗﺪ ﯾﺆدي إﻟﻲ ﻣﻀﺎﻋﻔﺎت‬ ‫ﺟﺴﯿﻤﺔ ﻟﺒﻌﺾ اﻟﻤﺮﺿﻰ ﻛﻜﺒﺎر اﻟﺴﻦ وذوي اﻷﻣﺮاض اﻟﻘﻠﺒﯿﺔ واﻟﺘﻨﻔﺴﯿﺔ‪ .‬ﻛﻤﺎ أﻧﮭﺎ‬ ‫ﺗﺘﺪاﺧﻞ ﻣﻊ أﺟﮭﺰة اﻟﻤﺘﺎﺑﻌﺔ ﻟﻠﻤﺮﯾﺾ ﻣﻤﺎ ﯾﻌﻄﻲ ﻗﺮاءات ﺧﺎطﺌﺔ ﻟﻠﻌﻼﻣﺎت اﻟﺤﯿﻮﯾﺔ‪.‬‬ ‫وﯾﺮﺟﻊ ﺳﺒﺐ ھﺬه اﻟﺮﻋﺸﺔ اﻟﻲ ﻣﺤﺎوﻟﺔ اﻟﺠﺴﻢ ﻟﺘﻌﻮﯾﺾ اﻟﻄﺎﻗﺔ اﻟﺤﺮار ﯾﺔ اﻟﺘﻲ‬ ‫ﯾﻔﻘﺪھﺎ أﺛﻨﺎء اﻟﺘﺨﺪﯾﺮ‪.‬‬ ‫وﻟﻠﺘﻐﻠﺐ ﻋﻠﻲ ھﺬه اﻟﻤﺸﻜﻠﺔ ظﮭﺮت اﻟﻜﺜﯿﺮ ﻣﻦ اﻟﺤﻠﻮل اﻟﻔﯿﺰﯾﺎﺋﯿﺔ ﻛﺎﻟﺒﻄﺎﻧﯿﺎت‬ ‫اﻹﻟﻜﺘﺮوﻧﯿﺔ وأﺟﮭﺰة اﻟﺘﺪﻓﺌﺔ ﻟﻜﻨﮭﺎ ﺗﺸﻜﻞ ﻋﺎﺋﻖ ﻓﻲ ﻏﺮﻓﺔ اﻟﻌﻤﻠﯿﺎت ﻟﺤﺠﻤﮭﺎ اﻟﻜﺒﯿﺮ‬ ‫ﺑﺎﻹﺿﺎﻓﺔ ﻟﻐﻠﻮ ﺛﻤﻨﮭﺎ‪.‬ﻟﮭﺬا ظﮭﺮ اﻟﻌﻼج اﻟﺪواﺋﻲ ﻛﺒﺪﯾﻞ أﻓﻀﻞ ﻟﻠﻮﻗﺎﯾﺔ واﻟﻌﻼج ﻣﻦ ھﺬه‬ ‫اﻟﺮﻋﺸﺔ‪.‬‬ ‫وﯾﺘﻨﺎول ھﺬا اﻟﺒﺤﺚ اﻟﻤﻘﺎرﻧﺔ ﺑﯿﻦ ﻛﻔﺎءة ﻛﻞ ﻣﻦ اﻟﻤﯿﺪازوﻻم ‪ ،‬واﻟﻤﯿﺪازوﻻم‬ ‫ﺑﺎﻹﺿﺎﻓﺔ ﻟﻠﻜﯿﺘﺎﻣﯿﻦ ‪ ،‬واﻟﺘﺮاﻣﺎدول ‪ ،‬واﻟﺘﺮاﻣﺎدول ﺑﺎﻹﺿﺎﻓﺔ ﻟﻠﻜﯿﺘﺎﻣﯿﻦ ﻓﻲ اﻟﻮﻗﺎﯾﺔ ﻣﻦ‬ ‫ھﺬه اﻟﺮﻋﺸﺔ‪.‬‬ ‫ﺷﻤﻞ ھﺬا اﻟﺒﺤﺚ ‪ ١٠٠‬ﻣﺮﯾﺾ ﺗﻢ ﺗﺤﻀﯿﺮھﻢ ﻹﺟﺮاء ﻋﻤﻠﯿﺎت ﻏﯿﺮ طﺎرﺋﺔ ﺑﻘﺴﻢ‬ ‫ﺟﺮاﺣﺔ اﻟﻌﻈﺎم ﺗﺤﺖ ﺗﺄﺛﯿﺮ ﻣﺨﺪر ﻧﺼﻔﻲ وﺗﺘﺮاوح أﻋﻤﺎرھﻢ ﺑﯿﻦ ‪ ٦٠-٢١‬ﻋﺎﻣﺎ ً ‪ .‬وﻗﺪ‬ ‫‪١‬‬




2010


‫ﺟﺎﻣﻌﺔ ﻃﻨﻄﺎ‬

‫ﻛﻠﻴﺔ اﻟﻄﺐ‬

‫ﻗﺴﻢ اﻟﺘﺨﺪﻳﺮ‬

‫اﻟﻤﻘﺎرﻧﺔ ﺑﯿﻦ اﻟﻤﯿﺪازوﻻم واﻟﻤﯿﺪازوﻻم ﺑﺎﻹﺿﺎﻓﺔ ﻟﻠﻜﯿﺘﺎﻣﯿﻦ واﻟﺘﺮاﻣﺎدول‬ ‫واﻟﺘﺮاﻣﺎدول ﺑﺎﻹﺿﺎﻓﺔ ﻟﻠﻜﯿﺘﺎﻣﯿﻦ ﻓﻲ اﻟﻮﻗﺎﯾﺔ ﻣﻦ اﻟﺮﻋﺸﺔ ﺑﻌﺪ اﻟﺘﺨﺪﯾﺮ‬ ‫اﻟﻨﺼﻔﻲ‬ ‫رﺳﺎﻟﺔ ﻣﻘﺪﻣﮫ‬

‫إﯾﻔﺎءا ﺟﺰﺋﯿﺎ ً ﻟﺸﺮط اﻟﺤﺼﻮل ﻋﻠﻰ درﺟﺔ اﻟﻤﺎﺟﺴﺘﯿﺮ‬ ‫ﻓﻲ‬

‫اﻟﺗﺧدﯾر‬ ‫ﻣن‬

‫اﻟﻄﺒﯿﺐ‪ /‬ﻣﺤﻤﺪ إﺑﺮاھﯿﻢ اﻟﻘﻠﻠﻲ‬ ‫ﺑﻛﺎﻟورﯾوس اﻟطب واﻟﺟراﺣﺔ‬

‫اﻟﻣﺷــــــرﻓون‬ ‫اﻷﺳﺗﺎذ اﻟدﻛﺗور‪ /‬ﺑدرﯾﺔ ﻋﺑد اﻟﺣﻠﯾم اﻟﻘﺳطﺎوي‬

‫أﺳﺗـــــــــﺎذ اﻟﺗﺧدﯾــــــــــر واﻟﻌﻧﺎﯾﺔ اﻟﻣرﻛزة‬ ‫ﻛﻠﯾــــــــﺔ اﻟطــــــــب‬ ‫ﺟﺎﻣﻌﺔ طﻧطﺎ‬ ‫اﻷﺳﺗﺎذ اﻟد���ﺗور‪ /‬ﺳﻼﻣﻪ إﺑراﻫﯾم اﻟﻬواري‬

‫أﺳﺗـــــــــﺎذ اﻟﺗﺧدﯾــــــــــر واﻟﻌﻧﺎﯾﺔ اﻟﻣرﻛزة‬ ‫ﻛﻠﯾــــــــﺔ اﻟطــــــــب‬ ‫ﺟﺎﻣﻌﺔ طﻧطﺎ‬ ‫اﻟدﻛﺗور‪ /‬رﺿﺎ ﺻﺑﺣﻲ ﺳﻼﻣﻪ ﻋﺑد اﻟرﺣﻣن‬

‫ﻣـــــــدرس اﻟﺗﺧدﯾــــــــــر واﻟﻌﻧﺎﯾﺔ اﻟﻣرﻛزة‬ ‫ﻛﻠﯾــــــــﺔ اﻟطــــــــب‬ ‫ﺟﺎﻣﻌﺔ طﻧطﺎ‬ ‫ﻛﻠﯾﺔ اﻟطب‬ ‫ﺟﺎﻣﻌﺔ طﻧطﺎ‬

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my thesis