LIST OF ABBREVIATIONS USED

ASA - American society of anaesthesiologist.

BP - Blood pressure.

BT - Bleeding time.

CNS - Central nervous system.

CSF - Cerebro spinal fluid.

CT - Clotting time.

CVS - Cardiovascular system.

DBP - Diastolic blood pressure.

GABA - Gama amino butyric acid.

Hb - Haemoglobin.

IM - Intramuscular.

IV - Intravenous.

LSCS - Lower segment caesarean section.

Min - Minute.

N/V - Nausea – Vomiting.

PR - Pulse rate.

RBS - Random blood sugar.

RR - Respiratory rate.

RS - Respiratory system.

SA - Spinal anaesthesia.

SAB - Subarachnoid block.

SBP - Systolic blood pressure.

SD - Standard deviation.

Sug - Sugar.

Ut - Uterus.

Brady - Bradycardia.

Hypo - Hypotension.

Drowsy - Drowsiness.

Pre-op - Pre-operative.

VAS - Visual Analogue Scale

1

TABLE OF CONTENTS

SI. NO TABLES PAGE

NO

1. INTRODUCTION

2. OBJECTIVES

3. REVIEW OF LITERATURE

4. MATERIALS AND METHODS

5. RESULTS

6. DISCUSSION

7. SUMMARY

8. CONCLUSION

9. BIBLIOGRAPHY

10. ANNEXURES

ANNEXURE I PROFORMA

ANNEXURE II CONSENT FORM

ANNEXURE III MASTER CHART

2

LIST OF TABLES

SI. No. Tables Page No.

1 DRUGS AND DOSES

2 TIME OF ONSET OF SENSORY BLOCKADE

3 DURATION OF SENSORY BLOCKADE

4 DURATION OF MAXIMUM MOTOR BLOCKADE

5 MEAN BLOOD PRESSURE

6 DURATION OF ANALGESIA

7 VAS EFFECTIVENESS OF PAIN RELIEF

8 COMPLICATIONS

3

LIST OF FIGURES

SI. No. FIGURES Page No.

1 VERTEBRAL COLUMN

2 VERTEBRA AND LIGAMENTS

3 SPINAL CORD AND RELATION WITH VERTEBRA

4 BLOOD SUPPLY OF SPINAL CORD

5 REXED SPINAL CORD LAMINAE

6 PAIN PATHWAYS

7 MATERIALS USED FOR SPINAL ANAESTHESIA

8 MIDAZOLAM AND BUPIVACAINE

SI. No. GRAPHS Page No.

1 TIME OF ONSET OF SENSORY BLOCKADE

2 DURATION OF SENSORY BLOCKADE

3 DURATION OF MAXIMUM MOTOR BLOCKADE

4 DURATION OF ANALGESIA

5 VAS EFFECTIVENESS OF PAIN RELIEF

INTRODUCTION

4

“For all happiness mankind can gain is not in pleasure, but in rest from pain”

- John Dryden

Pain is defined, according to the international association for the study of pain, as “an

unpleasant, sensory and emotional experience associated with actual or potential tissue

damage or described in terms of such damage”. The role of an anaesthesiologist is to

render patient pain free during surgical procedures. However, patient’s problem with

pain does not end with surgical procedure. Pain during postoperative period is a cause

of concern not only for the patient, but also for the surgeon and the anaesthesiologist.

Postoperative pain control is generally best managed by anaesthesiologist because

they offer regional techniques of anaesthesia as well as pharmacological expertise in

analgesics.

Apart from obvious humanitarian reasons, effective postoperative analgesia results in

decreased incidence of respiratory and cardiovascular complications early ambulation

and discharge from hospital.

Spinal anaesthesia by 0.5% Hyperbaric bupivacaine is characterised by a relatively

rapid onset of action, duration of anaesthesia at approximately 2-3 hours and profound

motor blockade. In these patients, rescue analgesia is necessary after 2-3 hours, even

though it provides effective pain relief in the initial postoperative period. In order to

maximize postoperative analgesia, a number of adjuvants have been added to spinal

local anesthetics.

5

One of them is midazolam, a water soluble benzodiazepine, used for induction of

anaesthesia and sedation. Midazolam has been reported to have a spinally mediated

analgesic effect. Clinically, single shot epidural or spinal administration of midazolam

has been shown to have added analgesic effect on postoperative pain.

Recent literatures have reported the usefulness of intrathecal midazolam-

bupivacaine mixture for relief of postoperative pain.

The present study is to compare the efficacy and practicability of using the

midazolam- bupivacaine mixture and bupivacaine intrathecally in patients undergoing

elective caesarian delivery.

6

OBJECTIVES

This study is undertaken to evaluate the comparison of intrathecal bupivacaine and

intrathecal bupivacaine – midazolam mixture as postoperative analgesia in patients

undergoing elective caesarian delivery. The following parameters are compared

between two groups:

Time for onset of sensory blockade

Duration of sensory blockade

Duration of motor blockade

Duration of analgesia

Incidence of complication

7

REVIEW OF LITERATURE

In a study 1, conducted on 53 adult ASA grade I/II patients, it was shown that intrathecal

combination of midazolam and bupivacaine provides longer duration of post operative

analgesia as compared to intrathecal bupivacaine alone without prolonging duration of

dermatomal sensory block. There were no episodes of bradycardia, hypotension,

sedation, vomiting, pruritis, and urinary retention.

In a study 2, it was shown that intrathecal midazolam provided a moderate prolongation

of post operative analgesia in patients undergoing caesarean delivery with decreased post

operative nausea and vomiting.

In a study 3, 4 sought to identify whether intrathecal midazolam was associated with

neuropathological symptoms, it was found that intrathecal midazolam did not increase the

occurrence of neurologic or urologic symptoms or bowel changes.

In a study 5, conducted for post operative pain relief in patients undergoing caesarean

delivery it was shown that intrathecal midazolam produced highly significant post

operative pain relief together with anti emetic effect and tranquility. Patients were calm

and sleepy and responding throughout the procedure.

In a study 6, 7 conducted on adult rat spinal cord slices it was shown that midazolam

augmented both the duration of GABA – mediated synaptic current and the amplitude of

GABA – induced current by acting on GABA A – benzodiazepine receptor in substantia

gelatinosa neurons, thereby increasing the inhibitory GABA ergic transmission.

In a study 8, it was shown that intrathecal midazolam caused spinally mediated

antinociception in rats by a mechanism involving ð opioid receptor activation.

8

In a randomized study13 comprising 52 patients scheduled for elective caesarean section

under spinal anaesthesia showed that intrathecal midazolam is safe and free of side

effects and also effective in post operative analgesia and in the control of post operative

nausea and vomiting.

A study14 comprising 40 women posted for elective caesarean delivery, showed that

intrathecal midazolam 2mg provides adequate postoperative analgesia and prevents

nausea and vomiting as an added advantage.

A cohort study15 was conducted in 1100 patients with intrathecal midazolam in 547

patients. They gave a conclusion that 0.03mg/kg intrathecal midazolam is safe without

adverse effects.

In a special article16 they stated that intrathecal midazolam in humans reduces post

operative nausea and vomiting, increases analgesic efficacy of other intrathecal drugs and

no side effects such as hypotension and bradycardia and is a safe intrathecal adjuvant

A double blind study17 was carried out in 53 patients to compare the effect of

intrathecal midazolam bupivacaine combination on post operative analgesia and conclude

that midazolam provides longer duration of analgesia and effectively reduces Nausea –

Vomiting.

In a study18 with 672 patients, intrathecal midazolam reduced the incidence of nausea

and vomiting and improves perioperative analgesia during caesarean delivery.

In a prospective randomized double blind study19 comprising 80 patients undergoing

lower limb orthopaedic surgery gave a conclusion that intrathecal midazolam in a dose of

2.5mg prolongs the post operative analgesia when used as an adjuvant to bupivacaine and

it significantly reduces nausea and vomiting.

9

A double blind study28 on 45 patients undergoing haemorrhoidectomy under spinal

anesthesia, showed that intrathecal midazolam effectively increases postoperative

analgesia.

10

ANATOMICAL ASPECTS20,21,22

The vertebral column composed of 33 vertebrae (7 cervical, 12 thoracic, 5 lumbar, 5

sacral and 4 coccygeal) has 4 curves. The cervical and lumbar curves are convex

anteriorly while the thoracic and sacral curves are convex posteriorly. The curves of the

vertebral column have a significant influence on the spread of local anaesthetics in the

subarachnoid space. In the supine position the high points of the cervical and lumbar

curves are at C5 and L5. The low points of the thoracic and sacral curves are at T5 and S2

respectively. The vertebral column is bound together by several ligaments, which give it

stability and elasticity. They are

i. Supraspinous ligament: It is a strong, thick, fibrous band connecting the apices of

the spinous processes from sacrum to C7, where it is continued upward to the

external occipital protuberance as the Ligamentum nuchae. At the lumbar region, it

is thick and broad.

ii. Interspinous ligament: it is a thin, fibrous structure connecting adjacent spinous

processes and blending anteriorly with the Ligamentum flavum and posteriorly

with Supraspinous ligament. The fibres are almost membranous and extend from

the apex and upper surface of a lower spine toward the root and inferior surface of

the next higher vertebrae.

iii. Ligamentum flavum: Consisting of yellow elastic fibers and connecting adjacent

laminae that run from caudal edge of vertebrae above, to the cephalad edge of the

lamina below. The fibres are perpendicular in direction. The ligament thus exists

as a right and left half in each intervertebral space, with the halves fusing in the

midline. This creates a thin central midline area between the halves of the ligament

11

flava. In the lumbar area, the ligament is 3 to 5 mm thick, and has an average

height of 15 to 16 mm and a width of 16 to 20 mm in adults.

iv. Longitudinal ligament: The anterior and posterior longitudinal ligaments bind the

vertebral bodies together.

Epidural space:

It is a circular space surrounding spinal meninges and extends from the foramen

magnum, where the dura is fused to the base of the skull, to the sacral hiatus, which is

covered by the sacrococcygeal ligament. It is widest posteriorly and varies with the

vertebral level, ranging from 1 to 1.5mm at C5 to 2.5 to 3mm at T6 to its widest point 5 to

6 mm at level of L2. There are strong lateral attachments of the dura at the cervical and

lumbar areas to the spinal canal wall.

In addition to nerve roots that traverse the epidural space, the contents of epidural space

are fat, areolar tissue, lymphatics, arteries and the extensive internal vertebral venous

plexus of Batson.

12

VERTEBRAL COLUMN

13

VERTEBRA AND LIGAMENTS

14

SPINAL CORD AND RELATIONS WITH VERTEBRA

15

Spinal meninges:

The spinal cord is protected by both the bony vertebral column and three connective

tissue coverings, the meninges.

Duramater:

It is the outer most membrane and is a tough, fibroelastic tube whose fibers run

longitudinally.

At the spinal level superiorly, it is firmly attached to the circumference of the foramen

magnum of the occipital bone. Inferiorly or caudally, the dural sac ends at the lower

border of S2, where it is pierced by the filum terminale. The spinal dura also provides a

thin cover for the spinal nerve roots, becoming progressively thinner near the

intervertebral foramina.

Arachnoidmater:

16

It is the middle of the three coverings of the brain and spinal cord. It is a delicate

nonvascular membrane closely attached to the dura, and with it ends at the lower border

of S2. It contains a minute quantity of serous fluid, but it has no connection with the

subarachnoid space that contains the CSF.

Piamater:

It is delicate, highly vascular membrane closely investing the spinal cord and the

brain. The space between arachnoid and pai is called the subarachnoid space, which

contains the spinal nerves and CSF. Many blood vessels that supply the spinal cord are

found in this space.

Spinal cord:

It is continuous above with the medulla oblongata, beginning at the level of foramen

magnum and ending below as the conus medullaris. At birth, the cord ends at the level of

L3, but rises to the lower border of L1 in adult life.

Spinal nerves:

There are 31 pairs of symmetrically arranged spinal nerves, which are attached to the

spinal cord by anterior and posterior roots.

Subarachnoid space:

It is bounded internally by the pia and externally by the arachnoid and is filled with

cerebrospinal fluid. It also contains numerous arachnoid trabeculae, which form a

delicate, sponge like mass. The subarachnoid space extends separately along both the

dorsal and ventral roots to the level of the dorsal root ganglion.

17

Cerebrospinal fluid:

It is an ultra filtrate of the blood plasma with which it is in hydrostatic and osmotic

equilibrium. It is a clear, colorless fluid found in the spinal and cranial subarachnoid

spaces and in the ventricles of the brain. At 370C, its specific gravity is 1003 to 1009, and

its pH is physiologic at 7.4 to 7.6. The total volume in average adult ranges from 120 to

150ml, of which 25 to 35ml are in spinal subarachnoid space. In horizontal position, the

pressure of CSF ranges from 60 to 80mm of water.

Cerebrospinal fluid is formed by secretion or ultra filtration from the choroid arterial

plexuses of the lateral, third and fourth ventricles. Normal daily secretion is believed to

be equal to the volume presents (i.e. 150ml). It has been shown that after removal of

small volumes of CSF, it is reformed at an increased rate of approximately 0.3ml/min

(432ml/day).

The circulation and elimination of CSF are important to the understanding and

treatment of post dural puncture headache. Although the choroid plexus are in all 4

ventricles, the bulk of the fluid is formed in the lateral ventricles and then passes in to the

third and fourth ventricles. In the fourth ventricle, it departs through the two foramen of

Luschka and circulates upward over the surface of the brain. It also passes through the

median foramen of Magendie to proceed downward into the medullary and spinal cord

areas.

Composition of CSF:

Protein 15 – 45mg%

Glucose 50 – 80 mg%

Non protein nitrogen 20 – 30mg%

18

Chloride 120 – 130mEq/L

Sodium 140 – 150mEq/L

Bicarbonate 25 – 30mEq/L

pH 7.4 – 7.6.

Blood supply to the spinal cord:

Spinal cord is supplied by an anterior spinal artery and two posterior spinal arteries.

The anterior spinal artery is formed between the pyramids of the medulla oblongata by

the union of a root from the terminal part of each vertebral artery and descends in front of

the anterior longitudinal sulcus of the spinal cord and the corresponding vein to the filum

terminale.

The posterior spinal arteries (two on each side) arises from posterior inferior

cerebellar arteries and descend medial to the posterior nerve roots, sending penetrating

twigs to the posterior white columns and the remainder of the posterior grey columns.

Fates of local anaesthetic solutions in the subarachnoid spaces:

Immediately following the injection of a local anaesthetic in to subarachnoid space,

there is a rapid decrease in the concentration of the anaesthetic agent in the CSF at the

point of injection. The greatest decrease occurs within the first 5 minutes, followed by a

more gradual decline. The amount present in solution are however, so small that after 20

to 30 minutes, they are insufficient to produce spinal anaesthesia. Hyperbaric solutions

spread predominantly in a cephalad direction when the patient is supine on a level table.

As the local anaesthetics solution spreads a differential block occurs that is , there is a

zone where the concentration of the local anaesthetic solution is highest and motor and all

19

sensory modalities are blocked; at the most cephalad extent , however, only the

sympathetic nerves are involved in the blockade.

A differential block exists between motor and sensory levels, averaging two spinal

segments. Immediately after injection, the local anaesthetic agent is taken up by neural

elements. It accumulates along the posterior and lateral aspect of the spinal cord itself, as

well as in the spinal nerve roots.

The regress is primarily by vascular absorption with no hydrolysis or degradation

taking place in the spinal fluid. Depending upon the type of local anaesthetic, the drug is

metabolized either in the plasma by pseudocholinesterase (eg, procaine and tetracaine) or

in the liver (eg, lidocaine, other amide type local anesthetic agents).

20

SPINAL CORD BLOOD SUPPLY

21

REXED'S SPINAL CORD LAMINAE

22

PAIN PATHWAYS

23

PHYSIOLOGY OF PAIN

Pain (nociception) is a protective mechanism that occurs when tissues are being

damaged. It causes the individual to react to remove the painful stimulus. For example,

pressure on certain part of the body during sitting that results in painful ischemia causes

the person unconsciously to shift the weight. Additionally, pain may promote healing by

motivating the organism to avoid motion of an injured area.

Types of pain:

Two qualitatively different types of pain can be readily appreciated. Fast pain is a short,

well localized, stabbing sensation that is matched to the stimulus, such as a pinprick or

surgical skin incision. This pain starts abruptly when the stimulus is applied and ends

promptly when the stimulus is removed. Fast pain results from stimulation of small,

myelinated type A- delta nerve fibres with conduction velocities of 12-30m/s.

The second type of pain sensation, slow pain, is characterised as a throbbing, burning,

or aching sensation that is poorly localized and less specifically related to the stimulus.

Slow pain results from stimulation of more primitive, unmyleinated type C have fibres

with conduction velocities of 0.5 to 2m/s. This pain may continue long after the

removal of the stimulus. The further from the brain the stimulus originates, the greater

is the temporal distinction of the two components. It is the immediate, stabbing pain

that instantly tells the person that tissue damage is occurring, whereas burning pain

becomes the source of sustained discomfort.

Nerve fibres for temperature follow the same pathways as fibres for pain. Although the

pain threshold is fairly constant among individuals, different people, nevertheless, react

24

very differently to the same intensity of painful stimulation, emphasizing the

importance of personality and ethenic origin on pain tolerance and the description of

gain.

Autonomic nervous System Responses:

Painful stimulation may evoke reflex increases in sympathetic nervous system

efferent activity. It is possible that associated vasoconstriction leads to acidosis, tissue

ischaemia, and release of chemicals that further activate pain receptors. Resulting

sustained painful stimulation produces further increases in sympathetic nervous system

activity, and the vicious cycle termed reflex sympathetic dystrophy (complex regional

pain syndrome) may develop.

After certain types of nerve injury, pain may occur without activation of pain

receptors. Spontaneous firing that occurs from injured peripheral nerves, especially in

response to sympathetic nervous system stimulation, may reflect a proliferation of

alpha-adrenergic receptors on the increased number of neuroma sprouts. Spontaneous

firing may also occur from dorsal root ganglia whose peripheral projections have been

interrupted, as after nerve transection or limb amputation.

Pain pathways:

Pain pathways appear to consist of peripheral plexuses of unmyelinated nerves,

activated by high intensity stimuli which may be thermal, mechanical, electrical or

chemical. Pain is conducted along two types of fibres in the periphery, Aδ and C fibres.

Aδ fibres are finely myelinated and relatively rapidly conducted. They would appear to

conduct the sharp pain produced by pinprick or electrical stimulation, as well as thermal

25

stimuli, and are for the withdrawal reflex. Aδ conducted pain is felt quickly and well

localized. C fibres are very fine non-myelinated fibres which conduct at a very slow

rate of 2.3m/sec or less. Their threshold for stimulation is higher than that of Aδ fibres

and they would appear to be responsible for more delayed and truly noxious, burning or

throbbing pain.

Inhibitory pathways:

There are various means by which pain transmission may be inhibited at spinal level.

They form part of a more modern and simplified explanation of the gate theory of

Melzack and Wall.

i) Large primary afferent fibres:

They mainly ascend in the dorsal columns and whose cell bodies lie in the dorsal

root ganglion, send collateral to synapse with and activate inhibitory interneurons in the

dorsal horn. These in turn inhibit the release of transmitter along pain pathways. Thus

stimulation of large A ß cutaneous afferents may inhibit pain transmission.

ii) Inhibitory fibres:

These fibres descend in the dorsolateral white funiculus and their cell bodies lie in

the medullary raphe nuclei. They may also inhibit pain transmission, presumably by an

action on the inhibitory interneurons.

iii) ß-endorphins:

They are released into the third ventricle from long axons originating chiefly in the

hypothalamus. They are conveyed in the cerebrospinal fluid to the spinal cord where it

may depress pain conduction in the substantia gelatinosa.

26

iv) Opiates:

They are also able to inhibit pain conduction in the cord either by activating

descending inhibitory pathways or by a direct action on opiate receptors in the

substantia gelatinosa.

Opiate receptors are widespread in the brain and spinal cord – amygdale and

limbic system, in the area postrema, associated with the stimulant effect upon the

chemoreceptor trigger zone, and along the course of pain pathways in medial thalamus,

in the periaqueductal grey mater and in the substantia gelatinosa of the trigeminal nerve

and spinal cord, and in gastrointestinal tract.

Opiate receptors have been classified by Martin as

Mu (μ) = Supraspinal analgesia, euphoria, dependence.

Kappa (k) = Spinal analgesia, sedation.

Delta (δ) = Dysphoria.

27

PHARMACOLOGY OF MIDAZOLAM 21,23,24,25

Midazolam is a water soluble benzodiazepine with an imidazole ring in its structure

that accounts for stability in aqueous solution and rapid metabolism. As with other

benzodiazepines, the amnestic effects of midazolam are more potent than its sedative

effects. It may be given orally or intramuscularly as sedative, or intravenously as a

sedative or as an induction agent prior to general anaesthesia. It produces five principal

pharmacological effects: anxiolysis, sedation, anticonvulsant, spinal cord mediated

skeletal muscle relaxation and anterograde amnesia.

Structure:

CH3 CH3

C = N C N

CH CH

N C PH<4 N C CH2N2

N PH>4

Cl Cl C = O

F

F

28

Chemistry:

Midazolam - C18H13CIFN3

8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo (1, 5-a) (1, 4) benzodiazepine

Molecular weight of hydrochloride 362.2

(Free base) (325.8)

pKa 6.2

Clinical pharmacology:

Midazolam is a water soluble benzodiazepine drug producing sedation, anxiolysis,

antiemetic and hypnosis. Doses of 3 – 6 mg intramuscularly produce a similar degree of

sedation and anxiolysis to papaveretum and scopolamine when used for premedication,

but with significantly more anterograde amnesia. The sedative effect of Midazolam 0.1 or

0.2 mg/kg in normal subjects is reversible by flumazenil, although resedation occurs

later.

Midazolam is commonly used intravenously to produce conscious sedation before

unpleasant such as dentistry, upper gastro intestinal endoscopy and bronchoscopy.

Satisfactory sedation can be achieved in majority of patients with a dose of 0.07 mg/kg.

A dose of 0.08mg/kg administered slowly intravenously produced excellent sedation

during surgery performed regional anaesthesia.

For induction of anaesthesia, Midazolam is less reliable than thiopental but preferable

to diazepam. Effective doses in adults have ranged from 0.15 to 0.5 mg/kg. Cardio

29

respiratory stability is a feature of induction of anaesthesia with Midazolam. There is an

increased sensitivity to Midazolam in the elderly.

When midazolam administered intrathecally along with Bupivacaine it produces more

intensive analgesia and prolonged duration of analgesia and thereby decreasing anxiety

mediated PONV.

It has been postulated that a possible mechanism for the antiemetic effect could be an

action at the chemoreceptor trigger zone reducing synthesis, release and post synaptic

effect of dopamine. Dopaminergic neuronal activity and 5 – hydroxytryptamine release

may also be reduced by binding of midazolam to the GABA benzodiazepine complex,

thus anxiolysis as a secondary effect may also contribute to antiemesis. It may also

decrease adenosine reuptake. This leads to an adenosine mediated reduction in the

synthesis, release and post synaptic action of dopamine at the CTZ.

Pharmacokinetics:

Midazolam undergoes rapid adsorption from the gastrointestinal tract and prompt

passage across the blood brain barrier. High performance liquid chromatography (HPLC)

is the preferred assay method. It can be used to separate Midazolam and its metabolites

with limits of detection of for Midazolam and α hydroxyl midazolam of 2 and 4 µg/lit

respectively.

At physiologic pH, midazolam is highly lipophilic, but this decreases with decreasing

pH. Fallowing intravenous administration, it is rapidly and widely distributed with a

steady state volume of distribution of 39 – 68 liters. Total body clearance is 6.4 – 11.1

ml/min/kg. There is no evidence of any significant enterohepatic circulation.

30

Midazolam is extensively bound to plasma proteins (94 – 98%) and small changes in

protein binding will produce large changes in the amount of available free drug, which

has important consequences in clinical practice. The free fraction is higher in patients

with chronic renal failure.

Less than 1% midazolam is excreted unchanged in urine and the drug is cleared

virtually entirely by liver metabolism. Prolonged sedation has resulted from use of drug

in severely ill patients with reduced hepatic blood flow.

Metabolism:

Midazolam is extensively metabolized by the p-450 dependent mixed function

oxidase system in the liver. The principal metabolite is 1, 4 - dihydroxymidazolam, has

half the activity of parent compound and which is rapidly conjugated with glucoronic

acid, although a small proportion is further hydroxylated to 1, 4- dihydroxymidazolam.

The other metabolite is 4-hydroxymidazolam. The metabolism of midazolam is slowed in

presence of drugs like cimetidine, erythromycin, calcium channel blockers, antifungal

drugs that inhibit cytochrome P-450 enzymes resulting in unexpected CNS depression.

Therapeutic use:

Indications:

1. As a hypnotic.

2. Preoperative medication.

3. As a sedative / for procedures such as dentistry, upper gastrointestinal endoscopy,

bronchoscopy and surgery performed under general anaesthesia.

4. As anti emetic.

5. Long term sedation.

31

6. Induction of general anaesthesia

Contraindications:

1. Known benzodiazepine sensitivity.

2. General precautions for all intravenous anaesthetic agents.

3. Respiratory insufficiency.

High risk groups:

1. Neonates.

2. Children.

3. Pregnant women.

4. Elderly.

5. Concurrent disease.

32

PHARMACOLOGY OF BUPIVACAINE 20-23,26,27

Source:

Bupivacaine, a synthetic drug, was prepared by A.F.Ekenstam in1957.

Chemistry:

The molecular weight of the chloride salt is 325 and that of the base form is 288. It has a

melting point of 2580 C. Solutions containing epinephrine have a pH of about 3.5

Chemical Name:

Bupivacaine is an anilide compound similar in chemical structure to mepivacaine. The

chemical name is 1-n- buty-DL-piperidine-2-carboxylic acid-2, 6 dimethylanilide

hydrochloride, which differs from mepivacaine in that a butyl group is substituted for a

methyl group on the piperidine nitrogen.

Bupivacaine is thus a homologue of mepivacaine, with a molecular formula of C18

N2O H28 HCl.

Chemical structure:

CH3

NHCO

CH3 H9C4

Lipophilic group Intermediary chain Hydrophilic group

33

N

Physiochemical properties:

Solubility:

Local anesthetic bases are sparingly soluble in water but are soluble in relatively

hydrophobic organic solvents. Therefore, as a matter of convenience, most of these drugs

are marketed as the hydrochloride is readily soluble in water. The pKa of the drug and

tissue pH determine the amount of drug that exists in solution as free base or as positively

charged cation when injected into living tissue.

Stability and sterilization:

Bupivacaine is highly stable and can withstand repeated autoclaving.

Anaesthetic properties:

Potency:

Bupivacaine is approximately three to four times more potent than lidocaine or

mepivacaine and eight times more than procaine. The duration of action of for local

anaesthesia is two to three times longer than that of mepivacaine or lidocaine and 20 to

25% longer than that of tetracaine.

Anaesthetic index:

Bupivacaine’s anaesthetic index is the same as mepivacaine’s – 3.0 to 4.0.

Bupivacaine is a reliable drug for infiltration and nerve block anaesthesia but is

unpredictable for spinal anaesthesia. It appears to have a slow nerve penetrating power.

Excellent sensory anaesthesia is produced and it has a prolonged duration, which is

probably its most outstanding characteristic.

34

Dosage: The recommended concentrations for various types of procedures is as follows:-

Infiltration: A concentration of 0.25% is used in healthy adults in volume – doses up

to 70 to 90ml with epinephrine. A 0.1% solution produces satisfactory anaesthesia in

debilitated patients and in children.

Nerve blocks: The 0.5% solution usually is used up to 35ml volume, which may be

increased to 45ml if epinephrine is added. This concentration is necessary to block

large nerve and to produce complete motor block. A 0.25% solution is satisfactory for

small peripheral nerves.

Caudal: For obstetric analgesia and perineal surgery, the 0.25% solution is effective.

A volume up to 30ml may be used by the caudal technique. For surgery of the lower

extremities, the 0.5%solution must be used and should be if good motor block is

desired.

Epidural block: For obstetric analgesia and perineal surgery, 20ml of a .025%

solution is effective. For lower extremity surgery, up to 20ml of the 0.5% solution is

satisfactory. For abdominal surgery good conditions are achieved only by the use of

0.75%solution up to volume 20ml.

Subarachnoid block: Concentrations of 0.5 – 0.75% of are effective. The maximum

recommended dose is 200mg. if epinephrine is used, one should not exceed 250mg.

These doses may be repeated in 3 to 4 hours, but 400mg is the maximum in 24 hours.

Cumulative toxicity is reported as in the case of other amide local anaesthetics.

However, the long duration of action makes it unnecessary for repeated frequent doses.

35

Pharmacodynamics:

The onset of action of bupivacaine is between 4 and 6 minutes, and maximum

anaesthesia is obtained between 15 and 20 min. The duration of anaesthesia varies

according to the type of block. The average duration of peridural block is about 3.5 to 5

hours.

In spinal anaesthesia 0.75% bupivacaine is equivalent to 1% tetracaine. The onset of

action is about 3to 4 minutes, and complete anaesthesia occurs in 5 minutes and lasts for

3.5 to 4 hours. The motor blockade is definitely inferior to tetracaine.

Toxicology

Systemic toxicity: The toxic plasma concentration is set at 4 to 5µg/ml. Maximum

plasma concentrations rarely approach toxic levels.

Cytotoxicity: Non specific local irritant effects on nerve tissue have been noted in

both, animals and human subjects. No evidence of permanent damage has been found

in clinical dosages. There is no alteration in the blood picture or methemoglobin

formation because of this drug.

Pharmacokinetics:

Bupivacaine can be detected in the blood within 5 minutes of infiltration or following

either epidural or intercostal nerve blocks. Plasma levels are related to the total dose

administered peak levels of 0.14 to 1.18µg/ml were found within 5 minutes to 2 hours

after the administration of anaesthesia, and they gradually declined to 0.34µg/ml by 4

hours.

36

Sympathetic effects:

Intravenous bupivacaine in doses of 80µg/min/kg have been shown to affect the

sympathetic nervous system. This accounts for its antiarrhythmic property. The following

is summary.

1. Definite β - adrenergic receptor block.

a) The hypotensive effect of isoproterenol is inhibited.

b) The pressor effect of adrenaline is enhanced.

c) Intestinal smooth muscle is inhibited.

d) The chronotropic effect of isoproterenol is decreased.

e) The inotropic effect of isoproterenol is decreased

2. No α - adrenergic receptor blocking properties.

3. No pressor effect of nor-adrenaline.

Adverse effects:

No serious adverse effects have been reported following clinical doses. Hypotension

and bradycardia are no greater than mepivacaine or lidocaine. Shivering is more frequent

with bupivacaine than with other local anaesthetic agents. Convulsions have followed

accidental injections of large amounts of the drug into blood vessels or after relative over

dosage.

Cardiovascular collapse / CNS ratio:

The CC / CNS dose ratio for bupivacaine is 3.7+/- 0.5, a finding indicating that three

times drug was required to induce irreversible cardiovascular collapse as was needed to

37

produce convulsions. It has also been suggested that some of the enhanced cardiac

toxicity of bupivacaine is due to greater myocardial uptake.

MATERIALS USED FOR SPINAL ANAESTHESIA

38

MIDAZOLAM AND BUPIVACAINE

MATERIALS AND METHODS

The present study was conducted on 100 patients belonging to ASA grade I and II

between 18 to 30 years of age who were scheduled for caesarean delivery in Bapuji

Hospital, Chigateri General Hospital and Women and Children Hospital, Davangere

during the academic year from December 2007 to July 2009.

Ethical clearance was obtained from the institution for this study purpose.

Inclusion criteria:

1) Patient scheduled for elective LSCS.

2) Patient aged between 18 to 30 years.

3) Patients with ASA grade I and II.

39

Exclusion criteria:

1) Patients belonging to ASA grade III and IV.

2) Patients on chronic analgesic therapy.

3) Patients with medical complications like

Diabetes

Cardiovascular disease.

Cerebrovascular disease.

4) Patients with obstetric complications like.

Pregnancy induced hypertension

Cord prolapse.

Placenta pravea.

Placental abruption.

Fetal malformations.

5) Patients with autonomic neuropathy, spinal deformities, infections in lumbar

area, hemorrhagic diathesis.

Pre-anesthetic Evaluation:

Pre-operatively a detailed history was carried out in all patients. Sex, weight,

hospital registration number and baseline data i.e., of pulse rate, blood pressure and

general condition was noted. The spinal column and back of the patient was examined

to rule out any spinal deformity. Cardiovascular, respiratory and central nervous system

were thoroughly examined.

Laboratory Investigations:

40

The following investigations were performed:

Haemoglobin %

Blood grouping

Total count

Differential count

Erythrocyte sedimentation rate

Bleeding time

Clotting time

Random blood sugar

Blood urea

Serum creatinine

Urine routine

HIV

Hbs Ag

Chest X-ray ( if required)

ECG

Pre-operatively

- Patient’s informed consent was taken.

- Nil per oral status was confirmed.

- The procedure of subarachnoid block was explained and the patient was

informed to communicate to the anaesthesiologist about the perception of

any pain or discomfort during surgery.

41

Procedure

The patients were randomly allocated into 2 groups of 50 each, namely

A) Group I – intrathecal bupivacaine 2 ml 0.5% hyperbaric + 0.4 ml of normal

saline

B) Group II – intrathecal bupivacaine 2 ml 0.5% hyperbaric + 0.4 ml (2mg) of

midazolam (preservative free).

Baseline pulse rate and blood pressure were recorded immediately before spinal

anaesthesia. A suitable intravenous line was secured and 500 ml of Lactated Ringer’s

solution was preloaded. Patient was then put in lateral position with head, neck, and

knees flexed and back arched. Hip and shoulders were maintained in vertical plane and

patient was brought to the edge of the table (positioned horizontally).

Under aseptic precautions, a sterile autoclaved spinal tray was used consisting of

A) Adequate cotton swabs with swab holding forceps.

B) Bowl containing betadine solution.

C) 2cc and 5cc syringes with 24G hypodermic needle.

D) Sterile drape.

E) Disposable 23G Lumbar puncture needle.

F) 0.5% (Heavy) bupivacaine – 1 ampoule.

G) An ampoule of preservative free midazolam to be used.

H) Xylocaine 2% for local infiltration.

42

A tray consisting of emergency drugs containing atropine, mephentermine,

dopamine, adrenaline, aminophylline, hydrocortisone, chlorpheneramine maleate, etc. is

kept ready along with emergency cardiopulmonary resuscitative equipment.

Under aseptic precautions, lumbar puncture was performed at L3-4 interspace

with 23G Quincke needle, after preparing local infiltration with 2cc of 0.2% lignocaine.

After free flow of CSF was obtained, 2ml of hyperbaric 0.5% bupivacaine with 0.4ml

of normal saline was injected in group I. 2ml of hyperbaric bupivacaine 0.5% with 0.4

ml (2mg) of midazolam was injected slowly over a period of 10 seconds in patients of

group II. After the drug was injected, the patient was turned to supine position. Pulse

rate and blood pressure were recorded immediately after spinal anaesthesia.

The following data were collected:

Time for onset of action:

It is defined as time interval between the completion of local anaesthetic

solution with or without midazolam to the onset of compete loss of sensation to

pinprick.

Level of sensory block:

It is defined as the highest dermatomal level of sensory blockade.

Duration of sensory blockade:

It is defined as time interval from injection of local anaesthetic solution with

or without midazolam to regression of 2 dermatomes of maximum level of analgesia.

43

Duration of maximum motor blockade:

It is denoted by ability of patient to flex feet, from the time when motor

paralysis set in according to Bromage scale.

Duration of analgesia:

It is defined as the time interval between administration of local anaesthetic

solution with or without midazolam to the first request for supplementary

analgesics.

Effectiveness of pain relief:

Effectiveness of pain relief in the postoperative period was assessed by Visual

Analogue Score. The patient makes a mark on a 10cm scale horizontal or vertical

one end of which is marked as ‘No pain’ and the other as ‘The worst pain one can

imagine’. The position of the mark on the line measures how much pain the patient

experiences.

Systolic and diastolic blood pressure, pulse rate and respiratory rate were

recorded at every 5 minutes till 20 minutes and then every 10 minutes till regression

of block.

After surgery, patients were monitored in the recovery room till spinal

anaesthesia wore off and were then shifted to the ward.

The patients were monitored for post operative complications viz., nausea,

vomiting, respiratory depression, drowsiness etc.

OBSERVATION AND RESULTS

A clinical study of 100 patients belonging to different age groups was done.

These patients belonged to ASA I or II and underwent elective caesarean delivery

44

under spinal anaesthesia. The study is undertaken to compare the analgesic efficacy

of bupivacaine – midazolam mixture and bupivacaine for post operative pain relief in

elective caesarean delivery.

TABLE 1 DRUGS AND DOSESGROUP NO OF PATIENTS DRUG ADMINISTERED

Group I 50 2 ml of bupivacaine + 0.4ml of saline

Group II 50 2 ml of Bupivacaine + 0.4ml of midazolam

This table shows two groups of patients studied and the doses of the drugs administered

intrathecally.

TABLE 2: TIME FOR ONSET OF SENSORY BLOCKADE

GROUP RANGE(MIN) MEAN(MIN) SD

45

Group I 4-6 4.8 0.6

Group II 3-6 4.6 0.7

t- value = 1.54 P = 0.13

In this table, time for the onset of sensory blockade is shown.

In group I, range for onset of sensory blockade is 4-6 minutes with mean onset time

being 4.8 minutes +/- 0.6(SD).

In group II, range for onset of sensory blockade is 3-6 minutes +/- 0.7(SD).

By applying student’s t-test, the t value is 1.54 and p value being 0.13, thus showing that

there is no statistical significance between the two groups with regard to mean onset time

for sensory blockade.

TIME FOR ONSET OF SENSORY BLOCKADE

46

4.5

4.55

4.6

4.65

4.7

4.75

4.8

Group IGroup II

TABLE 3: DURATION OF SENSORY BLOCKADE (TWO

SEGMENT REGRESSION)

47

Mea

n (m

in)

GROUP RANGE(MIN) MEAN(MIN) SD

Group I 85-98 90.8 4.1

Group II 100-140 115.8 8.1

t-value = 19.5 P < 0.001 Highly significant

Here, duration of sensory blockade (i.e,) two- segment regression is shown.

In group I, the mean duration of sensory blockade is 90.8 minutes +/- 4.1(SD) with a

range of 85-98 minutes.

In group II, the mean duration of sensory blockade is 115.8 minutes +/- 8.1(SD) with a

range of 100 – 140 minutes.

The duration of sensory blockade is increased from 90.8 minutes in group I to 115.8

minutes in group II and P value is < 0.001 which is highly significant.

DURATION OF SENSORY BLOCKADE

48

0

20

40

60

80

100

120

Group IGroup II

TABLE 4: DURATION OF MAXIMUM MOTOR BLOCKADE

49

Mea

n du

ratio

n (m

in)

GROUP RANGE(MIN) MEAN(MIN) SD

Group I 142 – 162 151.8 4.4

Group II 144 – 158 151.3 3.2

t- value = 0.66 P = 0.51 Not significant.

This table shows the duration of maximum motor blockade in groups I and II.

In group I, the duration of maximum motor blockade is 151.8 minutes +/- 4.4(SD) with a

range of 142 – 162 minutes.

In group II, the mean duration of maximum motor blockade is 151.3 minutes +/- 3.2(SD)

with the range being 144- 158 minutes. As the p value is 0.51 it is not statistically

significant.

50

DURATION OF MAXIMUM MOTOR BLOCKADE

151

151.1

151.2

151.3

151.4

151.5

151.6

151.7

151.8

Group IGroup II

51

Mea

n du

ratio

n (m

in)

TABLE 5: MEAN BLOOD PRESSURE

TIME OF

ASSESSMENT

(MIN)

GROUP I

SBP

GROUP I

DBP

GROUP II

SBP

GROUP II

DBP

0( basal) 134.8 +/-9.3 77.9 +/- 5.3 135.7 +/- 10.1 79.8 +/- 6.4

5 120.9 +/-9.5 70.9 +/- 5.4 122.2 +/- 9.3 73.2 +/- 6.8

10 118.2 +/- 10.9 70.7 +/- 5.5 120.4 +/- 11.6 71.4 +/- 7.3

20 122.4 +/- 8.3 71.7 +/- 4.3 120 +/- 11.6 72.3 +/- 5.1

30 126.3+/- 11.8 73.6 +/- 5.6 124.6 +/- 9.5 74.0 +/- 6.2

60 133.2 +/- 15.9 75.7 +/- 5.0 128 +/- 9.0 75.7 +/- 5.5

Values are expressed as Mean +/- SD.

This table shows mean systolic and diastolic blood pressure values in group I and group II

and there was no significant statistical difference found between the two groups.

TABLE 6: DURATION OF ANALGESIA52

GROUP RANGE(MIN) MEAN(MIN) SD

Group I 110 – 135 121.3 5.4

Group II 195 – 255 222.1 15.0

t-value= 44.0 P < 0.001 Highly significant

In this table, the duration of analgesia in both groups shown.

In group I, the mean duration of analgesia is 121.3 minutes +/- 5.4(SD) with range of 110

– 135 minutes.

In group II, the mean duration of analgesia is 221.1 minutes +/- 15(SD) with range of 195

– 225 minutes.

Here, the duration of analgesia has been increased considerably from 121.3 minutes in

group I to 221.3 minutes +/- in group II which is statistically highly significant with the p

value being < 0.001.

53

DURATION OF ANALGESIA

0

50

100

150

200

250

Group IGroup II

TABLE 7: VAS EFFECTIVENESS OF PAIN RELIEF

54

Mea

n du

ratio

n (m

in)

GROUP RANGE MEAN SD

Group I 3 – 5 3.8 0.5

Group II 3 – 5 3.7 0.5

t- value = 1.0 P= 0.32 Not significant

Here, the visual analogue score for effectiveness of pain relief is shown. In group I, the

mean score is 3.8 +/- 0.5 and in group II, it is 3.7 +/- 0.5. The t – value is 1.0 and p value

0.32 and based on them, there is no statistical significance between the two groups .

55

VAS EFFECTIVENESS OF PAIN RELIEF

3.64

3.66

3.68

3.7

3.72

3.74

3.76

3.78

3.8

Group IGroup II

TABLE 8: COMPLICATIONS

56

Mea

n

COMPLICATIONS GROUP I GROUP II

Bradycardia 4 1

Drowsiness - 2

Hypotension 6 3

Nausea and vomiting 9 0

Total 20 (40%) 6 (12%)

Numbers in parentheses are percentages.

X2 = 2.94 P < 0.004 (significant)

This table shows the complications (side effects) encountered in the group I and II.

In group I, 4 patients had bradycardia, 7 had hypotension, 9 patients had nausea and

vomiting.

In group II, 1 patient had bradycardia, 2 had drowsiness and hypotension was seen in 3

patients.

Here x2 = 2.94 and P < 0.004. Based on these values, there is high statistical difference

between the two groups.

DISCUSSION

57

Effective control of postoperative pain remains one of the most important and pressing

issues in the field of surgery and anaesthesia with significant impact on our health care

system.

Postoperative pain

Postoperative pain differs from other types of pain in that it is usually transitory,

with progressive improvement over a relatively short time course. Typically, the

affective component tends towards an anxiety state associated with diagnosis of the

condition and fear of delay in provision of analgesic therapy by attendants.

A number of postoperative dysfunctions are related directly or indirectly to

postoperative pain.

Pulmonary dysfunction:

A combination of factors, including reflex muscle spasm and involuntary splinting

of the thoracic abdominal muscles, produces ventilation:perfusion (V:Q) ratio

abnormalities. Fears of producing or aggravating pain can cause a patient to suppress

the urge to breathe deeply or to cough. The pain induced medullary stimulation (of

respiratory center) produces hyperventilation but this is offset by a decrease in chest

wall compliance, bronchiolar spasm and results in a net decrease in vital capacity (VC)

and in functional residual capacity (FRC), which produces hypoxemia.

Circulatory and metabolic dysfunctions:

58

Postoperative pain and the segmental and suprasegmental and reflex responses

produced by the continued nociceptive input cause increased cardiac output, blood

pressure, metabolism and oxygen consumption.

Gastrointestinal complications:

Ileus and accompanying nausea, and occasionally vomiting, are also the direct

result of postoperative nociceptive impulses arising in the viscera and in somatic

structures. Studies demonstrated the presence of powerful cutaneovisceral and

viscerovisceral reflexes, resulting in segmental sympathetic hyperactivity and

consequent inhibition of gastrointestinal function.

Impairment of muscle metabolism and muscle function:

These are pain- induced complications of major surgery in the hip, knee, and other

major joints. Persistent postoperative pain and consequent limitation of motion produce

marked impairment of normal muscle metabolism, cause muscle atrophy, and

significantly prolong return of normal muscle function.

Thrombus formation in the lower limbs:

This complication occurs with greater frequency in patients postoperatively whose

pain is inadequately relieved and who reduce their physical activity because of the fear

of aggravating the pain. Thrombus is caused by cortically mediated increased blood

viscosity and clotting, fibrinolysis and platelet aggregation.

Psychologic and emotional effects:

Severe postoperative pain, if unrelieved, can produce serious long term emotional

disturbance, which could impair the patient’s mental health.

59

By prompt and effective treatment of postoperative pain with the available

techniques, the above mentioned complications/ postoperative dysfunctions can be

prevented to a large extent, thereby promoting early patient ambulation, discharge and

minimizing hospital cost.

The most important factors that influence the occurrence, intensity, quality and

duration of postoperative pain include,

A. Site, nature and duration of operation, type of incision and amount of intra

operative trauma.

B. Physiologic and Psychologic make up of patient.

C. Preoperative Psychologic, physical, pharmacologic preparation of patient

D. Presence of serious complications related to operation

E. Anaesthetic management before, during and after operation, and most importantly

F. The quality of postoperative care.

Inadequate or improper application of available information and therapies is certainly the

most important reason for inadequate postoperative pain relief.

There are various modalities available for alleviating postoperative pain.

They are

A. Systemic analgesics and adjuvant drugs

B. Regional analgesia achieved with local anaesthetics

C. Regional analgesia achieved with intraspinal narcotics

D. Electrical analgesia achieved by transcutaneous electrical stimulation or

electropuncture, and

E. Psychological analgesia in the form of hypnosis or suggestion.

60

Advantages of spinal anaesthesia include :

1. It is reliable technique

2. Technique can be performed easily and quickly

3. Faster onset of action and long duration

4. Dense neural blockade with low risk of systemic toxicity

5. Anaesthesia limited to area of surgery

6. Good muscular relaxation

7. Parturient is awake, thus airway safe

8. Baby not sedated, usually born in good condition

9. Inexpensive

Indications:

1. Anticipated airway difficulty

2. Upper respiratory tract infection

3. History of asthma

4. Recent solid food intake

5. Mother's wish to remain awake

Contra indications:

1. Patient refusal despite proper information and reassurance

2. Infection of overlying site of injection or generalized sepsis

3. Preexisting neurological deficit in the part to be blocked

4. Psychiatric disorder or uncooperative patient

5. Trauma, surgery or burns at site of injection

6. Full anticoagulation or coagulopathy

7. Raised intracranial pressure.

61

During the past two decades, epidural and intrathecal narcotic therapies have been

used increasingly for the relief of postoperative pain.

Various drugs added with local anaesthetics have been studied with regard to

intrathecal administration for the treatment of postoperative pain viz –opioids –

morphine, pethidine, Fentanyl, Pentazocine, centrally acting alpha agonist – clonidine,

anticholinesterase – neostigmine, benzodiazepine – midazolam, non- steroidal anti

inflammatory drugs – tramadol etc.

Midazolam is a newer, water soluble imidazo benzodiazepine derivative which

has been tried for intrathecal use since early 1980’s. It is short acting and present in

aqueous solution.

Solubility:

In alcohol ---------

In water soluble

Octanol / water partition coefficient ---------

Midazolam is a colourless solution, supplied as the hydrochloride, with a pH of

less than 4 and available in concentration of 0.2 and 0.5%. At the physiological pH, the

ring structure closes and the drug becomes lipid soluble and rapidly penetrates the blood

brain barrier. It is prepared by chemical synthesis.

62

Pharmacology: Benzodiazepines modulate Gamma Amino Butyric Acid (GABA)

evoked chloride currents through a binding site on the GABA, a receptor operated

chloride channel. Midazolam binds to benzodiazepines receptors in various regions of

brain such as the spinal cord, brain stem, cerebellum, limbic system and cerebral cortex.

Benzodiazepines like Midazolam block EEG arousal from stimulation of brain stem

reticular formation. Midazolam acts as a CNS depressant on CNS reflexes via the brain

stem reticular formation. It is an anxiolytic in animal test system such as the fear of

electroshock in rats and or monkeys. It is a sedative as judged by reduction of fighting in

mice or monkeys. Hypnotic effects are also demonstrable in humans. It produces

anterograde amnesia similar to that produced by diazepam but neither benzodiazepine

produces retrograde amnesia. Midazolam has a more rapid onset of action and shorter

duration effect than diazepam in most animal systems. The antinociceptive effect of

intrathecal Midazolam has a marked anticonvulsant effect with a non linear relationship

between concentration and effect without an apparent ceiling at higher concentration.

Midazolam acts through GABA receptors which are abundantly present in the

dorsal horn of the spinal cord with the highest density of these receptors found within

lamina II of dorsal horn ganglia. Administration of exogenous benzodiazepines into the

CSF around spinal cord reached GABA receptors in high concentration and could have a

pronounced effect on local GABA activity. Therefore benzodiazepines can gain access to

analgesic system mediated by GABA. GABA is synthesized from glutamate in the

presynaptic nerve ending and is generally inhibitory in effect. GABA on binding with

GABAA receptors opens Ligand gate chloride channels. Chloride conductance is

increased, leading to hyperpolarisation and presynaptic inhibition of afferent terminals in

63

spinal cord. This results in less central propagation of action potential carrying

nociceptive stimuli information. Intrathecal midazolam has been used in man have been

described to provide pain relief without any side effects.

The mechanism of action of midazolam as an antiemetic is by decreasing

dopamine input at the chemoreceptor trigger zone in addition to decreasing anxiety. It

may also decrease adenosine reuptake. This leads to an adenosine – mediated reduction in

the synthesis, release and postsynaptic action of dopamine at the chemoreceptor trigger

zone. Midazolam may also decrease dopaminergic neuronal activity and 5 –

hydroxytryptamine (5 – HT) release by binding to the γ – aminobutyric benzodiazepine

complexes. Apart from the IV administration of midazolam, it has also been administered

sublingually, nasally and IM to alleviate PONV and has been found to be relatively

successful.

Intrathecal administration of midazolam has been reported to have antinociceptive

action because of the interaction of benzodiazepine and GABA on nociceptive systems.

Intrathecal benzodiazepine induced analgesia is spinally mediated and binding sites are

GABA receptors which are present abundant in dorsal root nerve cells and maximum

concentration found within lamina II of dorsal nerve cells, a region which plays a

prominent role in processing nociceptive and thermoceptive stimulation.

Effects of on Midazolam on organ systems:

Central nervous system: It produces decrease in cerebral oxygen requirements and

cerebral blood flow. Midazolam causes dose related changes in regional cerebral

blood flow in brain regions associated with the normal functioning of arousal,

attention and memory. Cerebral vasomotor responsiveness is preserved. There is little

64

or no change in intracranial pressure. It acts a potent anticonvulsant effective in the

treatment of status epilepticus.

Ventilation: Midazolam produces dose dependent decreases in ventilation. Patients

with chronic obstructive pulmonary disease experience even greater midazolam

induced depression ventilation. It also decreases upper airway activity and also

depress swallowing reflex.

Cardiovascular system: cardiac output is not altered and mild decrease in systolic

blood pressure is seen. There is also decrease in systemic vascular resistence.

Midazolam does not prevent blood pressure and heart rate responses evoked by

intubation of the trachea.

The present clinical study is a randomized prospective study in 100 patients

belonging to the age group of 18 – 30 years of ASA Grade I and II who were scheduled

for elective caesarian delivery under spinal anaesthesia. The patients of group I received

2ml of 0.5% bupivacaine Heavy with 0.4ml normal saline intrathecally and patients of

group II received 2ml of 0.5% bupivacaine Heavy with midazolam (preservative free)

0.4ml i.e 2mg intrathecally.

The results of the present clinical study were discussed under the following

headings:

65

Time for onset of sensory blockade:

In our study, the time for onset of sensory blockade for the two groups was not

statistically significant when compared. In group I, it was 4.8 ±0.6 min. whereas in group

II it was 4.6 ±0.7min with p value being 0.13(P< 0.05 being significant). So, the addition

of midazolam to bupivacaine has not made any apparent difference with regard to time

for onset of sensory blockade.

In 2003, Valentine J.M, Lyons G, Bellamy M.C study on 52 patients showed no

difference in onset and found better post operative analgesia and reduced complications

with use of intrathecal midazolam bupivacaine mixture.

In 2007, Gupta A, Prakash S, Deshpande S, Kale K.S study on 80 patients

found no difference in time of onset of sensory blockade.

66

Duration of sensory blockade:

The duration of sensory blockade (2 segment regression) was prolonged from

90.8±4.1 minutes in group I to 115.8 ± 8.1 minutes in group II and it was found to be

statistically significant as p< 0.001.

It can be attributed to the lipophilicity of midazolam and it synergism with the

local anaesthetic. The benzodiazepines and local anaesthetics exert their antinociceptive

effect at the spinal cord by different mechanisms. Midazolam exerts its action through

GABA A receptor complex i.e. GABA A on getting bound opens ligand gated chloride

channels. Chloride conductance is increased leading to hyperpolarisation and presynaptic

inhibition of afferent terminals in spinal cord and hence reduction in neuronal activity.

In 2007, Gupta A, Prakash S, Deshpande S, Kale K.S study on 80 patients found no

difference in time of onset of sensory blockade. They also showed that 2 segment

regression and duration of sensory blockade were satistically significant.

In 2004, Rudra P, study showed addition of midazolam to intrathecal local anesthetics

improved intra and post operative analgesia and decreased discomfort due to intra

operative manipulations.

67

Duration of maximum motor blockade:

In the present study, the duration of maximum motor blockade, when compared

between the two groups was not statistically significant. This is because in the both

groups, as soon as the action of local anaesthetic bupivacaine wears off, motor block is

not prolonged because midazolam does not have any motor action.

In 2004, Yaksh T.L, Allen J.W, study suggested that addition of intrathecal

midazolam does not cause motor blockade.

In 2009, Sarkar M, Dewoolkar L, prospective study done on 200 patients found

that addition of midazolam to bupivacaine did not prolong motor blockade.

68

Duration of analgesia:

The duration of analgesia in our study was prolonged from 121.3± 5.4 minutes in

Group I to 221.1± 15.0 minutes in Group II. This was statistically highly significant as p

value is < 0.001. This can be attributed to the fact that intrathecal benzodiazepine induced

analgesia is spinally mediated and binding sites are GABA receptors.

In Batra YK et al., study, duration of analgesia lasted for more than a mean

duration of 258 ± 46.8 minutes.

In 2001, M.H Kim and Y.M.Lee’s study suggested the presence of a dose

dependent effect of intrathecal midazolam with no evidence of neurological

complications. They concluded that the analgesic effect of intrathecal midazolam was

segmental, with no alteration in sympathetic tone or reflexes.

In 2001, Sen A, Rudra A, Sarkar S.K, Biswas B study suggested that intrathecal

midazolam produced highly significant post operative analgesia together anti emetic

effect.

In 2002, Saha J.K, Karmkar S study suggested that duration of analgesia in

midazolam bupivacaine group was 160 +/- 10.75 and was found to be highly significant.

In 2006, Joshi N, Gogia A.R, Prakash S study suggested that mean duration of

analgesia was 4.3 +/- 0.7 hrs with intrathecal midazolam bupivacaine combination.

69

In 2007, Gupta A, Prakash S, Deshpande S, Kale K.S study on 80 patients

showed the mean duration of analgesia in midazolam group were 412.1 +/- 57.3 min.

In 2005, Jahangiri B, Jahangiri R, double blind prospective study showed mean

duration of analgesia of about 7 +/- 1 hrs.

In 2003, Nishiyama T, Hanaoka K study suggested midazolam could enhance

the analgesic effects of bupivacaine synergistically in intrathecal administration.

Complications:

There was also high statistical difference observed between the two groups with

regard to complications like hypotension, bradycardia, drowsiness, nausea and vomiting.

It was found that addition of midazolam to intratheacal bupivacaine had an added

advantage in controlling post operative nausea and vomiting.

In 2004, Tucker A.P, Mezzatesta J, Nadeson R, Goodchild C.S, study showed

reduced incidence of post operative nausea and vomiting in midazolam bupivacaine

group than sole bupivacaine group.

In 2003, Bharti N, Madan R, Mohanty P.R, Kaul H.L study showed improved

quality and duration of spinal analgesia and provides prolonged post operative analgesia

without significant side effects.

70

SUMMARY

The present study was conducted on 100 patients in the age group between 18-30 years,

belonging to ASA grade I and II. These patients were scheduled for elective caesarean

delivery.

Group I patients received 2ml of 0.5% bupivacaine with 0.4ml of normal saline and

Group II patients received 2ml of 0.5% bupivacaine with 0.4ml (2mg) of preservative

free midazolam for subarachnoid block.

Under aseptic precautions, all patients were administered subarachnoid block in L3-4

interspace using 23G Quincke needle. Pulse rate, blood pressure were monitored.

The following parameters were compared between 2 groups:

Time of onset of sensory blockade

Duration of sensory blockade

Duration of motor blockade

Duration of analgesia

Incidence of complications.

It has been observed in the present study that the addition of preservative free midazolam

(2mg) to 0.5% bupivacaine offers a significant increase in the duration of analgesia with

no increase in the incidence of complications.

71

In conclusion, it can be inferred that Inj. Midazolam 2mg in combination with Inj.

Bupivacaine 0.5% Heavy can be safely administered intrathecally for better postoperative

analgesia in caesarean delivery.

CONCLUSION:

Postoperative pain relief is a growing concern to an anaesthesiologist since no single

analgesic is free from side effects. Moreover, it becomes a challenge after caesarean

section delivery to provide postoperative pain relief without much sedation, respiratory

depression or problems like nausea, vomiting, so that early baby acceptance and care by

the mother is promoted. Moreover intrathecally administered midazolam improves

quality of anaesthesia during the spinal procedure.

The present study demonstrated that intrathecal administration of bupivacaine-midazolam

mixture results in prolongation of postoperative analgesia without any significant

difference in the hemodynamic parameters and the incidence of side effects than when

bupivacaine alone was used as intrathecal agent.

72

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77

ANNEXURE

PROFORMAName:

Age:

ASA Status:

Surgery:

History:

GENERAL PHYSICAL EXAMINATION

Pallor Icterus Lymphadenopathy Cyanosis

Oedema Clubbing

SYSTEMIC EXAMINATION

Haemogram: Hb% Blood group Total count

Differential count ESR

Bleeding time:

Clotting time:

Urine routine: Albumin Sugar Microscopy

Blood sugar level:

Blood urea level:

Serum creatinine:

HIV:

HBs Ag:

ECG:

X-ray:

Drug: Bupivacaine 2ml 0.5% Heavy + 0.4ml (2mg) midazolam.

Needle gauge:

Volume:

Premedication:

78

Preoperative: Pulse Blood Pressure

MONITORING CHART

Time

in

min

P.R B.

P

Onset of

sensory

blockade

Sensory

level

2 segment

regression

Duration of

motor

blockade

Total

duration of

analgesia

0

2

5

10

15

20

30

60

90

120

150

180

210

240

270

300

POSTOPERATIVE:

1) Time to first pain medication.

2) At first pain medication Visual Analogue Scale

3) Complications.

79

CONSENT FORM FOR ANAESTHESIA / OPERATION

I ……………………..Hospital No……………in my full senses hereby give my

complete consent for ………………..or any other procedure deemed fit which is a

diagnostic procedure / biopsy / transfusion / operation to be performed on me / my

daughter / my wife……….age .……. Under any anaesthesia deemed fit. The nature and

risk involved in the procedures have been explained to me to my satisfaction. For

academic and scientific purpose the operation / procedure may be televised or

photographed.

Date: Signature / Thumb impression

Of the patient / Guardian

Name:

Designation: Guardian

Relationship

Full Address

80