Neuromuscular Monitoring

INTRODUCTION

1

INTRODUCTION

The introduction of neuromuscular blocking drugs revolutionized the practice of

anaesthesia. Before the advent of muscle relaxants, anaesthesia was induced and

maintained by intravenous or inhalation agents. Tracheal intubation and muscle

relaxation if needed was achieved by deep inhalation anaesthesia with its attendant

risks of respiratory or cardiac depression. After the introduction of muscle relaxants,

anaesthesia was redefined as a triad of narcosis, analgesia and muscle relaxation,

specific drugs being used to produce each of these effects. (1)

Curare was used for centuries by South American Indians to hunt game. Edward

Bancroft, a physician, spent five years in South America and brought back samples of

crude curare. Using these samples, Sir Benjamin Brodie demonstrated that small

animals could be kept alive after being injected with curare by inflating their lungs

with bellows. (2)

Griffith and Johnson in Montreal first described the use of curare to facilitate

muscle relaxation in a patient undergoing appendicectomy in 1942 (3,4).

Muscle relaxants belong to two groups, the depolarizers and the

nondepolarizers. Depolarizers mimic the effect of acetylcholine at the neuromuscular

junction, first causing muscle fasciculations and then paralysis. However,

succinylcholine has unwanted effects like malignant hyperpyrexia, increased

intraocular pressure and life-threatening hyperkalaemia (5).

This led to the search of an ideal neuromuscular blocking agent (NMBA)

Booij and Crul in 1983 (6) laid down the criteria for an ideal muscle relaxant. They

said that a muscle relaxant should have rapid onset, short duration of action, rapid

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recovery, no cumulative effects, no CNS side effects, no histamine release, inactive

metabolites, reversibility with anti-cholinesterases and high potency.

Nondepolarizing muscle relaxants have slower onset of action compared to

depolarising muscle relaxants. They work by competitive blockade of the

neuromuscular junction and are reversed with anticholinesterases such as

neostigmine. There is no initial muscle fasciculation. Newer NMBA like atracurium

and vecuronium were synthesised which had intermediate duration of action and

relatively better safety profiles.

Rocuronium is a steroidal muscle relaxant with a fast onset and intermediate

duration of action and has minimal cardiovascular side effects at effective

neuromuscular blocking doses (4,5).

Attention must be paid to dosing of the compound as residual neuromuscular

block is very much a risk of administering these agents (7). Special consideration

should be given to their use in the geriatric patient because physiologic changes that

accompany aging, including decreases in hepatic and renal blood flow and function,

which may impact the pharmacodynamics and pharmacokinetics of these NMBAs. (8)

Intraoperative neuromuscular monitoring is critical for judicious use of NMBAs.

Response of the muscle to nerve stimulation can be assessed to titrate the dose of

NMBA for desired clinical effect such as, intense block for intubation, moderate

block for surgical relaxation.

However, the most important role of neuromuscular monitoring is to detect

residual paralysis at the time of extubation. Undetected residual neuromuscular

blockade is common in the post-anesthesia care unit leading to postoperative

pulmonary complications (9).

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AIMS AND OBJECTIVES

4

AIMS AND OBJECTIVES

The aim of this prospective observational clinical study is to determine the

influence of ageing on the onset and duration of neuromuscular block produced by the

administration of a single bolus dose of Rocuronium.

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BASIC SCIENCES

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ANATOMY OF THE NEUROMUSCULAR JUNCTION

The neuromuscular junction (NMJ) is the synapse of the axon terminal of the

motor neuron with the motor end plate which is the excitable region of the muscle

fiber sarcolemma. It comprises of three parts :

Synaptic end bulbs

At the end of each axon terminal, there is a bulbous swelling called synaptic end

bulb which has many synaptic vesicles containing acetylcholine.

Motor end plate

It is the part of the sarcolemma of muscle cell which is thrown into multiple

folds called primary and secondary clefts. They greatly increase the surface area at

which the neurotransmitter can act.

Synaptic space

Synaptic space is the region between the motor end plate and synaptic end

bulb of the neuromuscular junction. It is 20 to 30 nanometers wide. This space is

traversed by the neurotransmitters.

Acetylcholine receptor

Acetylcholine receptor at the NMJ is a ligand gated ion channel. It consists of

5 protein subunits – 2 alpha, single beta, delta, epsilon subunits arranged

symmetrically around a central pore. This central pore is permeable to sodium and

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potassium. Only when both the binding sites are occupied by acetyl choline,

conformational changes in the subunits briefly open the ion channel at the core of the

receptor. Adjacent to the acetyl choline receptors, is the acetyl cholinesterase enzyme.

This substrate specific enzyme rapidly hydrolyses acetyl choline to acetate and

choline. The peri-junctional area of the sarcolemma contains high density of sodium

channels which helps in propagation of action potential.(10)

PHYSIOLOGY OF NEUROMUSCULAR TRANSMISSION

Acetylcholine is the primary neurotransmitter at the NMJ. It is synthesised

from choline and acetyl-coenzyme A (acetyl-coA) in the terminal axoplasm of motor

neurones .Once synthesised the molecules of acetylcholine are stored in vesicles

within the terminal button. The release of acetylcholine into the synaptic cleft occurs

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in response to a nerve impulse.

With the arrival of a nerve impulse, large numbers of P-type calcium channels

in the terminal membrane of the nerve open, allowing calcium to enter the cell. The

influx of calcium triggers 100-300 vesicles to fuse with the presynaptic membrane at

specific release sites and release acetylcholine into the synaptic cleft (exocytosis).

This causes a brief depolarisation in the muscle that triggers a muscle action potential.

Acetylcholine molecules bind to specific sites on the α subunits and when both

are occupied a conformational change occurs, opening the ion channel. The channel

allows movement of sodium ions which causes depolarization. The cell becomes less

negative compared with the extracellular surroundings. When a threshold of –50mV is

achieved (from a resting potential of –80mV), voltage- gated sodium channels open,

thereby increasing the rate of depolarisation and resulting in an end plate potential of

50-100mV. This in turn triggers the muscle action potential that results in muscle

contraction.

Pre-junctional receptors on the terminal bulb have a positive feedback role.

These receptors may also play a role in the “fade” seen in non-depolarising muscle

relaxant blockade by inhibiting replenishment of acetylcholine.

Acetylcholine is removed rapidly from the synaptic cleft. This is achieved by

hydrolysis of acetylcholine to choline and acetate in a reaction catalysed by the

enzyme acetylcholinesterase (AChE). This leads to closure of the ligand gated ion

channels. End plate repolarizes and action potential ceases. Sodium channels also

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close and calcium is sequestered back into sarcoplasmic reticulum and the myocyte

relaxes.(10,11,12)

MECHANISM OF ACTION OF NON-DEPOLARISING NEUROMUSCULAR

BLOCKERS

Non-depolarizing neuromuscular blocking drugs are competitive antagonists

at the cholinergic receptors at motor end plate. They compete with acetyl choline at

the cholinergic receptor. On binding with the cholinergic receptors, they do not induce

a conformational change necessary for ion channel opening. Also acetyl choline is

prevented from binding to its receptor. Hence, no end plate potential develops.

Neuromuscular block also occurs even if only one alpha subunit is blocked

because both alpha subunits must be occupied by acetyl choline to induce a

conformational change and open the ion channels.(13,14)

MONITORING OF NEUROMUSCULAR BLOCK

There is increasing evidence that residual neuromuscular block is common,

and also that it may adversely affect patient outcome. A study by Debaene and

colleagues (15) found that 45% of patients had residual curarization (train-of-four

ratio<0.9) in the postoperative recovery room after a single intubating dose of the

intermediate-acting drugs like atracurium, vecuronium or rocuronium. It interferes

with pulmonary mechanics as residual neuromuscular block impairs the ventilatory

response to hypoxia.(16) At low doses, these drugs significantly impair pharyngeal

function and lead to an increased risk of tracheal aspiration and airway obstruction.(17)

When neuromuscular monitoring is used, visual or tactile evaluation of the

degree of neuromuscular block is unreliable. It is clear that as well as monitoring

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neuromuscular block clinically, we should be using quantitative techniques to assess

the degree of recovery. On recovery, the anaesthetist can assess muscle power by a

variety of clinical tests, such as the ability to sustain head lift for 5 seconds, or the

ability to hold a tongue depressor between the teeth.(18) These are a crude assessment

of neuromuscular function, and can be influenced by many factors, for example,

residual sedation or inability to follow instructions.

A peripheral nerve stimulator is used to assess neuromuscular transmission

when NMBAs are given to block musculoskeletal activity. By assessing the depth of

neuromuscular blockade, peripheral nerve stimulation can ensure proper medication

dosing and thus decrease the incidence of side effects. It also results in use of less

medication, which can allow for quicker recovery of spontaneous ventilation,

accelerated neuromuscular transmission and recovery.

Indications

Though for optimal management of all patients receiving neuromuscular

blockers neuromuscular monitoring is prudent, it should atleast be considered in

patients with altered pharmacokinetics and pharmacodynamics. Such conditions

include patients with :

1) Severe renal or hepatic disease.

2) Neuromuscular disorders like myasthenia gravis, motor neuron lesions

3) Severe pulmonary disease

4) Marked obesity

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5) Lengthy surgical procedures, prolonged infusions of neuromuscular blockers being

used, long/intermediate duration neuromuscular blockers used.

6) Elderly patients.

Principles of neuromuscular monitoring

The degree of neuromuscular block can be assessed by applying a supramaximal

stimulus to a peripheral nerve, and then measuring the associated muscular response.

The nerve chosen to be stimulated must fulfill a number of criteria:

1. It must have a motor element

2. It must be close to the skin

3. Contraction in the muscle or muscle group which the nerve supplies must be

visible or accessible to evoked response monitoring.

In order to stimulate a nerve, an electrical current will need to be applied. The

current is usually applied transcutaneously, using ECG electrodes. The chosen nerve

will contain many motor nerve fibres. All of these fibres will need to be stimulated in

order to produce a maximal muscle contraction. Generating an action potential in all

of the nerve fibres in a motor nerve will require a current of sufficient magnitude and

duration.

Most nerve stimulators will apply a current for 0.1–0.3 ms, which is adequate.

The current which generates a response through all nerve fibres and hence a maximal

muscle contraction is termed a maximal stimulus. Traditionally, a current of 25%

above the maximal stimulus is applied when stimulating a peripheral nerve: this is

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termed a supramaximal stimulus.

At a constant voltage, current will vary depending on the resistance of the

skin. The two are related by Ohm's Law which is given by the equation V = IR, (V =

voltage, I= current and R = resistance). Skin resistance will range from 0 Ω to 5 kΩ,

and is affected by such factors as skin temperature, adequacy of electrode application,

and disease state, for example, diabetes mellitus or chronic renal failure. Adequacy of

electrical contact should be ensured.

Train-of-four stimulation

The principle is to produce a pattern of stimulation that does not require the

comparison of evoked responses to a control response obtained before administration

of a neuromuscular blocking drug. Acceleromyography is particularly suited to TOF

measurement. Acceleration of the contracting muscle is measured. Force can then be

calculated using Newton's second law of motion: Force = Mass × Acceleration.

Acceleration is measured by a piezoelectric ceramic wafer that is strapped to the

thumb. When the adductor pollicis is stimulated, the thumb will move and the

attached transducer will produce a voltage, which is proportional to its acceleration.

The voltage can then be converted into an electrical signal and displayed as a twitch

response. For accurate measurement, the accelerating digit must be free to move.(19)

Sites of monitoring

The muscles that need to be monitored include laryngeal muscles, diaphragm,

and abdominal muscles. But these muscles are not accessible. Hence, appropriate site

is chosen with similar response to muscle of interest. Different muscle groups vary in

their sensitivity to neuromuscular blockers. Vocal cords being most resistant,

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followed by diaphragm, orbicularis oculi, rectus abdominis, adductor pollicis,

masseter, pharyngeal muscles, extraocular muscles. The extraocular muscles are the

most sensitive.

In the present study, ulnar nerve is selected for neuromuscular monitoring.

This nerve innervates adductor pollicis, abductor digiti minimi, abductor pollicis

brevis, dorsal interosseous muscles. The adductor pollicis muscle is most commonly

used because of easy accessibility for visual (thumb adduction), tactile and

mechanographic assessment.

The pattern involved stimulating the ulnar nerve with a TOF supramaximal

twitch stimuli, with a frequency of 2 Hz, that is, four stimuli each separated by 0.5 s.

The TOF was then repeated every 10 s (train frequency of 0.1 Hz). It also enabled

comparison of T4 (fourth twitch of the TOF) to T1 which is known as the TOF ratio.

When a non-depolarizing agent is given, a typical pattern is observed. There is

a reduction in the amplitude of the evoked responses, with T4 affected first, then T3,

followed by T2, and finally T1. This decrement in twitch height is known as fade. As

the non-depolarizing block becomes more intense, T4 disappears followed by T3, T2,

and finally T1. The reverse is true during recovery from non-depolarizing block: T1

reappears first followed by T2, T3, and finally, T4. During onset of non-depolarizing

block, T4 disappears at about 75% depression of T1, T3 at 80–85% depression of T1,

and T2 at 90% depression. During partial non-depolarizing block, the number of

twitches (TOF count) correlates with the degree of neuromuscular block. Twitch

suppression of 90% would equate to a TOF count of 1 or less. Reversal of residual

neuromuscular block can safely be achieved when the TOF count is 3 or greater.(19, 20)

One of the most useful clinical applications of the TOF ratio is in monitoring

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recovery from neuromuscular block. It is now thought that a TOF ratio of 0.9 should

be achieved before tracheal extubation.

A. Pattern of evoked muscle responses to twitch stimulation after administration

of a non-depolarizing neuromuscular blocking drug (NDNMB), followed by

antagonism with neostigmine (NEOST). NOEST hastened the rate of

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recovery, if the twitch has already started to increase.

B. Pattern of evoked muscle responses to twitch stimulation after administration

of succinylcholine.

C. TOF monitoring of onset of neuromuscular block produced by a NDNMB,

followed by antagonism with NOEST, given when three twitches of the TOF

are detectable. (D) TOF monitoring of onset of, and recovery from,

neuromuscular block produced by succinylcholine.

Advantages :

1) With TOF monitoring there is no need of control measurement before NMBA

administration.

2) TOF is sensitive to lesser degree of receptor occupancy than single twitch.

3) TOF stimulation is less painful than tetanic stimulation.

4) The response to TOF stimulation can be evaluated manually or visually.

5) There is no post-tetanic facilitation with TOF stimulation. Hence, it can be

repeated every 10-12 seconds.

6) TOF stimulation does not affect degree of neuromuscular block.

7) TOF may be delivered at sub maximal current which is less painful and

associated with same degree of block.

Clinical uses:

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1) Assessment of adequate intubating conditions: To detect time of onset of

neuromuscular block at larynx, jaw, and diaphragm. Disappearance of TOF

corresponds to adequate intubating conditions.

2) Maintenance of block: Clinical relaxation usually requires 75-95%

neuromuscular block. This corresponds to 1-2 twitches present on TOF

stimulation.

3) Detecting reversible block: Adductor pollicis is an ideal site to monitor

recovery because of its increased sensitivity to muscle relaxants.

Neuromuscular block can be reversed with neostigmine when T1 is 10% of

control.

4) Ensuring adequate neuromuscular function: Safe extubation can be done only

when there is adequate restoration of neuromuscular function. This is

indicated by a TOF of 0.9. The response to stimulation should be correlated

with clinical assessment of neuromuscular function. i.e. 5 second head-leg lift

corresponds to TOF 0.6, normal grip strength to TOF , bite test to TOF 0.8.

(18,20)

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PHARMACOLOGY OF ROCURONIUM

Rocuronium bromide is a non-depolarizing, aminosteroid neuromuscular blocking

agent with a rapid to intermediate onset and an intermediate duration of action

depending on dose.

STRUCTURE OF ROCURONIUM

CLINICAL PHARMACOLOGY

Availability and mode of administration

Rocuronium is available only for intravenous administration. It is compatible

in solution with 0.9%NaCl, 5% glucose in water, 5% glucose in saline, sterile water

and ringer lactate. Available in 5ml or 10 ml multi dose vials (10mg/ml).(21)

Physical and chemical characteristics

Rocuronium bromide is chemically designated as 1-[17β-(acetyloxy)-3α-

hydroxy-2β-(4-morpholinyl)-5α-androstan-16β-yl]-1-(2propenyl) pyrrolidinium

bromide. It has a molecular weight of 609.70 and an acidic PH. The octanol/Krebs

partial coefficient is 0.5 at 20°C. It is stable in aqueous solution.(22)

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Pharmacokinetics

Rocuronium is administered intravenously and is associated with a rapid onset

of action of around 1-1.5 minutes. About 80% of the initially administered drug is

redistributed leading to termination of action. Action lasts for around 35-75 min after

single bolus dose.

The initial rapid distribution half life is around 1-2 minutes and a slower

distribution half life is 14-18 minutes. On continuous administration of rocuronium,

tissue compartments fill and within 4-8 hrs, less drug is redistributed from site of

action. Rocuronium is primarily taken up by liver and excreted unchanged in bile in

high concentrations. There is limited contribution by kidneys in the excretion of

rocuronium. Fraction of administered drug excreted by kidneys is around 30%.

Metabolites include 17 des acetyl rocuronium and N desallyl rocuronium. They have

no neuromuscular blocking properties and found in small amounts in faeces and urine.

Plasma clearance is 4-5 mg/kg/min.(21,22,23,24)

Single bolus dose of rocuronium required to produce a 95% neuromuscular

block at the adductor pollicis (ED95) is 0.3 mg/kg in adults and 0.35 to 0.40mg/kg in

children. 2xED95 is 0.6mg/kg produces a maximum block at thumb .Onset of action

at the laryngeal adductor muscles is faster than at the adductor pollicis. (23,25).

Duration of action after a dose of 0.6mg/kg is 30-40 minutes. The recovery

index, defined as the time required for T1 (first twitch) of TOF to recover from 25-75

% of baseline is approximately 20 minutes and a mean recovery to TOF of 0.7 is 42-

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72 minutes.(23,25)

Mean infusion rate for maintenance of 95% neuromuscular block is 10

micrograms/kg/minute with total intravenous anesthesia and 6 micrograms/kg/minute

with inhalational anesthesia. Recovery index after infusion of rocuronium under IV

anesthesia is 20 minutes. Protein binding is around 30%. Volume of distribution in

patients receiving rocuronium in dosed 2xED95 is around 200ml/kg (23).

Pharmacodynamics

Mechanism of action: Rocuronium is a non-depolarizing NMBA. Reversibility of

block occurs with:

1. Redistribution, gradual metabolism, excretion.

2. Administration of specific reversal agents. These include cholinesterase

inhibitors like neostigmine from a T1 of 10% of control and by edrophonium

when used at T1 of 25% of control. These drugs inhibit acetyl cholinesterase

activity and increase the concentration of acetyl choline at the synaptic cleft.

3. For rapid reversal of neuromuscular block regardless of depth of block, a

selective relaxant binding agent is being introduced. Sugammadex - gamma

cyclodextrin forms tight complexes with free molecules of rocuronium

thereby preventing their action at the neuromuscular junction. Excretion of

these rocuronium-Sugammadex complexes occurs via the kidney. Without

sugammadex only a small fraction of rocuronium is excreted in urine but

after reversal with sugammadex this fraction is increased to more than 60%

and dependant on amount of sugammadex administered. Dose of 4mg/kg of

sugammadex reverses the neuromuscular block with rocuronium 0.6mg/kg

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to TOF of 0.9 within 2 minutes.(26,27,28)

Effects on organ systems

Rocuronium is associated with good haemodynamic stability. After administration

of rocuronium no significant changes in heart rate, mean arterial pressure has been

observed in doses up to 1.2mg/kg. Rocuronium blocks the responses to either vagal or

preganglionic sympathetic stimulation. This vagal blocking effect may be associated

with slight increase in heart rate leading to increase in stroke volume index and

cardiac index.(29)

Rocuronium is also not associated with histamine release up to doses of

1.2mg/kg (29,30,31) Rocuronium may be associated with pain on injection and

withdrawal movements especially when administered in light planes of anesthesia.

This can be reduced by slow injection of rocuronium.

Potency

Rocuronium is a NMBA of relatively low potency, approximately 1/6th of

vecuronium.(23)

Special populations (21,26)

Paediatric populations

Rocuronium is associated with a fast onset of action in paediatric population

also, especially children as compared with infants. Duration of action is similar to

adults, being intermediate acting.

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Geriatric populations

Rocuronium is associated with prolonged duration of action secondary to

decreased hepatic/renal blood flow and decreased hepatic/renal function in geriatric

patients. Rocuronium is also associated with greater depth of block in the elderly

owing to the altered volumes of distribution.

Obesity

Rocuronium is associated with prolonged duration of action due to decreased

elimination of these drugs.

Renal disease

Though the duration of action of single or repeated doses of rocuronium is not

significantly affected, rocuronium administration in patients with renal failure is

associated with decreased plasma clearance, increased volume of distribution,

prolonged elimination half life.

Hepatobiliary disease

Prolonged onset of action and prolonged blockade is seen in patients with

hepatobiliary disease and administered rocuronium. The volume of distribution of

rocuronium is increased and clearance decreased.

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Uses

1. Aid in intubation - Rocuronium 0.6mg/kg provides good intubating

conditions within 60-90 seconds in most adults and pediatric patients.

Lower doses of rocuronium (0.03-1.5 ED95) allow tracheal intubation

within 60-180 seconds.

2. Rapid sequence intubation - Rocuronium is the second drug of choice after

Suxamethonium for rapid sequence intubation owing to its rapid onset of

action. Dose of upto 1.2 mg/kg is suggested for rapid sequence intubation.

3. Rocuronium administered prior to succinyl choline decreases the

fasciculations and muscle pain characteristic of succinyl choline.

4. Maintenance of neuromuscular block intraoperatively - Rocuronium can

be given as intermittent bolus or continuous infusion to maintain

intraoperative neuromuscular block.

Drug interactions

1. Rocuronium is physically incompatible when mixed with following drugs,

amphotericin, hydrocortisone sodium succinate ,amoxicillin ,insulin,

azathioprine, intralipid, cefazolin, ketorolac, cloxacillin, lorazepam,

dexamethasone, methohexital, diazepam, methylprednisolone,

erythromycin, thiopental, famotidine, trimethoprim, furosemide,

vancomycin.

2. Inhalational anesthetics potentiate neuromuscular block probably by

pharmacodynamic principles. Desflurane, Sevoflurane and Isoflurane all

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potentiate the neuromuscular blocking effect of rocuronium by augmenting

the intensity of neuromuscular block. There is an increase in the potency

of rocuronium by 25-40% under inhalational anesthesia. There is a

reduction of infusion requirement of Rocuronium by 30-40% to maintain a

90-95% neuromuscular block with Desflurane, Sevoflurane and Isoflurane.

There is also prolongation of the recovery indices of Rocuronium under

inhalational anesthesia.(21,32,33)

3. Propofol: No dose adjustments of rocuronium is required under Propofol

anesthesia because Propofol has no role in neuromuscular block.(21,32,33)

4. Succinylcholine: The onset time of rocuronium after succinylcholine was

significantly reduced (56 s) and the time to recover to a TOF of 70%

following rocuronium was increased by previous succinylcholine

administration.(26)

5. Antibiotics: Aminoglycoside antibiotics potentiate non depolarizing block

by decreasing acetyl choline release from prejunctional nerve endings by

competing with calcium. They interfere with mobilization of acetyl choline

vesicles from a central location to terminal membrane and have a weak

stabilizing action on the post-junctional membrane. The dose of

rocuronium must be reduced in patients receiving high doses of these

antibiotics. Also tetracyclines, polypeptide antibiotics, clindamycin,

lincomycin synergize competitive block. (21,26) A clinical report describes

the failure of neuromuscular blockade reversal in a patient who received

oral neomycin in anticipation of open bowel resection.(34).

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6. Calcium channel blockers also potentiate competitive block. Diuretics can

cause hypokalemia and enhance the neuromuscular block. Diazepam,

propranolol, quinidine intensify competitive block. Hence, when

rocuronium is co-administered with these drugs, dose adjustment is

required.(35,36)

7. Adrenaline and other sympathomimetics reduce the competitive block by

increasing acetylcholine release. Corticosteroids also reduce competitive

block. Hence, increased doses of rocuronium may be required to produce

desired degree of neuromuscular block.(35)

8. Anticonvulsant therapy reduces the duration of action of rocuronium. This

may be secondary to increased plasma protein binding of rocuronium,

hepatic enzyme induction or proliferation of acetyl choline receptors on

the muscle membrane (21, 36).

Adverse effects

1. Hypersensitivity reactions causing anaphylaxis have been reported (21).

2. Withdrawal movements are associated with rocuronium administration.

3. Pain on injection.

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REVIEW OF LITERATURE

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REVIEW OF LITERATURE

Muscle relaxants when used in the elderly must be given special consideration as

residual neuromuscular block and postoperative pulmonary complications are high in

this population. Lien AC(8) (2009) was of the opinion that aging is accompanied by

changes in neuromuscular junction like decrease in number of motor units,

preterminal axons, amount of acetylcholine in each unit; increased proliferation of

extrajunctional receptors and flattening of motor end plate folds. Decreased cardiac

output, hepatic and renal blood flow in the elderly also contributes to the delayed

onset and duration of action of NMBA in the elderly.

As early as 1993 Bevan et al (42) studied the pharmacodynamic behaviour of

rocuronium in the elderly. Hundred patients belonging to ASA 1-2 (60 patients aged

between 65-80 years and 40 patients between 20 – 45 years) were enrolled for the

study. Adductor pollicis contraction to TOF stimulation was observed. They observed

no difference in potency of rocuronium in the two groups. But they found that the

onset of maximum neuromuscular block was prolonged in the elderly 3.7 +/- 1.1 (SD)

Vs 3.1 +/- 0.9 min, p < 0.05.

Richard S. Matteo et al in 1993 (45) studied the effects of age on the pharmacokinetic

and pharmacodynamic responses to rocuronium in 20 elderly (>70 yr) and 20 younger

control patients (<60 yr). They found that the onset times were the same for both the

elderly and younger control group, but the duration of action of rocuronium was

significantly prolonged in the elderly patients. Elderly patients, also showed a

significant decrease in plasma clearance (3.67 ± 1.0 vs 5.03 ± 1.5 mL·kg−1·min−1,

mean ± SD) and volume of distribution (399 ± 122 vs 553 ± 279 mL/kg, mean ± SD).

The differences in action of rocuronium between the two groups was explained by the

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observed differences in the distribution and elimination of rocuronium .The decreased

total body water and decreased liver mass which occur with increasing age were

likely explanations for the pharmacokinetic changes found in the elderly in this study.

They concluded that the action of rocuronium is prolonged in patients aged more than

70 years because of its decreased elimination.

Motamed±, F. Donati et al (2000)(46) compared combinations of mivacurium and

rocuronium, and both drugs separately with respect to onset, intubating conditions,

and duration of action in young and elderly adults.

The researchers conducted a study in two groups of patients, one consisting of

patients aged between 16-45 years and the other of patients aged over 66 years. The

doses used were mivacurium 0.25 mg/kg , rocuronium 0.6 mg/kg and a combination

of mivacurium 0.08 mg/kg with rocuronium 0.2 mg//kg.

They found that the onset of action was similar in all age groups (204 – 276 sec). The

duration to 25% recovery was longer in the elderly for rocuronium, mean ± SD, (54 ±

17 min) when compared to young patients (39 ± 11 min).

Nur Baykara et al in 2003 (43) designed a study to determine the influence of aging on

the relationship between post tetanic count (PTC) and train-of-four (TOF) response

during intense neuromuscular blockade caused by rocuronium. 42 ASA 1 and 2

patients were selected and divided into 2 groups, ages 65-80 and 18 to 40 years. All

the patients received rocuronium 1 mg/kg. Neuromuscular block was monitored using

accelerometry of thumb. The average interval between appearance of post tetanic

response and TOF count of 1 (T1) was measured. This interval was found to be longer

in the elderly than the young (22.3 ± 8.1 vs 14.8 ± 4.2 min, p < 0.05) .They concluded

that the interval between the earliest appearance of a post tetanic response and the first

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response to TOF stimulation (T1) is greater in the elderly than in the young.

Arain S. R. et al in 2005 (41) studied the variability of duration of action of

neuromuscular blocking drugs in elderly patients. They administered 0.6 mg/kg

rocuronium, 0.1 mg/kg vecuronium, or 0.1 mg/kg cisatracurium. Duration of action

was defined as the return of T1 twitch height to 25% of control. The duration of

action were (range) – cisatracurium 37- 81 min, vecuronium 35 – 137 min and

rocuronium 33 – 119 min. They observed that when used with sevoflurane/N2O, there

was a two-fold greater variability of duration of neuromuscular blockade in elderly

patients receiving rocuronium or vecuronium compared with cisatracurium

Passavanti et al in 2008 (40) evaluated the effects of two different doses of rocuronium

bromide (0.5 mg/kg and 0.9 mg/kg) on the length of neuromuscular block, on the

haemodynamic stability and on the side effects in patients of different ages. The onset

time in the young and elderly in the group receiving 0.5 mg/ kg of rocuronium were

3.3 ± 3.2 min vs 4.1 ± 2.2 respectively. The duration of action was 36.3 ± 2.1 vs 46.8

± 3.5 min. The study showed a statistically significant prolongation of onset and

duration of action.

The difference was attributed to decreased plasma clearance due to reduction of

splanchnic blood flow, decreased blood volume and depressed liver and kidney

function.

Milan Adamus et al in 2011 (39) compared the pharmacodynamics of 0.6 mg kg-1

rocuronium in young and older patients of both genders during total intravenous

anesthesia. The patients were divided into 4 study groups: 37 males aged 20-40, 40

males aged 60-75 yrs, 43 females aged 20-40 and 38 females aged 60-75 yrs.

Neuromuscular block following rocuronium (0.6 mg kg-1) was monitored.

29

The onset time (from application of rocuronium to maximum depression of T1,

duration of action (from application to 25% recovery of T1) and time to full

spontaneous recovery (from application to TOF-ratio ≥ 0.9) were determined for each

patient.

The researchers found that effect of rocuronium is significantly influenced by both

gender and age. The mean onset and duration times respectively were 90 sec, 30 min

in young males; 135sec, 58 min in elderly males; 75 sec, 50min in young females;

120 sec, 85 min in elderly females. The differences were statistically significant

(p<0.05). The researchers concluded that female patients and elderly patients are more

sensitive to the action of rocuronium.

Suzuki et al in 2011 (44) compared the reversibility of rocuronium induced profound

neuromuscular block with sugammadex in younger and older patients. This study

shows that the total recovery time to a TOF ratio of 0.9 in older patients is

approximately three-fold longer than that in younger adults (3.6 vs 1.3min).

Furuya et al in 2012 (38) wanted to determine the influence of ageing on the recovery

of the post-tetanic count (PTC) from rocuronium-induced neuromuscular block. They

observed that times from the administration of 1 mg/kg and rocuronium until recovery

of the first detectable PTC were significantly longer in the older (mean 51 min, range

27-100 min) than the younger patients (mean 31.5 min, range 21-45 min), p < 0.05.

They concluded that times from rocuronium injection to reappearance of the first

response to PTC stimulation are approximately twofold longer and more variable in

older than younger patients. Hence, they recommended the dosing interval of

rocuronium should be adjusted using neuromuscular monitoring when maintaining

intense neuromuscular block, especially in older patients.

30

Piotr Pietraszewski et al in 2013(7) conducted an observational study which included

184 patients aged between 65 – 89 years and 231 patients between 19-57 years who

received rocuronium intraoperatively. Patients were transferred to the post anesthesia

care unit (PACU) where residual curarisation was monitored by acceleromyography

and TOF stimulation.

They found that post operative residual curarisation in the elderly was much more

frequent (44%) than younger patients (20%) (p < 0.05). Hypoxia was also more

frequent in the elderly (17.9% vs 8.2%) (p < 0.05 ).

They concluded that residual paralysis remains a major problem in geriatric

anaesthesia and that neuromuscular function monitoring is obligatory in this

subpopulation.

31

MATERIALS AND METHODOLOGY

32

MATERIALS AND METHODOLOGY

Study Design

This is a prospective comparative study of the onset and duration of action of

Rocuronium in the young (Group 1 - age 18- 60 years) and elderly (Group 2 – age >

70 years.

Study Setting

This study was carried out in the Department of Anesthesiology, Fortis Hospital Ltd.,

154/9, Bannerghatta Road Bangalore.

Approval

Approval from the institutional ethical committee was taken. Participant

confidentiality was maintained. All participants were explained about the study with

patient information sheet (attached in Annexure). Informed written consent from all

the study subjects was taken.

Inclusion criteria:

1.Age : Group 1 - 18- 60 years

Group 2 - above 70 years.

2. Indian nationals belonging to either sex.

3. American Society of Anesthesia (ASA) grade 1 or 2.

4. Patients undergoing elective surgeries (minimal access surgeries, general surgeries,

33

orthopedic surgeries, gynaecological surgeries, plastic surgeries, neurosurgeries)

under general anesthesia requiring neuromuscular blockade.

Exclusion criteria:

1. Patients with hepatic dysfunction as evidenced by abnormal liver function

tests.

2. Renal dysfunction as evidenced by raised serum creatinine values

3. Pregnancy

4. Patients who were on antibiotics which affect neuromuscular transmission.

5. ASA class III/IV patients.

6. Emergency procedures

Preoperatively, detailed history was obtained, physical examination was carried

out and appropriate investigations were reviewed. Intravenous access was secured

with 18/20 gauge cannula on the non-dominant arm. Premedication of Ranitidine 50

mg, Midazolam 0.01 mg/kg and Ondansetron 4 mg were administered intravenously

half an hour before the procedure.

The patient was taken into the operation theatre, safe surgical checklist was

performed and infusion of Ringer’s Lactate was commenced at the rate of

2ml/kg/hour. Monitoring of electrocardiogram (ECG), pulse oximetry, temperature,

invasive/non invasive blood pressure recording was commenced.

In the present study, the ulnar nerve and adductor pollicis brevis muscle were

34

chosen for neuromuscular monitoring using the TOF watch. The arm onto which the

TOF watch was to be attached was first secured onto an armboard. The electrodes

were placed on the volar side of the wrist. Distal electrode was placed 1cm proximal

to the point at which proximal flexion crease of the wrist crosses the radial side of

flexor carpi ulnaris tendon and the other electrode placed 1cm proximal to the first

electrode. Distal electrode was connected to the negative terminal (black) of the TOF

watch and proximal electrode to the positive terminal (white). The piezoelectric

crystal inlaid transducer was strapped to the thumb. The other fingers were fixed in

such a way as to provide minimal interference to the movement of the thumb.

Patient was preoxygenated for 3 minutes. General anesthesia was induced with

Fentanyl 2 micrograms /kg and Propofol 2mg/kg. 2% lignocaine 1.5 mg/kg was given

90 seconds before intubation to suppress response to laryngoscopy.

After induction, calibration of neuromuscular monitoring was done and the

baseline reading was recorded in the TOF watch with TOF stimulation. Following

this, rocuronium 0.6mg/kg was administered intravenously.

The time taken for TOF 0 to appear (end point to signify onset of action) was

noted. Airway was secured with cuffed endotracheal tube when TOF count of 0 was

35

obtained. An endotracheal tube with 7mm internal diameter was used in female

patients and 8mm internal diameter in males. Correct position of the airway device

was confirmed with 5 point auscultation and capnography. The endotracheal tube was

secured and connected to the anesthesia workstation and the patient was mechanically

ventilated. Forced air warming system was used to maintain normothermia.

Anesthesia was maintained with 50% oxygen and nitrous oxide, 1 MAC sevoflurane,

fentanyl infusion of 1 microgram/kg/hr.

Repeated stimulation using the TOF watch at 12 sec intervals was done. The

time taken for TOF 2 to appear (signifying the end point for duration of action) was

noted in all patients.

Reversal was initiated after a TOF count of 3 was obtained with Neostigmine

0.05mg/kg and Glycopyrrolate 0.01 mg/kg. The patients were extubated after the TOF

ratio was greater than 0.9 and the extubation criteria were met. Post extubation

patients were transferred to a Post Anesthesia Care Unit for further monitoring.

STATISTICAL METHODS

Descriptive statistical analysis has been carried out in the present study.

Results on continuous measurements are presented on Mean±SD (Min-Max) and

results on categorical measurements are presented in Number (%). Significance is

assessed at 5% level of significance. The following assumption on data is made.

Assumptions:

1. Dependent variables should be normally distributed

2. Samples drawn from the population should be random

36

3. Cases of the samples should be independent.

Student “t” test (two-tailed, independent) has been used to find the significance of

study parameters on continuous scale between two groups (Inter group analysis) on

metric parameters, Chi-square/Fisher Exact test has been used to find the significance

of study parameters on categorical scale between two or more groups.

1. Chi-Square Test

The chi-square test for independence is used to determine the relationship between

two variables of a sample. In this context independence means that the two factors are

not related. In the chi-square test for independence the degree of freedom is equal to

the number of columns in the table minus one multiplied by the number of rows in the

table minus one.

2. t-Test

Two-sample assuming unequal variances results of the t-test: If the p-value

associated with the t-test is small (< 0.05), there is evidence to reject the null

hypothesis in favor of the alternative. In other words, there is evidence that the means

are significantly different at the significance level reported by the p-value. If the p-

value associated with the t-test is not small (> 0.05), there is not enough evidence to

reject the null hypothesis, and you conclude that there is evidence that the means are

not different.

3. Significant figures

Suggestive significance (p value: 0.05<p<0.10)

Moderately significant (p value: 0.01<p≤ 0.05)

37

Strongly significant (p value: p≤0.01)

Statistical software: Statistical software namely SPSS 15.0, was used for the analysis

of the data and Microsoft word and Excel have been used to generate graphs, tables.

38

RESULTS

39

RESULTS

A comparative prospective clinical study of 100 surgical patients divided into

two groups, 50 patients in Group 1 (age 18 - 60 years) and 50 patients in Group 2( age

greater than 70 years) was conducted to study the onset and duration of action of

rocuronium in the two groups. Neuromuscular monitoring was done with TOF

stimulation till neuromuscular block was reversed with appropriate dose of

neuromuscular antagonist and patient extubated.

Observations made were:

1. The time taken to attain TOF count of 0 - signifying the onset of action of

rocuronium.

2. The time taken to attain TOF count of 2 - signifying the duration of action of

rocuronium.

40

Table 1: Age and gender distribution

Group * Gender Crosstabulation

GenderTotal

Male Female

Group1 (18- 60 yrs ) 21 29 50

2 (> 70 yrs) 31 19 50

Total 52 48 100

Graph 1: Age and gender distribution

Group 1 Group 20

5

10

15

20

25

30

35

Gender distribution Male Female

Coun

t

41

Table 2: Distribution of participants based on ASA grade

ASA Grade

Total1 2

Group 1 (18- 60 yrs ) 24 26 50

2 (> 70 yrs) 1 49 50

Total 25 75 100

Graph 2 Distribution of participants based on ASA grade

Group 1 Group 20

10

20

30

40

50

60

ASA Grade stratification

ASA 1ASA 2

Coun

t

Table 3 : Distribution of onset and duration of action between the study groups

42

Group Statistics

Group N Mean Std.

Deviation

T Sig

Onset time

(in seconds)

1 (18- 60 yrs ) 50 171.68 36.406 -3.054 .003

2 (> 70 yrs) 50 196.46 44.346

Duration of action

(in seconds)

1 (18- 60 yrs ) 50 2559.72 669.329 -10.167 .000

2 (> 70 yrs) 50 3865.08 613.424

This result shows that the onset of action of rocuronium in patients belonging

to group 2 (> 70 yrs) is longer when compared to group 1. (Mean time taken for onset

of action is 196.46 sec in group 2 vs 171.68 sec in group 1). Statistically the

difference is highly significant (p<.01)

The mean duration of action in group 2 was 3865. 08 sec vs 2559.72 sec in

group 1. This difference also shows high significance (p<.001).

Graph 3 : Onset Time

43

Graph 4 : Duration of action

Group 1 Group 20

500

1000

1500

2000

2500

3000

3500

4000

4500

Duration of action

Tim

e in

sec

Table 4: Distribution of gender and their mean onset and duration of action

44

Group 1 Group 2155

160

165

170

175

180

185

190

195

200

Onset timeTi

me

in se

c

Gender N MeanStd.

Deviationt p-value

Onset

( in seconds)

Male 52 193.58 40.5902.398 .018

Female 48 173.77 42.306

Duration of

action

( in seconds)

Male 52 3359.02 919.031

1.682 .095Female 48 3053.56 894.248

Graph 5: Gender variability in mean onset time

male female160

165

170

175

180

185

190

195

200

Gender variability in mean onset time

Gender

Tim

e in

seco

nds

45

Graph 6 : Gender variability in mean duration of action

Male Female2900

2950

3000

3050

3100

3150

3200

3250

3300

3350

3400

Gender variability in mean duration of action

Tim

e in

sec

This shows that there is a statistically significant shorter onset action of

Rocuronium in females (173.77 in females vs 193.58 sec in males , p value of 0.018).

However, the duration of action of Rocuronium, although prolonged in males,

(3359.02 sec in males vs 3053.56 sec in females, p value of 0.095) is not statistically

significant.

46

DISCUSSION

DISCUSSION

Rocuronium is used extensively in current day anaesthesia practice. It has an

47

intermediate duration of action which may be prolonged in patients with liver and

kidney failure. The rocuronium induced neuromuscular block is antagonized safely

with neostigmine. It has the added advantage of having minimal cardiovascular

effects and no significant histamine release. It is used in rapid sequence setting and

provides acceptable intubating conditions within 60-90 seconds. (23)

In the present study comparison was between the onset and duration of action

of rocuronium in two groups of patients, between 18 - 60 years ( Group 1 ) and in the

patients aged over 70 ( Group 2) . The mean time for onset of action in Group 1 was

171. 68 seconds as opposed to 196.46 sec in Group 2, which is statistically significant

(p -0.003). This shows that the onset of action of Rocuronium is prolonged in the

elderly.

The current study also found that the mean onset time in females was 173.77

seconds as opposed to 193.58 in males. This has a statistically significant p value of

0.018.

The duration of action of Rocuronium as determined with the appearance of

TOF 2 count, in Group 1 patients had a mean value of 2559.72 sec whereas Group 2

patients had a mean duration of action of 3865.08 sec. This difference also shows high

significance (p < 0.001).

The statistically significant prolonged onset of action of Rocuronium in the elderly

(196.46 in elderly vs 171.68 sec in the young, p < 0.01), as found in the present study,

is in accordance with studies conducted by Bevan et al in 1993 (3.7 +/- 1.1 SD vs 3.1

+/- 0.9 min, p < 0.05), Passavanti et al in 2008 (4.1 +/- 2.2 vs 3.3+/- 3.2 min).

However, the studies conducted by Matteo et al (1993), Donati et al (2000) failed to

48

demonstrate any difference in onset of action of rocuronium in the elderly when

compared to the young.

A prolonged duration of action of rocuronium in the elderly was demonstrated in the

studies conducted by Matteo et al in 1993 (52.4±16.5 min vs 33.9 ± 8.4 min), Donati

et al in 2000 (54 ± 17 min vs 39 ± 11 min), Passavanti et al in 2008 (46.8 ± 3.5 min

vs 36.3 ± 2.1 min), Furuya et al in 2012 (mean 51 min vs 31.5 min), in the elderly and

young respectively. A similar prolongation was observed in the present study

(3865.08 sec vs 2559.72 sec).

The increased time required for the onset and the prolonged duration of action

of rocuronium can be explained by certain changes occurring with advancing age (8)

like decreased cardiac output, increased time for circulation, decreased blood flow to

the muscles and slower biophase equilibration. Also, with aging, the structure and

composition of body tissues change along with with impaired functioning of liver and

kidney. Numerous changes occurring at the neuromuscular junction like decreased

number of motor units, increased extrajunctional receptors, decreased acetyl choline

content also contribute to this difference in action. Decrease in the total body water

leads to lower central compartment and a higher plasma concentration after a single

bolus dose of rocuronium is administered. A higher content of fat tissue may

potentially increase the clinical duration and interval to full recovery from

rocuronium-induced blockade in the elderly. (39)

A shorter time to onset of action of rocuronium was seen in the study conducted by

49

Milan Adamus et al in 2011 (120 sec in females vs 135 sec in males, p< 0.001). The

current study also found that the females have a shorter time of onset ( 173.77 sec in

females vs 193.58 sec in males). This has been attributed to different

pharmacokinetics of aminosteroidal muscle relaxants in females. The contributing

factors are increased fat content, decreased muscle mass, decreased glomerular

filtration rate, differential liver enzyme activity in females. (39)

50

SUMMARY

51

SUMMARY

This prospective observational study was conducted to determine the onset

and duration of action of Rocuronium in the elderly population ( age > 70 years). A

control group of patients belonging to the age group of 18 - 60 years was selected. A

bolus dose of 0.6 mg/kg of Rocuronium was administered and the onset and duration

of action was determined using a TOF Watch.

The mean onset time ( 171.68 sec vs 196.46 sec, in the young and elderly

respectively , p < 0.003) and mean duration of action of Rocuronium (2559.72 sec vs

3865.08 sec, p<0.001) had a statistically significant prolongation in the elderly

compared to the young.

Female patients had a significant shorter time of onset compared to males

(173.77 sec vs 193.58 sec).

The difference in the two groups can be attributed to the changes due to

differences in cardiac output, blood flow to the muscle, composition of body tissues,

impaired functioning of liver and kidney.

52

CONCLUSION

CONCLUSION

53

The results of our study demonstrate that the onset and duration of action of

Rocuronium is prolonged in the elderly population (age > 70 years) belonging to ASA

grade 1 or 2, undergoing elective surgeries under general anesthesia requiring

neuromuscular blockade.

We also found that female patients have a shorter time for onset of action of

Rocuronium.

54

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55

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Canadian Journal of Anesthesia 2000 / 47: 3 / pp 225–231

ANNEXURES

60

CONSENT FORM

Patient identification details

Name: Age: Sex:

Procedure to be performed:

Information /explanation given by:

Name: Date: Time:

I have been explained that the anesthetist will provide me general anaesthesia

and he/she has explained to me in detail regarding my condition and the procedure to

my satisfaction.

The doctor has also explained to me alternative methods of anaesthesia.

The doctor shall conduct tests which may be necessary as part of pre

anaesthetic assessment. He/She has discussed with me that Rocuronium will be used

for obtaining neuromuscular blockade, apart from other routine medications.

I have discussed in detail with the anaesthetist regarding my previous

exposure to any type of anaesthesia and allergies if I have any

The anaesthetist has discussed in detail the steps of the procedure, the kind of

monitoring used and that he/she will keep a close watch on my vital parameters.

After the procedure the anaesthetist will do an assessment of my condition

before shifting me to post anaesthesia care unit (PACU)

In the PACU my vital parameters will be monitored and then decided when to

shift me to ward.

The doctor has explained to me that during the procedure, he/she may use

assistants, such as hospital residents, nurses and para medical staff and I consent for

this.

I also agree to co operate fully with my doctor to the best of my ability to

his /her instructions and recommendation about my care and treatment. The data

recorded may be used for study/research purposes and I consent for this.

WITNESS: PATIENT’S SIGNATURE:

NAME: OR/ AND

RELATION TO PATIENT:

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SIGNATURE: DESIGNATORY SIGNATURE

STUDY PROFORMA

Clinical evaluation of onset and duration of action of Rocuronium in patients aged

over 70.

1. Study done by :

2. Details of the patient :a. Name -b. Age - c. Sex - d. Weight – e. ASA grade – f. Comorbidities -

3. Surgical procedure –

4. Dose of Rocuronium administered –

5. Time of Rocuroium administration –

6. Time at which TOF count is 0 –

7. Time at which TOF count is 2 -

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