History

CIS - ATRACURIUM
• The generic name Cisatracurium was given
(A to Z) by scientists at Burroughs Wellcome Co.
(now part of GlaxoSmithKline)
Dr. Tushar Chokshi
• Because the molecule is one of the
Article Outline three cis-cis isomers comprising the ten
isomers of the parent, Atracurium
Introduction
combining the name "Atracurium" with
- History of Cis-Atracurium "cis“, hence Cisatracurium

- Mechanism of Action of Cis-Atracurium • In 1989, D A Hill and G L Turner, PhD (both

chemists at Burroughs Wellcome Co.,
- What is Ideal Neuro Muscular Blocking Agent
Dartford, UK) first synthesized
- Different Systemic Actions of Cis-Atracurium Cisatracurium as an individual isomer
molecule
- Pharmacokinetics and Pharmacodynamics
• The entire clinical development
- Indications and Dosage of Cisatracurium was completed in a record
- Commercially available preparations short period from 1992 to 1994

- Compatibility of Cis-Atracurium • Its approval for human use was in 1995 by

the US FDA and marketed as Nimbex
- Contraindications and Adverse Effects by GlaxoWellcome Inc (Burroughs
Wellcome Co. + GlaxoSmithKline)
- Cis-Atracurium in different types of conditions

- Atracurium and Cis-Atracurium

The Ideal Neuromuscular Blocking Agent
* An ideal neuromuscular blocking agent needs to take
- Journal Articles
the shortest time in endotracheal intubation
- Future of Cis-Atracurium
• The best intubating condition and have the
- Take Home message shortest duration of muscle paralysis

Introduction • Non-depolarizing mechanism of action

• Full name is Cis-Atracurium Besylate • Rapid onset enabling quick intubation

• Also known as BW-51W and BW-51W89 • Rapid, complete and predictable recovery

• It is Benzylisoquinolinium neuromuscular- • Short elimination half life

blocking drug or skeletal muscle relaxant • No cumulative effect
with intermediate-acting action
• No histamine release
• It is in the category of non-depolarizing
neuromuscular blocking drugs • High potency

• Cisatracurium is one of the ten isomers of • Should have pharmacologically inactive

the parent molecule, Atracurium metabolites

• Reversible by cholinesterase inhibitors

• Elimination pathways less dependent on organ
function
• Lack clinically important cardiovascular side
effects
Mechanism of Action of Cis-Atracurium
• Cis acts by competitive antagonism
• It binds with nicotinic acetyl chonline
receptors (nAChRs) on the motor end-plate
of neuromuscular junction to produce
neuromuscular blockade
• This action is antagonized by acetyl
cholinesterase inhibitors such as
Neostigmine
• Sugammadex has no ability to reverse the
neuromuscular effects of
Benzylisoquinolinium-based relaxants such
as Cisatracurium
Pharmacokinetics and Pharmacodynamics
of Cis
• The neuromuscular blocking activity of Cis is
due to parent drug Atracurium
• IV bolus of Cis is best described by two-
compartment open model and volume of
distribution is limited by its large molecular
weight and high polarity
• The degradation of Cis is largely
independent of liver metabolism
• It undergoes 80 % Hofmann elimination to
form Laudanosine and the monoquaternary
acrylate metabolites
• Renal Excretion of Cisatracurium is only 16
% anaesthesia in hepatic disease
• Elimination half-life is 20–29 minutes
• Hypothermia and Hyperthermia, increase
and decrease the duration of action
• Sedative, Volatile agents, Local anaesthetics
and Anti-epileptic agents will prolong the
effect of Cis
• Recovery rate is not affected by age, renal
failure or end stage liver disease
• Cis is lung protective through its anti
inflammatory properties
• Pharmacokinetics and Pharmacodynamics o
f Cisatracurium in patients undergoing
surgery under acute
normovolemic hemodilution (ANH) and
acute hypervolemic hemodilution (AHH)
requires higher dose of Cis
• Effect will be prolonged in presence of
Sevoflurane anaesthesia
• Cis is not associated with dose related
histamine release even after 0.15mg/kg, so
it is cardiovascular stable in MI patients
Different Systemic Actions of
Cis-Atracurium
• Cisatracurium will not cause any change in
Heart Rate, Contractility, SVR and Blood
Pressure (Most favourable choice for
cardiac patients)
• It is lung protective through its anti
inflammatory properties and better than
any muscle relaxants in ARDS patients
• Cis metabolism is through Hofmann
reaction so best muscle relaxants in Acute
or chronic renal failure patients
• It is most safe and effective choice of
neuromuscular blocking agent for
• In neuroanesthesia Cis reduces ICP,
cerebral perfusion and lower blood
pressure, it is neuroprotective through its
active metabolites Laudanosine
• In chemotherapy and obese patient, Cis is
drug of choice
 • It does not produce any autonomic effect
Commercially available preparations
1) 5 ml Bulb 2 mg/ml (Total 10 mg)
2)10 ml Bulb 2 mg/ml (Total 20 mg)
3)20 ml Bulb 10 mg/ml (Total 200 mg)
4)5 ml Amp 2 mg/ml (Total 10 mg)
Indications
• It is intermediate onset and duration action
of drug
• Mainly indicated for inpatients and
outpatients adjunct to general anaesthesia
• To facilitate tracheal intubation
• To provide skeletal muscle relaxation during
surgery
• For mechanical ventilation in ICU
Dosage (IV)
• 0.15 to 0.20 mg/kg as bolus dose initially
after IV anaesthesia induction agents
• Gives excellent condition for intubation
within 1.5 to 2 minutes and last up to 50 to
60 minutes
• Maintenance dose is 0.02 to 0.03 mg/kg
and last approximately 20 - 25 minutes
• For shorter or longer duration of
maintenance smaller or larger dose is
adjusted
• Maintaining paralysis via infusion with
Cisatracurium is at 1 to 3 mcg / kg / min
In Paediatric Patients
• Children between 2 to 12 years of age dose
is 0.10-0.15 mg/kg administered over 5 to
10 seconds after induction of anaesthesia
• This initial bolus dose last for 40 to 50
minutes
• In infants from 1 month to 23 month dose
is 0.15 mg/kg
• This initial bolus dose last for 50 to 60
minutes in infants
• Cisatracurium is not studied in neonates
below 1 month, hence not recommended
In the ICU
• Normal infusion rate is 3 mcg/kg/min
for adult patients on mechanical
ventilation in ICU
• Repeated boluses and more time are
necessary to achieve complete muscle
relaxation in ICU patients if using the same
dose as for the routine induction of
anesthesia
• Doses of Cisatracurium should be higher
than those used in current anesthetic
practice for an adequate degree of
neuromuscular blockade
• It is advisable to use neuromuscular
monitoring during Cisatracurium use in ICU
Contraindications to use Cis
• Cisatracurium is contraindicated if there is a
known hypersensitivity
• Caution is advisable in patients with
myasthenia gravis or myasthenic syndrome
as a profound effect may occur
• Precautions are also advisable in those
patients with a history of prior anaphylactic
reactions to neuromuscular blocking
agents
• Cisatracurium should be kept refrigerated
at 2 to 8 degrees Celsius and protected
from light to preserve potency
• The rate of loss of potency is as high as 5%
per month at 25 degrees Celsius
 • Once removed from refrigeration to room
temperature storage, it should be used
within 21 days
Adverse Effects of Cisatracurium
• Adverse effects are uncommon with the
use of Cisatracurium
• Adverse reactions occurred at a rate of less
than 1%
Cis-Vec and Cis-Roc combinations are allowed but
Cis-Atr is only additive
The following lists diseases that can lead
to hypersensitivity to Cis
• Amyotrophic lateral sclerosis
Autoimmune disorders
• Systemic lupus erythematosus

Include • Polymyositis

Bradycardia, • Dermatomyositis

Hypotension, • Familial periodic paralysis hyperkalemia

Bronchospasm, • Guillain-Barre syndrome

Rash, • Muscular dystrophy (Duchenne type)

Anaphylaxis, • Myasthenia gravis

Prolonged neuromuscular blockade, and • Myasthenic syndrome

Myopathy Myotonia

No clinically relevant alterations in the recovery • Dystrophic

profile were observed in patients with renal
• Congenital
dysfunction or end-stage liver disease, making
Cisatracurium a good choice in a patient with • Paramyotonia
either of these diseases
The following lists diseases that can lead
Compatibility of Cis to a resistance to Cis
• Cis injection is acidic and not compatible • Burn injury
with alkaline solution with pH greater than
8.5 • Cerebral palsy

• Cis is compatible with • Hemiplegia (on the affected side)

5 % Dextrose • Muscular denervation (peripheral nerve

injury)
5 % DNS
Severe chronic infection
0.9 % NS
• Tetanus
• Cis is not compatible with
• Botulism
Ringer Lactate

Propofol

Ketorolac
Toxicity of Cis
• Overdose with Cisatracurium may result in Atracurium vs. Cis-Atracurium
neuromuscular blockade beyond the time
needed for surgery and anesthesia • The neuromuscular blocking potency of
Cisatracurium is roughly three times more
• The primary treatment is the maintenance potent than atracurium
of sedation, a patent airway, and controlled
ventilation until recovery of neuromuscular • The clinically beneficial duration of action
function is assured and rate of spontaneous recovery from
equipotent doses of the two drugs are
• It is important to note that reversal should similar
not be attempted if there is evidence or
suspicion of complete neuromuscular • Twice costly than Atracurium in market
blockade. Once recovery from blockade • Cisatracurium has Three major advantage
begins, from the evidence of peripheral
over Atracurium
nerve stimulation, the neuromuscular
blockade may be reversed with an 1) It releases less histamine
anticholinesterase agent (e.g., neostigmine)
2) It produces less Laudanosine as
in conjunction with an anticholinergic agent
metabolite
(e.g., glycopyrrolate)
3) It does not require any dose adjustment
• A typical dose of neostigmine is 0.4-0.8
in renal failure, liver failure, cardiac patients or
mg/kg, in conjunction with 0.2 mg
obese patients
glycopyrrolate for every 1 mg of
neostigmine Journals Conclusions
Extra Knowledge • Incidence of residual neuromuscular
blockade in children below 3 years after a
• In one study suggests that standard dosing
single bolus of Cisatracurium 0.1 mg/kg is 8
of Cisatracurium in patients with severe
%
sepsis results in a slower patient response
with a reduced effect. So use of a larger • Cis improves oxygenation only after 48 h in
dose may overcome this reduced delayed moderate, severe ARDS patients and has a
response lower barotrauma risk without affecting ICU
weakness
• Because of intermediate action , Cis is not
recommended for rapid sequence • Backward blood flow during diastole in
intubation (RSI) severe AR impaired distribution
of Cisatracurium from the central
• Long term infusion upto 6 days of Cis during
compartment to the peripheral
mechanically ventilated patients in ICU are
compartment, which accounted for the
safely used, but dose requirements my
lagged PD responses
increase or decrease
• Effects of different doses
• In pregnancy, Labour, Delivery and Nursing
of Cisatracurium besilate on hemodynamic
mother, Cis is not contraindicated but use
and postoperative cognitive function in
only if clearly needed
patients undergoing radical resection of
lung cancer, stabilize hemodynamic and
 reduce the incidence of postoperative
cognitive dysfunction
• A hyperthermic patient thought to have
ARDS and septic shock required a high rate
of Cisatracurium infusion for adequate
paralysis during mechanical ventilation.
The Cisatracurium did not appear to cause
prolonged neuromuscular blockade
• Successful Treatment of Idiopathic
Intractable Hiccup
With Cisatracurium Under Intravenous
General Anesthesia: A Case Report
• A single dose of 8 mg of dexamethasone
hastened the onset and total recovery
times of Cisatracurium-induced block by
approximately 15 and 9%, respectively if
administered 2-3 h prior to surgery
• Effective doses of Cisatracurium in the adult
and the elderly were not significantly
different
• Optimum dose of neostigmine to reverse
shallow neuromuscular blockade with
rocuronium and cisatracurium is 40 μg.kg
• The combination of the low dose ketamine
and Cisatracurium priming accelerated the
onset time and was improved the
intubating conditions (combination of
Cisatracurium 0.01 mg/kg, and ketamine
0.5 mg/kg)
• The effect of different storage temperature
on the pharmacodynamics dose-response
of Cisatracurium Besylate at 4-8°C or at
room temperature for 30 – 60 days found
that, compared with that stored under
refrigeration, the onset time was
significantly longer, clinical duration and
75% recovery time were significantly
shorter
• In patients having undergone
chemotherapy, the effect of Cis starts with
a longer lag time and finishes earlier too.
Thus, these patients are ready for
intubation after a longer time. Moreover,
we have to repeat Cisatracurium injections
after shorter intervals to maintain the
desired level of blockade
• Cisatracurium doses according to fat-free
mass is clinically reasonable for inducing
anesthesia in morbidly obese patients, but
due to a prolonged muscle relax onset time,
the timing of tracheal intubation should be
delayed by 1-2 min in morbidly obese
patients
Future of Cisatracurium
Cisatracurium will gain near to ideal muscle
relaxants of choice by all anaesthesiologists in their
practice in coming decade
Conclusion
• Cisatracurium is new generation,
intermediate acting, nondepolarising
muscle relaxant
• Its metabolism is through Hofmann
reaction independent of renal and liver
functions (Tissue and pH dependent)
• It is less histamine release agent compared
other muscle relaxants
• It is most ideal muscle relaxant in altered
functions of kidney, liver, lung, heart or
brain
• It can be given to any age, sex, disease,
altered body mass patients going under
anaesthesia except neonates
• It is not recommended for rapid sequence
intubation
• So it is choice of medium to long term
surgeries in haemodynamically unstable
patients
• Cis give uniform recovery from anaesthesia
Cis is the SOUL of all operation theatre

S – Stable hemodynamic

O – Organ independent Hofmann metabolism

U – Uniform recovery even after multiple doses

L – Lack of significant histamine release

chokshitushar@hotmail.com