REVERSAL OF NEUROMUSCULAR BLOCKADE

Speaker: Dr Srikanth alladi

Reversal agents are drugs that are given to counteract, or reverse, the effects of drugs used for NDMB.
Facilitates the speed of recovery from the skeletal muscle effects associated with NDMRs.

THE QUALITIES OF AN IDEAL REVERSAL AGENT

have a fast onset. efficient at any time, even soon after curarization of the patient. able to provide complete reversal either for light or profound block.

free of any side effects. able to restore sustained neuromuscular function rapidly even when NM blockade is profound at the time of administration. longer half life than the NM blocking agent.

THE DIFFERENT PHARMACOLOGICAL REVERSAL DRUGS ARE CLASSIFIED AS: A) Older drugs

Traditional & currently in clinical use-anticholinesterases.

Neostigmine ,
Physostigmine, Edrophonium,

Pyridostigmine .
B) Newer agents

1) Sugammadex(Org 25969) , 2) Cysteine.

Currently not much in clinical use : Ambenonium, 4-aminopyridine, Suramine, Gallantamine, Germine diacetate , Tetraethylammonium, Congo red, Chlorasol fast pink, Evans blue, Purified human plasma cholinesterase for mivacurium block.

Anticholinesterase Agents

Blocks the activity of both types of cholinesterase enzymes. Most noticeable effects are muscarinic ones. Cholinesterase enzyme has an active site, having an anionic site and an esteritic site. Esteritic site is more responsible for the hydrolysis of acetylcholine.

Mechanism of action

Depression of both true and pseudocholinesterase by reversible binding. mainly by inhibition of acetylcholinesterase which results in increased concentration of Ach at the NMJ . local conc. of Ach competes with NDMR.

Edrophonium electrostatic attraction

Neostigmine and pyridostigmine covalent bonding.

Organophosphates irreversible binding.

 Other

actions:

Ach mobilisation and release may be enhanced (Presynaptic effects) mainly seen with edrophonium. Neostigmine has direct but weak agonistic effect on nicotinic receptors.

Actions..
Muscarinic effects Myocardium = Bradycardia Gut = Contraction Bronchioles = Constriction Pupil = Contraction Salivary gland = stimulated Bladder = contracted Nicotinic effects Autonomic ganglia = stimulated Skeletal muscle = stimulated

Atropine is used to oppose the muscarinic effects. Excessive doses of anticholinesterase can paradoxically potentiate NDM blockade and also prolong Sch block.
Vd = 0.7 1.4 ltrs, t = 60 to 120 mins and clearance 8 to 16 ml/kg/min. Clearance is due to both hepatic (25 50%) and renal excretion (50-75%).

Pharmacodynamics

Onset of action
Edrophonium = 1 2 mins ( due to its presynaptic effect). Neostigmine = 7 11 mins. Pyridostigmine = 15 20 mins.
Elimination half lives of all agents are relatively long (80 120 mins) comparable in length to the half life of the long acting NDMR.

CVS effects

Bradycardia is the initial response. Its exaggerated in pts on blockers, elderly or in pts with abnormal sinus node function. So larger doses of anticholinergic may be required in these pts.

Atropine is usually combined with edrophonium. Glycopyrrolate is combined with neostigmine or pyridostigmine. Glycopyrrolate does not cross BBB hence incidence of memory deficits after anesthesia is less than that for atropine.

Total dose administered should be carefully titrated, monitoring the effect with nerve stimulator. Arrhythmias can occur use with caution in pts with autonomic neuropathy. Glyco preferable to atropine in such cases.

Drugs may be administered over a longer time(2-5 mins) in order to reduce the incidence and severity of disorders of rhythm.

Transient arrhythmias can occur, varies from innocuous changes in atrial pacemaker to junctional rhythm, ectopic ventricular foci, high grade heart block, including complete heart block and cardiac arrest. ECG must be monitored during reversal process to detect these and treat appropriately.

Neostigmine
Synthesized by Aeschliman and Reinert in 1931. Quaternary ammonium compound( low lipid solubility). Poorly absorbed by mouth and largely confined to the ECF phase. Partly broken down by serum cholinesterase and partly excreted unchanged by the kidneys.

 It

binds to esteratic site with its carbamate group- carbamylates the enzyme.

It

is also a depolariser and can cause on its own a depolarising type of block.High doses >5 mg can cause paresis.

Systemic effects:

CVS peripheral vagal stimulation will cause bradycardia, vasodilation and fall in BP.

Cardiac arrhythmias and arrest may occur following large doses especially in the presence of hypercapnia.
RS little effect, bronchoconstriction and increases secretion.

Skeletal muscle prolongs and intensifies local depolarisation produced at the endplate by Ach. Small dose will increase the muscle contraction, larger doses may cause depression.

In myasthenia gravis, the strength of muscle contraction is increased.

Smooth muscle peristalsis of stomach, intestine, ureter and bile duct is increased and may give rise to colic. Bladder and bowel may be emptied.

Others sweating, salivation and increase in mucus and other exocrine secretions, pupil constricted.
Neostigmine may increase the intensity and duration of action of analgesics.

Clinical comment

Neostigmine and atropine can be combined safely. Giving atropine prior may precipitate tachycardia and more serious arrhythmias in certain conditions.

Serious arrhythmias can occur in presence of resp acidosis and hypoventilation should be avoided during its administration.

Reversal agents should be administered slowly over about 60 secs. Initial tachycardia followed by bradycardia occurs because duration of action of neostigmine exceeds that of atropine. Glycopyrrolate has a longer duration of action and is therefore preferred by many.

Optimum time to administer reversal is when the pt is still being hyperventilated and CO2 level in the blood is low. Atleast 5 mins should be allowed for its effect and improvement in neuromuscular conduction may occur upto 10 mins.

Never administered in the presence of halothane or cyclopropane .

Recovery of respiratory muscles always precedes that of peripheral hand muscles. Should be used in particular care in the presence of asthma and heart disease.

In small children, cardiac case and in severely ill titrate the exact dose of neostigmine and atropine. Never exceed total dose of 5mg of neostigmine and 2mg of atropine.

Other uses:

In treatment of intestinal and bladder atony 15-30mg can be given by mouth of 0.5-1mg parenterally. MG 15mg orally tid, increasing upto two hourly according to tolerance. Glaucoma 1 drop of 3% solution, repeat every 10 mins upto 12 doses.

As an adjunct to intrathecal anesthesia causing a prolongation of sensory and motor blockade.

Over dosage:

Overdose of neostigmine may cause sudden death due to cardiac arrest. Restlessness, weakness, muscular twitchings, dysarthria, pinpoint pupils, nystagmus, sweating, salivation, nausea and vomiting, colic, defecation and a desire to urinate are other signs.

Respiration embarassed due to bronchospasm and excessive secretion.

Tx:

Death due to respiratory paralysis and pulmonary edema may follow . Atropine will antagonise these effects. Muscular twitchings may be relieved by small doses of competitive NDMR. Respiration must be assisted or controlled.

Physostigmine

Alkaloid obtained from calabar bean, the seed of physostigma venenosum. Tertiary amine structure, lipid soluble, crosses BBB, placenta and penetrates eye.

Used to treat anticholinergic syndrome produced by atropine, hyoscine and other alkaloids.
More potent than neostigmine, greater effect on CNS and CVS. Destroyed in body by hydrolysis.

Indications

It can antagonise psychomimetic side effects of ketamine without reversing analgesia. It abolishes the somnolent effect of morphine. Used to reverse sedative effects of CNS depressants like atropine, hyoscine, promethazine, BZD and TCAs.

NMB can be antagonised .

Pyridostigmine

Pyridine analogue of neostigmine, less potent. 10mg of pyrido = 2.5 mg of neo.

Less nicotinic action, onset and duration of action are longer. Muscarinic effects are weaker.
Duration of action 6 hrs, useful in renal failure.

It has minimal BBB penetration. Uses - Used for similar purposes to neostigmine, more useful when a prolonged action is required as in MG. 60mg by mouth, 1mg iv is the dose.

Edrophonium

Functions mainly by direct action but also as prosthetic cholinesterase inhibitor.

Action on skeletal muscle is more marked than on ganglia and visceral effector organ.
Less potent, 35 mg edro = 3mg of neo

It has rapid onset of action and plasma level is sustained at an effective level for 20 mins. It has anticholinesterase, depolarising and direct stimulating action on motor end plate. Recurarisation can occur coz magnitude and duration of inhibition is less.

Main advantage is rapid onset of action (5 mins compared to 7-10 mins for neo, 12-15 mins for pyrido).

It possess less potent muscarinic side effects than neostigmine and pyridostigmine.
Dose is 10 70 mg.

Indications

Antagonise the effects of NDMR. For diagnosis and assessment of therapy in MG. Differentiate b/w Myasthenic and cholinergic crisis.

 It

was discovered at the Newhouse Research site in Scotland. The first phase/ study of sugammdex in human voluntaries was published in 2005. It is the first compound in a new class of neuromuscular reversal drugs called Selective Reversal Binding Agents (SRBA).

SUGAMMADEX (ORG 25969)

Chemistry- It is a synthetic modified cyclodextrin. Su refers to sugar & -dex refers to the structural molecule -cyclodextrin.

Unmodified -cyclodextrin has a 3 dimensional structure which resembles the doughnut.

Hydrophobic interactions trap the drug molecule (rocuronium/ vecuronium) into the doughnut hole resulting in the formation of water-soluble guesthost complex.

Pharmacokinetics & dynamics- It has a plasma clearance at approaching the GFR (120ml/min). with upto 80% of the dose eliminated unchanged in urine within 24hrs.

Its clearance is decreased in patients with decreased creatinine clearance.

Hepatic impairment does not influence its excretion.

Doses of 0.1-8.0mg/kg sugammadex has a

clearance rate of 88ml/min. elimination half-life of 1.8hrs. volume of distribution of 11-14litres.

 Mechanism

of action- It exerts its effect by forming very tight water soluble complexes at 1:1 ratio with steroidal NMB drugs (rocuronium > vecuronium > pancuronium). The iv administration of sugammadex results in rapid removal of free rocuronium molecules from plasma.

This creates a concentration gradient favouring the movement of remaining rocuronium molecules from the NM junction back into the plasma where they are encapsulated by free sugammadex molecule thus resulting in fast recovery of NM function.

SUGAMMADEX

Roc

Org 25969

=
Gijsenbergh et al. Anesthesiology 2005;103:695

 The

rocuronium-sugammadex complex has a very low dissociation rate & hence chances of residual muscle weakness are very low.

It has no effect on acetylcholinesterase or any receptor system in the body.

Adult dosage

A) Reversal of shallow neuromuscular blockade induced by rocuronium Use at a dose of 2 mg/kg (reversal likely within 1.2 and 1.5 minutes). B)Reversal of profound neuromuscular blockade induced by rocuronium Use at a dose of 4 mg/kg (reversal likely within 2.3 and 3.3 minutes).

Adult dosage

c) Immediate reversal of neuromuscular blockade induced by rocuronium Use sugammadex at a dose of 16 mg/kg (reversal likely within 5.7 and 6.7 minutes.)

Cysteine

Gantacurium undergoes rapid degradation in plasma by chemical hydrolysis and inactivation by cysteine adduction. Exogenous administration of cysteine can accelerate the antagonism of gantacurium-induced neuromuscular blockade.

THE CLINICAL CRITERIA FOR ADEQUATE REVERSAL INCLUDE :

TOF ratio of 0.9 or greater is predictive of recovery of pharyngeal

muscles, masseter muscle and striated muscles of upper oesophagus. At TOF <0.9 there may be a substantial risk of aspiration. TOF ratio of 0.6-0.7 of adductor pollicis indicates ventilator adequacy.
Inspiratory force (maximum negative pressure that could be generated against an occluded airway) between -20 to -30 cm water pressure indicates sufficient ventilatory reserve to allow safe return of patient to PACU. TV and MV TV : 5-6ml/kg MV: 70-80ml/kg

 It tells us only that they are adequate at present but indicate nothing about the reserve strength available in the event of increased ventilatory requirements due to pain, shivering or airway resistance.

VC Better test of return of insp function. It indicates a reserve that would be required in the event of increased ventilatory requirement. To take a deep breath for prevention of atelectasis and enhance the velocity to cough to remove secretions. 15ml/kg is the minimum acceptable value.

Ability to sustain a 5 sec head lift. This indicates sufficient strength in normal patients to protect the airway against obstruction & aspiration of oral contents. It corresponds to TOF ratio of 0.75.

Grip strength (presence of a firm & sustained handgrip): More sensitive indicator of residual weakness than head lift. It requires the use of a dynamometer & pre-op control values. So, it is less useful as a clinical tool. At TOF of 0.9 the grip strength will be 70-100% of control.

Sustained leg lift for 5 sec: It is a valuable sign of adequate reversal in children as old as 12 weeks of age & it indicates adequate airway control and ventilatory function. It usually corresponds to TOF ratio of 0.75. Absence of double vision over 2hrs.

Masseter strength ability to prevent a wooden tongue depressor clenched between two incisors from being pulled out by even a vigorous effort. Difficulty in speaking, swallowing if TOF <0.75.

FACTORS WHICH INFLUENCE THE EFFECTIVENESS OF REVERSAL:

INTENSITY OF BLOCK the depth of NM blockade at the time of administration of reversal agents has a profound influence on the speed & efficacy of reversal.

Reversal of a profound blockade proceeds more slowly than reversal of less intense block.

CHOICE OF RELAXANT Intermediate acting drugs are easier & faster to reverse than are long acting relaxants.

CHOICE OF REVERSAL AGENT - Neostigmine has been found to be a more reliable antagonist than edrophonium for antagonism of deep blocks. Sugammadex can reverse very deep NM blockade induced by Rocuronium without muscle weakness.

DOSE OF REVERSAL AGENT Anticholinesterases like neostigmine, edrophonium & pyridostigmine have a ceiling effect. The effect of these drugs is dose dependent until a plateau is reached at which point an increase in dose does not produce further reversal of NM blockade. This is known as the ceiling effect. This plateau corresponds to a TOF ratio of approx 0.6.

PLASMA CONCENTRATION OF RELAXANT After a prolonged continuous infusion or after numerous boluses, the plasma concentration associated with a given level of NM blockade might be expected to be greater than after a single bolus. Hence the recovery after a single bolus dose of relaxant is more rapid compared with a prolonged continuous infusion.

ANAESTHETIC AGENT potent volatile agents result in slower recovery following pharmacologic muscle relaxant reversal if their use is continued during reversal. RENAL FAILURE - anticholinesterases like neostigmine are actively secreted into the renal tubules & their plasma clearance is reduced in renal failure. The plasma clearance decreases for neostigmine by 2 folds & edrophonium by 3 folds. The elimination of muscle relaxants eg: vecuronium is also delayed in renal failure. Hence, the rate of reversal may be unaffected or decreased.

DRUG INTERACTIONS any drug which potentiates NM blocking drugs will impede the reversal of NM blockade. Eg: aminoglycosides antibiotics, hypotensive drugs, immunosuppressants & anti-cancer drugs, mag sulphate, Ca channel blockers.

ELECTROLYTE & ACIDBASE DISORDERS respiratory acidosis, metabolic alkalosis & hypokalemia impede/delay reversal of NM block. The degradation of atracurium is partially pH dependant (hofmann elimination) but there is no evidence that acidosis impedes its antagonism by neostigmine in the clinical situation.

AGE the plasma clearance of anticholinesterases is reduced in the elderly in common with plasma clearance of NDMR because of age related decrease in hepatic metabolism & renal clearance. The speed & extent of recovery is no different between young & old if the reversal agent is given at the same level of NM blockade. Atracurium, because of metabolism by Hoffman elimination & enzyme hydrolysis is not affected by age.

Spontaneous recovery from NM blocking drugs is more rapid in children aged 1-10yrs than in adults. Recovery in infants is slower than in children for pancuronium, atracurium & vecuronium. Reversal occurs more rapidly & the dose of reversal agent required to produce equivalent effects is less in infants & children than in adults.

PRE EXISTING MEDICAL CONDITONS DM, underlying neurological diseases & obesity. Here, reversal of NM block is less predictable.

HYPOTHERMIA it can prolong the spontaneous recovery from NDPR & delay reversal.

RESIDUAL NEUROMUSCULAR BLOCK (RNMB)

FACTORS CONTRIBUTING TO RESIDUAL NM BLOCK

Use of long acting muscle relaxants. Many anaesthesiologists do not routinely use quantitative NM function monitor to ensure adequate recovery to a TOF ratio of 0.9 or more. Neostigmine has a ceiling effect & when administered at a deep level of NM blockade, it can result in an inadequate recovery of NM function. Failure to pharmacologically reverse the block.

SIGNS OF RESIDUAL CURARIZATION:

Typical myasthenic facies = ptosis, lack of expression & loss of tone in masseter. Inability to raise head from pillow & hold it up for atleast 5 sec. Loss of firm sustained hand grip. Tracheal tug, any paradoxical indrawing of intercostals muscles during inspiration in the absence of any CNS, CVS or RS problems RR > 20 breaths/min. TOF ratio < 0.7. Presence of double burst fade. Lack of sustained leg lift for 5 sec. Poor massetter strength by tongue depressor test. Presence of diplopia, blurred vision. Difficulty in speaking, swallowing. Hypoxaemia (SpO2< 90% on room air).

PREVENTION OF RESIDUAL NEUROMUSCULAR BLOCK:

Avoid using long acting muscle relaxants. Routine use of intra-op quantitative NM monitoring. Do not give reversal agents at deep levels of block. Use of newer agents like sugammadex which can reverse even deeper levels of rocuronium/vecuronium block. Return of TOF ratio of 0.9 should be one goal before shifting to PACU. Titrate muscle relaxants & their reversal agents to effect.

CONSEQUENCES OF RESIDUAL

NEUROMUSCULAR BLOCKADE:

Impairment of respiratory response to hypoxaemia.

Pharynx dysfunction & dysfunction of upper oesophagus- risk of aspiration.

Upper airway obstruction. Inadequate return of pulmonary function