NMB

SANKAR

1. Precurarization? 2. Ed95? 3. Suxa why brady? 4. Reversal needed for suxa?why not? 5. Cardiac stable relaxant? 6. How ll be effect of mr in myasthenia gravis? 7. Why cardiac muscle not affected? 8. END PRODUCT OF ATRACURIUM AMETABOLISM? 9. BILIARY MECH OF elimation for which relaxants?

Claude Bernards experiments

Pithed frog Isolated one limb & Injected curare in blood Findings: 1. Paralysis No response to nerve stimulus Response to direct muscle stimulation 2. Isolated limb responded to both 3. Stimulating nerves in paralyzed limb gave some movement in the isolated (circulation deprived) limb

Clinical Duration

IntermediateShort-Acting Acting (20-50 (15-20 min) min) Steroidal Pancuronium Vecuronium compounds Pipecuronium Rocuronium dBenzylisoquin Tubocurarine Atracurium olinium Mivacurium Metocurine Cisatracurium compounds Doxacurium Others Asymmetrical mixed-onium chlorofumarat es Phenolic ether Gallamine Diallyl derivative of Alcuronium toxiferine Class of Blocker Long-Acting (>50 min)

Ultrashortacting (<10-12 min)

Gantacurium

MECHANISM OF ACTION

Nicotinic Receptor at adult NMJ

ACh Epsilon / Gamma Alpha

Alpha
Ion Channel ACh Delta

Beta

Each of the two -subunits has an acetylcholine binding site.

The pulse stops when the channel closes and one or both agonist molecules detach from the receptor.

RELEASED Ach
Potent Very Short Lived Destroyed in Less than One m.sec

agonistic and antagonistic actions at postjunctional receptors for depolarizing and nondepolarizing relaxants.

Margin of safety
10 % receptors must be open for muscle action potential generation 75 % receptors can be occupied before fade is observed

95 % receptor occupancy required for complete twitch suppression

the depolarizing relaxants characteristically have a biphasic action on musclean initial contraction, followed by relaxation lasting minutes to hours. Because they are not susceptible to hydrolysis by acetylcholinesterase, the depolarizing relaxants are not eliminated from the junctional cleft until after they are eliminated from plasma. The time required to clear the drug from the body is the principal determinant of how long the drug effect lasts. Whole-body clearance of the relaxant is very slow in comparison to acetylcholine, even when plasma cholinesterase is normal. Because relaxant molecules are not cleared from the cleft quickly, they react repeatedly with receptors, attaching to one almost immediately after separating from another, thereby repeatedly depolarizing the end plate and opening channels.

Suxa always binding then why not continuous contraction?

Time gated channel close .. Channel has to come to resting stage .. But it is not happening because suxa is binding to it

PHASE II BLOCKSeveral factors are involved. The repeated opening of channels allows a continuous efflux of potassium and influx of sodium, and the resulting abnormal electrolyte balance distorts the function of the junctional membrane. Calcium entering the muscle through the opened channels can cause disruption of receptors and the subend-plate elements themselves. The activity of the sodium-potassium adenosine triphosphatase pump in the membrane increases with increasing intracellular sodium and, by pumping sodium out of the cell and potassium into it, works to restore the ionic balance and membrane potential toward normal. As long as the depolarizing drug is present, the receptor channels remain open and ion flux through them remains high.[78]

Some receptors that bind to agonists, however, do not undergo the conformational change to open the channel. Receptors in these states are called desensitized (i.e., they are not sensitive to the channel-opening actions of agonists).

Depolarizing neuromuscular blockers such as succinylcholine produce prolonged depolarization of the end-plate region, which results in (1) desensitization of the nAChR, (2) inactivation of voltage-gated sodium channels at the neuromuscular junction, and (3) increases in potassium permeability in the surrounding membrane. The end result is failure of action potential generation, and blockade ensues. It should be noted that although acetylcholine produces depolarization, it results in muscle contraction under physiologic conditions because it has a very short duration of action (a few milliseconds). Acetylcholine is rapidly hydrolyzed by acetylcholinesterase to acetic acid and choline. Administration of large doses of acetylcholine to experimental animals, however, produces neuromuscular blockade.

PHASE II BLOCK
Repeated boluses (infusion) of SCh May occur with single dose in E1a Fade, post tetanic facilitation Memb. potential returns to resting state despite presence of the drug and the transmission is blocked Possibly due to pre synaptic block, aggravated by inhalational agents

Receptor desensitization
If agonist present for longer time (> 1 sec.) Different conformation Receptor no longer activatable No role in normal transmission Safety mechanism

Ach Receptors
Immature,fetal,EJ
Spread Unstable life 24 hrs Longer burst duration Smaller conductance 2-10 times longer channel opening (slow closing) (reason for hyperkalaemia )

Mature
Localized Stable life 2 weeks Burst activity Normal conductance Channel opens for 0.5 millisecond

The fetal nAChR contains a subunit instead of an adult subunit. The mature nAChR has a shorter burst duration and higher conductance for Na+, K+, and Ca2+ than the fetal nAChR does.[14]

Extra junctional AChRs(immature)

Normally suppressed by neural activity When nerve activity is reduced (trauma, skeletal muscle denervation), they proliferate rapidly & spread over entire post junctional membrane Highly sensitive to agonists (Ach & SCh) Degraded soon after neural influence returns Mixture of junctional & extra junctional receptors in different clinical situations

Why resistant to non depolarising muscle relaxant?

fetal receptors have long opening of ion channels so when normal ach molecules are present it ll cause prolonged influx of Na,Ca so some contraction ll be present,,, it is called resistant to NDMR or higher doses are needed

Up & Down-regulation of AChRs

UMN lesions LMN lesions Muscle trauma Burn injury Immobilization Sepsis CHRONIC RELAXANTS

Up-regulation
Increased requirement for non-depolarizing Agents (resistance) Hyperkalemia after SCh

Normal
Myasthenia Organophosphates Cholinesterase inhibition

Receptor unaltered
Down-regulation
Reduced requirements For non-depolarizers

The fetal nAChR is a low-conductance channel, in contrast to the high-conductance channel of the adult nAChR. Thus, release of acetylcholine causes brief activation and a reduced probability of opening of the channel.[14] The upregulation of nAChRs found in states of functional or surgical denervation is characterized by the spreading of predominantly fetal-type nAChRs. These receptors are resistant to nondepolarizing neuromuscular blockers and more sensitive to succinylcholine.[18] When depolarized, the immature isoform has a prolonged open channel time that exaggerates the efflux of K+.[19]

Pre-synaptic AChRs
Different strains of only alpha and beta units Non depolarizing NMB agents (fade) block prejunctional Na+ channel but not Ca2+ channels Mobilisation of Ach from synthesis site to release sites depend on Na+ channel Release of Ach s calcium dependent

Pre-Jn Ach Receptors

Reason for Fasiculation due to Suxa & Prevention of Fasiculation by NDP ( inhibit mobilisation) Regulate Ach Release- Positive Feedback-More Mobilisation of Vesicles BlockInhibit Mobilisation of Vesicles

Inhibition of postjunctional acetylcholinesterase by anticholinesterases increases the concentration of acetylcholine, which can compete with and displace the nondepolarizer and thus reverse the paralysis

AChR blocking agents

Non competitive Local anesthetics, depolarizing agents, Acetylcholine Plug the channel & prevent ion movement Competitive Non-depolarizing agents Block of one or both Ach binding sites Affinity more at alphaepsilon site

Non-competitive mechanisms of neuromuscular block

Depolarizing agents Acetylcholine, Succinylcholine Desensitization block Inhalational, Thiopentone, Local anesthetics
Ion-channel block 1. Closed: TCA, Naltrexone, Naloxone 2. Open: High conc. of NMB

Structure / Activity Relationship

Contain at least one +ve charged quaternary amine (4 C atoms attached to nitrogen) like Ach

N+ attracted to Alpha sub unit of AChR (ve charge)

Absorption & distribution

Oral
not absorbed

IV
rapid onset, fast distribution & predictable elimination

S/C or IM
unpredictable absorption, high dose required, only in laryngospasm without iv line Succinylcholine rapid & effective absorption

Pharmacokinetics
Potency
Low affinity high dose High affinity small dose

Speed of onset
Fast injection high gradient quick onset

Perfusion
Delayed onset with reduced cardiac output Regional blood flow.

Muscle responses
More receptors in fast (glottis) than slow (adductor pollicis) muscle fibres Rapid onset at glottis muscles is due to rapid equilibrium (more blood flow) Dose required for diaphragmatic block is twice the dose required for similar block @ adductor pollicis Sequence of onset: small muscles (eyes, digits) larynx trunk & abdomen diaphragm

Pharmacokinetics
Age

Children: Larger Vd (more dose required) Sensitive NMJ (prolonged action) Higher HR & CI (faster onset) Aged: Widening of NMJ & reduced no. of receptors Delayed distribution & elimination Organ-dependent metabolism & elimination of steroid relaxants are affected

Obesity +ve charge prevents fat absorption Vd / kg and clearance markedly reduced Unaltered elimination half life Temperature Prolonged action with hypothermia Slowed Hoffman elimination Temp. independent degradation of Mivacr.

Pregnancy
Unaltered Magnesium increased potency & duration of action Ionized state minimal placental transfer (except prolonged use in ICU) May have reduced plasma cholinesterase activity

Burns
Up-regulation of receptors (at least 30% burns) Resistance to non-depolarizers (starts at10 peaks at 40 declines at 60 days.) Sensitive to Succinylcholine (hyperkalemia) Reduced plasma cholinesterase

The ED95 is the effective dose of a drug in 95% of individuals. One to two times the ED95 is usually used for intubation. Although a larger intubating dose speeds onset, it exacerbates side effects and prolongs the duration of blockade. For example, a dose of 0.15 mg/kg of pancuronium may produce intubating conditions in 90 s, but at the cost of more pronounced hypertension and tachycardiaand a block that may be irreversible for more than 60 min.

Succinylcholine 1951
Only NMBA with short onset (< 1 min) & short duration (5 10 min) Both N2 atoms are quaternary (+ ve) Almost exclusively used for RSI or to counteract laryngospasm (0.1 mg/kg) IV injection small fraction reaches NMJ Depolarizing effect within 20-40 sec (fasciculations) followed by relaxation (< 60 sec)
Manifestation by initial series of muscle twitches (fasciculation) followed by flaccid paralysis.

Succinylcholine Side effects

Stimulation of muscarinic AChR Sinus bradycardia, even sinus arrest AV node dysrhythmia, nodal rhythm Ventricular arrhythmia Usually with 2nd dose Ganglionic stimulation , hypertension Allergic Reactions

Depolarization of the endplate

Trigger for MH Masseter spasm Raised potassium

(0.5 - 1 meq/L) Muscular destrophy, myopathy, denervation, UMN, muscle trauma, burns, severe abdominal sepsis No benefit with precurarization

Myalgia
Prevented by precurarization, Benzo, Lido, Ca, Mg, repeated Thio)

Depolarization of the endplate Raised Intra Cranial Pressure

Due to increased cerebral perfusion. Prior hyperventilation can attenuate

Raised Intra Ocular Pressure

4-8 mm, peaks 1-2 min. Due to Increase in choroid blood vol., extra ocular muscle tone & aqueous outflow resistance

Raised Intra Gastric Pressure

Due to fasciculations & increased vagal tone. Unaltered barrier pressure). Prevented by precurarization

Doesnot require reversal rather cholinesterase inhibitors (neostigmine) can prolong the depolarizing block (because these agents also inhibits the pseudocholinesterase)

PRECURARISATION TO PREVENT FASCICULATIONS,myalgia,10-15% OF NDMR INTUBATING DOSE GIVEN 5 MIN BEFORE SUXA..ROCURONIUM AND TUBOCURARIUM IS EFFICACIOUS.. SUXA DOSE TO BE 1.5 mg/kg Not prevent hyperkalaemia and elevation in intraocular pressure
Synchronous contraction of the cells in a motor unit is called fasciculation

PRIMING DOSE Since the introduction of rocuronium, the use of priming has decreased considerably. Several groups of investigators have recommended that a small subparalyzing dose of the nondepolarizer (about 20% of the ED95 or about 10% of the intubating dose) be given 2 to 4 minutes before a large second dose for tracheal intubation.[ This procedure, termed priming, has been shown to accelerate the onset of blockade for most nondepolarizing neuromuscular blockers by 30 to 60 seconds, which means that intubation can be performed within approximately 90 seconds of the second dose. However, the intubating conditions that occur after priming do not match those that occur after succinylcholine. Moreover, priming carries the risks of aspiration and difficulty swallowing, and the visual disturbances associated with subtle degrees of blockade are uncomfortable for the patient.[167]

Succinylcholine
contraindications
Neuromuscular disease Denervation (after 2 days) Immobilization (after 3 days) Burns (after 2 days) MH susceptibility Homozygous for E1a Basal sr. K > 5.5 Sepsis / infection Allergy to SCh

 Hyperkalemia: Serum K > 5.5 is an absolute

contraindication for use of Sch. Head Injury : It increase ICP Newborns and infants: These have extrajunctional receptors which are sensitive to depolarizing agents & Sch can produce severe hyperkalemia by interacting with these receptors. Glaucoma & eye injuries. Up to 2-3 months after trauma, Up to 6 months after hemiplegia/paraplegia, Up to 1 year after burns. In these conditions the denervated/regenerating nerve develops extra junctional receptors which can produce hyperkalemia.

 Renal Failure : If associated with hyperkalemia. Prolonged intra abdominal infection can be associated with hyperkalemia. Diagnosed case of atypical pseudocholinesterase & low pseudocholinesterase. Duchene muscular dystrophy Dystrophia myotonica: Permanent contractures may develop if SCh is given in these patients. Tetanus. Gullian Barre Syndrome Metabolic Acidosis :Acidosis is associated with hyperkalemia. Shock : It is associated with acidosis which in turn is associated with hyperkalemia. Spinal cord injury.

Non-depolarizing agents
Bind to one or both Alpha units of AChRs Competitive antagonism of Ach No conformational change in AChR Dynamic binding (repeated association & dissociation) competition Presynaptic receptors also blocked 70 80 % receptor occupancy - twitch depression 92 % receptor block: complete block

Depolarizing Also called Phase I block Block preceded by muscle fasciculations Depolarizing blocking drugs are called Leptocurare Does not require reversal rather cholinesterase inhibitors (Neostigmine) can prolong the depolarizing block ( because these agents also inhibit the pseudocholinesterase).

Nondepolarizing No fasciculations Called pachycurare Reversed by cholinesterase inhibitors like Neostigmine.

Antibiotics Aminoglycosides: pre junctional effects like magnesium (decreased release of Ach) Stabilize post junctional memb. Calcium improves Ach release but stabilize pos tjunctional memb, so unpredictable effect

Local Anesthetics Enhance the block by interfering Ach release, stabilizing memb & depressing skeletal muscle fibres.
Esters compete with SCh for plasma cholinesterase activity

Magnesium Enhanced block by reduced Ach release and stabilizing the memb. SCh effect also enhanced (? Phase II block) Lithium Enhanced block Phenytoin Resistance to non-depolarizing NMBA

Steroids IV steroids -- no effect In myasthenia, ACTH or cortisol improve NM function Hypothermia Prolonged duration of action (Panc, Vec) Reduced hepatic, renal & Hoffman clearance

Atracurium
Non-organ dependent elimination Used in liver and renal failure patients Histamine release in 30% of patients Dosage: 0.3-0.6mg/kg (within 2 min) Metabolism Ester hydrolysis: 60% of elimination Hofmann elimination

Side-effects :
Hypotension and tachycardia Bronchospasm Laudanosine toxicity -breakdown product from Hoffmann elimination, may precipitate seizures. Cis-atracurium Minimal histamine release Rest similar like atracurium

Vecuronium
commonly used nowadays Non cummulative No histamine release Cardiovascular stability Easy reversibility Action depends primarily on biliary excretion and secondarily on renal excretion Intermediate acting Dosage : 0.08-0.12mg/kg

Pancuronium
Long acting 60-80% excreted in urine, Dosage : 0.08-0.12 mg/kg (2-3 min) Minimal histamine release Sympathomimetic and anticholinergic effects- vagal blockade and catecholamine release.
Hypertension, Tachycardia dysrhythmias and pulmonary vasoconstriction

Rocuronium
Mono quaternary aminosteroid
onset = 1 - 2 min and duration 60 - 90 min Resembles Vec but less potent (fast onset)
Largely excreted unchanged (upto 50%) in bile in 2 hrs (>30% renal excretion in 24 hrs) Prolonged action in renal, hepatic diseases and old age Absence of histamine release Slight vagolytic action

Derivative of vecuronium Dosage : 0. 5 -1.2 mg/kg Less potent : 7-10x < vecuronium Faster onset ( 60-90 sec), intermediate acting No metabolism, eliminated primarily by liver. Duration prolonged by severe hepatic failure and pregnancy. Free from histamine release and CVS effects

Cis-atracurium
benzylisoquinolinium
Purified form of one of 10 steroisomers of atracurium, 5 times more potent Similar to atracurium except slow onset, very little histamine & 1/5th less laudanosine (cerebral excitatory) onset 3 - 5 min & duration 20 35 min 77% Hoffman degradation at normal pH to inactive laudanosine + alcohol (again Hoffman) 17% renal clearance (non specific esterases not involved)
Stable hemodynamics, organ independent clearance

Mivacurium
Benzylisoquinoline
Only non-depolarizer with short duration onset 2 3 min, duration 12 20 min histamine release and hypotension Hydrolyzed by plasma cholinesterase (88 % rate of SCh) 7% unchanged in urine Inactive metabolites

METABOLISM
BILIARY EXCRETION- VEC,RO RENAL EXCRETION-PAN,PIPE,DOXA HOFFMAN- ATRACU,CIS-ATRA ESTER HYDROLYSIS-ATRA PSEUDOCHOLINEESTERASE-SUXA ,MIVA

Drug interactions

Factors Contributing to Prolonged Nondepolarizing Neuromuscular Blockade

Drugs Inhaled anesthetic drugs Local anesthetics (lidocaine) Cardiac antidysrhythmics (procainamide) Antibiotics (polymyxins, aminoglycosides, lincosamines [clindamycin], metronidazole [Flagyl], tetracyclines) Corticosteroids Calcium channel blockers Dantrolene Metabolic and Physiologic States Hypermagnesemia Hypocalcemia Hypothermia

Respiratory acidosis
Hepatic/renal failure Myasthenia syndromes

Factors Contributing to Prolonged Depolarizing Blockade Excessive dose of succinylcholine

Reduced plasma cholinesterase activity

Decreased levels Extremes of age (newborn, old age) Disease states (hepatic disease, uremia, malnutrition, plasmapheresis)

Hormonal changes
Pregnancy Contraceptives Glucocorticoids

Inhibited activity
Irreversible (echothiophate) Reversible (edrophonium, neostigmine, pyridostigmine) Genetic variant (atypical plasma cholinesterase)

Clinical characteristics of phase 1 and phase 2 neuromuscular blockade during succinylcholine infusion

Characteristic Tetanic stimulation Post-tetanic facilitation Train-of-four fade Train-of-four ratio Edrophonium Recovery Dose requirements (mg/kg) * Tachyphylaxis

Phase 1 No fade

Transition Slight fade

Phase 2 Fade

None
No >0.7 Augments Rapid 2-3 No

Slight
Moderate fade 0.4-0.7 Little effect Rapid to slow 4-5 Yes

Yes
Marked fade <0.4 Antagonizes Increasingly prolonged >6 Yes

Type of Butyrylcholinest erase Homozygous typical Heterozygous atypical Homozygous atypical

Genotype

Incidence

Dibucaine Number *

Response to Succinylcholine or Mivacurium

E1uE1u
E1uE1a E1aE1a

Normal
1/480 1/3200

70-80
50-60 20-30

Normal
Lengthened by 50%-100% Prolonged to 4-8 hr

The dibucaine number indicates the percentage of enzyme inhibited.

Histamine Release
True anaphylaxis: Antigen / Antibody (IgE) Complement activation (IgG or IgM) Direct action on mast cell surface tachyphylaxis Prophylactic H1 & H2 receptor blockers suppress

Muscle responses
More receptors in fast (glottis) than slow (adductor pollicis) muscle fibres Rapid onset at glottis muscles is due to rapid equilibrium (more blood flow) Dose required for diaphragmatic block is twice the dose required for similar block @ adductor pollicis Sequence of onset: small muscles (eyes, digits) larynx trunk & abdomen diaphragm

Monitoring
Features
Increased safety Cost effective Easy documentation

Techniques
Peripheral nerve stimulation (PNS) Mechanomyograph (MMG) Electromyograph (EMG) Acceleromyography (AMG)

Choice of muscle
Diaphragm (most resistant) > other resp, upper airway & facial muscles > peripheral & abdominal (least resistant) Adductor pollicis (hand) & Flexor hallucis brevis (leg): sensitive (may be unreliable for intubation), less chance of overdosing, Orbicularis oculi: Onset, duration & sensitivity same as resp. muscles Other: Laryngeal, masseter, other facial muscles (research purposes only)

Train of four (TOF)

ratio of 1st to 4th response

1. Progressively fade as relaxation increases 2. Clinical relaxation requires 75 to 95% blockade 3. DBS is more sensitive TOF for clinical evaluation of fade(visual) 4. recent international guideline a TOF ratio of 0.9 was recommended as an end point for recovery from a nondepolarizing neuromuscular block 5. they could oppose their incisors to retain a tongue depressor, their TOF ratio was, on average, 0.8 and at least 0.68. 6. maximum antagonistic effect of neostigmine occurs in 10 minutes or less 7. For neostigmine, this maximum effective dose is in the 60- to 80-g/kg range,[327] and for edrophonium, it is in the 1.0- to 1.5-mg/kg range. [339] [340]

SIGNS OF ADEQUATE REVERSAL

Regular respiration with adequate tidal volume i.e. patient

is able to maintain oxygen saturation on room air. Spontaneous eye opening Spontaneous limb movement Able to protrude tongue Upper airway reflexes returns like patient is able to cough & spit.Gag reflex present. Able to lift head for more than 5 seconds. This is the best clinical sign. Forceful hand grip Able to generate ins pressure of atleast -25 cmH20

CAUSES OF INADEQUATE REVERSAL

Inadequate dose of neostigmine. Overdose of inhalational agents/opioids. Renal Failure,Hepatic failure Hypothermia Electrolyte abnormalities (Hypokalemia, Hypocalcemia) Associated neuromuscular diseases. Shock Acid Base abnormalities especially acidosis. It is

impossible to reverse a patient with pCO2 more than 50mmHg.

Drugs which antagonise Neuromuscular Blockade

They reverse the block by NDMR only
Phenytoin Carbamazepine

Calcium
Cholinesterase inhibitors Azathioprine

Steroids.

Stimulating patterns
Single twitch (ST)
Reflects events at post junctional membrane Single supra maximal electrical stimuli applied to peripheral motor nerve Frequency every second (1 Hz) or every 10 seconds (0.1 Hz) Used for monitoring onset of block Same response to both groups of NMBAs Response influenced by position of muscle, muscle temp. Calibration required before relaxation (not suitable for day-to day clinical practice)

Stimulating patterns

Train of four (TOF) Reflects events at pre synaptic membrane Used successfully for onset, maintenance & recovery of block Four supra maximal stimuli q 0.5 seconds (2 Hz). May be repeated q 12 15 seconds Advantage: relative ratio of 4th to 1st response remains the same despite changes in absolute responses

Stimulating patterns
Tetanus

Normally 50 Hz for 5 sec Fade with non-depolarizing block Post-tetanic facilitation Painful May produce lasting antagonism

Stimulating patterns
Double burst stimulation Two short (0.2 milliseconds) bursts of 50 Hz tetanic stimuli separated by 750 milliseconds DBS with 3 impulses in each of bursts (3,3) most commonly used Ratio of second response to the first is equivalent to TOF ratio Easily seen or felt by the anesthesiologist

Mutations in the acetylcholine receptor that result in prolonged open-channel time, similar to that seen with the immature receptor, can lead to a myasthenia-like state, even in the presence of normal receptor numbers. The weakness is usually related to the prolonged open-channel time. The role of the immature isoform of the receptor in the muscle weakness associated with critical illness such as burns is unknown.

Benzylisoquinoline compounds
D- Tubocurare It is named so because it was carried in bamboo tubes &

used as arrow poison for hunting by Amazon people. It has highest propensity to release histamine It causes maximum ganglion blockade. Because of ganglion blocking & histamine releasing property it can produce severe hypotension. Due to histamine release it can produce severe bronchospasm.

Centrally acting muscle relaxants

These are drugs which produce muscle relaxation through

central mechanism both at supraspinal & spinal level Polysynaptic reflexes involved in maintenance of muscle tone are inhibited at both spinal & supraspinal level. It also produces sedation Uses Muscle spasms. Tetanus : IV diazepam is most effective. Spastic neurological diseases like cerebral palsy,Spinal injuries. Close reductions & dislocations in orthopedics.