Phys: NEUROMUSCULAR

Review of MNT
Muscle contraction:

• Occurs when the electrical signal is transmitted between the presynaptic neuron and the post synaptic neuron
• juction betwn the two is the Junctional (synaptic) cleft
• motor neurotransmission = ACh

PRESYNAPTIC

• action potential occurs
• Ca2+ is released
• this stimulate release of ACh
• Breakdown and synthesis of ACh occurs here.
• enzyme choline acetyltransferase (CAT) catalyzes acetylcoenzyme A (Acetyl-CoA) + Choline = ACh + CoA

NEUROMUSCULAR JUNCTION

• Fluid filled area
• ACh is released here
• Ca2+ is fused to ACh vesicles (Quanta) until it ruptures
• This is the site where drugs work

POST JUNCTIONAL MEMBRANE

• Contain nerve endings that are closely approximated
• also known as motor end plate
• Ca2+ binds to the receptors here
• influx of Na+ and Ca2+, outward K+
• resting membrane potential becomes depolarized
• action potential occurs

MOTOR NEURON

1. Presynaptic (Eaton Lambert)

2. Sarcolemma

3. synaptic vesicles

4. ACh nicotinic receptor (MG)

5. Mitochondria

6. Synaptic cleft

7. Postjunctional membrane (NMBD)

8. NMJ (Botox)

SKELETAL MUSCLE PATHYPHYSIOLOGY
Causes of skeletal muscle disorders

• autoimmune
• defect in muscle protein
• pharmacologic effects

Safety in anesthesia

• requires knowledge of pathophysiology
• condition or stae the patient is in
• drug therapy being used

Preop

• thorough preop assessment
• know degree of respiratory, cardiac and muscle involvement

Intraop

• how does the patient's drug therapy affect the anesthetic

Postop

• may requipre postop ventilation
• pain management

MYASTHENIA GRAVIS

Cause:

• autoimmune destruction or inactivation of post-synaptic ACh receptor
• leads to a decrease in receptors and loss of folds on the synaptic vesicles
• 85% antibody to ACh nicotonic receptors
• 65% of patients are thought to have hyperplastic thymus gland
• 10% thymus
• 10% other

Characteristics:

• episodes of remission/exacerbation
• exacerbation can be generalized or confined to a muscle group
• ocular muscles: diplopia or ptosis
• bulbar involvement: laryngeal weakness and dysphasia
• proximal muscles (severe dx): involves neck, shoulders and respiratory muscles
• muscle strength improves with rest
• exacerbation is enhanced: stress, pregnancy, surgery and infection

Treatment:

1. EDROPHONIUM (Tensilon, Enlon, Reversol): primarily used as a diagnostic tool to predict the response to longer acting cholinesterase inhibitors.  As with other cholinesterase inhibitors, it decreases metabolism of ACh, increasing the cholinergic effect at the myoneural junction
1. Dose:
1. Adult: test dose 0.1-0.2 mg IV; 1-2 mg IV if no reponse; 5-9 mg slow IV if still no response
2. Pediatric: 0.2 mg/kg slow IV; not to exceed 10 mg
2. Interactions: atropine, NDMR, procainamide, quinidine may decrease effects of endrophonium; succs, digoxin, IV acetazolamide, neostigmine, and physostigmine may increase effects.
3. Contraindications: documented hypersensitivity; GI or GU obstruction
2. PYRIDOSTIGMINE (Mestinon, Regonol): Acts in smooth muscle, CNS, and secretory glands where it blocks the action of ACh at PANS sites.  Longer acting cholinesterase inhibitor used for maintenance therapy
1. Dose:
1. Adult: 60 mg PO TID initially followed by a maintenance dose of 60-1500 mg/dose; 2 mg IV/IM q2-3 h or 1/30 of PO dose
2. Pediatrics: 7 mg/kg/dose PO in 5-6 divided doses; 0.05-0.15 mg/kg/dose; dose must be individualized
3. NEOSTIGMINE (Prostigmin): longer-acting cholinesterase inhibitor that can be used when edrophonium is efective.  Inhibits destruction of ACh by acetylcholinesterase, which facilitates the transmission of impulses across the myoneural junction
1. Dose:
1. Adult: 15 mg/dose PO q2-3h; max 375 mg/dose; 0.5-2.5 mg IV/IM/SC q1-3 h; max 10 mg/dose
2. Pediatrics: 2 mg/kg/dose PO divided q3-4h; 0.01-0.04 mg/kg IV/IM/SC q2-4 h

Other medical tx for MG

• Thymectomy: thymus produces T-lymphocytes which aids in immunity
• Plasmaphoresis: removal of antibodies from bloodstream
• Immunosuppresants: Imuran, cyclosporin
• Steroids: prednisone, solumedrol
• anticholinergics: cause reversal of cholinergic medication effects that induce bronchospasm.  These drugs can act synergistically or independently with beta agonists to produce bronchodilation.  Quaternary amines and are pooly absorbed across pulmonary epithelium - have minimal systemic side effects
• Beta 2 agonist

Differentiating between myasthenic crisis and cholinergic crisis
Edrophonium (Tensilon) Test

• used to determine whether weakness is caused from too much drug treatment or myasthenic crisis
• an increase in weakness with 10 mg indicates cholinergic crisis
• an increase in strength indicates myasthenic crisis

Preop Evaluation

• what surgery are they having?
• thymectomy: indicates deterioration of disease
• other: patient may be optimized or in remission
• determine how severe the disease is
• consider pretreatment with H2 blocker for aspiration prevention
• consider omitting sedatives
• edrophonium test to evaluate whether the patient is in myasthenic or cholinergic crisis

Intraop Management

• May use standard inhalation agents
• avoid muscle relaxants if possible; consider use of other techniques for relaxation
• may require increased doses of succs for resistance, but duration will also be increased; though to be r/t a decrease in the number of ACh receptors
• Sensitivity to NDMR
• there is a decrease in the number of functioning ACh receptors
• precheck TOF prior to administration of NDMR and base dose on response
• usually 1/10 of the normal intubating dose
• Anticholinesterase drugs
• will inhibit both true cholinesterase and plasma cholinesterase activity
• succs effects will be prolonged
• has not shown a clinical effect with NDMR
• use of smaller doses of NDMR along with drugs that are shorter acting is preferable (roc and vec)

Postop Care

• VC < 40 ml/kg
• disease > 6 mn
• pyridostigmine dose > 750 mg/dose
• --> all lead to post op ventilation support

EATON-LAMBERT SYNDROME (Myasthenic Syndrome)

• a rare disorder of neuromuscular transmission that resembles MD
• usually associated with small cell carcinoma of the lung
• paraneoplastic disorder affecting the lower extremities
• other causes:
• met. ca, sarcoidosis or autoimmune
• muscle weakness generally improves with exercise
• There is a prejunctional deficit in the release of ACh, which is thought to be related to antibodies on the calcium channels
• unaffected by anticholinesterase drugs
• autonomic deficits
• autonomic ganglionic neurons is modulated by preganglionic neurons
• failure of nicotinic cholinergic synaptic transmission
• patients may be prone to orthostatic hypotension and cardiac irritability
• gastroparesis and urinary retention
• muscle weakness
• usually the trunk, pelvic and legs
• fatigue and difficulty walking

Anesthetic Considerations

• these pts sensitive to depolarizers and nondepolarizers
• consider using deep inhalational anesthesia
• if MR is required you will need to decrease dose
• may use reversal agents
• antagonism of neuromuscular blockade may be inadequate
• consider postop ventilation support

DUCHENE'S MUSCULAR DYSTROPHY
(Pseudo Hypertrophic Muscular dystrophy)
Most common and most severe childhood progressive neuromuscular disorder
3 per 10,000 births
X-linked recessive gene
males 2-5 y/o

S&S

• waddling gait
• difficulting climbing stairs
• frequent falls; involves proximal skeletal muscles of pelvis

Characteristics

• progressive skeletal muscle weakness to eventually being debilitated in wheel chair by 8-11 y/o
• kyphoscoliosis
• skeletal muscle atrophy can lead to long bone fracture
• serum creatinine kinase is 30-300 x normal
• death can occur by ages 15-25
• skeletal muscle cell shows necrosis and phagocytes of the muscle fiber

L - normal   R - dystrophic cell

Anesthetic Considerations
Cardiac function

• degenerative cardiac muscle
• EKG shows tall R waves in V1, deep Q waves in limb leads, short PR and ST
• mitral regurg d/t papillary muscle dysfunction

Respiratory Function

• decreased function
• decreased cough ability
• loss of pulmonary reserve
• increased secretions
• kyphoscoliosis: restrictive or obstructive lung disease
• most common cause of death

Planned surgery

• succs is contraindicated: rhabdo, hyperkalemia, cardiac arrest
• NDMR: prolonged effect
• Dantrolene: should be readily available for these pts - at risk for MH
• plan for regional when possible
• monitor signs for MH
• delayed respiratory depression for up to 36 hours post op: monitored unit

MALIGNANT HYPERTHERMIA
Life threatening uncommon hypermetabolic state which is triggered by certain anesthetics
occurance in 52% of pts under age 15; mean age 18.3
1:50,000 adults; 1:15,000 children
Pathophysiology

• cause unknown
• inherited disorder
• defect in calcium regulation
• focus on Ryanodine receptor which modulates calcium release from SR
• what happens when a triggering agent is given:
• actin-myosin bridges are sustained
• uptake of calcium requires energy and that energy increases muscle cell metabolism 2-3 fold
• incr metabolism = incr O2 consumption = incr temp and CO2 = depletion of ATP stores and incr lactic acid

Triggering and Non-triggering agents

• triggering agents: succs, VAAs, K+ salts
• nontriggering: LA, N2O, opioids, barbiturates, propofol, ketamine

NEUROLOGICAL DISEASES

1. Multiple Sclerosis (MS)
2. Amyotrophic Lateral sclerosis (ALS)
3. Guillian Barre Syndrome (Acute demyelinating polyneuropathy)

MYELIN
Myelin:

• is an electrically insulating dielectric phospholipid layer that surrounds only the axons of many neurons
• its main purpose is to increase the speed of impulses along the nerve cells
• in the brain the myelinated area is known as white matter

Demyelination:

• refers to the loss of myelin sheath insulating the nerve
• this is what is seen with disease such as MS, ALS, Guillian Barre syndrome

MULTIPLE SCLEROSIS
demyelination of several sites of the brain and spinal cord with chronic inflammation and scarring
Diagnose early via MRI
Characteristics

• autoimmune response initiated by a virus
• occurs btwn 20-40 y/o
• episodes of exacerbation and remission
• S&S: motor weakness, paresthesia, visual disturbances
• increases in body temperature worsens symptoms

Treatment

• spasms: dantrolene, bachlofin, diazepam
• urinary retention: bethanechol
• decrease exacerbation: ACTH, glucocorticoids
• immunosuppressant: interferon B, AZT, cyclosphosamide

Anesthetic Considerations

• avoid elective surgery during relapse stages
• council patients on effects of stress on the disease
• avoid succs
• avoid elevations in body temperature; incr in temp of 0.5 degrees
• can decrease demyelinated nerve conduction
• spinal anesthesia can exacerbate symptoms
• GA and epidural have not been shown to have major effect

AMYOTROPIC LATERAL SCLEROSIS (ALS)
most common and most rapidly progressing neurologic disease in adults; occurs during 5-6th decade of life
Characteristics

• muscle weakness, atrophy, fasciculation and spasms
• progresses to involve the bulbar and skeletal muscles

Anesthetic Management

• aimed at keeping judicious respiratory care
• avoid succs
• these patients are more sensitive to NDMR
• monitor respiratory status post op
• extubate fully awake

GUILLIAN-BARRE SYNDROME
(Acute Demyelinating Polyneuropathy)

• immune mediated
• most common acute form of neuropathy
• seen 2-4 weeks after a viral infection
• there is nerve infiltration by lymphoid cells with phagocytosis of myelin
• patient develops acute ascending paralysis
• motor weakness and respiratory failure
• bulbar involvement
• remyelination occurs over 3-4 months with full recovery in most cases

Pathogenesis

• there is an immunologic response against myelin sheath of the PNS, especially the lower motor neurons
• usually follows a viral infection
• can also be seen in par-neoplastic disease such as Hodgkins lymphoma or HIV

Anesthetic Considerations

• autonomic lability; pt may have episodes of hypo and hypertension
• avoid succs
• monitor respiratory status

PSYCHIATRIC DISORDERS

DEPRESSION
disorder characterized by sadness and pessimism
treatment is based on the premise that depression is d/t decrease receptors in brain: dopamine and NE
Pharmacotherapeutics

1. MAOI
1. blocks the oxidative deamination of naturally occurring amines
2. MAOI are used when patients do not respond to other drug therapies
1. Phenelzine (Nardil)
2. Isocarboxazide (Marplan)
3. Tranylcypromine (Parnate)
3. MAOI do not sensitize the heart to the effects of Epi as dose tricyclics
4. Principle effect: systemic HTN occurs as a result of increased inhibition of monoamine oxidase which increases availability of NE
5. Ephedrine = incr release of NE
6. opioids = meperidine
1. decrease metabolism of opioid
2. massive sympathetic discharge from administration of the opioid
3. formation of toxic metabolite
4. increased CNS concentration of serotonin
2. SSRI
1. most commonly prescribed:
1. prozac (fluoxetine)
2. zoloft
3. paxil
4. lexapro
5. celexa
2. have little effect on reuptake of NE
3. lack anticholinergic effects
4. do not sensitize hear to effects of Epi
5. side effects: H/A, agitation, N, insomnia, sexual dysfunction
6. Fluoxetine (prozac) has been shown to inhibit the CYP450 system
7. mixing Prozac with MAOI:
1. can lead to serotonin syndrome
1. anxiety, restlessness, chills, ataxia, insomnia
2. this syndrome can be potentially life threatening. patients may develop tachycardia, HTN and hyperthermia (40*C)
3. Tricyclics
1. Tricyclic antidepressants commonly used:
1. amytriptyline
2. nortriptyline
2. these were most commonly used before SSRIs
3. can produce sedative effect and often used for insomnia
4. do have some anticholinergic effects
5. SE: CV abnormalities, orthostatic hypotension, slow atrial and ventricular depolarization, increased PR and QT and wide QRS

Anesthetic Considerations

• increased availability of NE in CNS may require an increase in anesthetic requirements
• increased NE in post synaptic receptors may cause exaggerated response to vasopressors
• phenylephrine
• hypertensive crisis is at greatest risk within first 14-21 days of treatment
• in studies tricyclics have been shown to cause an exaggerated analgesic response and ventilatory response to opioids

ECT

• used for the treatment of depression unresponsive to drug therapy, or for and acute episode with suicidal ideation
• SE: initial vagal response followed by HTN and tachycardia
• MI is most common cause of death with this treatment
• seizures: causing muscle spasms and long bone fractures
• decreased venous return from increased intrathoracic pressure
• increased CMRO2 and ICP

Anesthesia for ECT

• avoid premed may prolong recovery
• atropine or glyco, bradycardia
• patients at risk for MI, give nitro paste 45 min preop
• esmolol 100-200 mg ready, can give 2 minutes before treatment
• induction drugs
• methohexatol 0.5-1.0 mg/kg
• propofol 1.5 mg/kg
• succ 0.3-0.5 mg/kg
• ventilatory support
• have PNS in room

FROM JULIA:
1.      Know the difference and be able to identify Myasthenia Gravis and Eaton Lambert Syndrome.

2.      Know how the muscles are affected with each disorder.

3.      What is the significance of having a Thymectomy.

4.      What is a tensilon test used for?

5.      What effects do these disorders have on NMB agents?

6.      Know MAOI and effects in anesthesia from your Ppt.

7.      Know the equation for the breakdown of acetylcholine