Jefferson CRNA Program Notes

Sunday, July 29, 2012

Phys: FLUIDS

OBJECTIVE: HOMEOSTASIS

maintain constant physiologic fluid volume intracellularly and extracellularly
maintain a stable composition of solute in the above fluid compartments
intake = output ; equilibrium

STEADY-STATE CONDITION
Fluid intake and output are balanced during steady-state conditions. Fluid intake must be carefully matched with water output to prevent body fluid volumes from dramatically increasing or decreasing.

WATER
2100 ml per day is ingested
200 ml per day synthesized as result of oxidation of CHO (krebs cycle)
average total fluid volume intake: 2300 ml per day

variable on climate, habits, physical activity

INSENSIBLE WATER LOSS

not consciously aware of it
respiratory tract - 350 ml per day of insensible loss
inspired air becomes saturated with moisture at 47 mmHg at 37*C
because atmospheric water vapor pressure is less, lungs continually lose moisture via respiration ([ ] gradient)
in cold weather atmospheric vapor pressure decreases --> even more water loss from lungs as temperature decreases

BODY FLUID COMPARTMENTS

Extracellular (1/3)

75% interstitial
25% plasma

Intracellular (2/3)

DAILY INTAKE & OUTPUT OF WATER
Intake:

Fluids ingested: 2100 ml
fluids metabolized: 200 ml
total: 2300 ml

Output:

insensible loss skin: 350 ml
insensible loss lungs: 350 ml
sweat: 100 ml
bowel: 100 ml
bowel/urine: 1400 ml
total: 2300 ml

DURING PROLONGED HEAVY EXERCISE
Intake:

additional fluid from metabolism: 200 ml

Output:

insensible loss skin: 350 ml
insensible loss lungs: 650 ml
sweat: 5000 ml
UOP: 500 ml
Total: 6600 ml

IN THE AVERAGE 70 KG MAN

total body water is 60% of body weight --> 42 L
for women: 50%
elderly: percentage of total body water decreases as fat increases

less muscle, less water

newborn: water is 75% of body weight

IONIC COMPOSITION OF PLASMA AND INTERSTITIAL FLUID IS SIMILAR

higher concentration of proteins in plasma
capillaries have low permeability to plasma protein (so proteins stay in capillaries)
interstitial spaces contain small amounts of plasma proteins

PLASMA AND INTERSTITIAL FLUID ARE SEPARATED
by a highly permeable capillary membrane

THE DONNAN EFFECT

there are more cations in plasma (than in interstitial fluid)
plasma proteins are negatively charged --> attract cations Na+ and K+
The donnan effect is extra osmotic pressure attributed to cations attached to dissolved plasma proteins
accounts for 1/3 of intravascular osmotic pull
more anions in interstitial fluid - negatively charged proteins repel anions.

major intracellular ion: K+

extracellular ions: Na+, Cl-

BLOOD VOLUME

contains both extracellular fluid (plasma) and some intracellular fluid in RBC
average blood volume of adults approximates 5 L
60% is plasma, 40% is red cell mass

EQUILIBRIUM
In healthy states, intracellular and extracellular compartments are in equilibrium. Water moves across the cell membrane rapidly any intracellular fluid remains isotonic with the extracellular fluid

OSMOSIS
The net diffusion of water across a selectively permeable membrane from an area of high water concentration to one with lower water concentration.

If NaCl is removed from the extracellular fluid, water will diffuse from the extracellular fluid through the cell membrane into the cell because there is less solute and more water on the extracellular side.

MOLES & OSMOLES
The total number of particles in solution is measured in Osmoles

1 Osmole (osm) = 1 mole of solute particles = 6.02 x 10^23 (avogadros number)

The term osmole refers to the number of osmotic reactive particles in solution. The Osmole is too large for expressing osmotic activity in body fluids. The term Milliosmole (mOsm) is used instead = 1/1000 of an osmole

CALCULATION OF OSMOLARIY: VAN HOFF'S LAW
0.9% NS = 0.9 gm NaCl per 100 ml solution = 900 mg per 100 ml = 9 mg/ml
or
9gm per 1000 ml solution

Molecular weight of NaCl is 58.5 gm per mole

Find the molarity of the solution: 9 gm/L / 58.8 gm/mol = 0.154 mol per liter
each molecule of NaCl = 2 osmoles (NaCl dissociates into 2 osmotically active particles)

0.154 mol/L x 2 osmoles = 0.308 Osm/L = 308 mOsm/L --> potential osmotic pressure of the solution

Apply Hoff's osmotic coefficient: 0.93

0.93 x 308 = 286 mOsm/L

Normal osmolarity is 280-310 mOsm/L = isotonic

OSMOLARITY OF BODY FLUID

80% of total osmolarity of interstitial fluid and plasma is d/t Na and Cl ions
intracellular fluid relies on K+ ions to create 50% of its osmolarity

ISOTONIC, HYPOTONIC, HYPERTONIC FLUIDS

Impermeate solutes = particles that will not permeate the cell membrane (NaCl, protein)
the effects of the presence of various concentration of the solutes in solution effects the behavior of both cells and solution

the cells will not shrink of swell bc the water concentration is equal on both sides of the cell membrane
*D5W is isotonic in the bag. After it enters the body, it becomes hypotonic because dextrose is quickly metabolized to glucose (left with water)

<280 mOsm/L
has a lower concentration of solutes. water will rush into cell causing it to swell diluting intracellular fluid and concentrating extracellular fluid seeking equilibrium. cells swell --> lysis

> 280 mOsm/L
water will rush out of cell into extracellular fluid concentrating the intracellular fluid. The cell will shrink until the two concentrations are at equilibrium; crenation

Difference Between OSMOSIS & DIFFUSION:
Diffusion: one-way movement from areas of high concentration to low concentration: perfume, skunk --> can occur with any material

Osmosis: one way movement of water through a semi-permeable membrane from areas of high water concentration to low water concentration; skin wrinkling in bath water - more solutes in skin than water in tube

HYPONATREMIA
Cause: loss of NaCl from extracellular fluid --> dehydration, diarrhea, vomiting, diuretics, Addison's disease (adrenal insufficiency --> low cortisol and aldosterone), hypoaldosteronism
or, addition of excess water to extracellular fluid diluting the sodium load --> TURP syndrome, excessive secretion of ADH

Clinical Manifestations
serious symptoms occur when Na+ is < 120 mEq/L
symptoms are nonspecific: anorexia, nausea, weakness, progressive cerebral edema results in lethargy, confusion, seizures, death

Acute hyponatremia

rapid reduction in plasma Na+ concentration can cauase brain cell edema and neurologic symptoms
h/a, N/v, lethargy, disorientation
seizures, permanent brain damage and death
brain cannot increase volume by more than 10% without herniation

Hyponatremia & Edematous disorders

CHF, cirrhosis, renal failure, nephrotic syndrome
progressive impairement of renal water excretion parallels underlying disease severity, you may see an increase in total body sodium
Na+ is in the peripheral tissues not the central compartment
ADH release and decreased delivery of fluid to the diluting segment of the nephrons
the effective circulating volume is reduced

Hyponatremia:

may be en with normal total body sodium in the absence of edema or hypovolemia
glucocorticoid insufficiency
hypothyroidism
SIADH (too much ADH = antipee)
normal urine osmolality is usually greater than 100 mOsm per kg
normal urine Na+ concentration is normally greater than 40 mEq per L

Chronic hyponatremia

when this evolves more slowly, other tissue respond by: CSF recruits water from the ECF compartment to help protect the brain
the transport of (effective osmoles) Na, K, organic solutes such as glutamate and urea from cells into the extracellular compartment
this blunts the osmotic flow of water into the cells and subsequent swelling of the brain tissues

Correction of hyponatremia

rapid correction of chronic hyponatremia may result in osmotic demyelination injury to the neurons (pontine)
brain has pumped out its intracellular solute load for protection
pontine demyelination = quadraplegia, further CNS damage, death
demyelination can be avoided by limiting the correction of hyponatreimato 10-12 mmol per liter in 24 hours
slow correction permits the brain to recover the lost osmoles
water restriction is the treatment for hyponatremia ; patients with normal or increased total body sodium
loop diuretics encourage free water reduction
don't over diurese
water restriction allows the balance between plasma and sodium to achieve homeostasis
treat hormonal (adrenal, thyroid) dysfunction
antagonize ADH activity and water restrict patients with SIHADH (hypersecretion)
address the underlying sodium disorder
PSS is generally the treatment of choice in patients with decreased total body sodium content
**hyponatremia is the most common elyte disorder in clinical practice
>130 mEq/L is safe for general anesthesia
lesser values may result in intraoperative cerebral edema manifesting itself as confusion and combativeness, or lethargy upon awakening

HYPERNATREMIA

result of loss of water from the extracellular fluid such as dehydration
or an increase in sodium content in the extracellular fluid: salt water drowning
increasing osmolarity
may be caused by the inability to secrete ADH as in Central Diabetes Insipidus

Centralized hypernatremia may be caused by a lesion of the hypothalamus and pituitary stalk
transient DI is seen following neurosurgical procedures and head trauma
neurologic manifestations predominate and are caused by cellular dehydration
restlessness, lethargy, hyperreflexia, seizures, coma, death

Kidneys inability to respond to ADH such as Nephrogenic Diabetes Insipidus
excessive secretion of sodium retaining hormone aldosterone

may result in hypernatremia and over hydration
aldosterone also encourages water retention in addition to sodium, so the scenario is not usually serious

>160 mEq/L
causes cell shrinkage
promotes intense thirst helping thwart huge increases in plasma Na+ levels

not all thirst mechanisms are intact
hypothalamic lesions may impair the thirst sense
elderly patients with altered mental status

chronic hypernatremia is better tolerated than the acute form
after 48 hours of rising Na+, intracellular osmolarity begins to rise d/t increases in intracellular inositetol and amino acid concentrations

this increases intracellular solute concentrations slowly increasing neuronal water content
need time to equilibrate

Treatment

may have decreased total body sodium require isotonic fluids to restore plasma volume
only then should hypotonic solutions be given to restore intracellular volume status
patients will increased total body sodium require loop diuretic therapy and hypotonic solutions
rapid correction of hypernatremia may result in seizures, brain edema, permanent neurologic damage and death
plasma Na concentrations should not be decreased faster than 0.5 mEq/L/hr

LYMPHEDEMA
Impairement of function of lymphatic vessels
caused by blockade or surgical excision
Results in plasma protein leaking into interstitium - raising colloidal osmotic pressure of the interstitium - attracting fluid to diffuse across the capillary membrane

Causes:

parasitic infection can block lymph flow
filaria nematodes live in human lymph system
a mosquito disseminated infection
may develop elephantiasis in females
men may develop scrotal swelling (hydroseal)
lymphatic filariasis affects 120 million people

Causes of Extracellular Edema
(read notes)

Physiologic safety factors in preventing edema
abnormalities that cause edema must be severe in order to overcome intrinsic physiologic safety factors

negative interstitial pressure enhances low compliance of the interstitial space
lymph flow has the ability to increase up to 50 fold if called upon
"wash down" of interstitial fluid proteins concentration reducing osmotic load

COMPLIANCE
change in volume per millimeter HG pressure change
*in interstitial space, compliance is low; increases in volume result in significant changes in pressure
as long as the interstitium remains in the negative pressure range (-1 to -3)

CAPILLARY FILTRATION
read in notes

INTERSTITIAL GEL
Fluid in interstitium is in gel form; fluid is bound in proteoglycan network
Brush pile of proteoglycan filaments - add structure to the cell body and prevent occurence of free fluid in this space. if the pressure here becomes positive, the filaments are pushed apart and free fluid occurs.

proteoglycan filaments prevents fluid from flowing easily through the tissue spaces. Without these an individual simply standing up would cause huge amounts of fluid to shift from the upper to the lower body. When edema of the lower extrem occur, rivulets of free fluid form and fluid can move quickly bypassing the filaments. The best way to relieve lower extremity edema is to put your feet up.

Lymph flow as a safety mechanism:

The lymphatics return proteins leaking from capillaries into interstitium

without continuous circulation of proteins, plasma volume would rapidly be depleted and interstitial edema would develop. Lymphatic flow can increase from 10 to 50 x normal when fluid begins to accumulate in the tissues.

lymphatics carry away large amounts of fluid and proteins in response to increase capillary filtration; this prevents interstitial pressure from becoming +
The safety factor of increased lymph flow has ben calculated to be about 7 mmHg

WASHDOWN OF INTERSTITIAL FLUID PROTEINS
washout
The capillaries are relatively impermeable to proteins but not so with lymph vessels
lymph flow increases - proteins are washed out of the interstitial fluid and enter the lymph vessels as lymph flow increases

PROTEIN ENTOURAGE
net filtration pressure through capillary is then decreased; by decreasing interstitial fluid protein colloidal concotic pull

POTENTIAL SPACES

pleural cavity
pericardial cavity
peritoneal cavity
joint cavity and bursa
surfaces almost touch each other; only a thin layer of fluid separates them
to facilitate sliding, a viscous proteinaceous fluid lubricates the surface
capillaires adjacent to the space allows fluid to diffuse into interstitial space and into adjacent potential space; each potential space is connected with lymph vessels to facilitate the removal of protein from the space.
The pleural cavity and peritoneal cavity possess large vessels within the cavity itself to facilitate this removal

EDEMA IN THE POTENTIAL SPACE = EFFUSION
lymph obstruction cause excessive capillary filtration results in effusion similar to interstitial edema
effusion in abdominal cavity = ascites
20 L of ascites fluid may accumulate

EDEMA IN THE PLEURAL SPACE
fluid pressure is negative; pressure is subatmospheric in interstitial tissue
fluid hydrostatic pressure is normally about:

pleural cavity -7 to -8 mmHg
joint space -3 to -5 mmHg
pericardial -5 to -6 mmHg

TRANSCELLULAR FLUID COMPARTMENT

pleural
synovial
peritoneal
pericardial
cerebrospinal fluid
intraocular spaces
totals < 2 L
does not contribute greatly to total body water

BASELINE VOLUMES AND OSMOLALITY
notes

MOST IMPORTANT FUNCTION OF CIRCULATION OCCURS IN MICROCIRCULATION
transport of nutrients to tissue
removal of cell excretion --> shit

CAPILLARY WALLS
thin; constructed of single layer of permeable endothelial cells
water, cell nutrients, cellular end products (excreta) move quickly and easily btwn tissues and circulating blood

10 billion capillaries

total surface area 700 m2

1/8 of football field

no body cell is > 25 nm away from a capillary

DIFFUSION
*the most important means by which substances are transferred between plasma and interstitial fluid; water and dissolved molecules continuously diffuse back and forth through capillary wall; random motion occurs with molecules bounding in every direction.

VASOMOTION
blood flows intermittently turning on and off every few seconds or minutes; caused by intermittent contraction of meta-arterioles - precapillary sphincters and small arterioles
Lympho-Kinetic Motion

*Vasomotion is slower when tissue O2 demand is higher

LIPID SOLUBLE SUBSTANCES
diffuse directly through cell membrane; no not need to go through pores
O2 and CO2 readily and quickly diffuse through membranes
Na and glucose must traverse capillary endothelium through pores - slower

PERMEABILITY OF CAPILLARY PORES
varies according to size and size of substance trying to pass through
H2O - 0.35 nm
protein 7-8 nm
Na, Cl, urea, glucose somewhere inbtwn

H2O will diffuse 1000 x faster than protein molecules; various tissue present extreme difference in their permeability characteristics

In brain, capillary junctions are tight; H2O, O2 and CO2 pass freely in and out of brain tissue
In liver, clefts here are wide open; almost all dissolved substances of plasma can pass from blood into liver tissue; easily leaks out when channels are blocked (sweat)

NET RATE OF DIFFUSION THROUGH CAPILLARY MEMBRANE
[CO2] tissues > blood > alveolus
moves down concentration gradient

INTERSTITIUM AND INTERSTITIAL FLUID
1/6 of total volume of body water exists between cells - interstitial fluid; possess same constituents as plasma except for plasma proteins

STARLING FORCES

capillary pressure: +7
interstitial fluid pressure:-8
capillary plasma colloidal osmotic pressure: -28
interstitial fluid colloid osmotic pressure:-14

net filtration = -22

LYMPHATIC SYSTEM AS SCAVENGER SYSTEM

removes excess fluid
removes excess protein molecules
removes debris and other matter from tissue spaces
this overall process (of pumping fluid into central circulation) creates a slight negative pressure for fluid in the interstitial spaces

IN THE LUNGS

NORMAL VALUES FOR PLASMACOLLOID OSMOTIC PRESSURE
28 mmHg average colloid osmotic pressure
19 mmHg d/t molecular effects of dissolved protein
9 mmHg d/t Donnan effect - extra osmotic pressure from cations held in plasma by proteins

TOTAL PLASMA PROTEIN LOAD: consists of albumin, globulins, fibrinogen
80% of total colloid osmotic pressure results from albumin
20% from globulin
fibrinogen noncontributory

LYMPHATHIC SYSTEM

return of proteins to blood from intersitial spaces
with this we would die in 24 hours
lymphatics carry proteins and large particles which cannot be removed by absorption directly into blood capillaries
valves exist in all lymph channels
segmental valves allow lymph vessels to pump from valve to valve
each segment is capable of functioning as an independently pumping segment emptying into next segment
lymphatic system compressed by skeletal muscle, movement of body parts, arterial pulsations adjacent to lymphatics, compression of tissues by forces outside body, pneumatic stockings, blood pressure cuffs, padded armrests, OR tables
from lower part of body empty into thoracic duct --> empties into venous system at the juncture of the left IJ and L SC vein
L IJ lines may cause kylothorax (lymph in lungs)
lymph from L side of head, arms, and chest enters the thoracic duct for emptying into veins
lymph from R side of neck, head enters very small right lymph duct which empties into R SC and IJ

Lymph

derived from interstitial fluid that flows into lymphatics
protein concentration in interstitial fluid is 2 g/dL

intestines 4 g/dL
liver 6 g/dL
2/3 of lymph is derived from liver and intestine
thoracic duct 10 g/dl

major route for absorption of nutrients, especially fats

after fatty meal, thoracic duct lymph can contain as much as 2% fat

Macrophages
line lymph nodes
bacteria cannot be absorbed through capillary membrane into blood; bacteria enter lymph into lymph nodes located intermittently through lymphatic chain

Rate of lymph flow
100 ml/her through thoracic duct
20 ml flows into circulation /hr through other channels
total estimated lymph flow: 120 ml/hr x 24 hr = 2880 ml/day

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:

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

Dose:

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
Pediatric: 0.2 mg/kg slow IV; not to exceed 10 mg

Interactions: atropine, NDMR, procainamide, quinidine may decrease effects of endrophonium; succs, digoxin, IV acetazolamide, neostigmine, and physostigmine may increase effects.
Contraindications: documented hypersensitivity; GI or GU obstruction

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

Dose:

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
Pediatrics: 7 mg/kg/dose PO in 5-6 divided doses; 0.05-0.15 mg/kg/dose; dose must be individualized

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

Dose:

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
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

Multiple Sclerosis (MS)
Amyotrophic Lateral sclerosis (ALS)
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

MAOI

blocks the oxidative deamination of naturally occurring amines
MAOI are used when patients do not respond to other drug therapies

Phenelzine (Nardil)
Isocarboxazide (Marplan)
Tranylcypromine (Parnate)

MAOI do not sensitize the heart to the effects of Epi as dose tricyclics
Principle effect: systemic HTN occurs as a result of increased inhibition of monoamine oxidase which increases availability of NE
Ephedrine = incr release of NE
opioids = meperidine

decrease metabolism of opioid
massive sympathetic discharge from administration of the opioid
formation of toxic metabolite
increased CNS concentration of serotonin

SSRI

most commonly prescribed:

prozac (fluoxetine)
zoloft
paxil
lexapro
celexa

have little effect on reuptake of NE
lack anticholinergic effects
do not sensitize hear to effects of Epi
side effects: H/A, agitation, N, insomnia, sexual dysfunction
Fluoxetine (prozac) has been shown to inhibit the CYP450 system
mixing Prozac with MAOI:

can lead to serotonin syndrome

anxiety, restlessness, chills, ataxia, insomnia
this syndrome can be potentially life threatening. patients may develop tachycardia, HTN and hyperthermia (40*C)

Tricyclics

Tricyclic antidepressants commonly used:

amytriptyline
nortriptyline

these were most commonly used before SSRIs
can produce sedative effect and often used for insomnia
do have some anticholinergic effects
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

Phys: ENDOCRINE

CHEMICAL MESSENGERS:

Neurotransmitters:

released by axon terminals of neurons into synaptic junctions
act locally to control nerve cell functions

Endocrine hormones

released by glands or specialized cells into blood
influence the function of target cells at another location in the body

Neuroendocrine

secreted by neurons into blood
influenced function of target cells at another location

Paracrines

secreted by cells into extracellular fluid
affect neighboring target cells of a different type

Autocrines

secreted by cells into extracellular fluid
affect function of same cells at produced them

Cytokines

peptides (proteins) secreted by cells into extracellular fluid
*secreted substances may function as autocrines, paracrines or endocrine hormones
eg. interleukins and other lymphokines that are secreted by helper cells at act on other cells of the immune system

Endorine hormones affect many different types of cells throughout the body:

Growth Hormone: from anterior pituitary gland - causes growth throughout body
Thyroxine: from thyroid - incr rate of chemical rxns in almost all body's cells
Adrenocorticotropic Hormone (ACTH): from anterior pituitary gland - stim the adrenal cortex causing it to secrete adrenocortical hormones
Thyrotropin-releasing hormone (TRH): from anterior pituitary - stim secretion of thyroid stimulating hormone (TSH)

Growth hormone released during REM sleep

Neg feedback: somatostatin turns off growth hormone

somatomedia C (insulin-like) --> IGF1 (insulin like growth factor 1) stim condrocytes and osteocytes > bone matrix

3 CLASSES OF HORMONES

PROTEIN-BASED: *most hormones are polypeptides/proteins

hormones secreted by anterior and posterior pituitary
pancrease --> insulin, glucagon
parathyroid gland --> parathyroid hormone
H2O loving - hydrophylic
synthesized on rough endoplasmic reticulum of endocrine cell
release initiated by increase in calcium levels or incr in cAMP (2nd messenger)
stored in secretory vesicles until needed
packaged in Golgi Apparatus (post office)
exocytosed
polypeptides with 100+ amino acids = protein
less than 100 AA = peptides

STEROIDS

secreted by adrenal cortex (cortisol, aldosterone)
ovaries (estrogen, progesterone)
testes (testosterone)
placenta (estrogen, progesterone)
-en or -one = steroid-based
manufactured from cholesterold

lipid soluble (only lipid soluble hormone)
not storage material, no need to do so (liver conjugates it; when cirrhotic liver can't conjugate them --> incr estrogen --> 2ndary female sex characteristics in males)
d/t high lipid solubility they diffuse across cell membranes and readily enter the bloodstream and interstitial fluid
large volumes of cholesterol esters are readily available in cytoplasm
stores are quickly mobilized to create new steroid molecules

TYROSINE DERIVATIVES: an amino acid; amine hormones

secreted by thyroid --> thyroxine, triiodothyrinine
adrenal medulla secretes AA based epi and NE
formed by enzymatic action within cytoplasmic compartments of glandular cells
H2O loving
thyroid is stored as thyroglobulin (protein)

released from its protein storage matrix and enters bloodstream (slow releaser)
complexes in bloodstream with thyroxine-binding globulin which helps control its release to target tissues

AMINES: EPI & NE

Formed in adrenal medulla, released by adrenal medullary cells by exocytosis
Epi:NE 4:1
circulates in plasma in free form or in conjugation with other substances

Catecholamine Creation:

Phenylalanine --> Tyrosine --> DOPA --> Dopamine (+Dopamine B hydroxylate) --> NE --> Epi

Metabolism:

Extraneural (outside cell): Catechol-O-Methyl Transferase (COMT)

Epi --> metanephrine
NE --> normetanephrine
Dopamine --> methoxytyramine

Inside SANS nerve fibers: Monoamine Oxidase (MAO) deaminates amino neurotransmitters in SANS nerve fibers. Found near mitochondria membrane

MAO Type A: deaminates Epi, NE, dopamine
MAO Type B: deaminates only dopamine
Epi --> vanillylmandelic acid
NE --> vanillylmandelic acid
Dopamine --> homovanillic acid

Epinephrine:

Formed in adrenal medulla under action of: phenylethanolamine-N-methyltransferase
process called methylation found only in adrenal medulla
NE and epi differ in number of methyl groups they possess

Catecholamine Storage

stored in chromaffin vesicles located in adrenal medulla
NE complexes with ATP and is bonded to protein within chromaffin cells
NE released by exocytosis
Calcium essential for exocytosis of NE

HORMONE RECEPTOR ACTIVATION
Formation of hormone receptor complex: The activated receptor initiates hormonal effects

TYPES OF RECEPTORS:

Ion Channel Linked Receptors

eg. ACh or NE combined with receptors in the postsynaptic membrane
this results in opening or closing of ion channels for Na, K, Ca, etc

G Protein Coupled Hormone Receptors (Guanisine)

7 trans-membrane receptors or Trimeric G proteins
can be inhibitory or stimulatory

3. Enzyme-linked Hormone Receptors

Enzymes pass through the membrane receptor and initiate their intended response
eg. Leptin (secreted by fat cells) important in regulating appetite and energy balance
Leptin receptor is member of cytokine receptor family that rely on enzymes from outside the receptor as it possesses no enzymes of its own

HORMONAL CONTROL: NEGATIVE FEEDBACK
The action of released substance tends to suppress further release
Negative feedback prevents oversecretion of the hormone or over activity of the gland

DOWN-REGULATION

High plasma concentrations of NE result in decr density of B adrenergic receptors
chronic tx of pt with B2 agonists results in tachyphylaxis d/t down regulation and a decr in receptor density --> will require more drug to have same effect
the phosphorylation site in the GPCR is responsible for the down regulation process
the receptor becomes "uncoupled" and removed from sarcolemma membranes through a sequestration process

temporarily stored for later use or
destroyed and recycled

HYPOTHALAMUS
*Small but extremely important part of diencephalon
*contributes to control of endocrine, autonomic, and behavioral functions

Roles:

controls release of 8 major hormones by hypophysis (AKA pituitary)
temperature regulation
control of food and water intake
sexual behavior and reproduction
control of daily physiological cycles and behaviors
mediation of emotional responses (pleasure, rage, olfactory)
plays a role in pain perception and modulation

Hypothalamic control of Pituitary Hormones:

Hormonal secretion is controlled by nervous or hormonal signals from hypothalamus
The hypothalamus is connected to the pituitary by the hypophysial stalk

PITUITARY GLAND (HYPOPHYSIS)

1 cm; 1 gm
sits in sella turcica at base of brain (turkish saddle)
Has 2 distinct portions that are embryologically different
between the 2 structures (ant and post pituitary) a small avascular structure known as pars intermedia is found. Avascular divider that has no function in humans --> similar to corpus callosum in brain

Anterior Pituitary = Adeno-hypophysis

Arises from Rathkey's pouch, an invagination of the pharyngeal epithelium
cells are epithelial in origin
secretes 6 important hormones:

Growth hormone
adrenocorticotropin
thyrotropin
prolactin
follicle stimulating hormone
luteinizing hormone

Anterior Pituitary control:
Hypothalamic releasing or inhibitory hormones are secreted in the hypothalamus. These substances travel to the anterior pituitary via the hypothalamic hypophysial portal system.
This vascular system coalesces (comes together) at the median eminence ("prominence") where the substances are released to affect the anterior pituitary function.
The substances control the release or the non release of anterior pituitary hormones

Median Eminence:
considered Circumventricular --> secretions here circumvent the BBB (outside the ventricles; not inhibited by BBB)

Releasing and inhibitory factors control the secretion of the anterior pituitary:

Hypothalamic Factor --> Hormones released from the anterior pituitary
Thyrotropin releasing h. --> TSH
corticotropin releasing h. --> adrenocorticotropin
growth hormone releasing factor --> growth h.
growth hormone inhibitory factor (somatostatin) --> anti-growth h.
gonadotropin releasing hormone --> follicle stim h. and luteinizing h.
prolactin inhibitory and prolactin releasing h. --> release of prolactin or inhibition of prolactin release

Posterior Pituitary = Neuro-hypophysis (glial cells)

embyonic origins are from neural tissue growth from hypothalamus; large number of glial type cells (pituicytes)
pituicytes are supporting cells for terminal nerve fibers that originate in the super optic and paraventricular nucleic of hypothalamus
secretes 2 peptide hormones:

antidiuretic hormone (ADH) --> formed in super optic nuclei
oxytocin --> formed in paraventricular nuceli

each site is capable of producing about 1/6th as much of the second hormone as its primary hormone if needed (redundency)

GROWTH HORMONE

Stimulates cartilate and bone growth
releases fatty acids from stored adipose tissue for energy
fat is preferentially metabolized under growth hormone influence
may lead to ketogenic effect d/t acedo-acetic acid formation
contributes to fatty liver

Abnormalities:
Pan hypopituitarism: global decrease in all anterior pituitary hormones; may be congenital or acquired (cranial pharyngeoma; chromophobe tumor)

Dwarfism: all body parts develop in proportion to one another but at a greatly decreased rate. Most do not experience puberty d/t lack of gonadotropin hormones. 1/3 of dwarfs demonstrate normal sexual function and simply lack growth hormone

Gigantism: in children, all body parts grow rapidly and teenagers may grow 8 ft tall d/t open epiphyseal plates; hyperglycemia d/t beta cell burnout in pancreas is common

Acromegaly: in adults with closed epiphyseal plates, bones become thicker and soft tissues proliferate; commonly affects cranial bones and airway management (fiber optic; glidescope); skull, protrusion of madible, hands, feet

ADRENAL GLANDS
2 each, weighing 4 gm; located on superior poll of kidneys

Adrenal Medulla (20% of gland)
SANS system - secretes Epi and NE

Adrenal Cortex (80% of gland)
secretes corticosteroids synthesized from steroid cholesterol

Mineralocorticoids - Aldoesterone - affect minerals such as Na and K
Glucocorticoids - Cortisol - affect glucose levels, protein and fat metabolism and stress response; 3/4
Androgens - sex hormones

Zones of Adrenal Cortex

Zona Glomerulosa (15%) - secretes aldosterone, primarily controlled by angiotensin 2 and K levels
Zona Fasciculata (75%) - secretes cortisol and corticosterone controlled by ACTH; most important
Zona Reticularis (10%) - deepest layer, secretes androgen or sex hormones, controlled by ACTH; least important

G-F-R

THYROID GLAND
weighs 20 gm in adults

secretes thyroxin (T4) 93% of total secretion, and triiodothyronine (T3)
secretion increased the metabolic rate of all cells
lack of thyroid hormone can drop basal metabolic rate below 50% of normal
thyroid secretion is controlled primarily by thyroid stimulating hormone (TSH)
thyroid gland also secretes calcitonin important for calcium metabolism

Iodine is required for formation of thyroxine

1 mg/week required to prevent iodine deficiency
to prevent deficiency, common table salt is iodized
thyroid hormone have slow onset and long duration of action

Saturday, July 28, 2012

Advanced 1: LIVER DISEASE

The Liver:

Functional Unit is the Hepatic Lobule (-->Ascinis --> portal triad)
50-100 K present in normal liver
Primary blood supply is the Hepatic Artery (30%) and Portal Vein (70%) representing 30% of cardiac output
As the blood supply is from the gut, it contains large numbers of colonic bacilli

Filtering function of the liver:

primary physiologic function
bacterial cleansing (99% of the load) is cleansed by the macrophages (Kupffer's Cells) lining the hepatic sinuses
endothelial cells also line the hepatic sinuses. They are permeable to large plasma proteins allowing to move freely into the extravascular spaces of the liver.
phagocytize bacteria
cell ghosts

Kupffer Cells are Component of: Monocyte - Macrophage/Reticuloendothelial System
Responsible for:

processing antigens
release of some proteins, cytokines and mediators
removes bacteria, endotoxins, cellular debris, viruses, proteins, and other cellular garbage from portal circulation
inflammatory mediators
shit that comes from the gut (mesenteric and splenic veins)
pulls out nutrients and proteins that we eat

Stellate cell = Ito cell (become fibrotic in inflammatory process; proliferate, fill up Space of Dise; lumen of vessel shrinks and encapsulate vasculature. Normal pressure of portal vein is 7-10 mmHg [low pressure high flow system - similar to lungs])

Fat - CHO - Protein Metabolism:

Glucose absorbed postprandial (after meals)
Stored as glycogen
Sites of glycogen storage: muscle & liver
When storage is maximized, excess glucose is converted to fat (adipose)
Insulin enhances glycogen manufacture by the liver as does: glucocorticoids, thyroid hormone, epinephrine

Carbohydrates:

Epinephrine encourages glycogenolysis
The liberation of liver glycogen for energy source (Glucagon as well)
Glycogen storage is approximately 70gm (max)
Daily requirements are twice that
Glycogen stores are depleted after 24 hours of fasting

start using ketones from fat
Gluconeogenesis helps maintain normal BG levels (neo source; from a non carbohydrate source, usually lactate but also protein and fat)

Fats:

excess CHO are converted to fat when storage is maximized
fatty acids can then be used immediately for fuel or stored in tissue (3x as many calories from fat than from CHO)
RBCs and renal medulla are unique in that they can utilized only glucose as energy source
neurons in CNS utilized only glucose under normal conditions

in starvation states neurons can switch their metabolic machinery to break down ketone bodies, the result of anaerobic metabolism

Acetoacetate is the favorite ketone of the liver

converted to Acetyl-CoA for energy and to act as a substrate for building cellular membranes and organelles

Protein:

Deamination of amino acids (taking apart amino acids)
Converts AA to ketoacids producing an ammonia byproduct
Formation of urea from toxic and ammonia: produced here and in gut by enteric flora
Formation of plasma proteins:

Quantitative priorities (need volumes of them):

Albumin (& gamma globulins)
alpha-1 antitrypsin
other protease-elastases

Qualitative priorities:

coagulation factors

All factors but F 8 and von Willebrand Factor produced by the liver
tissue factor (F3) synthesized by endothelial tissue (= platelet tissue factor)

The first sign of reduced hepatic synthesis: PT - prothrombin time increases

albumin level decreasing is NOT an early sign bc 1/2 life is 14-20 days
hypoalbuminemia is a chronic sign

Metabolism of Anesthetic Agents:

Phase 1 Reaction: P450 oxidase pathways

Inducible --> can make those things work harder (ETOH)

"enzyme induced"
"circulation time"

oxidation/reduction reactions
Identify the patient that may require more drug/less drug? enzyme induced
Identifying agent that inhibits 450 oxidase
identify a breakfast drink that does the same - grapefruit juice, watercress
What does the high hepatic extraction rate of morphine, lidocaine, and trandate mean to you?

high extraction rate: significantly drops the dose (we need to give more drugs)

Phase 2 Reactions: Conjugation

Don't necessarily follow phase 1 reactions
become more polarized
fentanyl - fat - lipid soluble; liver conjugates it to a water soluble product
generally involve conjugation with:

glucuronide - primary conjugator
sulfate
glycine

BACK TO THE LIVER....

Blood flow depends upon Splanchnic & GI supply
Volatile agents will decrease blood flow
Halothane by up to 25%, and abolishes the vasoconstrictive response to increase CO2
Hepatic artery has capacity to vasoconstrict and vasodilate; portal vein cannot

Primary Functions of the Liver:

bile production
insulin clearance
lactate conversion to glucose (gluconeogenesis)

also from Alanine and Glycerol

drug metabolism and transformation
degradation of insulin
hormone metabolism

Thyroxin (liver) --> trithyroiodine, more active form
men develop feminine characteristics in hepatic disease

ADH, thyroid, glucagon, aldosterone, cortisol & estrogen
Vitamin storage in hepatocytes (A, B12, E & D)
Transferrin and heptoglobin synthesis effects Fe metabolism
Ceruloplasmin necessary for copper metabolism (Wilson's disease - 10% of hepatic transplants - women; neuropsych issues; copper accumulates in basal ganglia; copper in eyes - kaiser flasher ring)
A, D, E, K - fat soluble vitamins - a duck eats kake

Anatomic Considerations

blood supply to liver: hepatic artery and portal vein --> hepatic sinusoidal channels, serving as capillaries
endothelial cells and Kupffer's cells line the sinusoids
bile canaliculi, between the hepatocytes, empty into terminal bile ducts

Hepatic Blood Flow

Hepatocytes surround the central veins, empty to hepatic veins, emptying into inferior Vena Cava
extensive arcade of lymph channels are present within the layer of cells

Bile

Primary secretion of liver
1 L/day produced by hepatocytes
contains phospholipids, cholesterold, conjugated bilirubin: end product of Hgb breakdown
stored & concentrated in gall bladder (5-12x), released under influence to CCK into duodenum via Sphincter of Oddi
Aids in absorption of fat and fat soluble vitamins (ADEK)

metabolic end products of drug metabolism removed via bile
liver disease results in delayed bile production and/or flow

resulting in steatorrhea (fatty stool)
Vitamine K deficiency
delayed removal of active drug metabolites

Coagulopathy in Liver disease

All factors produced by liver except F8 and vWF produced by endothelial cells
50% liver function necessary for normal clotting factor production
impaired bile production results in decreased bile production impairing production of Vitamin K dependent clotting factors (2, 7, 9, 10)
Only need to replace FFP up to 50% (not 100%)

Follow the cascade:

Intrahepatic obstruction to blood flow results in portal HTN

congestive splenomegaly
sequestration thrombocytopenia (spleen captures platelets)
inducing coagulopathy

Due to:

impaired coagulation factors
diminution of circulating functioning platelets (left over plts don't work well)

Treatment of coagulopathy

Parenteral (injected) Vitamin K --> IM
significant disease may require administration of FFP and platelets
subarachnoid and epidural are not done in presence of frank coagulopahty-->subarachnoid hematoma
instrumentation of nasopharynx (NGT) or any invasive procedure must be approached cautiously in presence of clotting derangement (esophageal varices) - Afrin/oxymethazole

Proteins

all proteins except some immunoglobulin's produced in liver
low protein level

low plasma oncotic pressure
decreased drug binding in highly protein bound drugs (barbiturates, versed)

may result in exaggerated effect of these drugs
plasma oncotic pressures shifts results in large volume of distribution of drug
increased VD may result in need for increased dosing of NDMR (higher initial dose and lower redose)
VD curve is skewed
Rx ends up in ascites

Plasma Cholinesterase

produced by liver
may be dificient in disease states
cholinesterase deficiency prolongs: Succs, Mivacurium
Also may enhance the potential toxity of Ester LA: tetracaine, procaine, chloroprocaine and cocaine

metabolized by PC

Biotransformation
Phase 1 Reactions: oxidation/reduction reactions, deamination, methylation, hydrolysis
Phase 2 Reactions: conjugation with glycine, sulfates, glucuronide, then ready for elimination in bile or urine

Phase 1 + Phase 2 = deactivation and then transformation into water soluble byproducts; these products are then excreated in bile and/or urine

All Revved Up

overproduction of CYP450 system results in increased hepatic enzymes
Causes:

ETOH
Benzodiazapines
Ketamine
Barbiturates

Result: increased requirement for sedatives, opioids, neuromuscular blockers

Cimetadine

decreases the activity of these enzymes, increasing the effect of some anesthetic agents, potentially prolonging wake up
same thing with grapefruit juice

HEPATIC DISEASES:

Jaundice: not a disease, but a sign of disease

Post-hepatic Jaundice: Obstructive jaundice
Caused by an interruption of biliary release
Most common causes:

gallstones obstructing the common bile duct
pancreatic CA
parasites (liver flukes) can set up housekeeping in the common duct causing obstruction

Other causes: strictures of the CBD

biliary atresia (blind pouch) - no outlet for gallbladder
ductal or ampullary carcinoma
pancreatitis - gall stones (cholesterol stones) block pancreatic duct - autodigestion
pancreatic pseudocyst (not a complete wall) not a carcinoma - can rupture and aspirate pancreatic bolus of digestive enzymes --> RSI

*ERCP
*narcotic can cause sphinter of Oddi spasm - but not a big deal; glucagon

HEPATITIS

Hepatitis A

Short incubation: 15-45 days
Acute onset
highly contagious carried by hands, feces of infected carriers, or contaminated shell fish
may be transmitted by IV drug users and sexual contact
virus is shed in stool for up to 3 weeks before the onset of jaundice
immune globulin and Hep A vaccine provide immunity
does NOT lead to chronic liver disease

Hepatitis B

Long incubation: 45-160 days
subtle onset
often very sick
chronicity - children 80%, Adults 5%
transmission via infected blood products, bodily fluids or sexual contact with asymptomatic carrier
large population has serum antibodies conferring immunity to Hepatitis B
up to 30% may be asymptomatic infectious carrier as B surface antigen persists in the patients blood (HBs Ag)
post-exposure prophylaxis with hyperimmune globulin injection is effective for HBV but not HCV
infectivity correlates with the amount of viral RNA in patient's blood
infection confers immunity to further HBV infections

Hepatitis C

Incubation: 30-70 days
transmitted via parenteral routes, blood products, occupational exposure and IV drug use
may be transmitted by razors and toothbrushes
most common blood born infection in US
blood is screened for HCV and transmission rates are low
perinatal infection mom to fetus rates are also low
depends on the viral load

Formerly known as Non A Non B
1% become asymptomatic infectious carriers
predominant liver disease in USA
HCV progression to end stage liver disease is slow - cirrhosis in 20 yrs --> cancer
HCV is the leading indication for hepatic transplant (OLT)
HCV cirrhosis also responsible for large numbers of hepatocellular cancers (hepatoma)

HDV (Delta Virus)

HDV occurs only in patients with coexisting Hepatitis B and worsens the symptoms
you are protected from HDV if you have immunity to HBV

Hepatitis E

Enteric Non A-Non B
transmitted via oral fecal route
not found in USA

Hepatitis S&S

Gradual or sudden
dark urine, fatigue, anorexia, nausea, fever, headache, abdominal discomfort
pruritis
jaundice (but could be getting better) --> icteric; scleral icteris in dark-skin ppl
acholic or clay colored stools

Treatment of Hepatitis

Symptomatic and supportive care
HCV interferon with ribaviron administered
may rarely develop encephalopathy and coagulopathy necessitating hepatic transplant
administer gamma globulin and give vaccine within 24 hours of exposure (with Hep A or B)
for Hep C there is nothing you can do that will statistically change outcomes; routinely given ribaviron

Causes

CMV: cytomegalovirus; Epstein-Barr Virus (mononucleosis - kissing disease)
Herpes Simplex - Coxsackievirus
VAAs - any drug that decreases hepatic blood flow - Halothane....Sevo is the safest
drug induced hepatitis indigtinguishable from acute viral hepatitis

N/V - 2 weeks
Jaundice if it occurs when viral titers peak - last up to 12 weeks
return of serum transaminase to normal levels - possibly 4 months to return to normal

LABORATORY ANALYSIS OF LIVER FUNCTION

Large functional reserve allows significant disease to exist prior to its reflection in laboratory values

Bilirubin
In its original form, bilirubin is fat soluble
Glucuronyl transferase modifies bilirubin as it arrives at the liver and converts it to a water solube compound
This process is called bilirubin conjugation as bilirubin is attached to a water molecule
Green substance in bilirubin --> biliverdin
Bilirubin is yellow

conjugated bilirubin is then excreted into the bile and is released into the gut
impairment of any of these steps results in distribution of bilirubin, unconjugated, conjugated or both throughout the body
unconjugated bilirubin (fat soluble) accumulates in fatty tissues, most notably in the skin
the presence of this yellow pigment produces jaundice

If excretion of water soluble conjugated bilirubin is impaired, jaundice may also occur.

Jaundice indicates one of 4 problems:

increased RBC breakdown - prehepatic
failure of hepatocyte conjugation - hepatic
failure of hepatocyte excretion of conjugated bilirubin into the bile canaliculi - hepatic
extrahepatic obstruction (gallstones) - post hepatic

*In liver disease, problems 2 and 3 usually occur together; parenchymal disease --> obstructive disease

Normal values: 0-1.0
Marked elevation may signal:

prehepatic --> hemolytic process
hepatic --> failure of conjugation (parenchymal disease) unique to organ; excretion into canniliculi is blocked - goes to spaces of dise and lymph channels --> high conjugated bilirubin, acholic stools
post hepatic obstruction --> extrahepatic obstruction

Aminotransferases or Transaminases:

ALT: Alanine aminotransferase

*ALT more specific indicator of liver damage compared to AST
Always Liver Toxic (ALT)
Normal range: 10-55 u/L
Circulating T1/2 about 24 hours

AST: Aspartate aminotransferase

Nonspecific indicator of tissue damage
also found in brain, pancrease, and heart
Alternate source toxin - From somewhere else that has inflammation
Normal range: 10-40 u/L
Circulating T1/2 about 24 hours
AST/ALT > 2 suggests alcoholic liver disease or cirrhosis of any cause

AP: Alkaline phosphatase

May be elevated in many types of liver disease, extra or intrahepatic cholestasis or liver tumor - released from ductal cells in inflammation
found in disease involving bone growth and Paget's disease and intestinal tumors
found in normal states involving growth: children and teens experiencing rapid growth; prenancy
Normal: 45-115 u/L
Circulating T 1/2 is 7 days
AP = Also Paget's disease

GGTP: gamma glutamyl transpeptidease

Normal range: 0-30 u/L
stimulated by many of the intrahepatic factors that stimulate alkaline phosphatase
used as a marker for alcoholic liver disease GGTP/AP > 2.5 suggest alcoholic liver disease
also found in kidney, spleen, pancreas, heart
Get Granny the Pabst (Blue Ribbon)

Electrophoresis - can separate the AP entities
Allows separation of hepatobiliary isoenzymes from other isoenzymes (5NT and LAP found elevated in third trimester)

*Elevated GGTP levels reflects the most sensitive marker for hepatobiliary disease

Prothrombin Time

Normal values: 11-12.5 seconds
INR: 0.9 to 1.2
PT is the first marker in acute liver disease to decline
prolongation represents a decreased synthetic capacity of the liver
PT factors: 1, 2, 5, 7, 10

If PT is unresponsive to vitamin K, liver failure exists
extra hepatic prolongation may occur in Vit K deficiencies
Causes: malabsorption, malnutrition, long term antibiotics

Albumin

Normal values: 3.5-5 g/dL
low albumin levels represent the livers' decreased ability to synthesize albumin as seen in chronic liver failure
extra hepatic influences of hypoalbuminemia: malnutrition malignancy, infection, nephritic syndrome (protein and RBC loss)
albumin produced by the liver - easily measured and is main constituent of total protein
the remaining fraction is called globulin (including the immunoglobulin)
albumin levels are decreased in chronic liver disease, such as cirrhosis
also decreased in nephritic and nephrotic syndrome where it is lost through urine
poor nutrition and protein catabolism may also lead to hypoalbuminemia
T1/2 is approx 20 days

Blood Ammonia

Elevation reflects a disruption of hepatic urea synthesis
Normal: 82-110 mg/dL or 47-65 mmol/L
reflective of severe hepatocellular damage
ammonia levels do not correlate well with level of cellular destruction

CIRRHOSIS

The end result of a variety of progressive liver disease

Commonly:

ETOH
HBV
HCV
alcoholic cirrhosis (Laennec's cirrhosis)

scarring and fibrosis disrupts the liver architecture
unequivocal diagnosis: liver biopsy

Guidelines: INR < 1.5, Platelets > 50,000

CT scan, MRI, ultrasound, doppler flow studies may reveal findings consistent with cirrhosis such as:

splenomegaly
ascites
irregular enlarged liver an early sign
small hard liver a late sign d/t contracted fibrotic organ
spider nevi
gynecomastia
testicular atrophy
portal HTN
ascites & splenomegaly are characteristics of cirrhosis but not diagnostic

VAAs

Halothane: trifluroacetyl metabolites - autoimmune
Sevo does NOT generate trifluroacetyl metabolites
Halothane significantly decreases blood flow to liver

Acetaminophen overdose; 25 gm = fatal dose

causes profound hepatocellular necrosis
glutathione stores are exhausted
**toxic metabolite is unable to be conjugated for excretion
treatment: supportive
Administer N-acetylcysteine (Mucomyst) via NGT - precursor to glutathione
phase 1 metabolism - 20% of end product is toxic

Hepatotoxicity:

results not from Acetaminophen directly
actually from its Phase I metabolite: N-acetyle-P-benzoquinoloneimine (NAPQI) also known as "Toxic Metabolite"
Moving to phase II - glutathione stores are rapidly depleted
direct hepatocellular damage occurs and irreversible liver damage results

Drug Induced Hepatitis:

ETOH, ASA, tylenol, Shrooms
Idiosyncratic: Halothane, Phenytoin, Indomethacin, Sulfonamides
Primary cholestatic: chlorpromazine, oral contraceptive, anabolic steroids, e-mycin and methimazole

STAGES OF LIVER DAMAGE

ETOH 65 gm/ day x 15 years = cirrhosis

BLOOD FLOW IN PORTAL HYPERTENSION

TYPES OF CIRRHOSIS:

Primary Biliary Cirrhosis: autoimmune; occurs in women 30-50 y/o

Hemochromatosis: a disease of iron (Fe) deposition; DM and cardiomyopathic problems; die of CA

Wilson's Disease: hepatolenticular degeneration; neuro and hepatic dysfunction d/t copper metabolism error; copper desposited into basal ganglia --> mood swings and depression (10% of liver transplants); Kayser Fleischer ring (copper) around pts eyes

Non-Alcoholic Steatohepatitis: may occur with obesity, hyperlipidemia and diabetes mellitus; Fatty accumulation occurs in liver. Steato = fat

COMPLICATIONS OF CIRRHOSIS

Portal HTN
Gastroesophageal Varices: submucosal veins dilate d/t high pressure portal blood flow to low pressure azygoes and hemizygous thoracic veins
Bleeding may be significant

Diagnosis: EGD, may band - not usually intubated unless ascites is significant or actively bleeding

Hemorrhoids also d/t shunting of hyperdynamic blood flow to low pressure areas; not a life threatening issue, but unpleasant for patient (and clinician)
Hepatorenal syndrome: usually fatal d/t decreased blood flow and markedly reduced GFR
malnutrition
arterial hypoxemia

d/t ammonia accumulation
presence of ascites inhibiting diaphragmatic excursion
hyperdynamic shunting

hypoglycemia d/t inefficient glycogen stores
formation of gallstones (cholelithiasis) - obstruct pancreas --> pancreatitis
bleeding from duodenal ulcers
hepatic encephalopathy (ammonia levels)
asterixis --> liver flap/twitching
not able to metabolize insulin
Dupuytren's contractures
impaired estrogen metabolism

PREOP PREPARATION OF PATIENT WITH LIVER DISEASE

Postpone surgery until lab values return to normal

periop morbidity increases 12% and mortality increase 10% (with laparotomy) during acute viral hepatitis episodes

Postop, hepatitis patients are at risk for:

fulminant hepatic failure
encephalopathy
coagulopathy
hepatic renal syndrome

Objective: decrease the periop mortality and morbidity associated with liver dysfunction
identify cardio respiratory dysfunction
alcoholic cardiomyopathy
coagulopathy
renal function
assess IV volume
lab analysis
nutrition issues
PT is best indicator of hepatic synthetic function

if PT prolonged > 3 sec or INR > 1.5 following vit K admin, severe hepatic dysfunction is present
vit K usually beneficial in the presence of obstructive biliary disease (post hepatic) as opposed to parenchymal disease (hepatic)
bile salts are needed to facilitate absorption of vit K in gut

may need FFR/ platelets
evaluate blood glucose levels: generally labile
other comorbidities

RESCHEDULE FOR ACUTE ALCOHOL INTOXICATION

Perform serum ETOH level if you suspect ETOH consumption
alcohol withdrawal presents mortalities as high as 50%; only true emergencies should be considered
alcoholic patients present cross tolerance to anesthetic agents
requires close CV monitoring d/t cardiac depressant effects of ETOH and anesthetic agents
alcoholic cardiomyopathy may be present
VAAs, d/t their decreased metabolic profile, are preferred over IV agents

isoflurane has lowest effect on renal blood flow and hepatic blood flow; agent of choice

IV induction doses are ok as their action is terminated by redistribution not metabolism
Be aware of prolonged duration of action with repeated doses
avoid hypotension, SANS stim & high peak airway pressures in order to maintain steady-state hepatic blood flow
regional anesthesia may be employed in the absence of coagulopathy if arterial hypotension is avoided

INTRAOP MANAGEMENT OF PATIENT WITH LIVER DISEASE

Hepatic blood flow already decreased in this patient

d/t increased resistence to blood flow via portal vein
anesthetic induced depression of cardiac output or hypotension may jeopardize hepatic blood flow
be prepared for possible impaired response to catecholamines in presence of acute surgical blood loss

low protein levels promotes an increase in the pharmacological active fractions of injected drugs

more drug available to receptor sites

severely jaundiced patients are more likely to develop sepsis and renal failure postop

Serum bilirubin > 8 mg/dl
Rx: diuresis with mannitol and antibiotic therapy

hepatic artery becomes more important now as this vessel can dilate in response to decreases in portal blood flow
hepatocyte oxygenation is maintained with Iso, Sevo, and Des, but NOT halothane

limit dose but give what is needed
supplement with N2O and IV agents as appropriate
maintain BP; hypotension correlates with incr mortality

cumulative drug effect may be enhanced d/t decreased hepatic metabolism

Vec not a clearance problem until dose exceeds 0.1 mg/kg
Miva, Atra, and cisatra are good choices (non-organ dependent elimination)

stress induced SANS stim decreases hepatocyte O2
Monitor ABG: portosystemic and intrapulmonary shunts dilate in response to anesthetic agents = hypoxemia
CVP and PAC may be necessary to eval volume status
monitor blood glucose

admin glucose containing infusions as necessary
glucose containing solutions are hepatocyte sparing

when giving blood products:

give slowly
citrate is not cleared by liver and may precipitate hypocalcemia and hypotension

maintain UOP to help reduce the incidence of postop renal failure; give mannitol to establish diuresis & free radical scavenger
avoid unnecessary esophageal instrumentation: temp probe, stethoscope, OGT
avoid nasal instrumentation
preop discussion should include:

large bore IV access
invasive monitoring
blood and blood products

portocaval shunt procedures usually require full invasive lines (aline, CVP, PAC)

MASSIVE BLOOD TRANSFUSION IN LIVER RESECTION

Major complications of massive transfusion include:

citrate toxicity
acid-base abnormalities
hypothermia
hyperkalemia and hypocalcemia
DIC (disseminated intravascular coagulation)

Massive transfusion: the replacement by transfusion of more than 50% of a patient's blood volume in 12-24 hours

May be associated with a number of hemostatic and metabolic complications
Involves the selection of the appropriate amt and types of blood components to be administered.

Requires close attention to:

volume status
tissue oxygenation
management of coagulation abnormalities
ionized calcium/potassium
acid-base balance: metabolic alkalosis (citrate --> lactate --> HCO3)
hemostasis
hypotension d/t bradycardia (hypocalcemia decr contractility and rate)

one unit of PRBC = 300 ml
contains 200 ml of RBC (2/3 cells; 1/3 Na citrate - 100 ml)
One unit of PRBC will raise Hct by 3-4% without continued bleeding

O2 release at the tissue level by transfused RBCs is diminished compared with native red cells
storage reduces 2,3 DPG (diphosphoglycerate) levels
shift to the LEFT of the oxyhemoglobin dissociation curve during massive transfusion
the transfused cells regenerate 2,3 DPG to normal levels within 6-24 hours after transfusion

HEPATIC RESECTION CASE STUDY

Key Points:

most common cancers that arise in liver are d/t hepatocellular carcinoma and mets from colorectal cancer
majority of hepatic rxns are performed for removal of cancerous tissue
bleeding and hemorrhage are major risks associated with hepatic rxn
epidural analgesia can be used to attenuate the stress response and decrease postop pain

Anatomy and Physiology:
1.5 kg
4 lobes: right, left, caudate, quadrate
*Classic description does not include internal features such as vessels and biliary duct branching that are vital for hepatic surgery

*More common functional anatomic model - Couinaud Classification - is used for anatomic liver rxns --> divides liver into 8 functionally independent segments with each segment having own inflow and outflow vasculature
liver lobule: composed of hepatocytes, sinusoids, kupffer cells in trangular arrangement around central vein
Normal hepatic blood flow 1500 ml/min or 25-30% cardiac output

Functions performed by liver:

gluconeogenesis (glucose from AA, lactate, glycerol)
glucogenesis (glycogen from glucose)
glycogenolysis (glycogen to glucose)
cholesterol synthesis
lipogenesis (production of triglycerides)
clotting factors: I (fibrinogen), II (prothrombin), V, VII, IX, XI, protein C, S, antithrombin
storage for folate, glycogen, fat soluble vitamins (B12, ADEK), iron, copper
Hgb from RBC broken down to bilirubin and converted to biliverdin by liver to facilitate excretion
ammonia to urea

Hepatocellular Carcinoma (HCC):

AKA primary liver cancer or hepatoma

primarily caused by chronic HBV, HCV and cirrhosis d/t alcohol abuse

S&S:
initial - abdominal pain, unexplained weight loss
with cirrhosis - jaundice, ascites, esophageal varices, portal HTN

**In patients who have HCC WITHOUT cirrhosis - liver resection is treatment of choice.**

if patients have cirrhosis (as cause for HCC), liver rxn is limited --> high risk of postop liver failure
percutaneous ethanol injection and radiofrequency ablation may be an option for tx
Ultimately - liver resectability is judged by liver function, stage of liver CA and overall condition of pt.

Surgical Resection:
1. Segmental anatomic surgery: ligation of vasculature PRIOR to resecting liver parenchyma

2. Nonanatomic division of liver (wedge rxn): ligating and resecting vessels and ducts as they are encountered during rxn of parenchyma - only tumor with margin is removed

Preop Considerations:

labs: elytes, glucose, LFTs, coags, CBC, T&C
CXR, CT, ECHO, abdominal u/s
Lines
tx/optimize those who are coagulopathic by admin of blood products/antifibrinolytic meds
prepare to admin RBCs and albumin
rapid fluid infusing device in room
epidural catheter
3D mapping

Intraop blood loss is most important determinant of survival in first few days postop.
Methods to reduce blood loss:

hemostatic stapling
cavitron u/s surgical aspirator (CUSA) - ultrasonic dissection
clamp crushing technique
Pringle maneuver - occlusion of main blood vessels but can cause ischemia - 15-20 min clamp followed by 5 min reperfusion period
total vascular occlusion - occlusion of arterial and venous flow to liver and out of liver
managing CVP

Low CVP:

achieved by fluid restriction, postural changes, vasodilators, diuresis
CVP < 5 mmHg facilitates lower blood loss
IV nitrolycerine and lasix
Reverse T to decrease CVP
Oliguria may occur but rate of postop renal failure does not incr when SBP is maintained > 90 mmHg
at completion of liver rxn, volume resuscitation with crystalloid and albumin to normalize hemodynamic profile & discover areas of bleeding
low CVP may incr risk for VAE * common occurrance with liver rxn - usually does NOT result in physiologic compromise

VAE treatment:

100% O2
aspirate air via central line from RA
T-berg and L lateral decub
IV fluids
vasopressors to incr BP
ACLS prn

Laparoscopic liver rxn:
*can be done for CAs that are present on surface of liver where larger blood vessels are not affected
absence of larger incision, decr postop pain, decr LOS, decr recovery time

Intraop Period

routine monitors, CVP
Rx to reduce gastric volume and incr pH
RSI with cricoid
consider hemodynamic status prior to choosing induction agent
NMBD that are non organ dependent metabolism
N2O incr risk for VAE
fentanyl and sufentanil are ok
control BS
hypothermia inhibits coagulation cascade & contributs to blood loss
monitor coagulation: admin plts, FFP, cryo prn
antifibrinolytics (aminocaproic acid and tranexamic acid) preop for procoagulation

Postop Period

pain control: epidural or PCA +/-
Postop complications: Hemorrhage, respiratory complications (atelectasis, effusion, PNA), e-lyte abnormalities, hypothermia, hypoglycemia, DIC

Sunday, July 29, 2012

Phys: FLUIDS

Phys: NEUROMUSCULAR

Phys: ENDOCRINE

Saturday, July 28, 2012

Advanced 1: LIVER DISEASE

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