Neuro

• CP is not a risk for hyperkalemia after succinylcholine because acetylcholine receptors are not upregulated due to contractures
• For pts with MS, spinal anesthesia has been linked weakly to flareups so use epidural. 
• Lithium potentiates sux and non-depolarizing relaxants
• Pacemakers and epilepsy not contraindications to ECT
• 
  

• Sux and ALS - hyperkalemia 2/2 lower motor neuron involvement
• Sux and Duchenne's - high likelihood of MH and hyperkalemia
• Sux and Guillain-Barre syndrome - hyperkalemia
• Sux and Myotonic dystrophy - contractures making it hard to mask/ventilate
• Sux and Myasthenia Gravis - resistance
• Sux and Lambert Eaton - increased sensitivity
• Sux and MS - contraindicated if pt paretic

• In myotonic dystrophy, 4 concerns.
• contractures so no succinylcholine, neostigmine, and shivering (hypothermia)
• sensitivity to anesthetics, especially respiratory depressants
• aspiration risk
• possible MH

• Hypokalemic periodic paralysis vs Hyperkalemic
• Hypokalemic: Treat with diamox or spironolactone, avoiding carbs (insulin release), hyperventilation, alkalosis
• Hyperkalemic: treat with furosemide, carbs, calcium

http://www.aana.com/newsandjournal/Documents/p297-302.pdf

Comparing etomidate vs propofol vs thiopental for neuroprotection

Summary:
All three decrease ICP indirectly by decreasing CBF, which is directly decreased by reduction in CMRO2.

However, only etomidate exhibits properties where CBF and CMRO2 are decoupled. That is, etomidate decreased CMRO2 after CBF already reached a minimum. This may be good and bad depending on the goal. For example, inducing coma for poststroke may be bad with etomidate because increased BF with decreased metabolism means more oxygen lying around to develop free oxygen radicals.

Propofol seems to have anti-oxidant effects as in test animals, infarct size was smaller initially and animals had possibly better motor skills at day 21.

Brian waves/burst suppression/isoelectric
At sedative doses or at doses associated with excitation or disinhibition ("stage 2" anesthesia), median EEG frequency increases because alpha waves (7-13 Hz) typical of the awake state change to beta waves (13-30 Hz). As the depth of hypnosis increases, there is a decrease in frequency and an increase in amplitude (power) of the EEG waves. Surgical anesthesia is associated with an EEG characterized by a predominance of delta waves (0.5-3.5 Hz). Increasing the dose of thiopental further leads to burst suppression (characterized by alternating periods of delta waves and electrical inactivity) and, finally, a completely isoelectric ("flat-line") EEG.

IV Induction Agents

Thiopental: 4-7mg/kg, GABAa receptor positive allosteric  modulator (increase length that channels opens compared to benzos which increases frequency, aka efficiacy vs potency)

Special Properties:
- in subhypnotic dose, thiopental can be hyperalgesic (lowering pain threshold), can cause disinhibition and excitation

- acute tolerance: Early studies showed plasma thiopental concentration at awakening is proportional to the intubating dose rather than depth of anesthesia. The higher the induction dose, the higher the plasma levels at awakening. This was found to be not true in further studies and accounted for by studies that peripheral venous plasma thiopental concentrations poorly reflect brain (i.e., jugular venous) thiopental concentrations.
http://web.squ.edu.om/med-Lib/MED_CD/E_CDs/anesthesia/site/content/v02/020221r00.htm

- pH 10-11, long shelf life but precipitates NMBs, which come in acidic solutions

- Pain on arterial infection. DON'T DO IT because it extensive edema, gangrene, limb loss, and even death.

#Neuro
- See neuroprotection article. Basically thiopental is equal to etomidate and propofol.

#Resp
- decreases resp drive and airway reflexes. Airway responsiveness increases and this increased coughing and largynospasm more than other IV induction agents. Increases histamine circulation which can be bad for asthmatic.

#CV: unlike propofol, thiopental does not block sympathetic response and pts are more likely to become tachycardic with thiopental than propofol on inductoio

#Heme
- absolute contraindication in porphyrias. Thiopental induces CYP450 and delta-aminolevulinic acid (ALA) synthase, which builds up in pts with porphyria (downstream mutation). ALA is neurotoxic.

Propofol

Egg allergies to yolk (Lecithin) precludes its use.
Clearance is mostly hepatic but also extrahepatic, lungs play a role


#Neuro:
also acts on GABAa receptors. Also decreases CMRO2, CBP, ICP but may decrease CPP as propofol decreased MAP more than thiopental. (CPP=MAP-ICP). Does not produce hyperalgesia in sedative doses like thiopental. Has some amnestic qualities in sedative doses as well. Antiemetic effect as well.

#Resp:
Decreases vent drive, profound in COPD pts. Incidence of wheezing is lower with propofol than etomidate of barbituates.

#CV:
Profound hypotension from decreased preload (lower SVR), decreased afterload (cardiodepressant), and decrease baroreceptors and sympahtetic reflexes. More than thiopental

Fospropofol is a prodrug that is metabolized by alkaline phsophatase to form propofol, phosphate, and formaldehyde. Supposed to cause less pain in IV, less hyperlipidemia, and less risk of bacterial infection.

Etomidate
0.2-0.5mg/kg

- activates GABAa receptors and also some possible disinhibiting of extrapyramidal system causing myoclonus 40% of the time.
- dissolved in propylene glycol, which causes pain on injection

Ketamine
1-2mg/kg

#Neuro
- dissociates thalamus from limbic cortex causing dissociative anaesthesia
- elevates ICP, CMRO2, CBP but new research shows this may not be true when combined with benzos

#Resp:
Ketamine in USA is a bronchodilator and sialagogue. However, the S enantiomer found in Europe is the more potent version of ketamine and does not bronchodilate. Does not depress vent drive much

#CV
- cardiodepressant but potent stimulator of the sympathetic system. Increases HR, BP, and myocardial demand. Bad for CAD but may be good for shock.
- spinals or sympathectomies unmask the cardiodepression

Oxygen/CO numbers

Oxygen content of blood per 100ml = 1.34 * Hgb * SpO2 = ~20ml of O2/100ml of blood
Oxygen deliver is oxygen content * CO = 1L/min
Oxygen consumption = 250ml/min
Extraction ratio is O2 consump/O2 deliver, usual is 25% max is 50%

TV 3-5cc/kg spontaneous and 7-10 cc/kg mechanical
MV 50-70cc/kg/min

Regional and Anatomy

Epidural fat causes opioid sequestration: lipid soluble opioids such as fentanyl and sufentanil have decreased net transfer from epidural to intrathecal space. Lipid solubility reduces bioavailability.

Similarly, etidocaine, which is 7x more potent than lidocaine but more lipid soluble, is effective equipotent in the epidural space. 

• CSF volume is 100-160ml in adults and produced 500ml/day. CSF has very little movement and does not distribute drugs effectively. 

• Spinal cord extends to sacrum in utero and shrinks to L3 at birth to L1 as an adult. Spinal cord gives off 31 pairs of spinal nerves that are made up of an anterior motor root and posterior sensory root. T1-L2 intermediolateral gray matter contains cell bodies of preganglionic sympathetic neurons. 
• Epidural test dose with 3ml of local anesthetic containing 1:200,000 of epinephrine is used to detect increase in HR of 30 in 30. Pts who are beta-blocked may use BP elevation of >20mmHg. Women in labor who have natural HR elevations 2/2 contractions can use isoproterenol. 

Baricity and Positioning is the ratio of the density of a local anesthetic solution divided by density of CSF. Baricity affects block height and thoracic blocks can be achieved with hyperbaric solution in supine or trendelenberg positioning. Hypobaric with sitting position is not used because it results in too high of a block. Saddle blocks can be achieved with hyperbaric solution in sitting or hypobaric in prone. Hypobaric solution given in lateral supine position is also useful as unilateral block on the upward side. Distribution by gravity becomes fixed after enough dilution in CSF (can take 60 minutes). Isobaric solutions tend to have variable block concentrated in the lower thoracic. 

Dose, volume, and concentration

In isobaric solutions: Volume and concentration have no effect. Lower total dose can produce lower blocks (at least in bupivacaine but not tetracaine).

In hyperbaric solutions: positioning is king. But lower total doses again produces lower blocks in bupivacaine but not tetracaine (2.5 dermatomes lower). 

Dosing does affect duration of block with larger doses creating longer blocks. 

Injection site

Only in isobaric solutions does this matter. Decreasing injection site by 1 vertebrae can lower height by 2 dermatomes with bupivacaine.

• CSF volume down (higher block) - pregnancy, older, kyphoscoliosis, ascites (engorgement of epidural veins). Obesity increase CSF volume!
• Adding fentanyl to spinal quickens onset and deepens sensory block
• Intrathecal fentanyl compared to morphine: less respiratory depression, less urinary retention, less n/v
• Chassaignac's tubercle is C6 transverse process, which is the landmark for stellate ganglion block. Remember stellate ganglion is C7-T1 ganglion but you can't inject directly because overly vertebral artery.
• Infraclavicular is most dangerous for pneumothorax and chylothorax
• Axillary block has 3 nerves surrounding the axillary artery. The one across from the artery is radial, and one closest is median. Remember to block musculocutaneous nerve and also intercostobrachial nerves.
• Medial knee is covered obturator nerve
• Remember peroneal nerve wraps around lateral fibula, while tibial is medial to that
• 5 nerves in ankle block, superficial peroneal, deep peroneal, sural, tibial, and femoral

Anatomy
V3 - Anterior Tongue
IX - Posterior Tongue, Soft palate, oropharynx,
Internal branch of X - Hypopharynx above VC, VC
Recurrent branch of X - VC, Larynx, Trachea

Celiac plexus at L1
Artery of Adamkiewicz T8-L1

Hypertensive Meds

Labetalol:
blocks ₁-, ₁-, and ₂-receptors. The ratio of -blockade to -blockade has been estimated to be approximately 1:7. Reduction in BP w/o change in HR or CO. Onset 5 min, halflife 5 hours

B-blockers:
Atenolol excreted unchanged by kidney. Metoprolol, propranolol, labetalol have hepatic metabolism. Esmolol is metabolized by RBC esterases.
Esmolol has half life of 9min

POISE trial
8000 patients with CAD received metoprolol XL before surgery continued for 30 days. Decreased MI but increased mortality and stroke.

Pheo:
Avoid sux as abdominal fasciculates could release catecholamines. Ketamine should be avoided as it is sympathomimetic. Halothine potentiates dysrhythmias of epineprhine. Histamine release provokes catecholamines so no atracurium. Neuroaxial techniques block postganglionic discharge of catecholamines but do not block receptors so pheo still active. Chronic elevations of catecholamines can lead to cerebral hemorrhage, renal failure, heart failure, MI, dysrhythmias.

Hypotensive Meds

Norepinephrine receptors are G-protein linked and divided into a1, a2, b1, b2
a1 - raises intracellular calcium: vasoconstriction, mydriasis, uterine contraction, sphincter contraction
a2 - presynaptic endings, inhibits adenylate cyclase: vasodilatation, sedation, less addiction?
b1 - activates adenylate cyclase: positive chronotropy, dromotropy, inotropy
b2 - epi > norepi, activates adenylate cyclase: bronchodilation, vasodilation, tocolysis

Norepinephrine's action in the synapse is terminated by
1. Reuptake by postganglionic nerve ending (inhibited by TCA)
2. Diffussion by receptor sites
3. Metabolism by MAO and COMT (inhibited by entacapone, tolcapone, nitecapone)

Phenylephrine:
Continuous infusion (100 mcg/mL at a rate of 0.25–1 mcg/kg/min). Gradual tachyphylaxis

Epinephrine:
Used for vfib (50mcg to 1mg) and anaphylaxis (100-500mcg bolus followed by infusion). Volatile anesthetics such as halothane potentitate dysrhythmic effects of epinephrine.
Continuous infusion (4 mcg/ml at rate of 2-20mcg/min)

Norepinephrine:
Bolus (0.1 mcg/kg) followed by infusion at rate of 2–20 mcg/min

Ephedrine:
Used in obstetrics because does not decrease uterine Q. Non-catecholamine so longer-lasting. Some antiemetic properties particularly 2/2 hypotension from neuroaxial injections

Dopamine
1-20 mcg/kg/min infusion

Dobutamine
2-20 mcg/kg/min infusion

Clondine and Precedex:
A2 agonists, sedative, analagesic, sympatholytic effects. Reduces anesthetic requirements. Abrupt withdrawal leads to hypertensive crisis.
dexmedetomidine loading dose 1 mcg/kg over 10 min followed by an infusion at 0.2–0.7 mcg/kg/hr
Clonidine oral (3–5 mcg/kg), intramuscular (2 mcg/kg), intravenous (1–3 mcg/kg)

b1,b2 are G-proteins that stimulates adenyl cyclase increasing cAMP, which activates protein kinase A, which increases intracellular calcium

a1 is also a G-protein that stimulates phospholipase C which also increases calcium

NO stimulates guanyl cyclase and increases cGMP

Phosphodiesterases break down cAMP and cGMP, PDE5-I such as viagra causes increase in cGMP and PDE3-I such as milrinone causes increase in cAMP. Theophylline and Aminophylline are nonselective PDE-I

Opioids/NSAIDs

Alfentanil has lower lipid solubility than fentanyl but higher non-ionized fraction so it works really fast. 

All opioids can be retained by the lungs (first-pase uptake) and then redistribute once systemic concentrations fall.

Opioids have context-sensitive halflife because blood concentration is decreased from redistribution at small doses and biotransformation at large doses.

Normeperidine can cause seizures. Norfentanyl is nonactive but used to determine abuse. Codeine is a prodrug that has variable biotransformation depending on CYP enzymes. Pseudocholinesterase deficiency does not affect esmolol or remi. Both meperidine and morphine metabolites are excreted in urine. Alfentanil biotransformation is impaired by erythromycin

Meperidine has atropine-like affects (tachycardia) and causes cardiodepression unlike other opioids. Meperidine, hydromorphone, and morphine evoke histamine release and bronchospasm (benzylisoquinolones). Fentanyl-like opioids induce chest wall rigidity.

APNEIC THRESHOLD - greatest PaCO2 at which a patient remains apneic increases with opioids.

Opioids decrease CMRO2, cerebral q and volume, ICP but less than barbiturates, propofol, or benzos

NSAIDS inhibit COX, which catalyzes the production of prostaglandin H1, a key mediator of inflammation. COX2 is less selective than COX1 purely by size (ie. a bigger molecule fits in COX2 but not COX1). COX1 is widely distributed in the body and COX2 is made for inflammation. COX2 decreases the risk of platelet dysfunction but causes increased thrombosis.

Anticholinesterases

Acetylcholine is used in entire parasympathetic nervous system (parasympathetic ganglions and effector cells), parts of the sympathetic nervous system (sympathetic ganglions, adrenal medulla, and sweat glands), some neurons in the central nervous system, and somatic nerves innervating skeletal muscle

- anticholinesterases increase muscarinic stimulation, which is to be minimized by giving glycopyrrolate or atropine. Muscarinic stimulation causes SLUDGE syndrome to brady, bronchospasm, GI output

- Neostigmine onset 5 min, peak 10 min, lasts 70 min. Glycopyrrolate has similar onset compared to atropine which has faster onset. However, neostigmine crosses the placenta to cause fetal bradycardia so theoretical benefit in using atropine in preggers

- Edrophonium onset ins 1-2 min but shorter duration. Full dose should be given each time so that duration will be long enough. Use with atropine.


Anticholinergic drugs such as glycopyrrolate, atropine, scopolamine causes tachycardia, inhibits secretions, reduces GI secretions (but not enough to reduce aspiration), causes mydrasis and cycloplegia (inability to accomodate near vision), urinary retention.

Scopolamine causes reduction in motoin sickness (n/v), potent sialagogue (better than atropine), and drowsiness. Lipid solubility means it can be given via patch. Avoid in closed-angle glaucoma

Anticholinergic syndrome (alice in wonderland)

Nondepolarizing Muscle Relaxants

Metabolism/Excretion
- Liver metabolizes pancuro/vec. Biliary excretes vec/roc. Liver failure potentiates pancuro/roc> vec>>pipecuronium. Miva is metabolized by pseudocholinesterases, atra/cis metabolized by hoffman
- Kidney excretes pancuro/vec/pipe/doxa but not roc

Potentiation/Resistance
Potentiation:
- calcium channel blockers, beta blockers, magnesium, lithium, aminoglycosides, volatiles, local anesthetics
- Volatiles decrease nondepolarizer requirements by 15%. Des>Sevo>Iso>NO2 and pancuro>vec/atra
- Combining nondepolarizers of different classes (aminosteroid vs benzylisoquinoliniums) provide synergistic effects (greater than additive)
- Neuro disease potentiates N-NMBs except burn, CP, denervation, sepsis which causes resistance
- Newborns are more sensitive to NMB because of immature receptors but they also have greater extracellular space so no net effect in dosage. N-NMB have faster onset though. Vec is longer lasting.

Resistance:
- anticonvulsants (only aminosteroids?)
- Neuro disease potentiates N-NMBs except burn, CP, denervation, sepsis which causes resistance

Onset/Duration
- ED95 for NMB is the dose when 95% twitch suppression occurs in 50% of patients. Intubation dose is usually twice the ED95. Increasing the dose means faster relaxation but more side effects and prolonged block.
- Onset is 2.5 to 3 minutes except roc which works in 1.5 to 2 minutes
- Duration is 40-70 minutes except pancuronium which is 60-90 minutes
- histamine release by vec/atra can cause hypotension, vagolysis by pancuronium can cause tachycardia, older tubocurium and metocurium block sympathetics causing brady and hypotension
 -Dosage by Adjusted BW = 0.4(ABW - IBW)+ IBW. IBW = 50kg + 2.3kg*(each inch after 60)

Atracurium - histamine release (hypotension, tachycardia), bronchospasm (avoid in asthmatics, 2/2 histamine), laudanosine metabolite is degraded by liver (raises seizure threshold), hoffmann slowed by hypothermia and acidosis, anaphylaxis. Cisatracurium is 4x more potent and makes up 15% of atracurium but produces no histamine release and less laudanosine 2/2 potency.

Pancuronium - metabolized by liver with active metabolites, excreted by kidney and bile. Vagolytic and sympathetic effect. Vecuronium is similar. Prolonged infusion in ICU causes prolonged block for days.

Rocuronium - mainly excreted in liver/bile some in kidney.

Succinylcholine

Dose 1-1.5mg/kg
- higher in children who have more extracellular space
- use real weight (pseudocholinesterase increase with real weight)
- very weakly lipophilic

Duration 5-10 mins, Onset 30-60 secs

Metabolism by pseudocholinesterases
- dibucaine 80% normal, 20% homologous abnormal, 40-60% hetero; prolonged to 2-4 hours in homo, 20 min in hetero
- Medications that decrease pseduocholinesterases: phenelzine, neo, physo, edrothiophate, cyclophosphamide, metoclopromide, esmolol, OCPs
- metabolized to succinylmonocholine, which may sensitize SA node to 2nd dose of sux, causing brady

Interactions
- nondepolarizing blockers antagonize sux but prolongs phase II block
- cholinesterase blockers like neo, physo, organophosphate, echothiophate prolongs sux

CV
- brady and even asystole in children 2/2 muscarinic effects
- metabolized to succinylmonocholine, which may sensitize SA node to 2nd dose of sux, causing brady

Fasiculations and Mylagias
- possibly decreased by priming with non-depolarizing, but requires higher dose of sux 2/2 interactions

Hyperkalemia
- worst in day 7-10 after burn or trauma, minimal in 48 hours
- burns and traumas
- myopathies and GBS
- parkinsons, stroke, encephalitis, immobilization

aspergillosis

- colonizing

- ABPA requires hypersensitivity (anti-aspergillus abs, skin prick) + asthma
- Eosinophilia and elevated IgE
- CXR shows proximal bronchiectasis, fleeting infiltrates

Aspergilloma
- old bulla or cavity
- CXR shows dependent fungal ball
- no treatment

Chronic necrotizing aspergillosis
-

Invasive aspergillosis
- tissue biopsy
- surgery and anti-fungals

Thrombophilia - Thought Process

Congenital vs Inherited

• Congenital
• Type II most common and least serious
• Factor V Leiden - Mutation in Factor V so it can't be degraded by Protein C
• Prothrombin G20210A (2-3x) - high levels of prothrombin due to pre-mRNA stability
• Type I less common and more serious
• Protein S and C deficiency (5-10x)
• Antithrombin III deficiency (BTW heparin increases activity of antithrombin 3000x)
• Acquired
• Antiphospholipid syndrome - abs vs cell membrane phospholipids (lupus anticoagulant, anticardiolipin antibodies, anti-B2glycoprotein 1 antibodies)
• HIT
• Nephrotic syndrome, pregnancy, estrogen

ER shift, replacing Aviva

Pheochromocytoma - triad of headache, tachycardia, diaphoresis. Diagnosis involves 24 hour urine metanephrines and catecholamines. Treatment involves 10-14 days alpha blockade (phenoxybenzamine) and 2-3 days of beta blockade before surgery. CCB and metyrosine (inhibits catecholamine production) are alternatives. Surgery involves complete adrenalectomy if singular or cortical-sparing adrenalectomy if bilateral. Postop complications including hypotension (fluid replete) and hypoglycemia (catecholamine -> insulni resistance, give glucose infusion). If new suspicion during surgery, give phentolamine (non-selective alpha agonist).

Massive Transfusion: 50% of blood replaced in 12-24 hours. Usual ratio is 1:1:1 of FFP:platelets:pRBCs. Citrate toxicity includes hypocalcemia and metabolic alkalosis. Beware in pts with poor hepatic clearance.

TRALI: ALI/ARDS within 6 hours of transfusion. Accompanied by hypotension, fever, exudative pulmonary edema, but no hemolysis. Contrast with hemolytic rx vs TACO vs anaphylaxis. Treatment is supportive care with possible vent support.