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					0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                                                                                2010-05-           1
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THE MORRELL POS REVIEW NOTES
preface to the morrell pos notes ........................................................................................................................... 2
sutures .................................................................................................................................................................. 2
inflammatory mediators ....................................................................................................................................... 4
inflammatory cells ............................................................................................................................................... 9
bite injuries......................................................................................................................................................... 10
wounds ............................................................................................................................................................... 12
normal skin flora ................................................................................................................................................ 21
antibiotics ........................................................................................................................................................... 21
antibiotic prophylaxis......................................................................................................................................... 21
bacteria ............................................................................................................................................................... 22
burns................................................................................................................................................................... 23
cancer ................................................................................................................................................................. 26
chemotherapy ..................................................................................................................................................... 27
radiation therapy ................................................................................................................................................ 29
transfusions ........................................................................................................................................................ 30
transfusion reactions .......................................................................................................................................... 32
hemostasis .......................................................................................................................................................... 33
bleeding disorders .............................................................................................................................................. 36
procoagulant states ............................................................................................................................................. 42
hematologic drugs .............................................................................................................................................. 45
paediatric fluids and lytes .................................................................................................................................. 49
fluids and lytes ................................................................................................................................................... 51
acid-base ............................................................................................................................................................ 62
physiologic response to surgery ......................................................................................................................... 63
acls ..................................................................................................................................................................... 64
malignant hyperthermia ..................................................................................................................................... 67
tpn and nutrition ................................................................................................................................................. 68
enteral feeding .................................................................................................................................................... 72
hiv, htlv, and hepatitis ........................................................................................................................................ 72
liver dz and random facts ................................................................................................................................... 74
transplant ............................................................................................................................................................ 75
orthopedics ......................................................................................................................................................... 86
trauma ................................................................................................................................................................ 87
neurosurgery ...................................................................................................................................................... 96
vascular surgery ................................................................................................................................................. 97
E.n.t. surgery ...................................................................................................................................................... 98
critical care ......................................................................................................................................................... 99
diabetes ............................................................................................................................................................ 103
cardiac complications....................................................................................................................................... 105
dvt/pe................................................................................................................................................................ 107
respiratory failure ............................................................................................................................................. 110
perioperative respiratory complications ........................................................................................................... 112
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                                                                            2010-05-          2
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intubation ......................................................................................................................................................... 113
other lung stuff ................................................................................................................................................. 114
chylothorax ...................................................................................................................................................... 114
endocrine complications .................................................................................................................................. 114
gi complications ............................................................................................................................................... 118
infectious complications .................................................................................................................................. 120
renal complications .......................................................................................................................................... 121
local anaesthetics ............................................................................................................................................. 122
anaesthesia ....................................................................................................................................................... 124
anatomy ............................................................................................................................................................ 128
surgical devices ................................................................................................................................................ 128
critical appraisal ............................................................................................................................................... 129
appendices ........................................................................................................................................................ 131
PREFACE TO THE MORRELL POS NOTES
These notes were created in preparation for the 2003 POS exam by John Morrell. They were made by going
through all of Chris Nguan‟s old exams (1993 – 2000), many of the exams available at Office Depot, and the
2001 Dalhousie practice exam and making notes on all the topics covered by the questions. They have been
further modified/added to/upgraded in 2005 by Chris Hoag. The notes were made to contain the information
necessary to answer the questions on the exams. Extra information is included to provide sufficient
knowledge of the topic to, hopefully, be able to answer questions of a similar difficulty on the topic. The
source is mostly Sabiston 2001 with supplementation from Greenfield 2001, Scientific American 1998,
Schwartz, and Mastery of Surgery. The order of the topics is simply the order, more or less, in which the
topics came up working through old exams starting with 2000 and working back to 1993.

This represents the extent of my knowledge going in to write the 2003 exam. (Yes I passed.) If you know
these notes cold and go over the set of new questions that we remembered from the 2003 exam, you should
pass as well.



SUTURES

    Sizes (from small to big): 6-0, 5-0, 4-0, 3-0, 2-0, 0, #1, #2….

ABSORBABLE SUTURES
    Catgut and chromic catgut
    Dexon/Polyglycolic
    Vicryl/Polyglactic
    PDS/Polydiaxone
    Maxon/Polyglyconate
    Polyglecaprone 25 (monocryl)

CATGUT
    Absorption: 10 ds., effective strength: 4 – 10 ds
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                2010-05-   3
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   Absorption of chromic: 20 ds., effective strength: 10 – 14 ds.
   Acts as a foreign body
   Lower incidence of stitch marks than nonabsorbable skin closures.
   Uses: quick healing mucosa
   Mech of absorption: hydrolysis

POLYGLYCOLIC (DEXON)
   Absorption: 60 – 90 ds., effective strength: 14 – 21 ds
   Mech of absorption: hydrolysis
   Evokes the least inflammatory response of the absorbables.
   Strength: > gut
   Braided or monofilament
   Uses: sc sutures, mucosa, ligation

POLYGLACTIC (VICRYL)
   Absorption: 60 – 90 days, effective strength: 20 – 30 days.
   Second strongest behind behind polyglyconate
   Minimal tissue reaction
   Braided
   Mech of absorption: hydrolysis

POLYDIAXONE (PDS, BIOSIN)
   Absorption: 180 days, effective strength: 40 – 60 days
   Maintains integrity in presence of infection
   Minimal tissue reaction
   Monofilament
   Mech of absorption: hydrolysis

POLYGLYCONATE (MAXON)
   Absorption: 180 - 210 ds, effective strength: 40 – 60 ds
   Strongest of the absorbables and best knot characterisitics.
   Minimal tissue reaction
   Monofilament
   Mech of absorption: hydrolysis

RATE OF STRENGTH LOSS
   Gut
   Chromic
   Polyglycolic acid (dexon)
   Polyglactic acid (vicryl)
   Polydiaxone (PDS) = polyglyconate (maxon)
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                      2010-05-   4
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NONABSORBABLES
   Silk
   Polyester
   Nylon
   Polypropylene
   Steel

SILK
   Braided
   High tissue reactivity
   Will degrade and loss strength despite its classification as nonabsorbable
   Losses strength the fastest of the nonabsorbables.

POLYESTER (DACRON, ETHIBOND)
   Braided (mersilene) but usually coated with Teflon, silicone, or polybutilate.
   Excellent strength and durability
   Downside is poor knot characteristics of the coated sutures

NYLON
   Braided or monofilament
   Will degrade in about 2 yrs.

POLYPROPYLENE (PROLENE, SURGILENE)
   Monofilament
   Does not lose tensile strength
   Less reactive than polyglycolic/dexon but not as inert as steel

STEEL
   Monofilament or multifilament
   Strongest and least reactive suture




INFLAMMATORY MEDIATORS


ENDOTOXIN
   Cell wall component of Gram-negative bacteria.
   Potent mediator in septic shock.
   A lipopolysaccharide consisting of the O-antigen/side chain, the core, and the lipid A.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                      2010-05-    5
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   Lipid A = the region most responsible for most of the toxicity of endotoxin.
   Host response to endotoxin (5):
    1. Activation of macrophages
    2. Activation of complement cascade
    3. Activation of coagulation cascade
    4. Release of TNF-alpha, IL-1, IL-6, PAF, NO, various oxidants
    5. Renal failure (it is a nephrotoxin)


COMPLEMENT FRAGMENTS
   Complement cascade is activated in response to infection, shock, and tissue injury.
   C3a and C5a are the most potent ones.
   Effects of C3a and C5a (3):
     Both cause release of histamine from basophils and mast cells  vasodilation,  permeability, and
       bronchoconstriction.
     C5a is chemoattractant for neutrophils and mononuclear phagocytes.
     Stimulates IL-1 release.


EICOSANOIDS
   Includes: the leukotrienes, PG, prostacyclin and thromboxane families.
   Derived from membrane lipids by phospholipase.
   Phospholipid  Arachadonic Acid (ArAc) by phospholipase. ArAc  LT by lipoxygenase, or ArAc 
    PG, TX, or PC by COX (inhibited by NSAIDs or ASA)
   The principal PGs, I2 (prostacyclin), D2, E2, and F2 exert most of their influence locally.
   FX of prostacyclins(PG I2) produced largely by vascular endothelium (3):
    1. Vasodilation
    2. Bronchodilation
    3. Inhibition of plt aggregation
     PG I2 is inhibited by glucocorticoids
   Effects of thromboxane A2 (produced mainly by plts) (3):
    1. Vasoconstriction
    2. Bronchoconstriction
    3. Plt aggregation
   PG I2 and thromboxane A2 balance each other.
   Effects of PG E2 (4):
    1. Vasodilation
    2. Bronchodilation
    3. Pyrexia (like TNF- and IL-1)
    4. Immunodepression by inhibiting TNF-alpha, and IL-1 synthesis.

LEUKOTRIENES
   Produced by several cells (4):
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                            2010-05-   6
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    1. Mast cells
    2. Macrophages
    3. Neutrophils
    4. Vascular smooth muscle cells
   Effects of LT B4 (2):
    1. Chemoattractant for neutrophils
    2. Promotes neutrophil adhesion
   Effects of LT C4, LT D4, and LT E4 (3):
    1. Bronchoconstriction
    2. Vasoconstriction
    3. Increased vascular permeability


KININS
   Implicated in inflammation, anaphylaxis, septic shock
   Principal effects (5):
    1. Vasodilation
    2.  capillary permeability
    3. Pain
    4. Stimulate production of NO ( VD,  plt aggregation)
    5. Activation of phospholipase and thus amplification of inflammatory response, e.g.,  PG I2 and  plt
       aggregation.
    6. Potent bronchoconstrictor (Greenfield’s)


HISTAMINE
   Effects (3):
    1. Vasodilation
    2.  permeability
    3. Bronchoconstriction

NO
   Effects (2):
    1. Vasodilation
    2. Inhibition of plt aggregation
   Also seems to be involved in the pathophysiologic decrease in BP and SVR seen in sepsis.


CYTOKINES
   Interleukins, IFNs, TNFs, and CSFs.
   They all act directly on target cells and potentiate each other to amplify the host response.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                       2010-05-   7
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IL-1
   Produced by (5):
    1. Primarily monocytes and tissue macrophages
    2. Neutrophils
    3. Lymphocytes (B, Th, NK)
    4. Endothelial cells
    5. Keratinocytes
   Stimulants of release (6):
    1. Microbe particles (endotoxin, virus particles, yeast particles, peptidoglycans, etc…)
    2. Ag-Ab complexes
    3. Ig
    4. C5a (opsonization)
    5. Other cytokines (TNF, IL-2, GM-CSF, IFNs, IL-1)
    6. TGF-beta
   Effects (5 systemic and 4 local) (9):
    1. Induction of fever
    2. Stimulation of T and B lymphocytes
    3. Acute phase protein production and release
    4. Stimulates pit stress hormone release
    5. Myocardial depression
    6. Regulates skeletal muscle proteolysis in sepsis
    7. Potentiation of other inflammatory mediator release
    8. Chemoattraction of leukocytes
    9. Promotion of endothelial cell procoagulant effects

IL-6
   Produced by (3):
    1. Monocytes & Macrophages
    2. Neutrophils
    3. Fibroblasts
   Effects (3):
     Regulates hepatic response to inflammation.
    1. Induces fever
    2. Promotes of T and B cell activation
    3. Stimulates acute phase protein synthesis by liver

TNF-ALPHA
   Secreted by (5):
    1. Monocytes and macrophages primarily
    2. Lymphocytes (T, B, Natural killer cells)
    3. Mast cells
    4. Kupffer cells (hepatic macrophages)
    5. Glial cells in brain
   Stimulants of TNF-alpha production (2):
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                            2010-05-        8
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    1. Endogenous and exogenous factors from microbes (endotoxin is the most potent stimulator)
    2. Endogenous and exogenous factors from tumours
   The most important mediator of septic shock and MODS.
   Local effects:
    1. Leukocyte chemoattraction
   Effects of exaggerated systemic levels (7):
     Many of these effects are mediated through oxidants and eicosanoids.
    1. Fever
    2. Release of stress hormones such as catecholamines, glucagons, and cortisol
    3. Myocardial depression
    4. Systemic and pulmonary vascular permeability
    5. Hypotension
    6. Lactic acidosis
    7. DIC (procoagulant effect on endothelial cells)


PLATELET ACTIVATING FACTOR
   Effects (4 local and 4 systemic) (8):
    1. Amplifies actions of TNF- and IL-1
    2. Leukocyte activation
    3. Stimulates synthesis of leukotrienes
    4. Platelet aggregation
    5. Bronchoconstriction
    6.  Vascular permeability
    7. Cardiodepression
    8. Hypotension


OXIDANTS
   Produced by activated neutrophils among other cells.
   Effects (6):
    1. Lipid peroxidation and membrane disruption causing cell death
    2. Oxidative damage to DNA
    3. Oxidative damage to amino acids and proteins
    4. Inhibition of ATP synthesis in both glycolytic and mitochondrial pathways
    5. Reduction in cellular levels of NADH
    6. Interference of intracellular calcium regulation


NEUROENDOCRINE MEDIATORS
   Stress, injury, or infection causes increase in circulating catabolic or stress hormones including: catechols
    (EPI and NE), cortisol, and glucagons.
   Effects of EPI and NE (7) = mobilize glucose & run your ass off
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                          2010-05-       9
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    1. Tachycardia
    2.  Ionotropy
    3. Peripheral vasoconstriciton
    4.  Metabolic rate
    5.  Glycogenolysis
    6.  gluconeogenesis
    7. Inhibition of insulin secretion
   Effects of cortisol (3):
     Primarily a catabolic steroid
    1. Lipolysis
    2. Proteolysis
    3. Gluconeogenesis
   Effects of glucagon: gluconeogenesis

   RAA system → can also be activated by vasoconstriction in the kidney causing salt and water retention.



INFLAMMATORY CELLS


NEUTROPHILS
   The principal cellular component of the acute inflammatory response.
   First to arrive at site of inflammation and tissue injury.
   Activated macrophages in bone marrow produce G-CSF that is the primary stimulus for development and
    maturation of neutrophils.
   They circulate for 7 – 10 hrs before taking up residence in tissues for total of 1 – 2 days.
   They destroy bacteria by phagocytosis and release of toxic cellular contents.
   They express receptors for IgG and C3b  ADCC and phagocytosis.


MONOCYTES AND MACROPHAGES
   Blood monocytes circulate in the blood for 1 – 2 days before migrating into the tissue and differentiating
    into macrophages that reside there for months to years.
   Not found in lymph fluid.
   They phagocytize particulate material.
   They also act as APCs.
   Macrophages also release (4):
    1. IL-1, IL-6 that mediate further inflammation
    2. TNF- that mediates further inflammation and angiogenesis
    3. TGF-α that stimulates epidermal growth and angiogenesis
   TGF-β that chemoattracts and stimulates fibroblast production of collagen and fibronectin
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                            2010-05- 10
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   Glutamine required for lymphocyte and macrophage production.


EOSINOPHILS
   Recruitement of eosinophils is pronounced at sites of parasitic infection and allergen challenge.


BASOPHILS AND MAST CELLS
   Similar to eosinophils with respect to granule content, activating stimuli, and effector functions.
   Mast cells don‟t circulate freely but are fixed in connective tissue.


LYMPHOCYTES
   B, T and NK cells.
   CD4+ cells (Th cells) recognize MHC II molecules on APC surface and stimulate B cells to differentiate
    into Ab-producing cells (Plasma cells) or memory B cells.
   CD8+ cells (Tc cells) recognize MHC I molecules and can induce target cell lysis.
   Continuously migrate from the blood into tissues and lymph through specialized endothelium in post cap
    venules.
   NK cells are the first line of defense against viral infection. Virus infected cells loose their MHC I
    expression, which targets them for NK mediated destruction.
   Glutamine required for lymphocyte and macrophage production. Also needed for NH4 production in the
    kidney.


PLATELETS
   ADP is the most important plt agonist during plt plug formation.



BITE INJURIES

   Surrounding intact skin can be washed with 1% povidone-iodine.
   Wound should be irrigated with copious amounts of tap water or NS (or bactericidal & viricidal 1%
    povidone-iodine followed by NS or water) using a 19 G needle and syringe.
   Irrigation with penicillin or cephalosporin containing fluid may better prevent infection.
   Debride dirt and devitalized tissue.
   In cosmetically important sites (head, neck), primary closure provides the best outcome if done within 12
    hrs without increasing risk of infection.
   Healing of hand laceration is best done by secondary intention.
   Potentially deeper wounds to hand or infected bites presenting after 24 hrs require exploration and
    debridement in the OR with iv Abx.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                          2010-05- 11
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   Tendon and nerve injuries are best managed with delayed repair.
   Puncture wounds should not be sutured.
   High-risk wounds should be allowed to heal by secondary intention or delayed closure.
   Sterile dry dressings for all, early wound checks.

BITE WOUND INFECTION MICROBIOLOGY:
 usually polymicrobial with aerobes and anaerobes.
    Usual ones are staph, strept, and anaerobes in most infections.
    Pasteurella multocida is the primary one in cat infections, and occasionally dogs.
    E. corrodens has been isolated from human bites.
    Most common in humans: strept, staph aureus, H. parainfluenza, klebsiella pneumon, eikenella,
      bacteroides, fusobacterium, and anaerobic cocci (peptostreptococci).
    Dogs: Pasteurella, staph, strept, fusobacterium

PROPHYLACTIC ABX:
 recommended for patients with high-risk bites.
 Punctures from cats  pen + dicloxacillin (will cover pasteurella)
 Dog bites  nothing unless to hand then dicloxacillin or cephalexin (incidence of pasteurella is low)
 Alternative for dog and cat bites in pen allergic patients  TMP-SMX
 Human bites  2nd or 3rd generation cephalosporin or diclox + amp
 Alternative for all bites: cefuroxime or clavulin
 Presents after 24 hrs: usually don‟t need abx.

RABIES
   Wash all wounds with soap, irrigate with povidone-iodine or benzalkonium chloride.
   Leave open if suspicious for rabies.
   All wild carnivores should be considered rabid.
   In cases of bites by domestic animals, rodents, or lagomorphs (rabbits), local unit of health should be
    contacted for advice.
   Bite by healthy appearing domestic dog doesn‟t require prophylaxis if the animal can be observed for 10
    days.
   Passive immunization: 20 IU/kg of rabies Ig. Give as much as possible around the site and give the rest
    somewhere else intramuscularly. ½ and ½ is an alternative.
   Active immunization: 1 mL of human diploid cell vaccine, purified chick embryo cell vaccine, or rabies
    vaccine given into the deltoid in adults (or the anterolateral thigh in kids) on days 0, 3, 7, 14, and 28.
   Those with pre-exposure immunization need only active immunization on days 0 and 3. (essentially a
    booster; No passive immunization required.)


TETANUS PROPHYLAXIS
   Check tetanus status with any wound
   All with TBSA burns > 10% require tetanus prophylaxis
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   For clean wounds:
     If no reliable record of three prior toxoid injections or no booster for 10 yrs, give tetanus diphtheria
       toxoid (Td) → 0.5cc tetanus toxoid IM
     No further immunization is necessary.
     If that injection is not the third, patient should be scheduled to complete the entire series.
     TIG not necessary.
   For dirty wounds:
     Td given if it has been greater than 5 yrs since previous booster.
     No TIG if complete immunization series has been received.
     If status of series is unclear: give TIG (250 – 500 U IM, higher dose for long latency time and severity
       of injury) at same time as Td but different location.
     TIG inactivates the toxin. Debridement is best way to prevent infection.



WOUNDS

   Know collagen synthesis, where it is found, diseases of collagen, different types.
   Fournier‟s: mixed gram negative and anaerobe (gram positive rods)
   There is no difference in healing between vertical and transverse incisions.


PHASES IN HEALING
INFLAMMATORY PHASE
   From day 0 to ~ day 7.
   In order of appearance in the wound: plt, leukocytes, lymphocytes and macrophages.
   Hemostasis with involvement of plts that degranulate alpha and dense bodies.
     Alpha bodies contain GF and some coag cascade proteins. Most notable effect is chemotaxis and
        inflammation
     Dense bodies contain vasoactive amines (dilation and  permeability).
   Plt plug fibrin meshclot (activation of both intrinsic and extrinsic pathways)
   This clot of fibrin provides the strength until collagen is laid down (which starts around 3 or 4 days).
   Leukocytes are chemoattracted immediately (by IL-1 and TNF-alpha from local monocytes, inhibited by
    steroids) and activated. Resulting neutrophils/PMN scavenge, debride, and kill bacteria.
   Lymphocytes proliferate and release cytokines (inhibited by steroids). Minor role except when there is
    heavy contamination.
   Monocytes are chemoattracted (inhibited by steroids) at same time as the lymphocytes and reach peak
    number in 2 – 3 days. (They replace the neutrophils.) They are activated into macrophages that
    phagocytose necrotic tissue and bacteria. The macros also release (4):
    1. IL-1, IL-6 that mediate further inflammation
    2. TNF- that mediates further inflammation and angiogenesis
    3. TGF-alpha that stimulates epidermal growth and angiogenesis
    4. TGF-beta that chemoattracts and stimulates fibroblast production of collagen and fibronectin.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                          2010-05- 13
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   Macrophages are the dominant cell type in this phase.
   Mast cells and injured endothelial cells release histamine and PGs that, like dense body substances,
    cause  vascular permeability and dilation.

PROLIFERATIVE PHASE
   From day 3 or 4 to about 3 weeks.
   Consists of angiogenesis, fibroplasia, and epitheliazation.
   Angiogenesis is stimulated by (3):
     FGF
     TGF-alpha
     TNF-alpha
   Fibroblasts proliferate and become the dominant cell type in this phase.
   Collagen synthesis stimulated by (4)
    1. Ascorbic acid (Vit. C)
    2. TGF-beta
    3. IGF-1
    4. IGF-2.
   In first 3 weeks, wound strength and collagen content correlate.
   After 21 days, strength  with no  in collagen content, reflecting scar remodelling.
   Collagen turnover causes hydroxy-proline spillage in urine.

   Epitheliazation occurs from the remaining dermal appendages in partial thickness wounds. In full
    thickness wounds, epitheliazation migrates in from the edges at a rate of 1 – 2mm/d, however, this rate is
    critically dependent on the vascularity of the underlying granulation tissue.

COLLAGEN SYNTHESIS
   Translation of „procollagen gene’ mRNA occurs on ribosome of RER yielding preprocollagen.
   Preprocollagen is transported into lumen where some of the lysine and proline are hydroxylated →
    hydroxyproline & hydroxylysine. Vitamin C is necessary for the hydroxylation reaction.
   Required cofactors/coenzymes for this hydroxylation rxn(4): ferrous Fe, -ketoglutarate, ascorbic acid
    (vitamin c), and oxygen cofactors.
   Glycosylation of asparagine and hydroxylysine occurs.
   Hydroxylation of preprocollagen is rate limiting step.
   These „pro-α’ chains are then assembled into trimers and disulphide bonded together at cystines. This is
    referred to as the procollagen.
   Procollagen is packaged by Golgi into secretory vesicles (lysosomes).
   Extracellular peptidases cleave the extension peptides at both ends  collagen monomers.
   Collagen monomers aggregate. Lysine and hydroxylysine are oxidized to aldehydes that condense to form
    cross-links.
     -aminopropionitrile: inhibits lysyl oxidase.
     D-penicillamine: binds to collagen substrate directly to prevent collagen cross-link formation. (also a
        Cu-chelator used in Wilson‟s dz)
   Stimulants of collagen synthesis: ascorbic acid, TGF-beta, IGF-1 & 2
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                               2010-05- 14
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   Inhibitors of collagen synthesis (2): IFN-gamma, glucocorticoids (Inhibits collagen mRNA transcription.
    Inhibits secretion of procollagen, which can be prevented by giving vitamin A.)
   Hydroxyproline in urine = best indicator of collagen breakdown.

COMMON TYPES OF COLLAGEN
Type     Tissue Distribution
I        All connective tissue (bone) except cartilage & basement membranes
II       Articular cartilage, vitreous humour, and intervertebral disks
III      Elastic tissues (blood vessels, uterus, skin), usually found with type I (type III collagen is the initial
         one in scars)
IV       Basement membranes
V, VI    Widespread
VII      Fibrils that anchor epidermis to dermis
IX,      Hyaline cartillage
XI

ABNORMALITIES OF COLLAGEN
   Osteogenesis imperfecta: deletion of one procollagen -1 allele.
   Ehlers-Danlos syndrome: abnormal type III, deletion of part of type I collagen gene, abnormal copper
    utilization, or deficiency of lysyl hydroxylase.
   Epidermolysis bullosa: absence of type VII that is the main component of fibrils that anchor epidermis to
    dermis.

ELASTIC FIBRES
   Produced by smooth muscle cells and fibroblasts (basically mesenchymal)
   Elastic fibers are composed of: amorphous elastin and microfibrils.
   Elastic fibers are found in the normal and hypertrophic scars.
   Cu is required for crosslinking of the lysines.
   Slow turnover, usually lasts lifetime.
   Found mostly in thoracic aorta, also in peripheral arterioles, skin, vocal cords, sclera, lungs and pregnant
    uterus.
   Stimulants of elastin production: IGF-1, TGF-beta
   Inhibitors of elastin production: glucocorticoids, FGF.

GAGS
   Functions: support cells, provide tissue turgor, facilitate cell-cell interaction

MATURATIONAL PHASE
   From 2 or 3 weeks to beyond a year.
   Collagen synthesis/degradation equilibrates; ∆predominant collagen III→I
   Fibroblasts change into myofibroblasts that contract the wound. This can be inhibited by colchicines &
    corticosteroids
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                          2010-05- 15
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   Cross-linking of collagen occurs and random collagen fibrils are replaced with organized fibrils. (usual
    ratio of 4:1 type I:III collagen restored)
   Strength of wound increases rapidly in first 6 weeks, levelling off at ~ 70% of baseline in 6- 8 weeks.




GLUCOCORTICOIDS EFFECTS (14)
1. Suppress IL-2 production
2. Inhibit lymphocyte activation
3. Inhibit neutrophil migration to areas of inflammation
4. Inhibit monocyte migration to areas of inflammation
5. Inhibit histamine release and histamine-induced lysosomal degranulation by mast cells
6. Inhibit B cell activation and proliferation at high doses
7. Retards entry of free water into cells
8. Decreases capillary permeability to water
9. Weak mineralocorticoid effect
10. Stimulation of angiotensin release (maintains BP)
11. Inhibits PGI2 (potent vasodilator)  maintenance of BP
12. Impaired collagen mRNA transcription and fibroblast activity
13. Inhibit osteoblast activity
14. Promotes early closure of epiphyseal plates in kids
 Long term effects (5):
    1. Catabolic state with negative N balance
    2. Redistribution of body fat  truncal obesity
    3. Emotional and psychological disturbances
    4. Cataracts
    5. Corneal ulcers


FACTORS AFFECTING WOUND HEALING (DRAHMID)
    1. Diabetes
    2. Radiation
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                             2010-05- 16
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    3.   Advanced age
    4.   Hypoxia
    5.   Malnutrition
    6.   Infection
    7.   Drugs

INFECTION
   If the bacterial count in the wound exceeds 10^5 organisms/gram of tissue or if any beta-hemolytic
    streptococcus are present, the wound will not heal by any means.
   The bacteria prolong the inflammatory phase and interfere with epitheliazation, collagen deposition and
    contraction (thus infection interferes with all 3 phases of healing.) → hypertrophic scarring
   Skin grafts can be placed in the presence of 10^5 or less organisms (except beta-hemolytic strept).

WOUND HYPOXIA
   Wounds will not proceed without tissue oxygen levels above 35 mmHg.
   Below this level fibroblasts cannot replicate and collagen production is impaired.
   Ischemia can be caused by atherosclerosis, cardiac failure, tobacco induced vasoconstriction, venous
    stasis, edema, simple wound tension preventing local perfusion.

DIABETES
   DM impairs wound healing at all stages.
   The BM of the capillaries is thickened causing decreased perfusion.
   Lymphocyte and leukocyte function is impaired.
   There is increased collagen degradation and decreased collagen deposition. The collagen formed is more
    brittle.
   Exogenous insulin can improve wound healing but not completely reverse the impairment.
   In correcting the abnormalities associated with DM, the most crucial thing is to control the hyperglycemia
    with exogenous insulin.

IONIZING RADIATION
   Radiation causes endarteritis resulting in atrophy, fibrosis, and delayed tissue repair.
   Arterial fibrosis  impaired O2 delivery
   Progressive obliteration of blood vessels in the radiated area
   Intranuclear and cytoplasmic damage to fibroblasts and this appears to limit their proliferative potential.

ADVANCED AGE
   Healing slows as age progresses.
   All stages of wound healing are affected.
   Macrophages in particular are affected.
MALNUTRITION
   Protein catabolism can delay healing.
   Hypoalbuminemia can cause delay.
   Essential fatty acids are required for all new cell synthesis. Deficiency will be noted in areas of high cell
    turnover such as healing wounds.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                         2010-05- 17
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    Vitamin A, B, C, (and K) deficiency can adversely affect wound healing.
    Zn (R/DNA polymerase cofactor) or Cu deficiency (rare) can delay healing. Mixed evidence for Fe
     deficiency. (Note that Cu deficiency is listed as a factor in Sabiston ‟98 but not 2001 edition.)
    Vitamin C necessary for hydroxylation of proline and lysine. No hydroxyproline  collagen is not
     transported out of cell. No hydroxylysine  no collagen fibril cross-linking.
    Vitamin B6 (pyridoxine) deficiency impairs collagen cross-linking. (This is from Sabiston ‟98 but ‟01
     edition does not list it.)
    Vitamin K is involved in wound hemostasis.
    Vitamin B1 (thiamine) and B2 (riboflavin) deficiencies cause syndromes associated with poor wound
     repair. (Sabiston ‟98 but not ‟01.)
    Vitamin A involved in fibroplasia, collagen cross-linking, and epitheliazation.
    Vitamins involved in collagen (3):
     1. Vitamin A
     2. Vitamin C
     3. Vitamin B6 (pyridoxine)

EXOGENOUS DRUGS (9 → AB2CD-G-MNT)
1. Doxorubicin (adriamycin)
2. -aminoproprionitrile
3. Bis-chlorethyl-nitrousurea
4. Cyclophosphamide
5. D-penicillamine
6. Glucocorticoids effects on wounds (6):
   1. Impair fibroblast prolif
   2. Impairs collagen synth
   3. Decreases amount of granulation tissue formed
   4. Stabilize the lysosomal membrane. This effect can be reversed by administration of vitamin A.
   5. Decrease in breaking strength
   6. High doses will delay healing
    Despite all this, therapeutic range doses are unlikely to delay healing.
7. Methotrexate
8. Nitrogen mustard
9. Tamoxifen → decreases cellular proliferation


RISK FACTORS FOR WOUND COMPLICATIONS

RISK FACTORS FOR WOUND DEHISCENCE (7)
1. Improper/inadequate closure (adequate bites are more important than running or interrupting the suture
   line, although interrupted sutures are less likely to give rise to a disruption)
2. Increased stress/pressure/tension on closure: distension, ascites, massive obesity.
3. Advanced age: impaired tissue integrity, malnutrition and immune deficiency.
4. Comorbidities: DM, CRF, malignancy, catabolism, resp
5. Malnutrition: hypoprotein, hypovitamins (A, B, C, E), hypo-trace elements (Zn, Cu)
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                      2010-05- 18
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6. Drugs: high dose, long term roids, chemo within 1 – 3 weeks of operation
7. Wound events: bleeding, hematoma, contamination, ischemia, radiation.

RISK FACTORS FOR HEMATOMA(6)
1.   Myeloproliferative disorders
2.   Polycythemia vera
3.   Hyperthrombocytosis
4.   Hepatic insufficiency
5.   Coagulopathy
6.   Inadequate hemostasis

RISK FACTORS FOR NON-HEALING WOUND AND INFECTION
PATIENT FACTORS (13)
1. Old age
2. Malnutrition/catabolism
3. DM
4. Smoker
5. Obesity
6. Coexistent infection at remote site
7. Colonization of wound
8. Altered immune system (immunosuppressed, roids, AIDS)
9. Chemotherapy
10. Radiation therapy
11. Length of preoperative stay
12. Poor tissue perfusion
13. Malignancy

OPERATIVE FACTORS (14)
 These apply to infection especially
1. Length of scrub
2. Skin antisepsis
3. Preop shaving
4. Preop skin prep
5. Duration of surgery
6. Antimicrobial prophylaxis
7. Operating room ventilation
8. Equipment sterilization
9. Foreign material in surgical site
10. Drains
11. Poor hemostasis
12. Failure to obliterate dead space
13. Tissue trauma
14. Type of surgery (clean vs. contaminated)
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                          2010-05- 19
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MANAGEMENT OF WOUND COMPLICATIONS
   Dehiscence: urgent exploration and reclosure of fascia (mesh and retention sutures often needed)
   Hematoma: found immediately postop  exploration and evacuation, small hematomas found late 
    heat, immobilize/support, don‟t drain or re-explore, these get infected very easily.
   Seroma: aspiration followed by pressure dressing or closed suction drain (These are less likely to get
    infected than hematomas.)


ABNORMAL WOUND HEALING
KELOIDS
   AD genetic transmission in mostly dark skinned people
   Typically develops several months after injury and rarely subside
   On trunk above clavicles, upper extremities, and face
   Extends beyond the margin of the original tissue injury, behaving like a benign tumour
   Contain an over abundance of collagen without increased numbers of fibroblasts
   Cause unknown
   Some improvement is usually seen with excision and one of: 1) intralesional steroid injection; 2) short
    course radiotherapy but the resulting scar post radiation is unpredictable and can be worse.

HYPERTROPHIC SCARS
   Histologically similar to keloid except they respect the boundaries of the original injury
   More frequent in Asians and Blacks
   Upper torso and flexor surfaces
   Develop within the first month then subside gradually
   Improvement: pressure garments, topical silicone sheeting applications, or excision and reclosure (only
    useful if the wound was not closed primarily or was complicated by infection).


WOUND INFECTION
   Most common nosocomial infection in surgical patients.
   Microbial contamination is the primary cause although seeding is also possible.
   Common pathogens in order of involvement:
    1. S. aureus (causes clear slimy discharge and erythema)
    2. Coag neg staph (S. epi)
    3. Enterococcus
    4. E. coli
    5. Pseudomonas
    6. Enterobacter
   Best initial and perisitent agent for skin prep: US CDC SSI guidelines 1999 say that chlorhexidine is best
    for skin prep.
   Most immediate reduction of bacterial counts: alcohol. (See table)
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                          2010-05- 20
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SOFT TISSUE INFECTION
   Superficial abscesses of head, neck, and trunk usually from S. aureus and streptococci.
   Axillary abscesses usually from gram negatives.
   Abscesses below the waist frequently harbour mixed aerobes and anaerobes.

NECROTIZING SOFT TISSUE INFECTIONS
   Clostridial and non-clostridial.
   Marked by absence of clear local boundaries or palpable limits.
   Anatomically there‟s a layer of necrotic tissue which is not walled off by a surrounding layer of
    inflammatory reaction (no battle-front)
   Early on the overlying skin has a relatively normal appearance.
   Most clostridial infections typically involve underlying muscle (clostridial myonecrosis or gas
    gangrene).
   Most non-clostridial infections spread in the sc layer between skin and muscle (aka necrotizing fasciitis).
   Note that most soft tissue infections with gas are not gas gangrene. Most bacteria will produce insoluble
    gas when forced to use anaerobic metabolism.
   Human tissue can‟t survive in anaerobic conditions and so gas-containing infections imply dead tissue and
    a surgical infection.
   Early signs of necrotizing infection:
    1. Marked hemodynamic response
    2. Failure of response to conservative measures
    3. Rapid progression
    4. Apparent cellulites with bullae, any dermal gangrene, extensive edema, or crepitus
   Operative intervention → requires unroofing, excision, debridement of all dead tissue or amputation.
   Most common clostridial infections: C. perfringens, C. novyi, C. septicum. (These are gram positive
    bacilli.) Other bacteria often found in wound too.
   Most common single non-clostridial is beta-hemolytic S. pyogenes when no trauma or surgery preceded
    the infection.
   Post injury/surgery necrotizing infections most commonly are polymicrobial (anaerobes/aerobes, gram
    neg/pos).

CLASSIFICATION OF WOUNDS
   Clean: nontraumatic, no break in technique, no tract entered.
     Infection rate: 1.5 – 2.9%
   Clean contaminated: GI or resp tract entered without significant spillage; oropharynx, vagina, or
    noninfected GU or biliary tract entered, minor break in technique.
     Infection rate: 2.8 – 7.7%
   Contaminated: major break in technique, fresh traumatic wound, gross spillage from GI tract, entrance
    into GU or biliary tree in presence of infection.
     Infection rate: 6.4 – 15.2%
   Dirty/Infected: pus encountered, traumatic wound with retained devitalized tissue, foreign bodies, fecal
    contamination, or delayed treatment, or from a dirty source. This definition suggests that organisms were
    present in the operative field before the operation.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                            2010-05- 21
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NORMAL SKIN FLORA

 Staph. Areus
 Staph. Epidermidis
 Micrococcus luteus
 Corynebacterium diptheriae
 Proprionibacterium acnes (also a diptheroid)
Note: in general lipid on skin prevents Strep colonization (it‟s toxic to strep) & skin too dry for gram negs
(except intertrigonous areas & perineum)



ANTIBIOTICS

   See appendix
   Static antibiotics (5): clindamycin, chloramphenicol, macrolides (erythro, clarithro, azithro), TMP/SMX,
    tetracyclines (tetra and doxy). All others are bactericidal.



ANTIBIOTIC PROPHYLAXIS

   Best given as one dose prior to start of the case (no more than 1 hr preop.)
   In short → all clean-contaminated procedures should get prophylaxis; contaminated & dirty procedures
    need treatment; clean cases don‟t generally need prophylaxis unless high risk (neuroSx, breast Sx,
    prostheses, DM, obese)
   Operations where it is of benefit (17):
    1. H & N when aerodigestive tract is opened
    2. Esophageal except hiatal hernia
    3. GI except complications of hyperacidity
    4. Biliary tract for those > 70 yrs with acute cholecystitis and/or requiring choledochostomy
        (cephalosporins are best)
    5. Small and large bowel resections
    6. Appendectomy for gangrenous or perforated appendix
    7. Hysterectomy
    8. Abdominal and lower extremity revascularization
    9. Clean operations with implantation of high-risk prostheses (hip, knee, valves)
    10. Sternotomy
    11. Amputation for ischemic ulcer
    12. C-section (emergent only)
    13. Craniotomy
    14. Known gross contamination (contaminated procedures)
    15. Dirty wounds
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                           2010-05- 22
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    16. Injuries prone to clostridial infections (devitalized, heavy contamination, impaired blood supply)
    17. Pre-existing valvular heart disease

ENDOCARDITIS PROPHYLAXIS
   Abx:
     Oral/respiratory/esophageal: amoxil 2g PO 1 hr pre-procedure
     GU/GI (excluding esophagus): iv amp +/- gent 30 min pre-procedure (gent required if: prosthetic
        valves, previous IE, complex cyanotic congenital heart disease, surgically constructed systemic to
        pulmonary shunts or conduits)
   If pen allergy:
     Dental and upper respiratory procedures: oral clinda, keflex or azithro/clarithro OR iv clinda or
        ancef
     GI/GU/abscess drainage: iv vanco +/- gent (gent for high risk)
   Conditions: any cardiac flow problem basically or synthetic vascular graft.
   Procedures (10):
    1. Oral procedures that may cause bleeding or incision of mucosa
    2. Rigid bronchoscopy
    3. I&D of infection
    4. Cysto with urethral dilatation
    5. Endoscopy of upper urinary tract
    6. Urinary catheterization in presence of infection
    7. Vag hysterectomy
    8. Vag delivery in presence of infection
    9. GI procedures involving incision or resection of mucosa
    10. Endoscopic manipulation

ANTIBIOTIC BOWEL PREP
   Neomycin and erythromycin given given 19, 18, and 9 hours before surgery plus iv Abx.
   Thorough mechanical cleansing is critical component of this prep.



BACTERIA


ANAEROBES
   Most numerous inhabitants of normal GI tract including mouth.
   They can only grow in presence of low oxygen environments that are incompatible with living tissue so
    their presence implies dead tissue and since they come from the GI tract, their presence suggests defect in
    GI integrity.
   Required Abx coverage (6):
    1. Flagyl
    2. Clinda
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                             2010-05- 23
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    3.   Imipenem
    4.   Chloramphenicol
    5.   Penicillin + -lactamase inhibitor (tic/clav, amp/sulbactam, pip/tazo)
    6.   2nd generation cephalosporins (cefoxitin, cefotetan) or some 3rd generation (ceftizoxime)

TYPES OF ANAEROBES
   Bacteroides (mouth, vagina, colon)
   Clostridium
   Fusobacterium
   Peptostreptococcus
   Actinomyces

FUNGI
   Requires treatment when recovered from the urine, sputum, or abscess in a compromised patient.

OBLIGATE AEROBES
   Pseudomonas and acinetobacter
   Have tendency to develop resistance and so double coverage is suggested in critically ill.
   Possible Abx (6):
    1. Ceftazidime (3rd gen)
    2. Imipenem, meropenem
    3. Cipro
    4. Aminoglycoside
    5. Aztreonam
    6. Acylureidopenicillin

ENTEROCOCCI
   UTI, biliary tract infections, subacute bacterial endocarditis.
   No sigle agent is reliable for deep seated enterococci infections
   Best choices: (amp + gent) or vanco.



BURNS

   Look at inhalational injury, CO poisoning
   Pneumonia is most common cause of sepsis in burns patients.

DEPTH
   First degree: confined to the epidermis, painful, eythematous, blanch to touch, epidermal layer is intact.
   Second degree, superficial: superficial dermis, painful, blanch and often blister; re-epitheliaze from
    retained epidermal structures in rete ridges, hair follicles, and sweat glands; some discoloration.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                          2010-05- 24
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   Second degree, deep: into the reticular dermis, remain painful to pinprick, re-epitheliaze from sweat
    gland and hair follicle keratinocytes, severe scarring.
   Third degree, aka full thickness: hard leathery eschar that is painless, heal by re-epitheliazation from
    edges.
   Fourth degree: involves deeper organs/muscle




       Fluorescein = spectroscopic

SIZE
Body part            % TBSA
Head & neck          9
Upper extremity      9x2=18
Lower extremity      18x2=36
Anterior trunk       18
Posterior trunk      18
Genitals/perineum    1

INITIAL MANAGEMENT
   Remove sources of continuing heat
   Douse with room temp water within 15 min
   Dress with clean dry dressing or sheets (not damp or wet)
   NG tube
   Parkland formula: 4 mL of crystalloid/kg/% TBSA burn = fluid requirements for first 24 hours. (RL is
    fluid of choice except in kids < 2 yrs who should receive 5% dextrose RL.) Half is given in the first 8 hrs
    post injury, second half in remaining 16 hrs. This is in addition to maintenance. In second 24 hrs, give 20
    – 60% of calculated plasma volume of colloid-containing fluid equivalent to plasma and D5W as
    necessary to maintain u/o.
   Conditions which need  Parkland (9):
    1. High voltage electrical burns (aim for 2 cc/kg/hr in these)
    2. Inhalational injuries → add 2 cc/kg/%TBSA
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                           2010-05- 25
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    3. Peds burns (different formula altogether)
    4. Major trauma
    5. > 80% TBSA
    6. 4th degree burns
    7. Osmotic diuresis
    8. Burn while drunk
    9. Delayed resuscitation (6,7,8 = b/c they‟re behind on fluid)
   In high voltage burns, the key is that the most significant injuries are deep and subsequent edema
    formation can cause distal vascular compromise (cpt. Synd). They need early exploration of affected
    muscle beds and debridement.
   Tetanus prophylaxis: all with > 10% TBSA burns should receive 0.5 mL of tetanus toxoid, give 250
    units of IG if immunization status unclear.
   Most common infecting organisms: Staph (85%), enterococcus (55%), E. coli (40%), candida (40%),
    pseudomonas, -hemolytic.

BURN WOUND CARE
   First degree: requires no dressing and are treated with topical salves (gelatinous abx preparations) to
    decrease pain and keep skin moist. MAfenide acetate (sulfamylon), a salve, is associated with metabolic
    acidosis (MA).
   Superficial second degree burns: daily dressing changes with topical antiobiotics (salves or soaks),
    cotton gauze and elastic wraps, temporary biologic (xenograft vs allograft skin) or synthetic covering (e.g.
    opsite).
   Deep second degree and third degrees: excision and grafting for sizable burns.

SILVER SULFADIAZINE
   Broad spectrum anitmicrobial: gram pos, gram neg, and some fungi.
   Does not penetrate eschar
   May leave black tattoos
   Mild inhibition of epitheliazation
   Mild burning with application
   Transient leukopenia develops in 3 – 5 days. Generally harmless and resolves with or without treatment.


BURN NUTRITION
   Calories required: 25 kcal/kg lean body mass + 40 kcal/%TBSA (Curreri formula) In contrast normal
    caloric requirements are about 35 kcal/kg/day.
   Optimal dietary protein in burns: 1 – 2 g/kg/day
   TPN is associated with  complications and mortality compared with enteral therapy, nonetheless, acute
    burns is a primary indication for TPN.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                           2010-05- 26
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GRAFTING
   Deep second and third degree burns don‟t heal in timely fashion.
   Early excision and grafting has benefit over serial debridement in terms of survival, blood loss, and length
    of hospital stay.
   Most excise the burn in the first week. Early excision should be reserved for 3rd degree burns.
   Full thickness skin grafts that include the entire dermis and epidermis provide the best outcome in wound
    coverage, with diminished contracture, superior cosmesis, and better sensation compared to split
    thickness.
   Disadvantage of FTSG: lower rate of survival (less durable) and limited donor sites.
   Can be placed in presence of < 100 000 CFU/g of tissue of all but -hemolytic strep because they produce
    streptokinase, which breaks down fibrin and prevents graft take.


INHALATIONAL INJURY
   For mild inhalational burns warm, humidified O2 and incentive spirometry may be all that is required.
   2 cc/kg/%TBSA more on the parkland
   Prophylactic high-frequency percussive ventilaltion minimizes airway collapse and atelectasis and reduces
    pneumonia and mortality.




CANCER

   What is increasing in incidence?
   Leukemia = most commonly induced tumour post radiation.
   Most sensitive test for bone mets is radioactive Tc methylene-di-pyrophosphate scan (MDPP).
   Neuroblastoma arises from the sympathetic nervous system.
   Bone mets: most common source is lung.
   Adenocarcinoma is most common lung cancer histology, it is found in the periphery.
   Astrocytoma = 60% of all primary intracranial neoplasms (i.e. most common primary intracranial
    neoplasm); treated with debulking resection and radiation; high grade tumors ~uniformly fatal.
   Mediastinal Mass Incidence: neurogenic tumor > thymoma > (all cysts combined) > lymphoma > germ
    cell neoplasm > cysts taken individually (e.g. bronchogenic cyst, pericardial cyst, etc)


BRAIN METS
   Lung 35%
   Breast 25%
   Kidney 10%
   Testis
   GI 10%
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                       2010-05- 27
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   Malignant melanoma 10%


HYPERVASCULAR TUMOURS
   CRIMP: carcinoid, RCC, insulinoma, melanoma, pheochromocytoma

RADIATION
   Most sensitive target is DNA.
   Can induce: apoptosis, G2-phase arrest.


INCIDENCE
   Total: lung, breast, colorectal, prostate, non-hodgkin‟s lymphoma
   Males: prostate, lung, colorectal, bladder, non-hodgkin‟s
   Females: breast, lung, colorectal, uterine, non-hodgkin‟s

MORTALITY
   Total: lung, colorectal, breast, prostate, pancreas
   Males: lung, prostate, colorectal, pancreas, non-hodgkin‟s lymphoma
   Females: lung, breast, colorectal, pancreas, ovarian

TUMOUR BIOLOGY
   Gompertzian growth refers to rate that is exponential but simultaneously, exponentially decreasing with
    time.
   Systemic manifestations of malignant disease can be produced by (4):
    1. Ectopic hormones (SIADH)
    2. Hormone like peptides
    3. Autoimmune phenomena
    4. Tumour toxicity



CHEMOTHERAPY


CLASSIFICATION
   Alkylating agents
   Antimetabolites
   Antitumour antibiotics
   Plant alkyloids
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                           2010-05- 28
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ALKYLATING AGENTS (‘MIT-C4’)
   Chlorambucil
   Cyclophosphamide
   Ifosfamide
   Melphalan
   Thiotepa
   Carboplatin
   Cisplatin

GENERAL PHARMACOLOGY
   Produce alkylation through formation of intermediates.
   Primary mode: cross link the DNA.
   Cell cycle specific but not phase specific.
   Resistance related to capacity of cells to repair the damage and to inactivate the drugs by conjugation with
    glutathionine.
   See appendix

ANTIMETABOLITES
   Cytarabine
   Methotrexate
   Mercaptotpurine
   Hydroxyurea
   5-FU
   Fludarabine

GENERAL PHARMACOLOGY
   Either structural analogues of normal molecules or inhibitors of enzymes necessary for synthesis of
    essential compounds.
   Major effect is interfering with building blocks of DNA synthesis.
   Greatest activity in S phase.
   Most effective when cell proliferation is rapid.
   After a certain dose, no more cells are killed.
   Length of time exposed to drug is proportional to cell killing potential though.
   See appendix



ANTITUMOUR ANTIBIOTICS
   Bleomycin
   Mitomycin C
   Mithramycin
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                         2010-05- 29
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   Doxorubicin (adriamycin)

GENERAL PHARMACOLOGY
   Cell cycle non-specific
   Especially useful in slow-growing tumours with low growth fractions
   Variety of mechanisms
   Many are derived from microbes
   See appendix


PLANT ALKYLOIDS
   Vincristine
   Vinblastine
   Paclitaxel
   Etoposide

GENERAL PHARMACOLOGY
   Either topoisomerase inhibitor or mitotic spindle inhibitors
   See appendix


SUMMARY NOTES
   Chemotherapeutics whose primary dose limiting toxicity is not myelosuppression (5):
    1. Cisplatin (cumulative renal insufficiency, peripheral sensory neuropathy, tinnitus, high frequency
       hearing loss)
    2. Bleomycin (shaking, chills, febrile reactions, pneumonitis)
    3. Vincristine (peripheral neuropathy)
    4. Adriamycin/Doxirubicin (cardiomyopathy)
    5. Cyclophosphamide/Ifosfamide (hemorrhagic cystitis)



RADIATION THERAPY


RADIATION BASICS
   Apoptosis is induced.
   Cell division may be delayed: G2-arrest most common but also G1 and S phase delay.
   Sensitizers to radiation (5):
    1. Oxygen
    2. Hypoxic cell sensitizers
    3. DNA incorporating agents
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                         2010-05- 30
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    4. Heat
    5. Chemotherapeutics (hydroxyurea, 5-FU, Platinum, Gemcitabine)
   60 – 70 Gy → has emerged as acceptable standard dose.
   RAD = 0.01 J/kg of tissue
                                     Gy = 100 RAD = 1 J/kg tissue

   Higly coiled DNA with protein is relatively shielded from the indirect effects
   Cells are most sensitive during early S and mitosis since that when DNA is maximally uncoiled.

EARLY REACTIONS
   Occur during or immedialtely following treatment and may last for a few weeks.
   Basic mechanism = damage of actively proliferating cells.
   Daily fraction size and time between fractions is important in determining extent of these.
   Most sensitive target is DNA, in which SS and DS breaks or cross-links are induced. Alternatively,
    sugars, necleotides, or both are damaged.
   Early response gene transcription is induced (mostly TFs).

ACUTE EFFECTS ON NORMAL TISSUE
   Systemic: lethargy, fatigue
   Skin: erythema, dry pruritis, moist desquamation, hair loss
   Liver: radiation hepatitis
   Oral mucous membranes: mucositis
   Esophagus: esophagitis
   Lung: radiation pneumonitis
   Heart: acute pericarditis, myocarditis
   Small bowel: cramping, diarrhea, nausea, vomiting
   Bladder: frequency, urgency, dysuria
   Repro: sterility
   Rectum: tenesmus
   Hematopoietic: cytopenia
   Nervous system: radiation induced injury to peripheral nerves is usually painful and associated with
    paraesthesia, cerebral edema, conjunctivitis
   MSK: cessation of epiphyseal growth

LATE REACTIONS
   The dose limiting effects → necrosis, fibrosis, & ulceration
   Results from vascular damage and accumulation of cell dropout from organ population.
   Late response genes transcription encode mostly cytokines and GFs.
   Becomes apparent months to years afterwards.
   Often progressive as opposed to self-limiting.
   Usually local.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                       2010-05- 31
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TRANSFUSIONS


MASSIVE TRANSFUSION COMPLICATIONS (7)
1. Dilutional TCP (most common complication): requires plt transfusion if microvascular bleeding unrelated
   to hypothermia develops.
2. Hypothermia (next most common when dilutional thrombocytopenia isn‟t on the list) causing:  plt
   function,  clotting, hypoCa from  citrate.
3. K changes: theoretical risk of hyperK but most are in shock with lots of aldosterone, ADH, permissive
   roids, so they get hypoK.
4. Alkalosis because citrate gets converted to bicarb (except when liver is hypothermic). Don‟t give bicarb
   with massive transfusion
5. Citrate load: can cause hypoCa (hypotension, narrowed pulse pressure,  LVEDP,  PAP,  CVP,
   prolonged QT).
6. Low 2,3-DPG in transfused pRBCs ( O2 release in periphery)
7. DIC

   Approach to massive transfusion: pRBCs for O2 carrying capacity, plts for microvascular bleeding in
    normothermics, crystalloid for intravascular volume.


GUIDELINES FOR RED CELLS
1. Hb < 80 or acute blood loss in otherwise healthy patient with S&S of  O2 delivery with 2 or more of the
   following:
       a. Estimated/anticipated loss of > 15% (750 ml)
       b. DBP < 60
       c. SBP drop from baseline > 30
       d. Tachycardia
       e. Oliguria/anuria
       f. Mental status changes
2. Hb < 100 in those with risk of CAD or pulm insufficiency who have sustained or are expected to sustain
   significant loss.
3. Symptomatic anemia with any of the following:
       a. Tachy
       b. Mental status changes
       c. Evidence of myocardial ischemia
       d. SOB or dizzy with mild exertion
       e. Orthostatic hypotension
 1 unit of blood raises hematocrit by 3%.

GUIDELINES FOR PLTS
1. Plt < 10
2. Plt < 50 with microvascular bleeding or planned invasive procedure.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                         2010-05- 32
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3. Precipitous fall with microvascular bleeding.
4. Intraoperatively with microvascular bleeding (oozing) and: complicated procedure or required > 10 U
   pRBC.
5. Documented plt dysfunction (Bleeding time > 15 min) and microvascular bleeding or planned invasive
   procedure.
 Don‟t use for renal failure or vWD.

GUIDELINES FOR FFP
   Treatment of multiple/specific coagulation factor deficiency with abnorm PTT or INR.
   Abnormal specific factor deficiency or planned invasive procedure in presence of:
     Congenital deficiency of antithrombin III, clotting factors, protein C or S, plasminogen, or antiplasmin
     Acquired deficiency from warfarin, vit K deficiency, liver disease, massive transfusion, DIC

CRYOPRECIPITATE
   Contains: factor VIII, fibrinogen, fibronectin, vWF, fXIII
   Indications: hemophilia A (not usually), vWD, hypofibrogenemia (e.g. DIC), ?uremic bleeding.

AUTOLOGOUS BLOOD
   Hct > 30%
   Donate q3-4days, starting 1 month preop
   Fe supp and good nutition
   Can be done in those with cardiac disease and people of any age

INTRAOPERATIVE HEMODILUTION
   Remove 1 – 3 U and replace with colloid or crystalloid
   Do it just before and reinfuse as needed intraoperatively.
   Blood stored at room temp for up to 4 hrs




TRANSFUSION REACTIONS

   IgA reactions when recipient has no IgA  anaphylactoid reaction. This has incidence of 1/20 000.
   Acute haemolytic reaction: 1/25 000
   Fatal haemolytic reaction: 1/600 000
   In hemolysis, Hb turns to hematin in acid urine → it is a tubular toxin.
   Severe ones involve complement mediated RBC destruction. Most of these are result of ABO
    incompatible transfusions.
   Most severe reactions involve complement mediated RBC destruction and can occur within hours to days.
   Complement derived peptides are released and cause hypotension, compromised renal blood flow,
    activation of clotting cascade, and lead to DIC.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                            2010-05- 33
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   Most febrile transfusion reactions are due to WBC. These are non-hemolytic.

TREATMENT OF REACTION
   Stop transfusion and check all documentation.
   Hydrate
   Give mannitol and/or lasix
   Insert foley
   Check for urinary hemoglobin
   Type patients blood from a different site

INFECTION TRANSMISSION
   HAV very rare
   HIV 1:900 000
   HCV 1:500 000
   HBV 1:200 000
   HGV 1:50 (nonknown disease)
   CMV 1:7500 (most common virus transmitted) (immnuocompromised need CMV neg blood)
   Syphyllis can be transmitted in plt transfusions because they are stored at room temperature.



HEMOSTASIS


OUTLINE OF EVENTS
                                 1. Blood vessel injury with exposure of tissue
                                    factor and collagen
                                 2. Platelet aggregation and adherence with
                                    formation of platelet "plug". Plug forms
                                    within 1 – 3 mins. Fibrinogen and vWF is
                                    important for adherence of plts. ADP is
                                    released by plts and stimulates further
                                    adherence.
                                 3. Vasoconstriction mediated by TxA2 & 5-
                                    HT in small and medium vessels, NE and
                                    innervation in larger vessels
                                 4. Initiation of coagulation cascade by
                                    interaction of tissue factor with factor VII in
                                    presence of Ca, with conversion of
                                    prothrombin to thrombin and activation of
                                    the coagulation cascade.
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                            5. Thrombin converts fibrinogen to fibrin and
                                also activates VIII, X and XI in the diagram
                                below and IX indirectly through XI thereby
                                perpetuating the cascade. Thrombin also
                                activates anticoagulant pathways. It binds
                                thrombomodulin on endothelial cell
                                surfaces and activates protein C in presence
                                of protein S. Protein C inactivates VIIIa
                                and Va and inhibits tPA inhibitor.
                            6. Fibrin monomers and entrapped platelets
                                form a hemostatic thrombus
                            7. Stabilization of the fibrin clot by cross-
                                linking of fibrin monomers by XIII.
                                Retraction of the clot occurs within 10
                                mins.
                            8. Organized clot formation and arrest of
                                bleeding
                            9. Local blood flow, vasodilatory influences,
                                and regulatory feedback mechanisms limit
                                extension of thrombus. Prostacyclin from
                                endothelial cells inhibits plt aggregation.
                            10. Fibrinolysis with dissolution of the fibrin
                                thrombus. Main reaction is activation of
                                plasminogen  plasmin by tPA (from
                                endothelial cells) and urokinase (from
                                endothelials and duct-lining epithelials).
                                Thrombus protects itself from unimpeded
                                fibrinolysis by incorporating inhibitors
                                (PAI-1 from endothelials and plts and 2-
                                antiplasmin from liver) in the clot.
                                Streptokinase is a similar bacterial product
                                to urokinase & tPA.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                          2010-05- 35
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COAGULATION CASCADE




   Note how V belongs to the common pathway.
   Note below how Ca is involved in activation of VII, activation of X, cross-linking of fibrin, and the IXA-
    VIIIa-PL-Ca complex.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                       2010-05- 36
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BLEEDING DISORDERS


SCREENING FOR DISORDERS
   PT/INR measures: extrinsic pathway (VII) and common pathway factors including , V, X,
    prothrombin/thrombin (II), and fibrinogen/fibrin.
   PTT measures: intrinsic pathway factors (HMWK, prekallikrein, VIII, IX, XI, XII) and common pathway
    factors (II/thrombin, V, X and fibrinogen/fibrin)
   Thrombin time is time required to clot after addition of thrombin. May be prolonged in DIC,
    hypofibrinogenemia, dysfibrinogenemia
   Bleeding time estimates qualitative plt function.

   Normal INR and abnormal PTT = deficiency of proximal intrinsic pathway.
   Abnormal INR and normal PTT = abnormalities of vitamin K dependent factors such as II, VII, IX, X.

MIXING TEST:
 Patient‟s plasma mixed with normal plasma
 If test normalizes with mixing  deficiency of a factor.
 If test doesn’t normalize with mixing  inhibitor present (e.g. lupus anticoagulant, heparin, etc.)
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                           2010-05- 37
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MINOR FACTOR DEFICIENCIES
   Factor XII deficiency, defects/deficiency of HMW kininogen and prekallikrein  lab abnormalities
    (dramatic prolongation of PTT) but no clinical bleeding. No therapy required prior to surgery.
   Factor XI deficiency (autosomal recessive, especially common in Ashkenazi Jews) causes less
    spontaneous bleeding and than VIII or IX deficiency.


HEMOPHILLIA A (CLASSIC)
   Congenital coagulation disorder resulting from deficiency or abnormality of VIII.
   X-linked with many different mutations and up to 30% spontaneous mutations.
   Onset of bleeding following trauma is usually hours or days after injury since the platelet plug works fine.
   Bleeding may then persist.
   They usually present with bleeding into the deep tissues or joints as opposed to mucosal bleeding seen
    with plt abnormalities. (Long-term complications of hemarthroses can be crippling.)
   Labs: prolonged PTT, normal PT/INR, bleeding time and vWF:Ag (antigenic level of vWF which rules
    out vW disease.)
   Severity can be classified based on functional levels of VIII, termed VIII:C (VIII:Ag refers to the
    antigenic and not functional level of VIII).
   < 1% = spontaneous bleeding
   < 2% = severe bleeding
   2 – 5% = moderate bleeding
   5 – 30% = mild disease (Spontaneous bleeds are rare)
   >30% book doesn‟t say but ? no clinical significance.
   For surgery, usually aim for levels of 50-100%
   Minimum needed for hemostasis is 30%.
   Tx (3):
    1. DDAVP iv (0.3 mcg/Kg) or intranasal can raise VIII levels in mild to moderate disease (5 – 10%
        VIII:C) in preparation for minor surgery or following minor trauma. (causes release of stored VIII and
        vWF from endothelial cells → use in Type I vWDz also)
    2. Recombinant VIII and plasma based VIII concentrate for more serious bleeding. FFP isn‟t
        concentrated enough.
    3. Cryoprecipitate is good enough but not used when specific VIII is available.
    4. Recombinant fVIIa – used for patients with fVIII inhibitors (determined from mixing studies)


HEMOPHILLIA B (CHRISTMAS)
   Inherited X-linked deficiency or defect in IX.
   Dx:  PTT,  IX, normal INR/PT, bleeding time, and plt count in male patient. Do a mixing study since
    there are inhibitors of IX.
   Tx: prothrombin complex concentrate and pure IX concentrate.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                           2010-05- 38
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   Goal of treatment: level raised to 30% to protect against bleeding post dental extraction or to abort a
    begining joint hemarrthroses, to 50% if major joint or IM bleeding is already evident, to 100% in life
    threatening bleeeding or before a major operation.
   20 – 40% activity = moderate deficiency
   > 30% activity required for hemostasis


VON WILLEBRAND’S DISEASE
  Most common of congenital bleeding disorders (prevalence of about 1%.)
  VWF causes plt adhesion to collagen, initiating plt plg formation. It also forms a complex with VIII (acts
   as carrier protein) in the blood.
 Produced by endothelials and megakaryocytes unlike the rest of the coagulation proteins (except VIII)
   that are produced by the liver.
 Most have a mild bleeding disorder.
THREE TYPES:
      1. Type I: Autosomal dominant quantitative deficiency of normally functioning vWF. They have
          abnormal bleeding time, and mild reduction in VIII:C (b/c less carrier protein) and vWF.
      2. Type II: Variably inherited and qualitative defects in vWF. Dx is complicated by the many
          subtypes but in general there is a depressed ristocetin assay (which measures effectiveness of vWF
          in agglutinating platelets.)
      3. Type III: autosomal recessive with complete abscense of vWF and severe bleeding.
 The bleeding is similar to bleeding from platelet dysfunction, ie: mucosal bleeding, petechiae, epistaxis,
   and menorrhagia. (Coagulation factor problems result in joint bleeding.)
TREATMENT:
  1. DDAVP 0.3 mcg/kg. Give 1hr prior to surgery. 48 hrs must elapse before a second injection is given
      to allow time for VIII and vWF to reaccumulate in endothelials. (Stimulates release form
      endothelials.) (Epsilon-aminocaproic acid or tranexamic acid should be given to suppress
      fibrinolysis.) Useful in type I disease, no value in type II and III.
  2. Humate P – a fVIII product (not recombinant) which contains high concentrations of vWF
  3. Cryoprecipitate 1 bag/10 kg q8-12h for several days to prevent excessive bleeding after major
      operation. Pasteurized intermediate purity factor VIII concentrate contains large numbers of vWFs
      and is a safe alternative. Useful for all three types of the disease.


2-ANTIPLASMIN DEFICIENCY
   Homozygote will bleed as severely as a hemophilliac after surgery or trauma.


ACQUIRED BLEEDING DISORDERS
   Hepatic failure: liver is major source of all factors except VIII and vWF. DDAVP can be used to shorten
    bleeding times in cirrhotics except in presence of plt dysfunction or thrombocytopenia, large volumes of
    FFP may be necessary to maintain normal factor levels.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                          2010-05- 39
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   Renal failure leads to  in aggregation and adhesion of plts (causes defective GpIb and GpIIb/IIIa), treat
    with DDAVP, cryoprecipitate and conjugated estrogens.
   Thrombocytopenia (5)
    1. Failure of production
    2. Splenic sequestration
    3. Consumption
    4. Dilution
    5. Drugs (7): quinidine, sulfa, oral hypoglycemics, gold, rifampin, mithramycin (or any
        myelosuppressing chemotherapeutic), heparin
   Thrombocytopathy (14):
    1. Chemo drugs
    2. Thiazides
    3. Alcohol
    4. Estrogen (In contrast note that conjugated estrogens can be used to treat renal failure-associated
        coagulopathy.)
    5. Antiobiotics (sulphas)
    6. Quinidine
    7. Quinine
    8. Methyldopa
    9. Gold
    10. Heparin ( plt aggregability)
    11. ASA (7 days)
    12. NSAIDs (phenylbutazone, dipyridamole) (3 – 4 days)
    13. Dextran: a volume expander that  plt adhesiveness.
    14. Hypothermia
   Hypothermia (3):  fibrinolytic activity, thrombocytopathy, and  in collagen induced plt aggregation.
    Spontaneous bleeding occurs when temp < 30 – 34 degrees C.
   Vitamin K deficiency: necessary for carboxylation of glutamate in factors II, VII, X, and IX. (Also
    needed for carboxylation of protein C and S.) FFP rapidly corrects the coagulation deficit.
   Warfarin treatment.


PLATELET DISORDERS
   Bleeding associated with plts includes mucosal bleeding, easy bruisability, petechiae, purpura, and
    menorrhagia.
   Extracorporeal bypass circuits activate plts and can produce bleeding.

IDIOPATHIC (AUTOIMMUNE) THROMBOCYTOPENIC PURPURA
   Most common cause of isolated thrombocytopenia.
   IgG autoantibody
   Plt destroyed in the spleen but spleen not usually palpable.
   Peripheral blood smear shows decreased plts, large plts.
   Marrow shows plentiful megakaryocytes.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                            2010-05- 40
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   Management: steroids, spleenectomy if steroids fail. Others: immunosuppressives, plts, plasma exchange,
    danazol, and iv gamma globulin.

GLANZMAN’S THROMBASTHENIA
   Inherited defect of GpIIb/IIIa (plt membrane glycoprotein) characterized by impaired plt binding to vWF,
    fibrinogen, and fibronectin  severe mucosal bleeding.
   Lab findings: failure of plts to aggrgrate with any physiologic agent, absence of clot retraction, single plts
    without aggregates on a peripheral blood smear from finger prick.
   Treatment: Platelet transfusions → but…will develop antibodies, so must be selective when to expose
    patient to a platelet transfusion

BERNARD-SOULIER SYNDROME
   Inherited absence of surface glycoprotein GpIb-IX that binds vWF 
     Plts don‟t adhere and aggregate
     Absolute plt numbers are 
     Plts are larger.
   Treatment: Platelet transfusions

LARGE PLTS ASSOCIATED WITH FUNCTIONAL ABNORMALITIES
 May-Hegglin anomaly
 Chediak-Higashi syndrome.

DISORDERS OF AMPLIFICATION OF PLT ACTIVATION
   May result from (3):
    1.  ADP in dense granules
    2. Inability to generate TXA2
    3. Inability of plts to respond normally to TXA2
   Plt aggregation test results found in disorders of plt activation amplification (2):
    1. Impaired-to-absent aggregation after exposure to collagen, epinephrine, and a low concentration of
        ADP
    2. Normal aggregation after exposure to high concentration of ADP
   ASA and NSAIDs may produce the same results.


DIC
   A procoagulant state but tends to present as a bleeding disorder rather than as a procoagulant state.
    Thrombotic complications, however, can result.
   Think of it as massive, systemic activation of coagulation system (mostly microvascular  organ
    dysfunction) with consequential depletion of coagulation factors that results in a clinical bleeding
    disorder.
   With activation of both coagulation and fibrinolytic systems, both thrombin and plasmin are in circulation.
   Thrombin activates fibrin. Monomers of fibrin form soluble fibrin clots causing microvascular thrombosis
    with entrapment and depletion of platelets.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                       2010-05- 41
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    A simultaneous degradation of these factors by plasmin occurs.
    Result is depresed fibrinogen levels and high degradation product levels. (X, Y, D, and E fragments)
    Fragments D and E interpose themselves between fibrin and polymers forming a weak fibrin clot therby
     inhibiting the normal coagulation of blood.
    Plasmin also degrades V, VIII, IX, and XI and activates the complement system.




IN GENERAL (4):
1.   Procoagulant activation
2.   Fibrinolytic activation
3.   Inhibitor consumption
4.   Biochemical evidence of end organ damage or failure

ASSOCIATIONS (11)
1.   Complications of obstetrics
2.   Infection (bacteremia and viremia) & sepsis
3.   Malignancy including leukemia (especially metastatic)
4.   Shock from any cause
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                       2010-05- 42
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5. Burns
6. Crush injuries
7. Massive transfusion
8. Liver disease
9. Hemolysis
10. Inflammatory and autoimmune conditions
11. Malignant hyperthermia

LABS IN MASSIVE DIC
    Plt
    PT/INR
    PTT
    Fibrinogen
   + Fibrin monomer present
   High plasma D-dimer and fibrin degradation products
   Low levels of multiple clotting factors (V and VIII)
   Fragmented RBCs on smear
   Low thrombin-antithrombin and antithrombin III
    Coagulation factor degradation fragments (F1.2, FpA)
    Plasminogen and 2-antiplasmin inhibitor

TREATMENT (8)
1. Correct underlying illness
2. Heparin (when there are developing thrombotic complications) if treatment of underlying pathology
   doesn‟t ameliorate the condition in a few hours.
3. Antithrombin III concentrates
4. Washed pRBCs
5. Platelets
6. Cryoprecipitate to replace fibrinogen and VIII
7. FFP to replace V, clotting factors, and antithrombin III.
8. Epsilon-aminocaproic acid (or tranexamic acid) to inhibit fibrinolysis, which releases fagments D and E
   that interfere with normal clot formation.



PROCOAGULANT STATES


HIT
HIT I
   Non-immune
   Transient, normalizes once off heparin
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                          2010-05- 43
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HIT II
   Immune mediated (IgG)
   Ab recognizes a multimolecular complexe of heparin and plt factor 4 resulting in plt aggregation.
   Suspect in anyone on hep who develops thrombosis or when plt < 100.
   Typically occurs 5 – 15 days into treatment, sooner if hep in previous 3 months
   Plts drop to 25 – 100
   Dx: serotonin release assay
   Complications (4):
    1. Bleeding
    2. Intravascular thrombosis (venous and arterial) with unusual thrombotic complications
    3. Acute plt activation syndromes (fever, flushing)
    4. Skin necrosis

MANAGEMENT
   D/C heparin and wait for fx to wear off OR
   Protamine reversal if thrombosis has occurred (Greenfield‟s)
   Start warfarin under protection of another anticoagulant (patients with circulating plt microparticles have
    a heightened thrombotic risk and warfarin can potentiate this)
   Options: danaproid (~25% cross-reactivity), ASA (some but limited utility), ancrod, lepirudin (a direct
    thrombin inhibitor), argatroban, dextran
   No mention of plt transfusion anywhere in books.
   LMWH has 90% cross-reactivity → thus, can’t use it!!!


ANTITHROMBIN III DEFICIENCY
   The most important plasma protease inhibitor.
   Uncommon but significant risk for recurrent, life threatening thrombosis.
   Most cases apparent before 50 yrs.
   Can present with arterial thrombosis.
   Antithrombin III is a serine protease inhibitor of thrombin (II), VIIa, IXa, Xa, XIa, and kallikreinin.
   Suspect when patient cannot be adequately anticoagulated with heparin (heparin acts by potentiating
    antithrombin III activity).
   Dx: measure levels (heparin will  antithrombin levels by 30% for up to 10 days) and activity.
   Causes (7):
    1. Nephrotic syndrome (loss of factor)
    2. Liver disease (site of production)
    3. Malignancy
    4. Malnutrition
    5. Decreased protein production
    6. DIC
    7. Genetic (qualitative defects and quantitative defects)
   Treatment of patient who needs anticoagulation: 1) antithrombin III concentrates (if available) or FFP
    while on heparin followed by 2) oral anticoagulants as per usual.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                               2010-05- 44
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PROTEIN C AND S DEFICIENCIES
   Both protein C and S are made by liver.
   Both are vitamin K dependent.
   Protein C is activated when thrombin binds to endothelial cell R thrombomodulin. Thrombomodulin
    brings protein C in proximity to thrombin to be activated.
   Protein S is an activated protein C cofactor and deficiency results in clinical states identical to protein C
    deficiency.
   Activated protein C/protein S/procoagulant tissue factor (another cofactor) actions (2):
    1. Inactivates Va and VIIIa   thrombin production (anticoagulant)
    2. Inhibits tPA inhibitor (PAI-1)   plasminogen activity and  fibrinolysis (fibrinolytic)
   Overall Protein C can be thought of as a anticoagulant and fibrinolytic.
   Causes of protein C deficiency (4):
    1. Congenital (homozygosity is incompatible with life)
    2. Liver failure
    3. DIC
    4. Nephrotic syndrome
    5. Inflammatory states
   Most cases of protein C or S deficiency involve venous thrombosis but arterial thrombosis has been
    reported.
   Thrombosis usually occurs between 15 and 30 yrs.
   Dx: Protein C levels and activity are measured. For protein S, only antigen levels are measured.
   Mgmt: Only needs treatment after thrombosis:  heparin then oral anticoagulants for life.
     Start with low dose warfarin to minimize the transient hypercoagulable state that warfarin induces
        (risk of syndrome of warfarin-induced skin necrosis esp. over fatty areas → e.g. breast, abdomen,
        buttock)


RESISTANCE TO ACTIVATED PROTEIN C (FACTOR V LEIDEN)
   .A common polymorphism of factor V that results in resistance of Va to activated protein C is present in
    about 1 – 2 % of the population.
   Most common cause for thrombosis (fV leiden mutation present in 40-60% cases of idiopathic
    thrombosis)
   By itself is a relatively low risk factor (2.4x ↑ risk) → esp. ↑ risk when other risk factors present (e.g. oral
    contraceptives, protein C or S deficiency, etc.)
   Homozygosity is compatible with life (80x ↑ risk thrombosis vs. 7x ↑risk in heterozygote)
   Associated with increased incidence of venous thrombus (arterial also occurs)
   Indications for long-term anticoagulation remain undefined for these patients (recurrent episodes need
    anticoagulation)
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                          2010-05- 45
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LUPUS ANTICOAGULANT
   A misnomer because it results in a hypercoagulable state.
   Is usually associated with antiphospholipid antibodies.
   Syndrome consists of presence of antiphospholipid antibodies in association with episodes of thrombosis,
    recurrent fetal loss, thrombocytopenia, and livedo reticularis.
   Thrombosis can be venous or arterial (venous more common)
   Etiology of thrombosis: multfactorial (no single cause attributed)
   Dx: suspected when PTT , antiphospholipid or anticardiolipin antibodies detected, and other coagulation
    tests are normal.
   Mgmt: anticoagulation during thrombotic events
     Warfarin with goal INR >3.0 (can monitor fX levels)
     Heparin or LMWH for recurrent fetal loss throughout pregnancy (monitor with TT or antifactor Xa
        levels)



HEMATOLOGIC DRUGS

   IV Fe dextran can cause anaphylactoid reactions.

PROTAMINE
   Weak anticoagulant.
   Forms a salt with heparin resulting in loss of anticoagulant activity of both drugs.
   Used to reverse heparin effects. (1 mg/100 U of heparin in circulation)
   Too rapid administration can cause hypotension and anaphylactoid reactions.
   Common side effects (7):
    1. Hypotension (most common)
    2. Bradycardia
    3. Pulmonary artery HTN or hypotension
    4.  oxygen consumption
    5. Transitory flushing
    6. Leukopenia
    7. Thrombocytopenia 5%


WARFARIN
   Warfarin and vitamin K deficiency results in:  INR and slight elevation in PTT
   Interferes with: II (prothrombin), VII, IX, X, protein C, and protein S.
   In the liver these factors are carboxylated in a reaction catabolised by the reduced form of vitamin K.
   Warfarin prevents the reduction of vitamin K once it has functioned as a cofactor in the carboxylation
    reaction.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                       2010-05- 46
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   Major complications: bleeding, skin necrosis (occurs more frequently in those with protein C
    deficiency).
   Indicated in patients with mechanical prosthetic heart valves.
   T1/2 = 40 hrs.
   Reversal/treatment: vitamin K and/or FFP.
   Common drugs that  warfarin effectiveness (ABCD-H-PRST-V):
     Alcohol
     Azathioprine
     Barbiturates
     Carbamazepine
     Cortisone
     Corticotropin
     Cyclophosphamide
     Dicloxacillin
     Haldol
     Phenytoin
     Prednisone
     Ranitidine
     Rifampin
     Spironolactone
     Sucralfate
     Trazodone
     Vitamin C (high dose)
   Common drugs that  warfarin effectiveness (A-C-F-H-N-PQRST):
     Alcohol
     Allopurinol
     5-ASA
     Amiodarone
     ASA
     Azole antifungals
     Cephalosporins
     Clarithro/erythro
     5-FU
     Flagyl
     Heparin
     NSAIDs
     Neomycin
     PPIs
     Penicillins
     Prednisone
     Propranolol
     Quinolones
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                           2010-05- 47
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       Ranitidine
       Thyroxine
       TMP/SMX
       Tylenol
       Thrombolytics

GENERAL PATTERNS TO HELP REMEMBER ABOVE DRUGS:
 Antibiotics (with exception of Rifampin) ↑ warfarin effect
 Cardiac meds & anticoagulants ↑ warfarin effect
 Pain & Stomach meds (with poss. exception of ranitidine) ↑ warfarin effect
 Psychotropics & anticonvulsants (Poss. exception: alcohol) ↓ warfarin effect
 Endocrine meds (with exception of thyroxine +/- prednisone) ↓ warfarin effect
 Immunosuppressants & chemotherapeutics (exception: 5-FU) ↓ warfarin effect

HEPARIN
   Mechanism (3):
    1. Accelerates the reaction between thrombin and anti-thrombin III, accelerating the inhibition of
       thrombin (II) and other serine proteases (VII, IX, X, XI, and Kallikreinin) by antithrombin III. It is not
       consumed by this reaciton
    2. Directly binds and inhibits coagulation proteases and is important for the selective inhibitor of
       thrombin, heparin cofactor II.
    3. Decreases platelet aggregability.
   Prolongs PTT by depleting intrinsic factors, will also prolong INR slightly.
   Dose cleared in ~ 6 hrs.
   Complications (4):
    1. Bleeding (most common, intracranial least likely spot)
    2. HIT I and II (measure plt every other day starting on fourth day of treatment)
    3. Alopecia
    4. Osteoporosis

LMWH
   Inhibits activated factor X (Xa) but has less effect on antithrombin and on coagulation in general than the
    unfractionated heparin.


ASA
   Mechanism: irreversibly blocks cycloxygenase (prostaglandin synthase), which catalyzes conversion of
    AA to endoperoxide compounds.
   At appropriate doses it decreases formation of prostaglandins and TXA2 but not the leukotriennes.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                         2010-05- 48
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ANCROD
    A thrombin like enzyme produces anticoagulation by cleaving fibrinogen into fibrinopeptides that don‟t
     form stable microthrombi.
    Blood is much less viscous as result as well.
    Does not activate plasminogen and does not degrade preformed fibrin clots consequently, it can be used
     postop.
    Half-life: 3 – 5 hrs.


EPO
    Can cause HTN, MI, thrombosis, CHF, stroke, seizures.
    Does not cause anaphylactic reactions.
    Fe dextran does cause anaphylactic reactions.


MEDICINAL LEECHES
    Hirudo medicinalis
    Question in 2003 exam on effect of leeches.
    Produce hirudin, a powerful and specific thrombin inhibitor.
    Action is independent of antithrombin III which means in can reach and inactivate fibrin-bound thrombin
     in thrombi.
    Little effect on plts or bleeding time.
    Recombinant hirudin is being investigated for clinical use.


THROMBOLYTICS
CONTRAINDICATIONS (6)
1.   Eye or CNS surgery within previous 2 weeks
2.   Intracranial/spinal neoplasia or vascular anomalies
3.   Stroke in previous 2 months
4.   Active bleeding
5.   Severe hypertension
6.   Allergy to agent

UOFT CONTRAINDICATIONS IN SETTING OF MI
Absolute                    Relative
Active bleeding             GI, GU hemorrhage or
                            stroke in last 6/12
Aortic dissection           Major surgery or trauma
                            in last 2 – 4/7
Acute pericarditis          Severe uncontrolled
                            HTN
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Cerebral hemorrhage    Bleeding diasthesis or
                       intracranial neoplasm
                       Puncture of
                       noncompressible vessel
                       Significant chest trauma
                       from CPR




                                                  (Greenfield)
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                    2010-05- 50
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PAEDIATRIC FLUIDS AND LYTES

   Know physical exam in kids to assess fluid loss.
   Preop blood work required for kids < 6 months and menstruant teens.
   NPO rules: CF up to 2 hrs preop for < 6 months.

INTAKE REQUIREMENTS
   Neonate insensible losses: 30 – 35 ml/kg/day (adult: 15)
   Water requirements in neonate: 150 ml/kg/day; ↓ to 4,2,1 rule when kid >10 kg
   Neonate maintenance: D10/0.25%NS, may add 10 – 20 meq/l KCl on 2nd or 3rd day of life, may change to
    D5/0.25%NS in 2 or 3 weeks
   K and Na requirements: 2 – 3 mEq/kg/day

ESTIMATING FLUID REQUIREMENTS
Weight (kg)   Fluid requirement (ml/d)
0 – 10        150/kg
10 – 20       1000 + 50/kg over 10
> 20          1500 + 20/kg over 20

RESUSCITATION
   Trauma access in kids: saphenous, antecubital veins
   Newborn BV = 80 cc/kg, Tfusion = 10 cc/kg, plts = 10 cc/kg.
   Boluses: 10 – 20 ml/kg of RL over 30 minutes.
   SV is fixed in infants. The only way they can  CO is by  HR.

REPLACEMENT OF ENTERAL LOSSES
   Replacement of bilious losses: RL
   Replacement of clear gastric losses: D5/0.45%NS
   Replacement of large volume enterostomy losses: RL

REPLACING LOSSES
Source       Replacement
Gastric      ½ NS + 10 meq/l KCl
Pancreatic   RL or ½ NS + 50 meq/l NaHCO3
Bilious      RL or ½ NS + 50 meq/l NaHCO3
Ileostomy    RL or ½ NS + 25 meq/l NaHCO3
Diarrhea     RL or ½ NS + 25 meq/l NaHCO3
Pleural or   RL + 5% albumin
Peritoneal
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                       2010-05- 51
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METABOLIC DERANGEMENTS IN PYLORIC STENOSIS
   Dehydration
   Hypochloremic, hypokalemic metabolic alkalosis
   Replacement: D5&1/2NS until they void then D5&1/2NS with KCl.
   Paradoxically urine is acid because K is so depleted that kidney shifts to H+ excretion.

PHARMACOKINETICS IN KIDS
    protein binding
    hepatic glucoronidation  slow clearance rate
    GFR in newborns until 2 yrs of age, then adult values after that



FLUIDS AND LYTES

   Osmolality (approx) = 2Na + Urea + Glc + alcohol (in Canadian units)
   TBW = 600 cc/kg (60% of body weight)
   Whole blood = 66 cc/kg
   Plasma = 40 cc/kg
   Erythrocyte volume = 26 cc/kg


PARENTERAL SOLUTIONS
   RL ideal for replacing losses of fluid with the same ionic concentration as plasma such as edema and
    small bowel losses. Disadvantage is low Na content  hyponatremia with long term use or in those who
    can‟t excrete the excess free water.
   Normal saline provides excess of Na and Cl. Large volumes can lead to total body Na overload and
    hyperchloremia. Added Cl can  hyperchloremic MA (pH is 4 – 5, and chloride load overwhelms
    kidneys  hyperchloremia and acidosis).
                                Secretion            Na K Cl HCO3 H
                                Salivary             50 20 40 30
                                Basal gastric        100 10 140               30
                                Stimulated gastric 30 10 140                  100
                                Bile                 140 5 100 60
                                Pancreatic           140 5 75 100
                                Duodenum             140 5 80
                                Ileum                140 5 70 50
                                Colon                60 70 15 30

                         Solution           Na     K Ca Mg Cl            HCO3 Osm

                         ECF                142 4      5    3     103 27          295
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                         NS                  154                   154           308
                         RL                  130 4    2.7          109 28        273
                         D5 / NS             154                   154           560
                         D5/0.45%NS          77                    77            406
                         2/3 & 1/3           56                    56            ?271
                         D5W                  -  -     -       -    -     -      252

                         Albumin 5%      145                       145           300
                         Albumin 25%     145                       145           1500
                         Pentastarch 10% 154                       154           326

REPLACEMENT OF ENTERAL LOSSES
                                Source       Replacement
                                Gastric      ½ NS + 10 meq/l KCl
                                Pancreatic   RL or ½ NS + 50 meq/l NaHCO3
                                Bilious      RL or ½ NS + 50 meq/l NaHCO3
                                Ileostomy    RL or ½ NS + 25 meq/l NaHCO3
                                Diarrhea     RL or ½ NS + 25 meq/l NaHCO3
                                Pleural or   RL + 5% albumin
                                Peritoneal

ALBUMIN
   Main determinant of plasma oncotic pressure.
   Half-life: 20 days.
   On electrophoresis, it accounts for 52 – 66% of protein.


MAINTENANCE
   Insensible water loss: 8 – 12 ml/kgday,  10% for every degree > 37.2.
   4-2-1 rule of fluid requirements.
   Na 1 – 2 meq/kgday
   K 0.5 – 1 meq/kgday
   0.33% NaCl with 20 – 30 meq/L KCl best fits a patients daily requirements.
   Metabolic acidosis caused by saline from retention of Cl.


CALCIUM
HYPOCALCEMIA
PREDISPOSING CONDITIONS (4)
   Hypoparathyroidism
     Post-surgical
     Hypomagnesemia
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      Post-neck irradiation
    PTH resistance
      PseudohypoPTHism
      Hypomagnesemia
    Vit D deficiency
    Vit D resistance (VDDR II)
    Acute hypocalcemic syndromes can occur when there is acute chelation or precipitation of Ca. This can
     happen when patients are infused with large volumes of fluid in resuscitation, following large transfusions
     when lots of citrate is infused, when there is a rapid infusion of phosphate, and in acute pancreatitis when
     the Ca is saponified.
    Tumour lysis syndrome (4): hypocalcemia, hyperphosphatemia (chelates Ca  hypoCa), hyperuricemia,
     and hyperkalemia all due to massive tumour death. These pateints end up often needing hemodialysis.

MANIFESTATIONS
    Neuromuscular excitability (7):
     1. Paresthesias (circumoral / fingers / toes)
     2. Hyperreflexia & laryngospasm
     3. Seizures
     4. Tetany
     5. Chvostek‟s sign (nonspecific)
     6. Trousseau‟s sign (they flex their arm with 3min of BP cuff inflation)
     7. Paralytic ileus
    Cardiac dysfunction (6):
     1. Direct suppression of contractility
     2. Hypotension
     3.  pulse pressure
     4. Delayed repolarization
     5. Heart block
     6. Long S/QT segment

MANAGEMENT
    PO maintenance for 0.65 – 0.8.
    IV replacement only when symptomatic or < 0.65 mmol/L
    Note that hypoCa will be refractory to Tx if there is concomittant hypoMg (Mg essential for action of vit
     D). If this is the case, give concurrent Mg sulphate.

HYPERCALCEMIA
PREDISPOSING CONDITIONS (9)
1.   Primary hyperparathyroidism (most common in all comers)
2.   Malignancy (most common cause in hospitalized patients)
3.   Drugs (thiazides, lithium, tamoxifen)
4.   Immobilization
5.   Familial hypocalciuric hypercalcemia
6.   Granulomatous disease (sarcoid, TB)
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                          2010-05- 54
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7. Thyrotoxicosis
8. Milk alkali syndrome
9. Malignant hyperthermia

MANIFESTATION (6 SYSTEMS)
   CNS
      LOC
   NEUROMUSCULAR
     Proximal muscle weakness
     Hyporeflexia
   GI
     A/N/V
     Constipation
     Paralytic ileus
     PUD
     Pancreatitis
   RENAL
     Polyuria (nephrogenic DI)
     Nephrocalcinosis
     Nephrolithiasis
   CVS
     HTN
     Short QT
     Exacerbates dig toxicity
   MSK
     Bone pain

MANAGEMENT (9)
1. Forced diuresis with isotonic saline and lasix (mainstay in those with normal kidneys, dialysis possible in
   those with RF)
2. Bisphosphonates
3. Calcitonin
4. Mithramycin
5. IV phosphates (disodium or monopotassium phosphate, use as absolute last resort)
6. Corticosteroids (in sarcoidosis)
7. Chloroquine phosphate (in sarcoidosis)
8. Gallium nitrate
9. Surgical excision of excess functioning tissue

PAGET’S DISEASE OF BONE
   X-ray:  bone density, cortical thicknening, abnormal architecture, bowing, and overgrowth.
   Labs:  ALP,  urinary excretion of pyridinoline cross-links, Ca and P levels are usually normal but Ca
    may  during bed rest.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                       2010-05- 55
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   Bone scans show  localization to affected sites.

HYPOMAGNESEMIA AND HYPERMAGNESEMIA
   Mg is essential in hydrolysis of ATP.
   20% protein bound.
   The concentration of it in RBC is an indication of total body stores (4.4 to 6.0 mEq/L.)

HYPERMAGNESEMIA:
 Seen in RF & Mg-containing antacid abuse
 High Mg blocks entrance of Ca into myorcardial cells and causes heart failure.

HYPOMAGNESEMIA:
 Diseases that deplete Mg have a parallel effect on Ca.
 Mg stores in the intracellular fluid can become substantially depleted from chronic diarrhea or prolonged
  aggressive diuretic therapy.
 Etiology of HypoMg (6):
  1. Chronic diarrhea
  2. Prolonged aggressive diuresis
  3. DM with persistent osmotic diuresis
  4. Heavy EtOH
  5. Pancreatitits
  6. HypoP
 Clinical Manifestations of Mg
   Cardiac manifestations (7):
     1. Prolonged PR interval
     2. Prolonged QT
     3. T-wave flattening
     4. Tachyarrhythmias (unstable VT)
     5. A. fib
     6. Torsades de pointes
     7. Digitalis toxicity enhanced as both inhibit the membrane pump
   Neurologic manifestations:
      Changes in mental status, seizures, Tremors, Hyperreflexia
      All uncommon, non-specific and have little clinical value
      Tremor is the most characteristic finding with hypomagnesemia but tetany is first sign.
 Tx: iv Mg sulphate.


FLUID DISTRIBUTION
   TBW = 0.60 x male weight, = 0.50 x young female weight
   ECF = 1/3 of TBW, plasma is ¼ of this, ¾ is interstitial/lymphatic.
     Plasma represents 8% of TBW and 5% of body weight.
     Red cell volume represents ~1/3 of plasma (i.e. Hct. Value)
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                       2010-05- 56
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   ICF = 2/3 of TBW


SODIUM
   Exchangeable Na measured by indicator dilution is about 40 meq/kg body weight.
   Synonyms: AVP (vasopressin) = ADH (antidiuretic hormone) = DDAVP (synthetic ADH)

REGULATION OF OSMOLALITY
   Osmolality tightly controlled in 285 to 295 mOsm range.
   AVP/ADH secretion stimulated by (4):
    1. osmolality > 280 mOsm
    2. a reduction in intravascular volume > 10%
    3. reduction in mean arterial pressure of > 10%
    4. pain and emotional stress.
   Aldosterone secretion stimulated by:
    1. Hypovolemia (via RAS)
    2. Hyperkalemia
   Roles of ADH and Aldosterone:
       o ADH → regulates sodium concentration (via H2O reabsorption)
       o Aldosterone → regulates total body sodium
   Serum osmolality = 2Na + urea + glucose (+EtOH)

APPROACH TO HYPONATREMIA:
1. Measure serum osmolality:
    Hypertonic Hyponatremia → hyperglycemia (for every 10↑ glucose above 10, Na ↓ by 2.5),
     mannitol, other effective osmole
    Isotonic Hyponatremia → lab artefact from ↑lipids or ↑proteins OR absorption of glycine or sorbitol
     (e.g. during TUPR)
    Hypotonic Hyponatremia → most common scenario → evaluate volume status and work up as
     below…

HYPOVOLEMIC HYPOTONIC HYPONATREMIA
   Depletion of Na and depletion of volume can result from loop diuretics, thiazides, Addison‟s disease,
    osmotic diuresis, vomiting, diarhea, fistulas, third spacing, weeping wounds.
   UNa < 10 = kidney holding onto sodium → therefore, extrarenal loss
   UNa > 20 = kidney not holding onto sodium → therefore RENAL loss
   Treatment:
     For Na above 120 use NS. Several litres may be required.
     For Na less than 120, 3% hypertonic NS is needed. Go slow.
     In neurosurgical patients ANP can cause hypovolemic hyponatremia and is treated with iv or po Na
       replacement with minimal fluid resuscitation.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                      2010-05- 57
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HYPERVOLEMIC HYPOTONIC HYPONATREMIA
   DDx: CHF, nephrotic syndrome, cirrhosis, psychogenic polydipsia, and SIADH.
   UNa < 10 = kidney holding onto sodium → therefore, extrarenal cause or nephrotic syndrome (kidney
    still able to hold onto sodium, however)
   UNa > 20 = kidney not holding onto sodium → therefore renal FAILURE
   Treatment:
     For Na > 120 volume restriction to as little as 10 ml water/kg/day may be required.
     For Na < 120 small volumes of 3% NS may be required +/- dialysis.

EUVOLEMIC HYPOTONIC HYPONATREMIA
WORKUP:
 Measure Urine osmolality
   UOsm > 100 → SIADH, adrenal insufficiency, or hypothyroidism
   UOsm < 100 → psychogenic polydipsia or low solute intake (‘tea & toast’)
   UOsm variable → screwed up „osmostat‟

SIADH
 Euvolemic (or hypervolemic) hyponatremia with low plasma osmolality and high urine osmolality.
 Renal and adrenal functions are normal.
 No K loss.
 DDx of SIADH (5):
   1. Malignancy: small cell lung, pancreatic, head & neck epithelial carcinomas, hematological
       malignancies (Hodgkins).
   2. Pulmonary disorders: bacterial, fungal, tuberculous infections
   3. CNS disorders: infection and injury
   4. Medications: carbamazepine, clofibrate, clorpropramide, thiazides, cyclophosphamide, cisplatin,
       vinblastine, vincristine, NSAIDs, SSRIs
   5. Medical conditions: rarely: hypothyroid, renal impairment with salt losing nephritis,
       mineralocorticoid deficiency, psychogenic polydipsia, alcohol w/d
   6. Other: pain, nausea, post-operative state
 Dx of SIADH supported by urine Na > 20 mEq/l and urine osmolality that exceeds plasme osmolality.
 Management (3):
   1. For Na < 120: water restrict to 7 to 10 mL/kg/day (50% maintenance).
   2. In maligancy demeclocycline antagonizes renal action of ADH and is useful. Li is also effective.
       Monitoring required.
   3. Osmotic diuresis and furosemide can be used when water restriction is inadequate.
 Note there is no role for saline therapy in SIADH.
 Correction of chronic hyponatremia should not exceed 10 to 15 mEq/L over 24 hours. Correction rate of
   less than 0.5 mEq/L/hr is advisable.
 Correction of acute hyponatremia should not exceed 1 mEq/L/hr until 120 level is reached then it can be
   speed up.
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POSTOPERATIVE HYPONATREMIA
 Stress of surgery increases AVP/ADH release.
 Rapid, precipitious decline in Na to 100‟s level has been described after GA for routine surgery.
 At risk in particular are menstruant women with high U/O (> 3 litres in first 24 hrs postop)
 This can be exacerbated by the administration of hypotonic fluids.

HYPERTONICITY
   Hypernatremia is most common cause of hypertonicity.
   Etiology: DI, burns, exfoliative dermatitis, vomiting (gastric Na 30 – 100), diarrhea (colon Na 60),
    fistulas, endoluminal tubes, diabetic KA (diuresis), hyperglycemic induced diuresis, sweating, fever,
    respiratory losses, inadequate AVP secondary to ethanol intoxication.
   Thirst is such a powerful drive to correct this that it is often self-corrected. Problems occur in elderly,
    infants and unconscious patients that can‟t drink when thirsty.
   When these patients get hypotensive the kidneys can no longer produce hypertonic urine and thus they
    can‟t achieve a net water balance.

TREATMENT OF HYPERNATREMIA
 IV isotonic solution is first step because they are often hypovolemic.
 Goal of rehydration should be to decrease osmolality slowly, ie: decrease Na by 10 to 15 mEq/L24hr.
 DDAVP can be used in Central DI patients. Desmopressin is the preparation of choice that is given
  intranasally. Chlorpropramide can be used to enhance renal affects of DDAVP.
   Thiazides may also be used paradoxically.
   Carbamazepine and clofibrate can be used with caution.
   Indomethacin may be modestly effective.

DIABETTES INSIPIDUS
 Central and nephrogenic
 The opposite of SIADH
 Central is endocrine disorder resulting from blunted or non existent synthesis or release of AVP/ADH.
    (Posterior lobe of pituitary is source.)
 Nephrogenic DI is when kidney doesn't respond to the AVP/ADH
 These patients develop thirst and dilute polyuria. If they can't replenish their water they can become
    hypovolemic.
 Etiology of central (6):
   1. Brain injury (especially basal skull #)
   2. Brain surgery
   3. Brain tumour
   4. SAH
   5. Reset DI (osmoreceptors that trigger AVP release are reset to go off at an osmolality greater than the
      usual 280)
   6. Idiopathic (autoimmune)
 Etiology of nephrogenic (3):
   1. Renal disease: post obstructive diuresis, sickle cell nephropathy, medullary cystic disease, end stage
      renal disease.
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    2. Medications: Li, glyburide, amphoterecin B, foscarnet, demeclocycline, methoxyflurane
    3. Electrolyte disturbances: hypercalcemia, hypokalemia.
    Presentation: sustained u/o > 100 cc/hr with hypernatremia.
    Dx: urine osmolality < 300 in a patient with serum Na > 150. Elevated serum AVP suggests nephrogenic
     DI while decreased u/o (i.e. positive response) in response to DDAVP challenge suggests central cause.
      Complete water deprivation should give  urine osmolality of 30 in 1 hr.
    Water deprivation test: patients with DI generally can‟t concentrate urine more than plasma.
    Treatment of DI:
           o Central: rehydration with isotonic sol‟n (avoid rapid correction → cerebral edema), DDAVP
               (desmopressin), chlorpropramide (enhances endogenous AVP action)
           o Nephrogenic: rehydration with isotonic sol‟n (avoid rapid correction → cerebral edema),
               correct underlying renal dz

MANAGEMENT OF POST-OBSTRUCTIVE DIURESIS:
   Low risk get po replacement
   Mod risk gets D51/2NS with 20 KCl at ½ previous hours u/o rate when they have > 200 cc/hr.
   For those with  Cr, CHF, mental obtundation, or peripheral edema AND hyponatremia replace u/o
     mL for mL with NS
   Note that afferent vasodilation and efferent vasoconstriction is not a mechanism of POD. Mechanisms
     include: volume overload, renal insensitivity to ADH, urea osmotic diuresis (most important in
     physiologic POD), elevated ANP.


POTASSIUM
   Beta-2-adrenergic agents can increase Na-K-ATPase activity and thus reduce extracellular K.
   Most filtered K is reabsorbed in proximal tubules. Excretion of K is carried out by cortical collecting
    ducts under influence of aldosterone.
   3800 mEq total body intracellular K+, 20mEq total body extracellular K+ (5L * 4.0mEq/L)
   Foods rich in K: potatoes, tomatos, bananas, oranges

HYPOKALEMIA
    K < 3.5
   Signs and symptoms (5):
    1. Serious arrhythmias including U waves, flattening Ts or inverted Ts, QT prolongation (especially if
       digitized) HypoK does not cause the arrhythmias, it enhances proarrhythmic effects of hypoMg and
       digitalis.
    2. Weakness
    3. ARespF if marginal resp function to begin with
    4. Worsening hepatic encephalopathy
    5. Nephrogenic DI.
   Hypokalemia exacerbates digoxin toxicity. Use cholestyramine to  dig toxicity.
     Other things that  dig tox (5):
       1. HyperCa
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        2. HypoK
        3. HypoMg
        4. Hypothyroid
        5. Renal Failure
   Etiology (3&4):
    1. Excessive renal loss (4)
         loop diuretics including lasix (they cause hypovolemia and activation of RAA sytem and thus
            increased exchange of Na for K in the distal convoluted tubule – urinary K will be greater than the
            usual 10 to 15 mEq/l)
         Barter‟s syndrome & Gitelman‟s syndrome (rare salt wasting disorders that result in hypokalemia
            too)
         primary hyperaldosteronism (adrenal cortex tumour)
         excess renin production (renal artery stenosis causing ischemia.)
    2. Uncompensated GI losses (villous adenoma)
    3. Medications: salbutamol, insulin, cortisol, vitamin B12.
   Total body K is distributed as 1 mmol per Kg in ECW and 30 to 40 mmol/Kg in ICW hence small drop in
    serum K means a big drop in total body K.
   Refractory hypoK suggests hypoMg requiring Mg replacement.
   Types of K salts: KCl, K acetate, K citrate, K bicarb, K phosphate.
   Cl in KCl enables absorption of Na in proximal tubule and thus aids with volume expasion.
   K bicarb if diarrhea is cause and there‟s bicarb loss.
   K phosphate for nutrional support of catabolic patients and in recovery of DKA.
   Hypokalemic, hypochloremic alkalosis happpens when the litres of gastric juice is lost. The patients
    become hypochloremic and alkalemic from loss of HCl. Low Cl in nephron reduces the Cl dependent
    reabsorption of Na in the proximal tubule. The resultant delivery of increased Na to distal tubule results in
    aldosterone driven excretion of large amounts of K. Urine K exceeds 20 mEq/L and is paradoxically
    acidic. Treat with KCl fluids.
   A surgically correctable cause of hypokalemia is a villus adenoma which produces large Q of K rich
    diarrhea.

HYPERKALEMIA
   Serum K > 5.0
   Greater risk when onset is rapid eg: reperfusion of a large vascular bed after greater than 4 hours of
    ischemia. Prevent with iv bicarb before reperfusion.
   Etiology (DDx)
     Pseudohyperkalemia
        - hemolyzed sample
        - leukocytosis
        - thrombocytosis
        - prolonged tourniquet
        - upstream IV with KCl
     Redistributional
        - acidosis
        - hypoinsulinism
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       - tissue necrosis (crush injury, burn, electrocution)
       - Reperfusion syndrome
       - Digoxin poisoning
       - Succinylcholine (malignant hyperthermia)
     Elevated Total Body K+
       - renal failure
       - excessive intake
       - aldosterone deficiency
       - diabetes mellitus
       - spironolactone use
     Drugs (trimethoprim, pentamidine, amlodipine, ACE inhibitor, succinylcholine)
   EKG changes (5):
    1. Prolongation of PR interval
    2. Tall & narrow T‟s
    3. Loss of P wave
    4. Slurring of QRS
    5. Terminal broad V tach (sign of impending cardiac arrhythmia/asystole)
   Tx if therapy needed in minutes: 10 mL of 10% Ca gluconate over 3-5 minutes then another 10 mL over
    10 min + 50 – 100 mEq of Na bicarb iv over 10 – 20 min.
   Tx if therapy required within 1 hour: D50W 50 mL iv + 10 units regular insulin + hemodialysis.
   Tx if therapy required within hours: rectal Kayexalate and lasix

PHOSPHATE
HYPOPHOSPHATEMIA
   Lassitude
   Fatigue
   Weakness
   Convulsions
   Death
   RBC hemolysis
   Impaired O2 delivery
   Impaired WBC phagocytosis

HYPERPHOSPHATEMIA
   Asymptomatic
   Treat with diuresis and phosphate binding antacids


DIURETICS
Drug          Class/Mechanism S           K pH Other
                              it
                              e
Acetazolamide CAI             P                   Cl
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                                 C
                                 T
Lasix            Loop (inhs      T           urate,
                 Na/K/2Cl        hi             Mg
                 reabsorption)   n
                                 A
                                 s
                                 c.
                                 L
                                 o
                                 o
                                 p
HCTZ,          Thiazides (Inhs   D           urate
chlorthaladone Na reabsorption;  C              Ca
, metolazone   Promotes excret‟n T              Na
               K/Cl/Mg/HCO3)                    Mg
Spironolactone K sparing-blk aldo D           Cl
                                  C
                                  T
Amiloride      K sparing-blk Na D 
                                  C
                                  T



ACID-BASE
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   If pH normal, but pCO2 and HCO3 both ↑↑ → mixed respiratory acidosis with metabolic alkalosis
   If pH normal, but pCO2 and HCO3 both ↓↓ → mixed respiratory alkalosis with metabolic acidosis
   If pCO2 or HCO3 don‟t change as much as expected, look for mixed d/o
   For AG acidosis:
        o If ∆HCO3 > ∆AG → concomitant Non-AG met. acidosis
        o If ∆HCO3 < ∆AG → concomitant Metabolic alkalosis

EXPECTED COMPENSATION FOR ACID-BASE DISORDERS

Disturbance              ∆CO2    ∆HCO
                                   3

Metabolic acidosis       1.25       1
Metabolic alkalosis      0.75       1

Acute resp acidosis       1        0.1
Chronic resp acidosis     1        0.4
Acute resp alkalosis      1        0.2
Chronic resp alkalosis    1        0.4

   Normal anion gap: <12 mmol/L
   Normal Osmolal Gap: <10 mOsm/L
   Effect of low albumin: for every 10↓ albumin → normal AG ↓ by 3

DDX OF  ANION GAP
   MUD PILES: methanol, uremia, DKA (or starvation/EtOH), polyethylene glycol & paraldehyde, iron &
    INH, lactate, ethanol, salicylates.

RTA
TYPE 1
   Characterized by hypokalemic, hyperchloremic, non-anion gap metabolic acidosis and a urinary pH
    consistently above 6.
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   The primary abnormality is the inability of the distal nephron to establish and maintain a proton gradient
    between the tubular fluid and the blood.

TYPE 2
   Like type 1 is characterized by hypokalemic, hyperchloremic,non-anion gap metabolic acidosis.
   Can still have acidic urine
   The primary defect is the failure of bicarbonate resorption in the proximal tubule leading to urinary
    bicarbonate excretion.

TYPE 4
   Hyperkalemic



PHYSIOLOGIC RESPONSE TO SURGERY

   Sudden outpouring of ACTH from ant pit   cortisol that remains  for 24 – 48 post-op. The cortisol
    serves to mobilize AA for acute phase proteins and gluconeogenesis.
   Sympathetic NS  Epi and NE from adrenal medulla.
   Alterations in serum osmolality and tonicity of body fluids secondary to the stress of surgery and
    anaesthesia  ADH and aldosterone  salt and water retention. Diuresis of this 3rd space fluid
    commences day 2 – 4 postop.
   Glucagon  and insulin .
   The period of catabolism postop last 1 – 3 days and is referred to as adrenergic-corticoid phase. It is
    followed by the adrenergic-corticoid withdrawal phase lasting 1 – 3 days.
   In absence of complication, anabolism will set in again 3 – 6 days postop.



ACLS

   Source: 2001 American Heart Association

PROTOCOLS
PULSELESS VT/VF
   Shock 200 J, 300 J, 360 J
   Epi 1 mg iv q3-5min or DDAVP/vasopressin 40 U iv x 1.
   360 J x 1 within 30 – 60 seconds
   amiodarone 300 mg iv, MgSO4 5 g iv for hypomagnesemia/torsades

PEA
   Epi 1 mg iv q3-5min
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   Atropine 1 mg q3-5min if PEA rate is slow (max 0.04 mg/kg = 2.8 doses for 70 kg)

CAUSES (5 H’S, 5 T’S)
   Hypovolemia, hypoxemia, H + acidosis, hyper/hypokalemia, hypothermia
   Tamponade, tension pneumothorax, thrombosis (coronary or PE), toxins (drug OD)

ASYSTOLE
   Epi 1 mg iv q3-5min
   Atropine 1 mg iv q3-5min up to max (about 3 mg)
   Transcutaneous pacing

BRADYCARDIA
   If clinically significant (5)
    1. Atropine 0.5 – 1.0 mg
    2. TC pacing if available
    3. DA 5 – 20 mcg/kg/min
    4. EPI 2 – 10 mcg/min
    5. Isoproterenol 2 – 20 mcg/min

   If not clinically significant
     If type II 2nd degree or 3rd degree AV block  transvenous pacing (TC pacing as bridge).
     If not may observe.

UNSTABLE TACHYCARDIAS
   Indications for synchronized cardioversion (4):
    1. Unstable VT (polymorphic VT, i.e., irregular form and rate, is treated like VF)
    2. Unstable PSVT
    3. Unstable AF
    4. Unstable atrial flutter
   Basically → if they have a palpable pulse and are unstable → SYNCHRONIZE

VOLTAGE USED
   Synchronized monophasic (or equivalent biphasic): (50 J for PSVT and atrial flutter), 100 J, 200 J, 300 J
    360 J.

STABLE TACHYCARDIAS (6)
   Afib
   Aflutter
   Narrow complex tachycardia (junctional tachycardia, PSVT, ectopic or multifocal atrial tachycardia)
   Stable wide complex tachycardia of unknown type
   Stable monomorphic VT
   Stable polymorphic VT
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ATRIAL FIBRILLATION
   Goals: control rate, convert rhythm, anticoagulate (coumadin)
   How it is managed depends on cardiac function.
   Make sure they don‟t have WPW.

NORMAL CARDIAC FUNCTION
   Rate control: CCB (verapamil), BB (metoprolol)
   Convert rhythm:
     < 48 hrs  DC cardioversion, amiodarone, procainamide, or propafenone.
     > 48 hrs  anticoagulate x 3 wks then DC cardioversion then antocoagulate x 4 weeks OR iv heparin,
       TEE to exclude atrial clot, then cardioversion and anticoagulant x 4 wks.

IMPAIRED HEART
   Rate control: Digoxin (diltiazem, amiodarone 2nd choice)
   Convert rhythm:
     < 48 hrs  DC cardioversion or amiodarone.
     > 48 hrs  anticoagulate x 3 wks then DC cardioversion then antocoagulate x 4 weeks or iv heparin,
       TEE to exclude atrial clot, then cardioversion and anticoagulant x 4 wks.

WOLF PARKINSON WHITE
   This is when there is an aberrant short circuit into the ventricle so that it depolarizes early and causes delta
    waves.
   Rate control:
     Normal heart function  cardioversion, amiodarone, procainamide, propafenone, or sotalol. Do not
       give: adenosine, BB, CCB, digoxin (all block AV-node → current preferentially follows aberrant
       pathway & perpetuates dysrhythmia)
     CHF  cardiovert or amiodarone.
   Convert rhythm:
     < 48 hrs with normal heart  cardiovert or amiodarone, procainamide, propafenone, or sotalol.
     < 48 hrs with CHF  cardiovert or amiodarone.
     > 48 hrs  anticoagulate x 3 wks then DC cardioversion then antocoagulate x 4 weeks or iv heparin,
       TEE to exclude atrial clot, then cardioversion and anticoagulant x 4 wks.

STABLE NARROW COMPLEX SVT
   DDx (3):
     Junctional tachycardia
     PSVT
     Ectopic/multifocal atrial tachycardia
   When narrow complex SVT happens, attempt a therapeutic diagnostic manoeuvre: vagal stimulation or
    adenosine. This will hopefully make the rhythm become apparent.
   Management depends on cardiac function
   The only ones who are coardioverted are CHF patients with PSVT in contrast to stable VTs where you can
    go directly to cardioversion as a first step.
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   ‘Very Active Ventricles’: vagal manoeuvre, adenosine, verapamil but BB shows up higher on ACLS 2001
    guidelines list.
   Junctional rhythm (no cardioversion):
     Normal heart  BB, CCB, or amiodarone
     CHF  amiodarone
   Ectopic/multifocal (no cardioversion):
     Normal heart  BB, CCB, or amiodarone
     CHF  amiodarone, diltiazem
   PSVT:
     Normal heart  1st choice = BB, CCB, digoxin; 2nd choice = cardiovert; 3rd choice = amiodarone,
       procainamide, sotalol.
     CHF  (in order of priority) cardiovert, digoxin, amiodarone, diltiazem.

STABLE VENTRICULAR TACHYCARDIA
   Is it monomorphic or polymorphic?
   Note that you may go directly to cardioversion.
   Monomorphic VT:
     Normal heart  procainamide, sotalol (amiodarone, lidocaine)
     CHF  amiodarone then lidocaine then cardioversion
   Polymorphic VT:
     Prolonged QT interval  correct lyte abnormalities then: Mg, overdrive pacing, isoproterenol,
         phenytoin, or lidocaine.
     Normal QT interval  treat ischemia, correct lytes and BB, lidocaine, amiodarone, procainamide, or
         sotalol. If normal heart function may give amiodarone then lidocaine then cardioversion.

ACUTE CORONARY SYNDROMES
   MONA greets all patients (morphine, oxygen, nitro, aspirin) with chest pain.

   ST elevation or new/presumed new LBBB  strongly suspicious for injury.
   Start (4): iv BB, iv NTG, iv Heparin, ACEI (after 8 hrs or when stable)
   Time from onset:
     < 12 hrs  reperfusion with angio or fibrinolysis
     > 12 hrs  high risk patients get cathed for consideration for possible PCI or CABG; stable low risk
        patients go to CCU

   ST depression or dynamic T-wave inversion  strongly suspicious for ischemia.
   Start (5): Hep, ASA, Glycoprotein IIb/IIIa receptor inhibitors, iv NTG, BB.
   If stable go to CCU; if high risk go to cath for consideration for possible PCI or CABG.
   Non-diagnostic ECG but meets criteria for UA or new onset angina or troponin positive  strongly
    suspicious for ischemia.
   Start (5): Hep, ASA, GpIIb/IIIa inhibitors (e.g. integrillin), iv NTG, BB.
   If stable go to CCU; if high risk go to cath for consideration for possible PCI or CABG.
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MALIGNANT HYPERTHERMIA

   Due to a genetic defect in Ca metabolism at the sarcoplasmin reticulum of skeletal muscle  
    intracellular Ca  hypercatabolism and  ATP.
   Triggers:
    1. Some inhalational agents (“ane” drugs)
    2. Depolarizing muscle relaxants such as SCh and decamethonium.
    3. Amide based local anaesthetics (Sabiston 2001 is only source that list these as a trigger.)

S&S (11):
   Usually within minutes but can occur hours after contact with trigger agent.
    1. High fever/diaphoresis (may be delayed)
    2. Tachycardia/dysrhythmia
    3. Hypertension
    4. Rigidity
    5. Trismus (masseter spasm)
    6. Tachypnea/Cyanosis with respiratory acidosis, hypercapnia,  ET CO2 (can be the first sign)
    7. Hyperkalemia
    8. Hypercalcemia
    9. Metabolic acidosis
    10. Myoglobinemia/myoglobinuria
    11.  CK

COMPLICATIONS (6)
    1.   Death
    2.   DIC
    3.   Coma
    4.   Muscle necrosis/weakness
    5.   Myoglobinuric renal failure
    6.   Electrolyte abnormalities

TREATMENT (5):
    1.   Stop anaesthetic and SCh
    2.   Hyperventillate with 100% O2
    3.   Dantrolene (2 – 10 mg/kg to block release of Ca from SR, give in 1 mg/kg increments)
    4.   Active cooling
    5.   Correction of lyte and acid-base abnormalities

PREVENTION
   Avoid triggers
   Prophylactic dantrolene no longer indicated
   Regional anaesthesia if possible
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   Thiopental & propofol are safe to use in someone with a history.
   Adrenalin is not safe to use.




TPN AND NUTRITION


NUTRIENT REQUIREMENTS
CALORIES
   Calories: 35 kcal/kgday. Supply is usually hypertonic dextrose.
   Alcoholics get deficient of thiamine, folate, phosphate, Mg, vit K. Least likely to develop deficiency of
    Potassium.
PROTEIN
   Requirements: 250 mg of N/kgday or 1.7 g of protein equivalent/kgday. (Range: 0.8-2.0 g/kg/day)
   Energy Value: 4 kcal/gm
   6.25 g protein:1 g N; 0.16 g N:1 g protein
   Protein is a mixture of single amino acids.
   Nitrogen to caloric ratio is given as g of N:kcal
CARBOHYDRATE
   Should compose 75-80% non-protein calories
   Requirements:
        100 g/day to suppress gluconeogenesis
        Normal max ~7 g/kg/day
        Stressed state: 7.2-8.6 g/kg/day (5-6 mg/kg/min)
   Energy Value: Dextrose has 3.4 kcal/g, glucose has 4 kcal/g.
   Special Circumstances:
     Hypercapnea (difficult vent wean) → < 4 g/kg/day
     Hepatic steatosis → < 4 g/kg/day
     Hyperglycemia / glucose intolerance → < 5 g/kg/day
LIPID
   20 – 25% of nonprotein calories.
   Requirements:
         Max is 2 g/kgday of fat emulsion; 4 g/kg/day for kids.
         Usual recommendation: 1 g/kg/day
   Energy Value: 10 kcal/g (all products
   Usually 10 – 20% emulsions of soy or safflower oil stabilized with egg phosphatide and lecithin.

AMINO ACIDS
   Essential AA: valine, leucine, isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan. (“Very
    Little In Life Tops Tight Moist Pussy”)
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    Conditionally indispensable:
      Cysteine is made from methionine, tyrosine is made from phenylalanine.
      Conditionally indispensable because synthesis rates fall below requirements in times of high need:
        histidine, proline, hydroxyproline, glutamine, arginine.
    Nonessential: alanine, aspartic acid, asparagine, glutamic acid, glycine, proline (?, also listed as
     conditionally indispensable), and serine.

VITAMINS & MINERALS
    Copper: microcytic anemia, delayed wound healing
    Chromium: glucose metabolism, peripheral neuropathy
    Zn: decreased immnunity, decreased wound healing, hair loss, dermatitis,  taste
    Selenium: cardiomyopathy, weakness, anergy
    Fatty acids: dry flaky skin, alopecia, thrombocytopenia
    Vitamin A: poor wound healing
    Vitamin B12 & folate: megaloblastic anemia
    Biotin: skin rash, neuromuscular changes, and EKG changes
    Vitamin C: poor wound healing
    Vitamin K: hemostasis
    Vitamin B6: wound healing (collagen cross linking)
    Vitamin B1 (thiamine) and B2 (riboflavin) deficiencies cause syndromes associated with poor wound
     repair.
    Arginine is semiessential. Used by macrophages, lymphocytes and perhaps other cells in the healing
     wound.


BENEFITS OF TPN
    Improved wound healing
    Decreased catabolic response to injury
    Improved GI structure and function
    Imroved clinical outcomes (↓complication rates & length of stay)

INDICATIONS FOR TPN
PRIMARY THERAPY
EFFICACY SHOWN (5)
1. GI-cutaneous fistula
2. Renal failure (ATN)
3. Short bowel syndrome
4. Acute burns (although the Burns chapter says that TPN is associated with  M&M compared to enteral
   feedings, bottom line is that TPN is used only when enteral feeding is not tolerated)
5. Hepatic failure (acute decompensation superimposed on cirrhosis)
EFFICACY NOT SHOWN
    Crohn‟s disease
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    Anorexia nervosa (when patient won‟t eat)

SUPPORTIVE THERAPY
EFFICACY SHOWN (4)
1.   Acute radiation enteritis
2.   Acute chemotherapy toxicity (enteritis)
3.   Prolonged ileus beyond 7 days
4.   Weight loss preliminary to major surgery
EFFICACY NOT SHOWN
    Before cardiac surgery
    Prolonged respiratory support
    Larger wound losses
UNDER STUDY
    Cancer
    Sepsis


COMPLICATIONS
    Classified as early and late technical, metabolic, and septic.

EARLY TECHNICAL
    PTx
    Arterial laceration
    Hemothorax
    Mediastinal hematoma
    Brachial plexus injury
    Hydrothorax
    Sympathetic effusions, substernal pain, fever from mediastinal effusion
    Thoracic duct injury
    Air embolism
    Catheter embolism

LATE TECHNICAL
    Erosion of catheter into bronchus, right atrium, or other structures
    Subclavian vein thrombosis
    Septic thrombosis

METABOLIC COMPLICATIONS
    Deficiency states
    Disorders of glucose metabolism: hypoglycemia with sudden slowing of infusion, hyperglycemia (the
     most dangerous complication; commonly caused by sepsis), HONK
    Hepatic steatosis (AST, ALT, GGT, ALP. Hyperbilirubinemia is rare, when it occurs it‟s usually from
     sepsis)
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   Fat overload syndrome: fever, back pain, chills, pulm insuff, blockage of reticuloendothelial system.
   Gut mucosal atrophy
   Overfeeding

SEPTIC COMPLICATIONS
   Catheter infection (triple lumens have higher infection rate, subclavian is preferred line site)
   Aspiration
   Bacterial colonization of stomach

MANAGEMENT OF SUSPECTED TPN CATHETER SEPSIS
   Remove catheter when surrounding skin shows colonization > 103 orgs/sq cm
   If no skin cultures, take down the bottle and all tubing and replace. Culture the old stuff. Blood cultures
    too.
   If fever then persists for > 8 hr after this, remove catheter and culture tip.
   No antibiotics are necessary unless fever persists for > 24 hr after this.
   Catheters are not changed over guide wires when catheter sepsis is suspected. (Changing over wires is
    acceptable when another source is suspected.)
   If catheter is eventually shown to be the source, peripheral antibiotics are needed, and catheter will have to
    be replaced after an interval when blood cultures remain sterile.


SPECIAL NUTRITION SITUATIONS
   Mild – moderate infection  20 – 30%  in energy requirements.
   Severe infection  50%  in energy requirements.
   Respiratory insufficiency: large Q of carbs generate large Q of CO2 after oxidation that may slow
    weaning process,  carbohydrate load to 50% of caloric requirements and use fat to make up the rest.
   Renal failure: proteins of high biologic value but in smaller Q are given (0.5 g/kg/day) along with
    adequate calories in the form of dextrose TPN or glucose enterally. (Assuming caloric intake of 35
    kcal/kgday and 6.25 g of protein/g of N  the 0.5 g/kgday of protein used in ATN is equivalent to a
    N:kcal ratio of 0.08 g N:35 kcal or 0.0023 g N:kcal/, or 435 kcal:g N.)
   Gut dysfunction: glutamine for enterocytes.
   Hepatic dysfunction: when the inflammatory process persists after the resolution of the sepsis, the carb
    load is usually reduced to no more than 50% of metabolic requirements. Protein load needs reduction if
    encephalopathy develops.
   Cardiac dysfunction: these patients may be sensitive to volume overload so more concentrated solution
    can be used.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                          2010-05- 73
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ENTERAL FEEDING


COMPLICATIONS
   Malpositioning of the catheter
   Aspiration
   Solute overload  diarrhea, dehydration, lyte imbalances, hyperglycemia
   Loss of K, Mg, and other ions with diarrhea
   Pneumatosis intestinalis with perforation
   Bowel necrosis perhaps because of dehydration and hypoperfusion
   HONK



HIV, HTLV, AND HEPATITIS


NEEDLE STICKS
   With known infected source:
     HBV: 2 – 40%
     HCV: 3 – 10%
     HIV: 0.2 – 0.5% (mucosal or broken skin contact 0.1%)
     CMV: negligible (spread by mucosa-mucosa contact)

 FREQUENCY IN AIDS
   Acute abdomen
   Perforation of GI tract (duodenum, SB, and colon due to CMV in particular)
   Hepatitis B, C and candida, & mycobacterium infection
   Splenomegaly
   Infection post vascular procedures
   Neoplasia: B-cell lymphoma (NHL), kaposi‟s, SCC

HIV
   Retrovirus
   Target cells (4):
    1. Monocytes
    2. Macrophages
    3. TH cells
    4. Microglial cells (CNS)
   Damage inflicted is due mainly to the direct active viral replication and destruction of CD4+ TH cells.
   Lymphoid tissue and CNS are the major reservoirs.
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   Males:females = 85:15
   Diagnosis: 2 or more reactive screening tests (ELISA) that detect HIV Abs followed by a confirmatory
    test (Western Blot or recombinant ELISA) that detects specific Abs against HIV Ag.
   Other tests: viral culture, p24 Ag detection, PCR

HTLV
   HTLV-I → Adult T-cell lymphoma, Tropical spastic paraparesis (Jamaica)
   HTLV-II → Hairy cell leukemia
   HTLV-III=HIV-1; HTLV-IV=HIV-2

HAV
   Fecal-oral spread
   Clinical acute hepatitis in most adults
   Serology: IgM acutely and in convalescence, IgG subacutely then stays up conferring immunity

HBV
   Transmission parenteral or equivalent
   Infectivity during HBsAg positivity
   HBeAg is marker of viral replication and high infectivity
   HBsAg and HBeAg present in acute infection
   Anti-HBc and anti-HBe appear early but don‟t confer immunity
   Anti-HBs follows clearance of HBsAg and confers immunity (e.g. immuniz‟n)

HCV
   Chiefly parenteral transmission
   HCV RNA detected by PCR assay
   Anti-HCV develops in most but doesn‟t confer immunity
   More than half progress to chronic liver disease

HDV
   Infection occurs only in presence of HBV because HBV proteins are required for HDV replication

HEV
   Fecal-oral transmission in endemic areas; mild disease for most part
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                     2010-05- 75
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LIVER DZ AND RANDOM FACTS


9 ACUTE PHASE PROTEINS MADE BY LIVER
1.   Fibrinogen
2.   Haptoglobin
3.   C-reactive protein
4.   Complement-3
5.   Ceruloplasmin
6.   α-antitrypsin
7.   α-antichymotrypsin
8.   α-acid glycoprotein
9.   Amyloid A

LAB FINDINGS IN LIVER DZ
    Hepatocellular Injury → ↑AST/ALT
    Obstruction → ↑ALP, GGT, Direct(conjugated) bilirubin, 5‟-nucleotidase, leucine aminopeptidase
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                          2010-05- 76
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   Decreased function → ↓albumin, ↓transferrin, ↓coagulation factors (↑INR), may get hypoglycaemia in
    severe liver dysf‟n due to failure of gluconeogenesis, altered glucose metabolism (d/t porto-systemic
    shunting in cirrhosis)

HEPATORENAL SYNDROME
   ↓cortical blood flow (vasoconstriction)
   Reversible with liver transplant




TRANSPLANT

   Best predictor of LRD kidney function: donor kidney u/o just prior to nephrectomy.
   Transplant survival: kidney>heart>lung

MHC
   Gene products are called human leukocyte antigens (HLA).
   Located on chromosome 6.
   Class I molecules important in Tx: HLA-A, HLA-B, and HLA-C. (E, F, and G are more conserved.)
   Class II molecules are: HLA-DR, HLA-DQ, HLA-DP, and HLA-DM.
   MHC restriction when used in the context of T cell function refers to T cells recognizing foreign antigen
    best in association with self MHC.

CLASS I MHC
   Class I molecules are expressions of HLA-A, B, and C.
   Present on all nucleated cells.
   Expression is  by cytokines and interferons.
   They are recognized by cytotoxic CD8+ T cells.
   Contain molecules from within the cell.

CLASS II MHC
   Class II molecules are expressions of HLA-DR, DQ, DP, and DM.
   Constitutively expressed on professional APCs, including dendritic cells, lymphocytes, and macrophages.
    Expression can be induced on endothelial cells with cytokine stimulation.
   Interactions are limited to CD4+ cells.
   Contain peptides that were outside the cell, have been internalized and degraded.

DIRECT & INDIRECT RECOGNITION
   Indirect antigen presentation/indirect pathway is conventional antigen recognition by way of antigen
    presented in context of MHC protein.
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    Direct antigen presentation/direct pathway occurs when a solid organ is transplanted, the professional
     (dendritic cells, macrophages) and nonprofessional (activated vascular endothelial cells) APCs can present
     themselves.
    Both pathways involved in rejection.


IMMUNOGLOBULINS
    Usually contain 2 light and 2 heavy chains.
    Amino terminal end is the variable end.
    See appendix


TYPING
    ABO compatibility is done to avoid hyperacute rejection.
    Donors and recipients are typed for HLA-A, B and DR. Humans have 2 alleles for each of these.
    Methods of typing include: lymphocyte and leukocyte typing and mixed lymphocyte culture.
    The larger the number of matches between donor and recipient, the better the survival rate, particularly in
     the first year.


SUITABILITY FOR DONATION
    Cardiorespiratoty arrest is not a contraindication.
    Arbitrary age limits on donors are unnecessary.
    Overall premorbid health
    Hemodynamic stability: kidneys appear to tolerate hypotension relatively well whereas liver and pancreas
     may be more severely damaged.

CONTRAINDICATIONS
    Sepsis however local infections such as UTI and pneumonia are not absolute contraindications. Start Abx
     before procurement.
    Viral infection. All are screened for HTLV-1, HIV, HBV, and HCV. Donors with evidence of HBV and
     HCV infection are being considered if recipient is immune. Checking for EBV, CMV and HSV is done so
     that recipient can be can be treated accordingly.
    Cancer. This is absolute contraindication except CNS tumours which don‟t cross the BBB.
    No consent


CONTRAINDICATIONS TO TX (7)
1.   HIV
2.   Malignancy
3.   Irreversible brain damage
4.   Irreversible infection
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5. Irreversible multiple organ failure
6. Irreversible significant cardiopulmonary disease
7. Recurrent non-compliance with medical therapy


CONTRAINDICATIONS TO RENAL TRANSPLANT
   Recurring renal disease (FSGS, haemolytic uremic syndrome, MPGN)
   Liver (see below)
   Psychosocial


CONTRAINDICATIONS TO LIVER TRANSPLANT
   Inability to withstand the operation usually due to bad heart or lungs.
   Recent IC hemorrhage (post-op coagulopathy)
   Irreversible neurologic impairement
   Active substance abuse (e.g. EtOH)
   Intractable hypotension
   Evidence of systemic infection
   Extrahepatic malignancy
   Inability to comply with f/u


REJECTION
   Blood transfusion effect refers to the improved graft survival believed to be secondary to suppression of
    rejection mechanisms in patients who receive blood before their Tx.
   Second set rejection occurs more rapidly than first set rejection.
   HLA matched kidney has half life of > 15 yrs.

HYPERACUTE REJECTION
   Occurs within minutes to hours.
   Can occur when transplant occurs across ABO groups. (Liver is the exception. Transplant across ABO
    groups is possible.)
   Mediated primarily by preformed antibodies (IgG) directed towards foreign proteins (MHC).
   Prevented by screening recipient for preformed antibodies that bind the endothelium and activate
    complement  rapid thrombotic occlusion of vasculature.

ACUTE REJECTION
   First occurs between 1 – 3 weeks post Tx.
   Mediated by T lymphocytes.
   Most common in first 3 – 6 months.
   Two types: vascular and cellular.
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   Acute vascular: IgG develops against endothelial antigens and activates complement. T cells also
    involved. End result is endothelial necrosis. This will occur within the first week of Tx in absence of
    immunosuppression.
   Acute cellular: necrosis of parenchymal cells caused by infiltration of T cells and macrophages.
   Need biopsy to prove
   Treat with methylprednisolone followed by tapering prednisone dose

CHRONIC REJECTION
 Appears as atherosclerosis, obliteration, and fibrosis in all organs currently being transplanted.
 RFs (6):
  1. Donor issues (age, HTN, …)
  2. Organ recovery related issues including preservation and reperfusion injury
  3. Initial delayed graft function
  4. Recipient diabetes, HTN, infections, …
  5. Inadequate immunosuppression
  6. Previous acute rejection episodes
CHRONIC LIVER TX REJECTION
   Aka „vanishing bile duct syndrome‟ → paucity of bile duct epithelium with significant lymphocytic
     infiltration
   Obliterative vasculopathy
   Parenchymal fibrosis


TERMINOLOGY
   Autogeneic: same individual
   Isogeneic: same species and genetically identical
   Allogeneic (homo): same species, genetically different
   Xenogeneic (hetero): different species

ANTIREJECTION DRUGS
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IMMUNOSUPPRESSIVE REGIMENS (DR. GILL – SPH)
LOW RISK PATIENTS:
    No prior transplant, low panel reactivity, leukocyte crossmatch negative
    Typical Regimen:
          o Induction: IL-2 inhibitor (started intra-op) & steroids (first 4 days)
          o Maintenance: Calcineurin Inhibitor & Antimetabolite +/- steroids (sirolimus may replace
              calcineurin inhibitor)
          o All patients put on CCB (to decrease nephrotoxicity of calcineurin inhibitor), may need
              valgancyclovir (CMV)
HIGH RISK PATIENTS
    Prior transplant, high panel reactivity, historical serum leukocyte crossmatch positive
    Typical Regimen: same as low risk, but add thymoglobulin or OKT3 to induction drugs & definitely
      on steroids for maintenance regimen
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INDUCTION AGENTS (4)
1.   Antilymphocyte globulin
2.   Monoclonal antibody OKT3
3.   IL-2 receptor inhibitors
4.   Radiation

ANTILYMPHOCYTE GLOBULIN
    Polyclonal sera produced when human lymphocytes are injected into a different species.
    Action is directed mainly at T cells.
    Can be given prophylactically, during early posttransplant period, or used effectively to reverse ongoing
     rejection.
    Most common complication: allergic reaction (urticaria, anaphylactoid reactions, serum sickness including
     joint pain, fever, and malaise)
    Anemia and TCP can also occur.

OKT3
    Anti-CD3 MAb.
    Binds to a site associated with the TCR (CD3) and blocks function of naïve T-cells and established Tc
     cells thereby blocking cell mediated cytotoxicity.
    Major limitation is that it is immunogenic and can elicit immune reactions.
    Cytokine release syndrome: chills, rigors and fever. Usually with first dose.
     incidence of lymphoproliferative disorders.

IL-2 RECEPTOR INHIBITORS
 Basiliximab and daclizumab
 MAb‟s that bind to alpha chain of IL-2 receptor without activating it thus leaving the cell with no free Rs
   for IL-2 to bind.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                        2010-05- 83
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RADIATION
    Limited use in clinical transplantation.

MAINTENANCE AGENTS (6)
1.   Steroids
2.   Azathioprine (imuran)
3.   MMF
4.   Cyclosporine
5.   Tacrolimus
6.   Sirolimus

ADRENAL CORTICOSTEROIDS
    Mechanisms (4):
     1. Profound  in blood lymphocyte count occurs within 6 hrs (causes redistribution to the lymphoid
         depots)
     2. Decreases ability of macrophages to respond to lymphocyte-derived signals
     3. Inhibits cytokine gene transcription and cytokine secretion by macrophages
     4. Suppresses PG synthesis
    Side effects (11):
     1. HTN (mineralocorticoid effects)
     2. Weight gain
     3. Peptic ulcers
     4. GI bleeding
     5. Euphoric personality changes
     6. Cataract formation
     7. Hyperglycemia (could  DM)
     8. Pancreatitis
     9. Muscle wasting
     10. Osteoporosis
     11. Avascular necrosis

AZATHIOPRINE (IMURAN)
    6-MP plus side chain to protect labile sulphydryl group
    Inhibits enzymes resulting in blocking of DNA, RNA, cofactor, and active nucleotide synthesis
    Actions (3):
     1. Inhibits development of both humoral and cellular immunity (i.e.: B and T lymphocytes)
     2. Reduces neutrophil production
     3. Reduces macrophage activation
    Toxicity (2):
     1. Marrow suppression leading to leukopenia (primary)
     2. Hepatotoxicity, cholestasis.

MYCOPHENOLATE MOFETIL (MMF)
    Mechanism: inhibition of purine metabolism  inhibits T and B lymphocyte responses.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                           2010-05- 84
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   Based on mycophenolic acid from the mold Penicillium glaucum
   Major side effects (2):
    1. Leukopenia
    2. GI upset (diarrhea)

CYCLOSPORINE
   Cyclic polypeptide isolated from fungus Tolypocladium inflatum
   The most cost effective renal transplant immunosuppressive strategies use this.
   Selective inhibitor of TCR-mediated activation events
   Possible loss of therapeutic effect with rifampin (rifampin induces hepatic p450)
   Less powerful than tacrolimus.
   Actions (5):
    1. Inhibition of IL-1 production
    2. Inhibition of IL-2 production by activated T cells.
    3. Inhibition of IL-2 producing T cells and Tc cells.
    4. Inhibtion of mitogen activation of IL-2 producing T cells
    5. Inhibition of resting T cell activation in response to alloantigen and exogenous lymphokine. (Note it
        does not inhibit activation of T cells in response to exogenous IL-2.)
   Toxicity (3 Ns/7 Hs):
    1. Nephrotoxicity by  GFR, usually reversible with dose reduction (additive nephrotoxicity with
        NSAIDs and Cipro)
    2. Neoplasia
    3. Neurotoxic (tremor, paraesthesia)
    4. Hyperuricemia
    5. Hypertension
    6. Hyperglycemia
    7. Hyperkalemia
    8. Hyperplasia of the gingiva
    9. Hepatotoxic
    10. Hirsutism
   Note the absence of myelosuppression

TACROLIMUS (FK 506)
   Isolated from fungus Streptomyces tsukubaenis
   Calcineurin inhibitor
   Binds an intracellular protein and blocks phosphatase activity of calcineurin that is important in IL-2 gene
    transcription.
   Actions (4):
    1. Inhibits IL-2 gene expression and production
    2. Inhibits lymphocyte IL-2R appearance
    3. Inhibits Th-mediated T cell proliferations
    4. Inhibits Tc cell generation
   Side effects (similar to cyclosporine – hirsutism + alopecia) (7):
    1. Nephrotoxicity
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    2.   Neurotoxicities (tremor, paraesthesia)
    3.   Hyperglycemia
    4.   Hyperkalemia
    5.   Hypertension
    6.   Hepatotoxic
    7.   alopecia

SIROLIMUS
   Binds same R as tacrolimus
   Does not block T cell cytokine gene expression
   Instead it inhibits the transduction of signals from IL-2 R to the nucleus

DRUG INTERACTIONS WITH CYCLOSPORINE
Drug         FX
Rifampin     Activates p450; ↓Cyclo levels
Steroids     Competitive inhibition liver
             metabolism; ↑ Cyclo levels
CCB‟s        Improve renal bl. Flow →
             decrease cyclo toxicity
Nephrotoxins Additive effect


DRUG FX ON CYCLOSPORINE LEVELS
↑ Cyclo levels    ↓ Cyclo levels            ↑ Nephrotoxicity
H2-antagonists    Sulfinpyrazone            NSAIDs
Cephalosporins    Anticonvulsants           Cipro
Thiazides         Rifampin
Lasix
Androgenic „roids
Acyclovir
Warfarin

CYCLOSPORINE VS. TACROLIMUS SIDE FX
Side Effect          Comparison
Allopecia            Tac > Cyclo
Induced Diabetes     Tac >>> Cyclo
Cosmetic (hirsutism) Cyclo > Tac
HTN                  Cyclo > Tac
Hyperlipidemia       Cyclo > Tac
All else being equal Use Tac first (Dr. Gill)

MMF VS. IMMURAN SIDE FX
Side Effect          Comparison
Cost                 MMF >>> Immuran
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                         2010-05- 86
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Myelosuppression           Equivalent
GI upset                   MMF > Immuran
All else being equal       Use MMF first (Dr.
                           Gill)



POST TRANSPLANT COMPLICATIONS
   Overall risks of transplant: infection, malignancy, CV disease.

INFECTION
   Viral infx greater problem than bacterial
   CMV is the single most important pathogen seen in solid organ transplant.
   Prophylaxis includes: acyclovir or ganciclovir for CMV; septra for pneumocystis; nystatin, clotrimazole
    or fluconazole for fungus.
   Other opportunistic infections: aspergillosis, blastomycosis, nocardiosis, toxoplasmosis, cryptococcosis,
    pneumocystis.
   (Bacterial infection is the most common complication from immunosuppression. It is also the most
    common cause of death in transplant patients. Source: Nguan)

CMV INFECTION
   Infects most normal people at some point in their lives.
   Seronegative recipients who receive a seropositive kidney can experience CMV disease.
   It varies from mild fever and malaise to a debilitating syndrome marked by leukopenia, hepatitis,
    interstitial pneumonia, renal insufficiency…death
   May be difficult to distinguish from acute rejection due to ↓renal f‟n
     Need Bx to sort out prior to ↓ or ↑ immunosuppressants
   Gancyclovir has been shown to be effective.

NEOPLASIA
   NHL:HL lymphoma is higher in Tx patients than in non Tx patients.
   B cell lymphomas are more common than T cell lymphomas.

POST-RENAL TX HYPERTENSION

CAUSES:
   Allograft dysfunction
        o Rejection
        o Renal transplant artery stenosis (RTAS) – up to 23% transplants
   Native kidneys (10%) → native nephrectomy
   Corticosteroids
   Cyclosporine
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                             2010-05- 87
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RENAL TRANSPLANT ARTERY STENOSIS (RTAS)
   peak incidence 6 mos. Post-Tx
   70% at anastamotic site, 20% in renal a. proper (therefore, can happen with a Carrell patch!)
   Due to:
        o Improper anastamotic technique
        o Kinking of redundant vessel
        o Damage of renal a. intima during kidney prep
        o Atherosclerotic dz of transplant artery or iliac a.
        o Intimal proliferation or subintimal fibrosis
   Diagnosis of RAS/RTAS
        o Imaging (e.g. MRA or angiogram)
        o Peripheral renin (elevated in RAS/RTAS)
        o Captopril stim. Test → after 50 mg captopril given, BP will fall more in pt. with RAS than pt.
            with essential HTN; Renin will rise more in pt. with RAS
        o Differential renal vein renin sampling (+/- captopril stimulation)
   Treatment:
        o #1 = percutaneous angioplasty
        o #2 = open surgical correction



ORTHOPEDICS


BONE REMODELLING
   Five stages of bone remodelling:
    1. Quiescence
    2. Activation
    3. Resorption
    4. Reversal
    5. Formation


LOWER EXTREMITY
   Fractures of distal third tibia should be covered with „free flap‟ muscle, as there is little muscle available
    for a pedicle flap at this level
   Dislocation of the knee required reduction, followed by angiogram to rule out injury to popliteal artery →
    should be repaired in <6 hrs.

VOLKMANN’S CONTRACTURE
   Ischemic flexion contracture of forearm muscles secondary to compartment syndrome in forearm
    (compartment pressure > closing pressure of bl. Vessels = ~40mmHg)
   Due to occlusion of brachial artery (which supplies this compartment)
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                           2010-05- 88
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        o Most common cause = supracondylar # or proximal forearm #
        o Basically any injury around the elbow can cause it
    Signs & Symptoms
        o Cool / cyanotic fingers
        o Absent radial pulse
        o Pain on passive extension
        o Weak hand strength
        o May have (but not nessessarily) paresthesia of fingers
        o LATE: flexion contracture of wrist and fingers (scarring)
    Treatment
        o Reduce # / dislocation
        o Fix brachial artery / relieve vasospasm (papavarine)
        o LATE: reconstructive procedures (muscle grafts etc)

LEFORT FRACTURES
 Classification system of facial fractures
LEFORT I:
   Thru maxilla (separates maxilla from rest of skull)
LEFORT II:
   Maxilla → inferior orbit → lacrimal bone (bridge of nose) →←
LEFORT III:
   Zygomatic arch → lateral orbit → inferior orbit → lacrimal bone →←

FASCIOTOMY CLOSURE OPTIONS
1.   Healing by secondary intention
2.   delayed primary closure
3.   Delayed skin grafting
    Loose closure with a drain is not the right answer



TRAUMA

    Most common site of laceration of aorta is distal to left subclavian artery (ligamentum arteriosum)
    Most common organ injured in blunt abdominal trauma: spleen.
    Most common organ injured in penetrating trauma: SB (solid organ is liver).
    Trimodal distribution of death.
      50% trauma deaths within seconds (exanguination & brainstem/SCI)
      30% deaths within hours ( ½ bleeding, ½ CNS injury)
      10-20% >24 hrs after (infection, M.O.F.)
      Late death also important (e.g. PE)
    RTS: revised trauma score = SBP, RR, and GCS
    ISS = sum of squares of 3 worst regions from AIS
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                               2010-05- 89
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   AIS = list of injuries given value of 1 – 6 (6 is worst), injuries are identified in 6 body regions.


ANTISHOCK GARMENTS
    Peripheral vascular resistance in both arterial ( afterload) and venous channels
   Indication (1): stop massive blood loss in pelvic #s.
   Potentiates ischemia and shock syndrome
   They don‟t  survival
   Contraindications (4): cardiogenic shock, diaphragmatic rupture, pregnancy, and significant chest injury.


CLASSIFICATION OF HYPOVOLEMIC SHOCK
   See appendix


HEAD INJURY
GCS
   Eye: spontaneous, to command, to pain, none.
   Verbal: speaks, confused, words, sounds, nothing.
   Motor: follows, localizes, withdraws, flexes, extends, nothing. Changes here are most predictive of
    serious anatomic injury and correlate most strongly with outcome. Always use BEST motor response

TRIVIA
   Suspect basal skull # with: Lefort I and II midlface #s.
   Most commonly injured cranial nerve: olfactory (I).
   Extradural/epidural hematoma (the lens) from temporal-parietal skull #  middle meningeal artery
    rupture. Delayed symptoms. Tx: craniotomy flap.
   Subdural hematoma is less uniform on CT. Usually associated with violent trauma and brain injury. Tx:
    craniotomy flap.
   Early complications of brain injury (4):
    1. SIADH (hyponatremia is most common lyte abnormality after head injury)
    2. DI (the opposite of SIADH, brain doesn‟t release ADH)
    3. Cerebral edema and raised ICPherniation
    4. Seizures
   Late complications of brain injury (3):
    1. Seizure
    2. Meningitis
    3. Hydrocepalus

THERAPY
   In order that they should be tried (4):
    1. Keep head elevated at 30 degrees
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    2. Keep ICP below 20 mmHg with ventriculostomy as most direct method.
    3. Hyperventilate to 30 – 35 mmHg (40 mmHg) (I’d try mannitol 1st – CH)
    4. Mannitol (maximum serum osmolality = 305 – 315). Free water replacement may be necessary when
        large amounts of mannitol are given.
    5. Last ditch is barbiturates.
   Steroids have no proven benefit in head injury.

BRAIN DEATH (8)
1. Lack of Cortical function
    Lack of motor response to noxious stimuli, excluding spinal reflexes
2. Lack of brain stem function
    Fixed dilated pupils
    Gag
    Corneal reflex
    Occulocephalic (doll‟s eye)
    Vestibulocephalic (cold-water calorics)
3. Apnea Test
    Only do after steps 1&2
    No movement / respiratory effort for 3min off vent (with PCO2 > 60)
4. No cerebral blood flow (e.g. on angiogram → due to cerebral edema)
    This test is good enough on it‟s own to define brain death
5. No narcotic, sedatives or anesthetics
6. No relaxants
7. No severe metabolic dysfunction
8. Normothermic


SPINE INJURY
   C3, 4, 5 keeps the diaphragm alive.
   Use alpha agonist (phenylephrine) to treat spinal shock when hemorrhage has been ruled out and cardiac
    function is unaffected. Spinal shock happens when cord is severed within or above the sympathetic chain
    resulting in compromise of cardiac sympathetic innervation and unopposed vagal parasympathetic
    stimulation. When cardiac function is affected, give mixed chronotrope/inotrope (DA, NE).
   High dose corticosteroids are used in first 24 hrs.
   Bulbocavernosus (and other sacral cord) reflexes lost in initial „spinal shock‟ (lasts ~48hrs after injury) →
    thus absence initially indicates hope for some recovery from initial neurologic exam (thus initial presence
    may indicate slim chance of recovery of deficits on neuro exam as indicates NO SPINAL SHOCK)
SPINAL SHOCK
       Hypotonia and loss of all reflexes below level of injury after acute SCI
       Lasts days to weeks (usually recovery starts withing 24 hours)
       Spinal reflexes start to come back
       Can‟t determine prognosis until spinal shock resolves
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                          2010-05- 91
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NEUROGENIC SHOCK
       Distributive and thus „warm‟
       Hypotension
       Bradycardia due to loss of sympathetic outflow

BASIC ANATOMY OF THE SPINAL CORD
Tract Name      Location            Function
F. gracilis     Medial post.        Leg vib & propr
F. cuneatus     Lat. Post & central Arm vib & propr
Corticospinal Postero-lateral       Motor (leg→arm)
Spinothalamic Antero-lateral        Pain, Temp, Light touch
     All tracts except spinothalamic cross in medulla
     Spinothalamic crosses immediately
CENTRAL CORD INJURY
   result of brief compression of cervical cord and disruption of central gray matter. (e.g. whiplash →
    hyperflexion/hyperextension injury)
   Usually occurs in patients with an already narrow spinal canal (congenital, spondylosis).
   weakness of arms (distal>proximal) with pinprick loss over arms and shoulders.
   Relative sparing of leg and trunk power and sensation. Bladder function is variable.
   Prognosis is good.
   Depressed DTR‟s in arms, may be ↑ in legs
   In other words LMN weakness above level of injury, UMN weakness below

BROWN-SEQUARD SYNDROME
   Occurs due to partial transection of cord
   Contralateral pain and temperature sensory deficits (1 – 2 levels below the injury)
   Ipsilateral proprioception loss
   Ipsilateral weakness (UMN)
   Bottom line: pain and temperature gone on one side, proprioception and motor gone on the other; Light
    touch often preserved

                                                              Motor
                              Nerve Root         Muscle    Examination
                                           UPPER EXTREMITY
                             C5             Deltoid      Shoulder
                                                         abduction
                             C6             Biceps       Elbow flexion
                             C7             Triceps      Elbow extension
                             C8             Flexor carpi Wrist flexion
                                            ulnaris
                             T1             Lumbricales  Finger abduction
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                                                             Motor
                          Nerve Root      Muscle         Examination
                                    LOWER EXTREMITY
                         L2          Iliopsoas         Hip flexion
                         L3          Quadriceps        Knee extension
                         L4          Tibialis anterior Ankle
                                                       dorsiflexion
                         L5-S1       Extensor hallucis Great toe
                                     longus            extension
                         S1          Gastrocnemius     Ankle plantar
                                                       flexion

                         Nerve Root           Site of Assessment
                         C2         Occipital region
                         C3         Supraclavicular region, near head of
                                    clavicle
                         C4         Top of shoulder, near acromion
                         C5         Lateral aspect of arm, just above
                                    elbow
                         C6         Dorsum of thumb
                         C7         Dorsum of middle finger
                         C8         Dorsum of little finger
                         T1         Medial arm, just above elbow
                         T2         Axilla
                         T4         Thorax at level of nipples
                         T10        Abdomen of level of umbilicus
                         L1         Region of femoral pulse
                         L2         Medial thigh, midfemur
                         L3         Medial aspect of knee
                         L4         Medial leg, above medial malleolus
                         L5         Dorsum of great toe
                         S1         Lateral aspect of heel
                         S2         Popliteal fossa
                         S3         Medial gluteal region
                         S4-S5      Perianal region
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NECK INJURIES
ANATOMICAL DIVISIONS:
   TRIANGLES:
     Anterior → contains trachea, esophagus, major vessels (ant. To SCM)
     Posterior → relatively little chance vascular/aerodigestive injury
   ZONES:
     I: thoracic inlet → cricoid cartilage (difficult surgical access)
     II: cricoid cartilage → angle of mandible (easy surgical access)
     III: angle of mandible → upwards (difficult surgical access)

RESUSCITATIVE PRIORITIES
#1 = Secure the airway
#2 = control hemorrhage

MANAGEMENT
   Unstable patients go straight to OR
   Wounds penetrating platysma must be further evaluated.
   Penetrating injury to zone II (cricoid to angle of jaw) goes directly to OR. (Controversial, the other option
    is angio, tracheobronchoscopy, and esophagoscopy + esophagography. Esophagoscopy is not very
    specific for small wounds that will kill.)
   Penetrating injury to zone I (thoracic inlet to cricoid) and III (angle of jaw to base of skull which goes up
    to roof of orbit, penetrating neck injury to the roof of orbit is a/w problem till proven otherwise) goes to
    angio first.
   The problem is that surgical access to zone III takes hours.
   Problem with zone I is that who knows where to go without angio guidance.

OUTCOME
   Exsanguination and airway are the main killers.
   Certain blunt neck injuries are associated with delayed stroke → these people need CTA of head.
        GCS < 8
        certain thoracic injuries
        C-spine injuries
        LeFort #s

CAROTID ARTERY LACERATION
   If patient alert with no deficit, reanastomosis. Anything short of coma indicates primary repair.
   If patient comatose neither repair nor ligation does anything, just observe.
   Indications for ligation (2): no prograde flow, uncontrollable hemorrhage. Otherwise reanastomosis.


MAXILLOFACIAL INJURY
   Secure a/w and deal with these later.
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   Deal with the a/w since by definition, it is at risk.
   Emergent management is to wrap the head, pack all pharynxes.
   If surgery can be performed in 3 to 6 hrs with other cranial surgery, do it.
   Otherwise wait 3 – 6 days.


THORACIC INJURY
   Most frequent injuries leading to immediate death after MVA include:
     Blunt cardiac injuries with chamber disruption
     Thoracic aorta injury
   5 immediate killers (golden hour): tension pneumothorax, open pneumothorax, hemothorax, flail chest,
    and cardiac tamponade.
   When to remove a chest tube (thoracostomy):
     No air leak
     <100cc drainage over 24hrs.
   Indications for emergent thoracotomy (7):
    1. Cardiac arrest
    2. Massive hemothorax (> 1500 ml blood through chest tube or 200 – 300 ml/hr after initial drainage)
    3. Penetrating injuries of the anterior chest with cardiac tamponade
    4. Large open wounds of the thoracic cage
    5. Major thoracic vascular injuries in the presence of hemodynamic instability
    6. Major tracheobronchial injuries
    7. Evidence of esophageal perforation
   Non-emergent Indications for Thoracotomy (6)
    6. Empyema not resolved with chest tube
    7. Clotted hemothorax
    8. Lung abscess
    9. Thoracic duct injury
    10. Tracheoesophageal fistula
    11. Chronic sequelae of vascular injuries (A-V fistula, pseudoaneurysm)

FLAIL CHEST
       Requires at least 2 #‟s in at least 3 adjacent ribs
       Get paradoxical movement of chest wall
       Increases work of breathing & very painful
       May require intubation for respiratory distress

TAMPONADE
   Beck‟s triad of cardiac tamponade:
    1. Muffles heart sounds
    2. Distended neck veins
    3. Hypotension
   Pulsus paradoxicus can also occur as can pulsus alternans.
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   Wide pulse pressure does not occur.
ESOPHAGEAL RUPTURE




ABDOMINAL TRAUMA
   Blunt:Penetrating = 9:1
BLUNT TRAUMA
   Most commonly injured solid organ in blunt trauma: spleen.
   Blunt abdo trauma with hemodynamic instability should undergo DPL or FAST to rule out intra-
    abdominal injury.
   Indications for laparotomy in blunt trauma:
     positive examination
     positive DPL or FAST.

PENETRATING TRAUMA
   Most commonly injured solid organ in penetrating trauma: liver.
   Note that abdomen goes right up to nipple line. Implication is that penetrating trauma to lower chest
    needs penetrating abdo work up too.
   Indications for laparotomy in isolated penetrating trauma:
     hypotensive/shock
     evisceration
     peritoneal signs
     positive DPL or FAST.
DIAGNOSTIC PERITONEAL LAVAGE
   Indications for DPL (7):
    1. Anyone you can‟t reliably examine:
        Unconscious patient with question of potential abdominal injury
        Patient with spinal cord injury
        Intoxicated patient in whom abdominal injury is suspected
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                       2010-05- 96
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         Patient who has a suspected intraabdominal injury with equivocal diagnostic findings and who will
          be undergoing prolonged general anesthesia for another injury, making continued reevaluation
          impossible.
    2. Anyone with mechanism of injury c/w possible abdo injury:
        Patient with a high-energy injury, suspected intraabdominal injury, and equivocal physical findings
        Patient with multiple injuries and unexplained shock
        Patient with major noncontiguous or thoracoabdominal injuries

   Positive DPL criteria (8):
    1. > 10 mL of gross blood aspirated
    2. Bloody lavage effluent
    3. RBC count > 100 000/ml (> 1000/mL in penetrating trauma)
    4. WBC count > 500/ml
    5. Amylase > 175 IU/dl
    6. Bile
    7. Bacteria
    8. Food

   Contraindications to DPL (4)
    1. Clear indication for exploratory laparotomy
    2. Relative: previous exploratory lap, pregnancy, obesity
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SPLENIC INJURIES
   >70% can be managed non-operatively (>90% success)
   Success of „splenic salvage‟ operations = 40-60%
   Criteria for nonoperative management (6):
    1. Hemodynamic stability
    2. Negative abdominal exam
    3. Absence coagulopathy
    4. Absence of contrast extravasation on CT
    5. Grade 1 – 3 injuries
    6. Absence of other indications for laparotomy/surgical intervention
   Post splenectomy: polyvalent pneumococcal (pneumococcus, hemophillus, menningococcus) vaccination
    with booster

GENITOURINARY INJURIES
   Renal Injury → if stable with microhematuria: d/c, repeat u/a in 3 weeks.
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                     2010-05- 98
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   Testicular injuries → need exploration if there is any suspicion of ruptured testicle

ABDOMINAL COMPARTMENT SYNDROME
   See Critical Care Section

FAT EMBOLISM
   Classic triad: respiratory insufficiency (PO2 < 60), neurologic signs, and petechial rash.
   Pyrexia, tachycardia, retinopathy, and oliguria are additional features.
   No diagnostic test although fat droplets may be present in blood, urine, and/or sputum.
   Radiographically apparent in 24 – 48 hrs.
   Management: supportive care with mechanical ventilation and ICU monitoring, fix the fracture
   RF: long bone #, young age, orthopedic procedures.



NEUROSURGERY


BRAIN METS
       Lung
       Breast
       Kidney
       Melanoma (most common to bleed)

UNCAL HERNEATION
       Gcs<15
       Contralateral hemiparesis
       Ispilateral blown pupil

BASAL SKULL FRACTURES
       Orbital roof fracture: hallmark is racoon eye, blood coming out nose
CSF LEAK
       Most will resolve on their own
       Do not put on prophylactic antibiotics for meningitis
       Do admit them for observation

ICP
    Intracranial volume = brain vol + CSF vol + blood vol + S.O.L. vol
TREATMENT:
   Decrease brain vol → mannitol (1-2 gm/kg) unless v. hypotensive; hypothermia decreases ICP
   Decrease blood vol → hyperventilation (ok in short term, but no more)
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       No proven role for steroids
       Abx may be useful for brain abscess



VASCULAR SURGERY


A-V FISTULA
   Hemodynamically significant ones all are associated with (5):
    1.  Blood volume but no  in CVP
    2.  Cardiac output ( HR and  SV)
    3. Usually decrease in diastolic BP with big pulse pressure
   Compressing inflow → ↑BP, ↓PP, ↓preload → bradycardia?

CAUSES OF ISCHEMIC BOWEL
       Thrombotic (underlying atherosclerotic dz)
       Embolic (arrhythmia, valvular lesions, PFO, MI & mural thrombi)
       Non-occlusive mesenteric ischemia (e.g. systemic hypoperfusion → shock)
       Mesenteric vein thrombosis (hepatobiliary surgery, hypercoaguable states)

INDICATIONS FOR IVC FILTER
ABSOLUTE:
   Failure of heparin anticoagulation
   Active hemorrhage (contraindication to anticoagulation)
   Post-pulmonary embolectomy
   Failed other aggressive interventions
RELATIVE:
   Little cardiopulmonary reserve (second PE would be fatal)
   Free-floating thrombus in iliofemoral vessels
   Post-major trauma

Note: for upper extremity DVT, you anticoagulate them & treat cause (pull line, treat thoracic outlet
syndrome, etc), is possible to put SVC filter if needed (rare)

DVT
   Treat any clots above the knee (incl. superficial femoral vein!!!)
   Controversial about treating clots below the knee
   Superficial thrombophlebitis → NSAIDs & follow; if at saphenofemoral junction, should probably ligate
    saphenous vein
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                        2010-05- 100
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REASON FOR EXPLORING LEG AFTER KNEE DISLOC’N
HARD SIGNS
   Ischemic
   Pulseless
   Expanding hematoma
   Pulsatile hematoma
SOFT SIGN
   Proximal injury

POPLITEAL ANEURYSMS
   Most common true peripheral aneurysm (femoral a. aneurysm is most common aneurysm overall → but
    is false aneurysm)
   Most common complication of popliteal a. aneurysm is thrombosis (embolism distally also occurs but not
    #1)



E.N.T. SURGERY


THYROID NODULE
   After Hx & Px, 1st step in w/u of thyroid nodule is FNA (not U/S or nuclear imaging, which are reserved
    for more difficult cases)
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CRITICAL CARE


HYPOTHERMIA
   Core temp < 35.
   Transition between a safe hypothermia when physiologic adaptations to heat loss are working to a danger
    zone of core temp (when shivering stops, metabolism slows, and heat loss is passively accepted) occurs
    between 30 and 33 degrees.
   37 – 35: Hyperdynamic heart, lungs, and metabolic response with shivering and vasoconstriction.
   35 – 33: Confusion, ataxia, amnesia with severe shivering.
   33 – 30: Falling CO, bradycardia, hypoventilation, cold diuresis, spontaneous bleeding, muscle rigidity,
    and complex acid-base status.
   31: Shivering stops.
   Below 30: arrhythmias.
   23: Apnea.
   21: Asystole.
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BOHR EFFECT (‘RIGHT = RELEASE; LEFT = LOAD’)
    O2-Hb association curve shifts to the right with  H+, pCO2, temp, or 2,3-DPG.
    This facilitates O2 unloading in peripheral caps where it is needed.
    In hypothermia, O2 doesn‟t unload as easily since dissociation curve shifts to the left.




CONTRAINDICATIONS TO SUCC (7):
     1. recent trauma
     2. burns
     3. chronic abdominal infection
     4. extensive denervation of skeletal muscle
     5. upper motor nerve injury
     6. conditions causing degeneration of the CNS
     7. SAH
    Reason is potential for causing severe hyperkalemia.

PROVEN STRATEGIES IN SEPSIS (6)
1.   Vt 6 – 8 ml/kg
2.   Activated Protein C for those in shock with high Apache > 25
3.   Early goal directed therapy (resuscitation)
4.   Low dose steroids when refractory to pressors
5.   Intensive insulin (controversial still)
6.   Daily HD better than q2days (Prisma = 24x7 HD)

INVASIVE MONITORING
    CVP 1 – 8 unvented, for vented just add the PEEP
    MAP 75 - 100
    PCWP 6-12
    CI 2.4 – 4
    CO 4 – 6
    SVRI 1600-2400 (SVR 800 – 1400)
    PVRI 200-400 (PVR 100 – 200)
    SVO2 (mixed venous O2) 70-75%
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   O2ER (extraction ratio) 20-30%
       O2ER = (CaO2 – CvO2)/CaO2

ICU DRUGS
   See appendix

IABP
    TABLE 54–31. Physiologic Effects of Intra-
           aortic Balloon Pumping

 MAP                                          
 Aortic systolic pressure                     
 Aortic diastolic pressure                    
 Left ventricular systolic pressure           
 Left ventricular end-diastolic pressure      
 Cardiac output                               
 Cardiac afterload                            
 Cardiac preload                              
 Left ventricular wall tension                
 Left ventricular volume                      
 Left ventricular stroke work                 
 Coronary blood flow                          
 Renal blood flow                             
 Idea is that decreasing area under systolic part of pressure tracing by decreasing afterload effectively
  supports the failing heart.
 Major effects are  in LV afterload and  in coronary artery perfusion pressure. This leads to  CO.

CONTRAINDICATIONS TO IABP
   Severe aortic insufficiency (mild AI may be improved) → d/t ↑↑dBP
   Aortic aneurysm is relative contraindication
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                         2010-05- 104
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   Post cardiotomy refers to weaning from bypass post cardiac surgery.


MOF
   Mortality
     Single organ: 10 – 20%
     Double organ: 25 – 30%
     Triple organ: 50 – 60%
     Quadruple organ: 60 – 80%
   Global immunosuppression (may be associated with sepsis or SIRS) plays important role in progression of
    MOF
   Lungs are often first organ to fail (Sabiston)
   Biventricular dilation with reduction in right and left ventricular ejection fractions is apparent in MOF.
    The mechanism of RV dysfunction is often LV dysfunction.


SIRS
   Two or more of the following:
    1. T > 38 or < 36
    2. HR > 90
    3. RR > 30 or PaCO2 < 32
    4. WBC > 12 or < 4 or with 10% immature bands
   Shock is important risk factor
0d27a8c8-4ecf-43e0-a19b-15ccb79a826d.doc                                                         2010-05- 105
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ABDOMINAL COMPARTMENT SYNDROME
Return to trauma section
 Grade I: IAP 10 -15 cm water. Subtle alterations in organ physiology but treatment is rarely needed.
 Grade II: IAP 15 - 25 cm water. Need for treatment is based on patient's clinical condition. Volume load
   first before resorting to decompression.
 Grade III: IAP 25 - 35 cm water. Most will require decompression.
 Grade IV: > 35 cm water. All require decompression and exploration to exclude ongoing bleeding
   amenable to surgical control.

   Most common cause: intraabdominal bleeding d/t post-trauma coagulopathy
   Occurs in patients with:
        o Profound shock → require large volumes resuscitation fluid/blood
        o Major abdominal visceral or vascular injury
   Organ systems most affected: cardiovascular, pulmonary, renal
   Signs & Symptoms: tensely distended abdomen, progressive oliguria despite good CVP/MAP, rising
    airway pressures, refractory hypoxemia, ↑bladder P.
                               Decreased                Increased
                                Blood Pressure             Heart Rate
                                Cardiac Output             PCWP
                                Central venous return      Peak Inspiratory Pressure
                                Visceral blood flow        CVP
                                Renal blood flow           Intrapleural pressure
                                GFR                        SVR


   Treatment: decompress abdomen & treat the cause (e.g. laparotomy to control bleeding)



DIABETES

   2-3% of general population; 16-23% of surgical population (Schwarz)
   They require insulin infusions during illness and operative stress to maintain euglycemia.

PATHOPHYSIOLOGY OF DIABETES
   Due to lack of metabolically active circulating insulin
   Glucose derived from dietary CHO, liver glycogen, and formed from protein & fat (muscle glycogen
    confined to muscles for their use only → can‟t be mobilized)
   FFA → (liver) → acetoacetate → β-hydroxybutyric acid & acetone (all 3 are ketone bodies)
   Ketogenesis → acidosis → H+/K+ shift (may get sl. Hyperkalemia)
   Hyperglycemia → glycosuria → osmotic diuresis → dehydration & enhanced excretion Na & K (that‟s
    why total body K is depleted, despite ↑serum K)
   Stress of sugery → increased circulating catecholamines and glucocorticoids → ↑ liver glycogen
    breakdown, ↑ protein metabolism-derived liver glucose, ↑ insulin antagonist levels (d/t glucocorticoid
    effect)
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COUNTER-REGULATORY HORMONES
   A counterregulatory hormone is a hormone that opposes the action of insulin → raise the level of
    glucose in the blood by promoting glycogenolysis, gluconeogenesis, ketosis, and other catabolic processes
        o glucagon
        o epinephrine
        o norepinephrine
        o cortisol
        o growth hormone
   In healthy people, counterregulatory hormones constitute a principal defense against hypoglycaemia →
    levels as the glucose falls
   Persistent elevation of a counterregulatory hormone can reduce a person's sensitivity to insulin.

PERIOPERATIVE MANAGEMENT OF DIABETIC PT.
   Diabetic patients should be booked earlier in the day (minimize fasting fx)
   Be wary of pre-op sedation/narcotics in eldery diabetics → propensity for hypercapnia/hypoxia
   Goal of pre-op IV fluids/enteral nutrition is to give enough glucose to avoid ketogenesis and also avoid
    hyperglycemia
   Oral hypoglycemics should be discontinued ~ 24 preop (Schwarz)
   Insulin-dependent diabetics should not receive their full dose of either intermediate or long acting
    insulin on the day of the operation (i.e. give 1/3 - ½ dose of NPH & Reg morning of surgery → to avoid
    DKA; start on D5W drip; monitor BG) Source: K. Morrison & Lange book
   Most effective management is to omit intermediate and long acting insulin altogether and use an insulin
    infusion (1 – 2 U/h to start and titrate to BG levels) Source: Lange Surgical Dx & Tx book.

HYPEROSMOLAR COMA (HONK)
   Hyperglycemia without ketosis because there is enough insulin to prevent lipolysis (occurs in insulin-
    resistant group)
   Occurs in: elderly diabetics, non-diabetic obese pts, pts receiving TPN
   Characterized by (6):
    1. Extreme hyperglycemia
    2.  osmolarity that may be > 350 (spurious hyponatremia, Na 3:Glc 10)
    3. Severe dehydration
    4. Prerenal azotemia
    5. Mild acidosis
    6. Changes in mental status are common
   Tx: rehydrate (start with hypoosmolar fluids), +/- insulin (10u. Reg test dose, then titrate from there), treat
    underlying cause

DKA MGMT
   1 L NS bolus then 1 L over next hour
   10 U regular insulin bolus then 0.1 U/kg/hr iv maintenance
   When blood glc < 15 add 100 cc/hr D10W with NS as rest of maintenance
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    Add KCl to iv fluids when K < 5.4
    Frequent bloodwork
    Don’t take patient in frank DKA to OR → treat them first!




CARDIAC COMPLICATIONS

    Most common source of embo: L atrium
    Most common cause of isolated aortic insufficiency: congenital bicuspid valve then Marfan‟s.
    MVO2: wall tension, preload, afterload, contractility, HR


CLINICAL PREDICTORS OF INCREASED PERIOPERATIVE CV RISK
 Source is American Heart Association
MAJOR (4)
1. Unstable coronary syndromes (recent infarction within 1 month or unstable angina) (This is the single
   most important RF for periooperative infarction.)
2. Decompensated heart failure
3. Significant arrhythmias (high grade AV block, symptomatic ventricular arrhythmia in presence of
   underlying heart disease, SV arrhythmias with uncontrolled ventricular rate)
4. Severe valvular disease (AS in particular)

INTERMEDIATE (5)
1.   Mild angina
2.   Previous MI
3.   Compensated or prior heart failure
4.   DM
5.   Renal insufficiency

MINOR(6)
1.   Advanced age (increase risk > 35-40yrs, big  beyond 70 yrs)
2.   Low functional capacity (can‟t climb one flight of stairs with bag of groceries)
3.   Uncontrolled systemic HTN
4.   Previous stroke
5.   Rhythm other than sinus (A fib)
6.   Abnormal ECG (LVH, LBBB, ST-T abnormalities)

OTHERS FROM OTHER SOURCES
    Smoking
    Purely elective surgery should be postponed for 6 months following an MI.
    Risk with peripheral vascular disease is not known.
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CARDIAC RISK STRATIFICATION FOR NONCARDIAC PROCEDURES
HIGH
   Emergent major operations
   Aortic and other major vascular surgery
   Peripheral vascular surgery
   Anticipated prolonged surgical procedures associated with large fluid shifts and/or blood loss
INTERMEDIATE
   Carotid endarterectomy
   Head and neck surgery
   Intraperitoneal and intrathoracic surgery
   Orthopedic surgery
   Prostate surgery
LOW
   Endoscopic surgery
   Superficial procedures
   Cataract surgery
   Breast surgery

WHAT TO DO WITH INFO
   Major clinical predictors  surgery on hold, cardiology workup
   Intermediate or minor clinical predictors  look at functional capacity & surgical risks.


GOLDMAN RISK ASSESMENT (ANN INT MED, 1983)
Criteria                                         Points Cardi   Cardi
                                                        ac Cx     ac
                                                                Death
S3 gallop, neck vein distention                  11    34%      20%
Transmural or subendocardial MI in last 6        10    37%      23%
mos
Premature ventricular beats, > 5/min             7     30%      14%
Rhythm other than sinus OR presence of           7     19%      9%
PACs on last preop ECG
Age > 70                                         5     11%      5%
Emergency Surgery                                4     13%      5%
Intrathoracic, intraperitoneal, or aortic site   4     9.5%     2.5%
of surgery
Evidence for important aortic stenosis           3     17%      13%
Poor general medical condition*                  3     11%      4%

   *Poor GMC = PO2 < 60, PCO2 >50, K<3.0, HCO3 <20, BUN>50, Creat >3mg/100mL, AbN AST or
    chronic liver dz, or Bedridden
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Total        Risk of life-threatening     Risk of
points       cardiac complication         death
0–5          0.7%                         0.2%
6 – 12       5%                           2%
13 – 25      12%                          2%
>25          22%                          56%

PERIOPERATIVE MI
   Mortality rate as high as 50-90% (vs. 12% in non-surgical AMI pts.)
   Majority deaths in 1st 48 hrs post-op
   Most common associated finding = perioperative shock (>10min)

COMPLICATIONS OF MI
   Papillary muscle dysfunction/rupture  mitral insufficiency  CHF,  CO, and hypotension
   Ventricular septal defect
   Ventricular arrhythmias
   Ventricular aneurysm

RISK OF REINFARCTION
   < 3 months post MI: 37%
   3 – 6 months post MI: 15%
   > 6 months post MI: 5% and remains constant
   Mortality of reinfarction: 50%
   Risk can be lessened with postop invasive monitoring in ICU with aggressive therapy of hemodynamic
    disturbances to 6, 3 and 1% respectively.

PREVENTION OF PERIOPERATIVE MI
   Identify high risk patients (clinical/operative risk factors, Goldman criteria)
   Optimize peri-operative hemodynamics (avoid shock)
   Maintain high index of suspicion



DVT/PE

   PCWP does not  with PE
   Other changes:  CVP,  PAP,  JVP,  pCO2 (?d/t hyperventilation)
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RISK FACTORS FOR DVT (VIRCHOW’S TRIAD)
   Stasis (6):
    1. Immobility
    2. Prolonged/type of surgical procedures (THA is highest risk)
    3. Paralysis
    4. Obesity
    5. CHF
    6. Pregnancy
   Hypercoagulable state (7):
    1. Trauma
    2. Pregnancy
    3. OCP ( VII, VIII, IX, X and  antithrombin III,  plt aggregation)
    4. Malignancy
    5. Inherited coagulation deficiencies (Factor V Leiden – aka resitance to APC - is most common, protein
       C/S deficiency, antithrombin III deficiency, lupus anticoagulant)
    6. Heparin induced thrombocytopenia
    7. Age > 40
   Endothelial damage (1)
    1. Previous DVT/PE


SYMPTOMS OF DVT BY LOCATION
   Pelvis: thigh swelling/whole leg swelling.
   Femoral: calf swelling
   Popliteal: asymptomatic
   PEs originate from DVTs of iliofemoral vessels 90% of time.


THROMBOPHLEBITIS
   Management of superficial thrombophlebitis: excision and Abx (S. aureus is most common organism in
    peripheral thrombophlebitis.)
   Gram negative and polymicrobial infections are common when a contiguous infection is the cause.
   Management of deep vein thrombophlebitis: Abx, heparin. Surgery is last resort.


PRESENTATION OF PE
CLINICAL
   Dyspnea
   Chest pain
   Tachycardia
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INVESTIGATIONS
   ABG
   CXR
   ECG (tachycardia, afib, ectopic beats, heart block, enlargement of P, ST segment depression, T wave
    inversion, S1Q3T3)
   Leg Doppler
   V/Q scan
   Pulmonary Angiogram
   Spiral CT
   TEE
   Impendance plethysmography has low sensitivity and is seldom used.


MANAGEMENT OF PE
   Heparin x 5 - 7 days while warfarin is started.
     INR target 3 for prosthetic valves, 2.5 for DVT.
   Thrombolysis if hemodynamically unstable
   Transvenous or surgical embolectomy if unstable
   IVC filter if anticoagulation contraindicated or a major bleed happens while on anticoagulation.


INDICATIONS FOR IVC FILTER
   Absolute (5):
    1. Recurrent embolism despite anticoagulation
    2. DVT or embolism in patient with contraindication to anticoagulation
    3. Complication of anticoagulation that forces therapy to be stopped
    4. Recurrent PE with associated pulmonary hypertension and cor pulmonale
    5. Immediately after pulmonary embolectomy for massive PE
   Relative (3):
    1. PE of more than ½ of pulmonary vascular bed in patient who cannot tolerate additional emboli
    2. Propagating ileofemoral thrombus despite anticoagulation
    3. High-risk patient with large free-floating iliofemoral thrombus on venogram
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RESPIRATORY FAILURE




                                  TLC = FRC + IC = (RV+ERV) + (VT + IRV)
                                          FVC = TLC – RV

   TLC = total lung capacity
   FVC = forced vital capacity (TLC – RV)
   FRC = functional residual capacity → everything below VT
   IC = inspiratory capacity
   IRV = inspiratory reserve volume
   ERV = expiratory reserve volume
   RV = residual volume
   VT = tidal volume

APPROACH TO OXYGENATION STATUS
   A-a gradient = PAO2 alveolar – PaO2 arterial
   PAO2 alveolar = (150 – 1.25PaCO2)
   A-a gradient = (150 – 1.25PaCO2) – PaO2
   Calculate this when PaO2 < 95.
   Normal A-a gradient (AaDO2): < 15 for patients < 30 yrs and increases by 3 per decade thereafter.
   DDx of N A-a but PaO2 < 95: hypoventilation, low FiO2.
   If A-a > N, give 100%:
      PaO2 = V/Q mismatch: a/w disease (asthma, COPD), interstitial lung disease, alveolar disease,
        pulmonary vascular disease (e.g. PE).
     No ∆PaO2 = shunt: atelectasis, pneumonia, pulmonary edema, R→L cardiac shunt, & pulmonary
        vascular shunts (i.e. AVM).
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              A-aDO2 = [FiO2(Patm – PH2O) – PaCO2/RQ] – PaO2

              A-aDO2 = [150 – 1.25PaCO2] – PaO2 (on r/a)




CLASSIFICATION AND DIAGNOSIS OF RESP. FAILURE
HYPOXEMIC RESP FAILURE
   Predominantly caused by shunting (collapsed or flooded alveoli).
   Etiology: pneumonia, contusion, alveolar hemorrhage, high pressure pulmonary edema (CHF), low
    pressure pulmonary edema (ARDS).

HYPERCAPNIC RESP FAILURE
   Elevated PCO2 from hypoventilation is hallmark.
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   Etiology: impaired drive, impaired mechanics, or excessive load.
   Those with depressed drive may not be tachypneic or dyspneic.
   Those with impaired mechanics have a depressed negative inspiratory force and maximal minute
    ventilation.
   Those with increased load have decreased tidal volume while spontaneously breathing and high peak and
    plateau a/w pressures when intubated.
   Common presentation is acute on chronic resp failure.

HYPOXEMIC & HYPERCAPNIC RESP FAILURE
   Typical in postoperative patients.
   Has both hypoxemia and hypoventilation.
   Etiology: COPD,  sensorium, MSK weakness.
   Often result of worsening atelectasis and it results in progressive respiratory distress.
   Airways close when FRC drops below 25% TLC (normally is 50%).
   They close at even higher FRC in elderly, smokers, and those in pulmonary edema.
   FRC is decreased by supine posistioning, abdominal incisions, ilieus, ascites, and obesity.



PERIOPERATIVE RESPIRATORY COMPLICATIONS


PERIOPERATIVE ATELECTASIS & PNEUMONIA
   Prevention: PFT‟s pre-op on anyone with significant lung dz, optimize pre-op meds/puffers, quit
    smoking, aggressive post-op pulmonary toilet (incentive spirometry and chest physio)
   Treatment: incentive spirometry, chest physio, O2, culture-guided Abx, positive pressure ventilation prn
    (BiPAP or intubation)

PERIOPERATIVE ASPIRATION
   Risk factors: induction of anesthesia/intubation, post-op sedation, NG tubes, altered swallowing
    mechanics
   Prevention: proper intubation technique c cricoid pressure, NPO pre-op, pre-op maxeran and ranitidine,
    early removal of NG tubes, avoid oversedation, ad-lib swallowing assessments before restarting PO intake
   Treatment: aggressive initial suction (+/- bronchoscopy) immediately post-aspiration, supportive care,
    Abx only req‟d if +‟ve culture

ACUTE LUNG INJURY & ARDS
   Acute Lung Injury (ALI) is precursor to ARDS (in ALI → PaO2/FiO2 < 300)
   ALI = „normal manifestation of immune response to a wide variety of dz states (some degree of ALI
    found in most patients under surgical stress)‟ - Sabiston
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DEFINITION OF ARDS (4)
1.   Acute change in lung function
2.   Bilateral infiltrates on CXR (24 – 48 hrs for XR changes)
3.   PCWP < 20 mmHg and no evidence of CHF
4.   PaO2/FiO2 < 200

VENTILATOR STRATEGIES IN ALI/ARDS
    Vt 6 – 8 ml/kg
    Peak plateau pressure < 35 cm water
    Allow permissive hypercapnia
    Adjust level of PEEP to inflection point



INTUBATION


INDICATIONS FOR INTUBATION
Clinical                     Laboratory
Shortened speech             PaO2/FiO2 < 250
Use of accessory muscles     PaCO2 > 50
Subjective air hunger        PH < 7.25
Change in mental status      RR > 35 breaths/min
                             Ve > 12 L/min
                             Vc < 15 ml/kg
                             NIF < 25 cm H2O
                             AaDO2 > 35

    FEV1 < 1 L is big risk for postop ventilation.
    VC < 35% is big risk for postop ventilation.


PARAMETERS PREDICTIVE OF SUCCESSFUL EXTUBATION (11)
1.   Negative inspired pressure > 25 cm H2O
2.   Tidal volume (Vt) > 5 – 7 mL/kg
3.   Resp rate ( f ) < 20
4.   f / Vt < 100 (so-called „rapid-shallow‟ index)
5.   Vital capacity > 10 – 15 mL/kg
6.   Ve 6 – 8 L/min
7.   PEEP 5 cm H2O or less
8.   Pressure support ventilation (PSV) 5-8 cm H2O or less
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9. Glasgow Coma Scale 14 or greater or patient is cooperative and responds to commands
10. Patient hemodynamically stable and breathing comfortably
11. Absence of excessive secretions requiring suctioning more often than q4h



OTHER LUNG STUFF

   Tracheal stenosis diagnosed with flow volume curve.
   In vocal cord paralysis, they close on inspiration but blow open on expiration.



CHYLOTHORAX


MANAGEMENT
   TPN or medium chain triglycerides
   Drainage of the pleural space by thoracentesis or chest tube
   If chylothorax persists for 3 or 4 days, talc pleurodesis may be tried
   If medical management fails after 2 – 4 weeks, the duct should be ligated at the injury site (because of
    excellent collaterals, the duct can be ligated with impunity)

COMPLICATIONS
   Nutritional (fat and fat soluble vitamins)
   Hypovolemia
   Hypoproteinemia
   Decreased immune status (loss of immune proteins and lymphocytes)



ENDOCRINE COMPLICATIONS


ADRENAL INSUFFICIENCY (‘ADDISONIAN CRISIS’)
ETIOLOGY
   Primary (6): autoimmune (most common in N/A), infection (most common in 3rd world), vascular
    (hemorrhage, thrombosis, trauma), metastatic dz, deposition dzs (hemochromatosis, sarcoid, amyloid),
    drugs (ketoconazole, rifampin, anticonvulsants)
   Secondary (3): pituitary failure, glucocorticoids (1-3 wks is enough to suppress for 8-12 months!),
    megestrol
   Tertiary: hypothalamus failure
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SIGNS & SYMPTOMS
   Fatigue
   Weakness
   Anorexia
   Nausea & vomiting
   Weight loss
   Cutaneous and mucosal pigmentation
   Hypotension  shock
   Hypoglycemia
   Decreased cold tolerance
   Dizziness, syncope
   ECG:  voltage, prolonged PR and QT intervals
   Early symptoms: weakness, fatigue, orthostatic hypotension

LABS
 Na 
 Cl 
 Bicarb 
 Hypoglycaemia
 K
 +/- Hypercalcemia
COSYNTROPIN STIMULATION TEST
 Used to distinguish primary from secondary/tertiary dz
 Give synthetic ACTH (cosyntropin), then measure cortisol at 0, 30, 60 min
 Baseline cortisol > 15 ug/dl = normal adrenal f‟n (i.e. secondary/tertiary d/o)
 Cortisol rise > 20 ug/dl = normal adrenal f‟n (i.e. secondary/tertiary d/o)
 Abnormal test = primary disorder (i.e. adrenal) or chronic secondary d/o (adrenal is so atrophied d/t lack
  of ACTH stimulation, it fails to respond)

TREAMENT
   IV volume & sugar replacement (D5NS)
   Acutely: Dexamethesone 4 mg + hydrocortisone 100 mg q6h until condition stabilizes (no need for
    mineralocorticoid replacement acutely – Sabiston)
   Chronic/once acute phase has past: fludrocortisone (mineralocorticoid) + hydrocortisone


ADRENAL SUPPRESSION
   If supplemental corticosteroids are given over weeks to months, adrenal suppression occurs → patient
    needs supplemental therapy in times of stress.
   It takes pituitary 2 – 3 months to become responsive again and 6 – 9 months for cortisol levels to
    normalize after discontinuation of exogenous cortisol.
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   20 mg for 3 weeks can be stopped cold turkey.
   Indications for stress dose steroids: supraphysiologic steroid doses for >1 week in past year (if in doubt
    → stim. test), known adrenal insufficiency
   Stress dosing: 1st dose pre-op, 300mg hydrocortisone/day (100mg q8h) x24hrs then rapid taper over 72hrs
    (to avoid wound healing & infx complications)
   Muscle weakness associated with steroids commonly begins in the pelvifemoral muscle groups.

THYROID PROBLEMS
HYPOTHYROIDISM
   Primary: thyroid gland (Hashimoto’s, iodine deficiency, surgery, radiation, amiodarone, recovery phase
    of thyroiditis)
   Secondary: pituitary
   Tertiary: hypothalamus
   Thyroid hormone resistance: peripheral tissues

   Note: post-op hypothyroidism can occur in any patient who is chronically hypothyroid whose meds aren‟t
    restarted within a few days (e.g. prolonged ileus); rare in patients < 50 y/o
   Mortality rate: approaches 50% (Sabiston)

PRECIPITATING FACTORS (4):
   General anaesthesia
   Cold exposure
   Infection
   Narcotic use

PRESENTATION
   Hypothermia
   Hypotension not responding to fluids or pressors
   Hypoventilation
   Obtundation
   Myxedema coma (combination of ↓MS and 3 hypo‟s above)
   Psychosis
    dig toxicity

LABS
    TSH
    Thyroxine
   Hyponatremia
   Hypoglycaemia
    cholesterol
    CPK
    AST
    LDH
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MANAGEMENT
   300 mg hydrocortisone to avoid precipitating Addisonian crisis.
   L-Thyroxine (after hydrocortisone) → PO for mild dz
   Give thyroxine iv if myxedema coma

HYPERTHYROIDISM
   DDx: Grave’s, toxic mutlinodular goiter, thyrotoxic phase of subacute thyroiditis, toxic adenoma, TSH
    secreting tumour, ectopic thyroid production, factitious hyperthyroidism
   Thyroid storm → an acute exacerbation of thyrotoxicosis and is a medical emergency with high mortality
    (20-50%).
     May result from withdrawal of anti-thyroid meds or from stress (peri-op)

PRESENTATION
   Signs and symptoms involve all organ systems.
   CVS symptoms predominate in elderly whereas neurologic ones predominate in young.
   Heat intolerance and warm moist skin
   Proximal muscle weakness
   Tachyarrythmias (this is the most immediate danger in the surgical patient)
   Dyspnea
   Restlessness
   Oligomenorrhea or amenorrhea

LABS
   Hypercalcemia
   Hypercalciuria
   Hypochromic macrocytic anemia
   Pernicious anemia (in Grave‟s disease)
   Neutropenia

MANAGEMENT
   Propanolol is used adjunctively (controls HR, ↓ T4 → T3 conversion)
   Propylthiouracil (PTU) blocks hormone synthesis and peripheral conversion of T4 → T3 (can also use
    methimazole)
   Radioactive iodine (RAI) → must give PTU first to avoid thyroid storm
   Surgery
   Treatment of thyroid storm (8):
    1. Propranolol
    2. Propylthiouracil
    3. Lugol solution or NaI
    4. Hydrocortisone (300mg, then 100mg q8h)
    5. Hydration/resuscitation
    6. Oxygen
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    7. Cooling blanket
    8. Nutritional support



GI COMPLICATIONS


C. DIFFICILE COLITIS
   Gram positive bacilli, spore-forming, anaerobic bacteria.
   Causative antibiotics: clindamycin, ampicillin, cephalosporins.
   Treatment: oral flagyl, oral vancomycin.


FISTULA
   FRIEND: foreign body, radiation, infection, epitheliazation, neoplasia, distal obstruction
   Metabolic acidosis associated with loss of bicarbonate or retention of chloride anions is characterized by a
    normal anion gap acidosis.
   Diarrhea, small bowel fistula, and ureterosigmoidostomy all cause significant losses of bicarb hence NAG
    metabolic acidosis.
   Also note that massive replacement of ECF with bicarbonate free solutions may cause dilutional acidosis
    associated with normal anion gap.
   Fistulas of the esophagus, duodenum, and jejunum are more likely to close than those of stomach,
    ligament of Treitz, or ileum.
   Specific characteristics of the bowel that are associated with the likelihood of requiring surgery are
    (8):
    1. bowel discontinuity
    2. severely diseased adjacent bowel
    3. large adjacent abscess
    4. an opening in the bowel greater than 1 cm2 in diameter
    5. a short fistula tract (less than 2 cm from the skin)
    6. the presence of a foreign body, including mesh in and around the fistula
    7. Previous adjacent radiation therapy
    8. Associated inflammatory bowel disease

MANAGEMENT
   Broad spectrum Abx
   Drainage of abscess
   Hyperalimentation (TPN)
   Somatostatin (Octreotide) → antiperistaltic; inhibits VIP, GH, LH, Ins.&Gluc.
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ILEUS
   Normal return of gut function: SB almost immediately, gastric function within 2 – 3 days, colon
    function within 3 – 5 days. In kids complete return is within 1 – 2 days.

ETIOLOGY
NEUROGENIC
   Spinal cord lesion
   RP process, hematoma, or tumour
   Ureteral colic

METABOLIC
   Hypokalemia (hyperkalemia not listed in all sources)
   Ca, Mg imbalance
   Uremia
   Hypothyroidism
   Diabetic coma or DKA

PHARMACOLOGIC
   Anticholinergics
   Narcotics
   Autonomic blockers
   CCB
   Antihistamines
   Psychotropics
   Phenothiazines
   Haloperidol
   Tricyclics
   Clonidine
   Vincristine

INFECTIOUS
   Sepsis
   Pneumonia
   Peritonitis
   Herpes zoster
   Tetanus
   Bacterial overgrowth of bowel


COLONIC PSEUDOOBSTRUCTION (‘OGILVIE’S’)
   Paralytic ileus of large bowel (often painless) characterized by rapidly  abdominal distension.
   Wall of large bowel can become sufficiently distended so that blood supply is compromised.
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   AXR may reveal air in SB and distension of segments of or entire length of abdominal colon.
   Hypaque contrast enema can establish nonmechanical nature of dilation.
   Colonoscopy is diagnostic and therapeutic.
   Management:
     Expectant management (NPO, NG suction, resuscitation and iv hydration)
     Neostigmine (a sympatholytic agent) if 24 hrs of conservative mgmt fails
     Colonoscopic decompression
     Bowel resection & ostomy if dead bowel



INFECTIOUS COMPLICATIONS

   Most common nosocomial infections in surgical patients = surgical site infections (2/3 are superficial &
    deep incisional tissues, 1/3 organ/space)
   Most common non-surgical infection in postop patients: UTI
   Most common cause of death from nosocomial infection in surgical patients: pneumonia
   Most common cause of sepsis in burns: pneumonia
   Most common source of Creutzfeld-Jacob: corneal transplant


SURGICAL ASEPSIS
STERILIZATION
   Source: Schwartz

STEAM
   Steam under pressure is most reliable means of sterilization
   Steam at 15 psi for 15 – 45 min will destroy all life.
   Vacuum autoclaves can sterilizes in 3 minutes.

DRY HEAT
   120/250 takes 6 hrs
   170/350 takes 1 hr
   For items injured by moisture or poorly penetrated by steam

GAS STERILIZATION
   Ethylene oxide, takes 3 – 6 hrs
   Used for delicate instruments (eg: scopes)
   24 hrs of aeration necessary to let ethylene oxide out because it irritates tissues (except solid metal or
    glass)

RADIATION
   Used for commercially bought, disposable stuff
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CHEMICAL
   2% glutaraldehyde aq
   Used for heat sensitive stuff
   Cidex is buffered alkaline solution of glutaraldehyde
   Sonacide is potentiated acid solution
   Alcohol is effective in absence of spores

DEGERMING THE SKIN
   Hexachlorophene is active against GP but not GN.

GUIDELINES FOR PREVENTION OF SSI
   EtOH is quickest.
   Chlorhexidine is best for residual effect.
   Clippers good, shaving bad (night before = 5x ↑ risk; 1hr before = 2x ↑ risk)
   Masks do no good
   Scrubbing → 2 min as good as 10 min

EFFECTIVENESS OF HAND DISINFECTION
Agent                 Immediate      Reduction
                      reduction      after 3 h
Soap                  40             0
Povidone-iodine soap 90              20
Povidone aq solution 97              75
Chlorhexidine soap    75             70
Hexachlorophene       40             91
detergent
Isopropyl EtOH 60% 96                90
Isopropyl 70%         99.3           99.1
Isopropyl 70% +       99.4           99.7
chlorhexidine 0.5%
Return to wound healing/complications



RENAL COMPLICATIONS

   Renal failure  dig toxicity.

ACUTE RENAL FAILURE
NEPHROTOXINS (10)
1. Myoglobin
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2. Hemoglobin (hematin from Hb breakdown)
3. Aminoglycosides
4. Penicillins
5. Cephalosporins
6. NSAIDs
7. Amphotericin B
8. Contrast agents
9. Endotoxin
10. Cyclosporin

DIFFERENTIATING ARF
                    Prerenal   Renal     Postrenal
Urine Osm           > 500      < 350     Variable
U/P Osm             > 1.5      1 – 1.5   1 – 1.5
Urine/plasma urea   >8         <3        Variable
Urine/plasma Cr     > 40       < 20      < 20
Urine Na            < 20       > 40      > 40
FeNa (%)            <1         >3        >3

   Where FeNa = (UNa x PCr)/(PNa x UCr)
   GFR = (140 – age)(weight)/PCr x 1.2(or 0.85 for women) (normal is 120 ml/min)
   All ATN damage causes reflex vasoconstriction of afferent arterioles   GFR.


INCREASED URINE SPECIFIC GRAVITY
   Temperature
   Proteinuria
   Glucosuria
   Sucrosuria
   Radiological contrast
   Mannitol
   Dextran
   Diuretics
   Antibiotics
   Detergent



LOCAL ANAESTHETICS

   See appendix
   Note that all the commonly used ones are amides (all have 2 „i‟s in name)
   Max dose of lido/xylocaine is 5 mg/kg, 7 with epi.
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   1% = 1 g/100 cc = 10 mg/cc (for 70kg pt, 35cc 1% w/o epi can be used)
   Quick Rule: 1% without = Wt/2; 2% w/o = Wt/4; With epi = multiply by 1.4
   7-5-3-1 mg/kg rule: with epi, without epi, bier block, iv.
   Quick Rule for 0.25% Marcaine Without Epi: dose (cc) = weight
   Mech is they bind the Na channel on the cytosolic side and prevent Na influx
   Weak bases, given in basic solution to help absorption, stored as ions for longer storage.
   Hepatic metabolism, excreted in urine. Need to decrease dose in liver disease.
   Toxicities: mainly manifest in CNS then CVS (Amide based local anaesthetics are also implicated in
    malignant hyperthermia. Sabiston 2001 although you won‟t see this in any other source.)

    Drug         Duration     Comments
                 (hrs)
    Amides
    Lidocaine   1              Fast onset
    Bupivicaine 4 – 12        Slow onset, long
                              effect, exaggerated
                              cardiotoxicity
    Ropivicaine 4 – 12        Less cardiotoxic
                              than bupivicaine
    Esters
    Tetracaine   ~ 10 hrs     Slow onset


TOXICITIES
CNS
   This is the first system affected
   Numbness of tongue, perioral tingling
   Disorientation
   Tinnitus
   Visual disturbances
   Muscle twitching
   Convulsions, seizures
   Generalized CNS depression → coma → resp arrest

CVS
   Vasodilation, hypotension
   Decreased myocardial contractility
   Dose-dependent delay of cardiac impulse transmission
   Prolonged QRS, PR intervals
   Sinus bradycardia, asystole
   CVS collapse (this is the last thing to happen)
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   Cocaine (ester) blocks NE reuptake causing vasoconstriction and hypertension. All others depress
    cardiac contraction and cause arteriolar dilation.

TREATMENT
   ABC, epi for cardiac collapse.
   Diazepam, thiopental, succ. (szrs)



ANAESTHESIA

   Incidence and severity of headache post spinal anaesthesia is primarily related to the diameter of the
    needle used to inject the drug.
   Acceptable methods of intubation in someone with full stomach:
     RSI with pentothal and succ then intubation
     Awake intubation and then induction with pentothal
   Sympathetic fibres exit from the ventral root.
   Neonates have a higher percentage of body water. Drug metabolizing activities are lower in neonates.
    GFR is lower in neonates.
   In elderly, there is  body water,  fat, and  GFR.

RISKS OF ANESTHESIA
   Risk of Death: 1:100 000 risk of death or serious neurologic impairment for healthy people.
   Uncontrolled HTN → higher incidence of intra-op hypotension & MI vs. those with well controlled HTN
   25% operative candidates have CVDz
   Post-MI risk of re-infarction stabilizes at 6% at 6 mos.
   Stopping cardiac meds (BB, CCB, NTG) pre-op → ↑risk MI & death
   Higher incidence post-MI reinfarction with intra-abdominal/thoracic surgeries >3 hrs long (not if <3 hrs)
   Can drastically ↓ reinfarction rate post-MI with invasive HD monitoring (Swan-Ganz), aggressive therapy,
    & ICU admission
   CHF represents single most important RF for predicting post-op cardiac Cx (should NOT do elective Sx
    until it‟s treated)
   Restrictive lung dz is not a big problem → may need better ventilator
   Obstructive lung dz → reversible component must be optimally Rx‟d (puffers) prior to surgery; ↑ risk of
    FB-induced bronchospasm at intubation and extubation
   Lung dz patients → may benefit from regional anesthesia if only below T6 required (or Baer block for
    arm Sx)
   Analgesia → use of epidural narcotics and local anesthesia → ↓systemic narcotic use → ↓adverse
    respiratory drive fx & subsequent respiratory complications
   Obesity: ↓FRC (esp. when supine) → rapid desaturation, sleep apnea → pulmonary HTN & R-sided HF,
    limited cardiac reserve, ↑incidence GERD → ↑ risk aspiration, slow clearance of anesthetics due to excess
    fat deposits
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   Multiple comorbidities: worst combo is CRF, CHF, elderly, emergency abdominal surgery (76%
    mortality)

IV INDUCTION AGENTS
   Thiopental, ketamine, propofol, etomidate, midazolam.

THIOPENTAL/PENTOTHAL
   Rapid induction and emergence because of redistribution.
   Induces vasodilation and cardiac depression
   Hepatic metabolism eliminates 10%/hr.

KETAMINE
    BP (bad for CAD)
    HR (bad for CAD)
    bronchomotor tone (good for asthma)
    ICP (bad for trauma craniotomy)
   Cardiac depressant but at low doses (15 – 20%), it causes the least  BP of any induction agent.
   Can be used as sole anesthetic agent as produses profound amnesia and somatic analgesia
   Emergence delirium and bad dreams → avoid by giving benzos

PROPOFOL
   Short acting induction agent with nausea free emergence
   Bronchodilation
   Vasodilation
   Pain on injection

ETOMIDATE
   Preserves BP

MIDAZOLAM
   Minimal CV side effects

OPIODS
   Reduce MAC of inhalational agents
   Blunt the hypertensive and tachycardic esponse to endotracheal intubation and incision
   Provide analgesia that extends through the early postemergence interval


INHALATIONAL AGENTS
   Depressants of consciousness, pain, cardiopulmonary function, motor function and recall.
   In general, all  BP by myocardial depression and vasodilation.
   Generalized  in cerebral function and cerebral metabolic rate of O2 consumption.
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   Renal blood flow and GFR are  by 20 – 50%.
   Blood flow to skin is  and cutaneous autoregulation is reduced  vulnerable to hypothermia.
   MAC is measure used to compare potency (lower MAC = more potent)
   Greatest risk from halogenated agents (halothane) and nitrous oxide is spontaneous abortion. Other risks:
    liver and kidney disease.

NITROUS OXIDE
   MAC 105
   Minimal influence on respiration and hemodynamic.
   Often combined with another inhalational agent to reduce amount of 2nd needed.
   Main problem is that nitrous oxide is 30 fold more soluble than nitrogen therefore contraindicated in
    presence of closed gas spaces.
   High MAC means limitation of FiO2.

HALOTHANE
   MAC 0.75
   Almost completely replaced by newer agents.
   Powerful cardiac depressant ( contractility and SV, HR unchanged  overall  CO)
   Inhibits baroreceptor-increased HR usually seen with lowered BP.
   Sensitizes myocardium to catecholamines.
   Associated with fulminant hepatitis.
   Suitable for mask induction (pleasant smell).

ENFLURANE
   MAC 1.68
   Metabolized to fluoride and is associated with mild renal dysfunction.
   Relatively contraindicated in those with seizure disorder.
   Not widely used.

ISOFLURANE
   MAC 1.15
   Stable cardiac rate and rhythm (less  in CO than halothane).
   Pungent odour precludes inhalational induction.

SEVOFLURANE
   MAC ~ 2.0
   Rapid induction and emergence.
   Good for mask induction.
   Minimal CV side effects.
   Metabolized to fluoride.
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DESFLURANE
   MAC 6
   Rapid induction and emergence but pugent odour.
   Generally hemodynamically benign.

QUESTIONS
   Potency: halothane, isoflurane, enflurane, sevoflurane, desflurane, nitrous oxide.
   Suitable for mask induction: sevoflurane, halothane.
   Minimal hemodynamic effects: desflurane, sevoflurane < isoflurane.


NEUROMUSCULAR BLOCKERS
   Diaphragm is most resistant muscle to relaxants. Head and neck muscles are most sensitive.

SUCCINYLCHOLINE
   Depolarizing, the only such agent still in use.
   Agonist effects at cholinergic Rs of NMJ initially causing contractions (fasciculations) and then interval of
    profound relaxation.
   Fast onset of action: 30 – 60 s.
   Short duration of action: 5 m.
   Side effects (6):
    1. Bradycardia and arrhythmias
    2. Life threatening hyperkalemia in patients with burns, paraplegia, quadriplegia, and massive trauma,
        skeletal muscle myopathy. (risk of hyperkalemia peaks 7 – 10 days post injury)
    3. Malignant hyperthermia when combined with a volatile agent in susceptible patients
    4. Postop muscle pain
    5.  intraocular pressure
    6.  intragastric pressure

NONDEPOLARIZERS
   Usually need to be pharmacologically reversed at end of case with acetylcholinesterase inhibitor
    (neostigmine or edrophonium) accompanied by atropine or glycopyrrolate to counteract the muscarinic
    effects of the acetylcholinesterase inhibtor.

PANCURONIUM
   Slow onset
   Long duration
   No histamine release
   Tachycardia

ROCURONIUM
   Fast onset
   No CVS effects
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ASA CLASSIFICATION
   1: normal, healthy
   2: mild systemic disease that causes no limitation of function
   3: severe systemic disease that results in functional limitation
   4: severe systemic disease that is a constant threat to life
   5: moribund patient that is not expected to survive without the operation
   6: declared brain dead, for organ retrieval
   E: when it is an emergency



ANATOMY

   Transverse facial artery arises from the superficial temoporal artery within the parotid.
   Retromandibular vein descends within the parotid gland.
   Deltoid muscle is supplied by the axillary nerve.
   The posterior, lateral and medial cords of the brachial plexus are defined by the axillary artery.
   Vertebral artery arises from the subclavian.
   Contents of the carpal tunnel: flexor digitorum profundus x 4, flexor digitorum superficialis x 4, flexor
    pollicis longus, median nerve (and flexor carpi radialis).
   Palmar branch of median nerve branches off about 5 cm proximal to the crease of the wrist.



SURGICAL DEVICES


ELECTROCAUTERY
   High frequency (> 10 000 Hz) oscillating currents don‟t depolarize excitable membranes.
   Most electrocautery devices work in the 500 000 Hz – 3 MHz range.
   Occasionally sparks of current at the contact site can give rise to signal degeneration and demodulation
    that results in localized depolarization. It is this demodulation that results in localized muscle contraction
    when muscle comes into direct contact with the active electrode.
   Effect of electrical current on tissue is dependent on the power of the current and the waveform that is
    generated. (P=I2R)
   Heat is proportional to the power. Avoid excessive power and contact time.
   High frequency current with sinusoidal current  pure cutting effect. High energy transfer over small
    area  600 degrees C  instant tissue vaporization and pyrolysis. No coagulating effect.
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   Series of dampened sinusoidal waves produced in rapid bursts. Requires less energy and results in
    dessication and destruction of surrounding tissue. Dessication occurs as water evaporates from the cells
    and a coagulam of dried, shrivelled, cellular debris forms as tissues boil in their own fluid and surrounding
    lymph.
   Combination of cutting and coagulation can be achieved with a blend current that consists of pure
    sinusoidal cutting current and a periodic dampened coagulation current.
   Obliterative coagulation for vessels < 0.5 mm
   Coaptive coagualtion for vessels 0.5 – 1.5 mm

   Bipolar advantages (5):
    1. Less thermal injury to surrounding tissue
    2. Less risk of patient burn
    3. No interference with ECG
    4. No interference with pacemakers
    5. Can be used in wet fields


ARGON BEAM COAGULATOR
   Works just like monopolar cautery.
   High-frequency oscillating current flows through spray of pressurized, ionized argon gas rather than the
    metal blade like in monopolar cautery.


LASERS
   POS 2002 questions: which laser has wavelength outside visible spectrum?

   Visible spectrum = ~ 400 (violet) – 700 (red) nm.

   Laser with wavelengths within visible spectrum: Argon (~ 500), tunable dye (577), potassium titanyl
    phosphate=KTP (530).
   Lasers with wavelengths outside visible spectrum: Nd:YAG (1060), Ho:YAG (2100), Er:YAG (2940),
    CO2 (10600).
   Note: Nd = neodymium, Ho = holmium, Er = erbium

   Tissue penetration depths of lasers: Nd-YAG > CO2 > Argon




CRITICAL APPRAISAL

               Disease (Effect)
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    Factor Present Absent
    Present A            B
    Absent C             D
    Total      A+C       B+D
   Odds ratio (case control study) = AxD/BxC
   Relative risk (cohort study) = (A/A+B)/(C/C+D)
   Attributable risk = (A/A+B) - (C/C+D)

              Disease
Test +          -       Total
+     TP        FP      TP+FP
-     FN        TN      FN+TN
Total TP+FN FP+TN
 Sensitivity = TP/TP+FN
 Specificity = TN/FP+TN
 PPV = TP/TP+FP
 NPV = TN/FN+TN

                Actual Situation
    Result    No effect      Effect
    No effect No error       Type II (beta)
    Effect    Type I (alpha) No error


   Power (1-beta) is probability of rejecting null hypothesis when it is false
   Level of statistical significance depends on the alpha.
   If  is tightened to  type I error, the power suffers (or likelihood of type II error is )


STATISTICAL CALCULATIONS
   Z-test/t-test tests differences between two sample means for continuous data.
   In t-tests, each sample must be normally distributed.
   Chi-square test tests difference between proportions or tests for association between categories. Used
    when variable is categorical.
   Analysis of variance compares mean values from three or more groups simultaneously.
   Linear regression: technique to describe relationship between two variables when both are continuous.
   Logistic regression: requires discrete outcomes and produces an adjusted OR.
    SD  var iance
    var iance  [(mean  X ) 2 /(n  1) ]
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APPENDICES


LOCAL ANAESTHETICS
Return to main document
Drug             Dose               Potency (1 – Duration       Comments
                 (mg/kg)            16)
Amides
Mepivicaine      5–7                2           Medium
Prilocaine       6–8                3           Medium
Lidocaine        7, 5, 3, 1         4           1 (medium)      Fast onset
                 rule
Etidocaine       3–5                16          Long
Ropivicaine      4 – 12             16          Long            Less cardiotoxic
                                                                than
                                                                bupivicaine
Bupivicaine       2–4               16          4 – 12 (long)   Slow onset,
(marcaine)                                                      long effect,
                                                                exaggerated
                                                                cardiotoxicity
Esters
Procaine          10 – 12           1           Short
Cocaine                             2           Medium
Tetracaine        2                 16          Long
Benzocaine                                                      Surface use
                                                                only
 TABLE 11-4. Doses and Toxic Levels of Commonly
  Used Local Anesthetics

                              Dose                     Toxic Blood
                              (mg./kg.)                Levels
                                                       (m./ml.)

 Esters
  Procaine                    10–12                    20
  Chloroprocaine               7–10                    20
  Tetracaine                  2                        1.5–4
  Cocaine
 Amides
  Lidocaine/xylo              5–7                      5–10
  Mepivacaine                 5–7                      5–10
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  Bupivacaine/marcaine          2–4                            1.5–4
  Prilocaine                    6–8                             5–10
  Etidocaine                    3–5                            1.5–4

MAJOR NERVE BLOCK




ALKYLATING AGENTS
Return to main document
Drug              Mechanism           Dose Limiting             Common s/e              Unique thing
                                      Toxicity
Chlorambucil       Alkylating         Myelosuppression          GI upset, mild LFT      Least toxic alkylating
                                                                , sterility            agent
Cyclophosphamide   Alkylating,        Myelosuppression,         Alopecia, stomatitis,   Bladder ca, delayed
                   inhibits DNA       hemorrhagic cystitis      aspermia,               wound healing,
                   synth                                        amenorrhea, n & v       SIADH
Ifosfamide         Alkylating         Myelosuppression,         Alopecia, n & v,        Neurotoxicity, give
                                      hemorrhagic cystitis      neurotoxicity           with mesna
Mephalan           Alkylating         Myelosuppression,                                 Prolonged recovery
                                      may be cumulative                                 from
                                                                                        myelosuppression
Thiotepa           Alkylating         Myelosuppression,         Abdo pain,              Urinary side fx
                                      may be cumulative         hematuria, irritative   common
                                                                voiding symptoms,
                                                                ureteral obstruction
Carboplatin        Alkylating         Myelosuppression,         N & V, pain at          Thrombocytopenia is
                                      especially platelets,     injection site          especially common
                                      cumulative suppression
                                      of erythros
Cisplatin          Alkylating         Cumulative renal          N & V,                  Mild
                                      insufficiency,            hypokalemia,            myelosuppression,
                                      peripheral sensory        hypomagnesemia,         SIADH, needs lots of
                                      neuropathy, tinnitus,     mild                    antiemetics, hydration,
                                      high frequency hearing    myelosuppression        furosemide, mannitol
                                      loss

ANTIMETABOLITES
Return to main document
Drug            Mechanism             Dose Limiting             Common s/e              Unique thing
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                                         Toxicity
Cytarabine         Inhibits DNA          Myelosupp (nadir in 5-     N&V, diarrhea,              Cerebellar toxicity
                   polymerase            7 days, recovery by 2 –    conjunctivitis,
                                         3 weeks                    cerebellar toxicity
Fludarabine        Inhibits DNA          Myelosupp                  N&V
                   primase,
                   polymerase, and
                   ribonucleotide
                   reductase
5-FU               Blocks                Myelosupp,                 Nasal d/c, eye              Log-linear cell killing
                   thymidylate           mucositis/stomatitis,      irritation                  action
                   synthetase            diarrhea
Hydroxyurea        Inhibits nucleotide   Myelosupp with rapid                                   Megaloblastosis, used
                   reductase             recovery                                               as radiosensitizer
Mercaptopurine     Purine                Myelosupp                  N&V,                        Allopurinol increases
                   antimetabolite                                   anorexia,cholestasis        the toxicity
Methotrexate       Blocks DHFR           Myelosupp, stomatitis,     Neurotoxicity,              Cytotoxic effects can
                                         renal dysfunction          encephalopathy              be reduced with
                                                                                                leucovorin (folinic
                                                                                                acid), delayed wound
                                                                                                healing

ANTITUMOUR ANTIBIOTICS
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Drug          Mechanism             Dose Limiting            Common s/e                    Unique thing
                                    Toxicity
Bleomycin         Binds to DNA      Shaking chills and       Hyperpigmentation of          Radiosensitizer,
                                    febrile reactions,       skin stretch areas,           pneumonitis/pulmonary
                                    pneumonitis              anorexia                      fibrosis
Doxorubicin       Intercalates      Myelosupp,               CHF, ECG changes,             Cardiomyopathy,
(adriamycin)      DNA               cardiomyopathy           alopecia,                     radiosensitizer, delayed
                                                                                           wound healing
Mithramycin       Inhibits DNA-     Thrombocytopenia         N&, hypoCA, hypoK,            Used for refractory
                  dep-RNA synth                              hypoMG, hypoPO4               hypercalcemia, inhibits
                                                                                           osteoclasts
Mitomycin C       Acts as a         Myelosupp,               N&V, anorexia
                  alkylator         especially TCP

PLANT ALKYLOIDS
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Drug       Mechanism               Dose Limiting                 Common s/e                 Unique thing
                                   Toxicity
Etoposide      Topoisomerase II    Neutropenia                   N7V, alopecia,
               inhibitor                                         hypotension
Paclitaxel     Antimicrotubule     Neutropenia,                  Alopecia, TCP,             For breast and relapsed
                                   hypersensitivity,             arthralgias, myalgias      ovarian cancer
                                   peripheral neuropathy
Vinblastine    Antimicrotubule     Myelosuppression,             Cramps                     Cramps, SIADH
                                   Neutropenia
Vincristine    Anitmicrotubule     Peripheral neuropathy,        Mild hypoesthesia,         Paralytic ileus, SIADH
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                                     myelosuppression          paraesthesias,             Vincristine is more
                                                               necrosis if                neurotox than blastine
                                                               extravasation              but less myelotox



CLASSIFICATION OF SHOCK
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                 Class I                        Class II                              Class III              Class IV
EBL:             0 – 15%                        15 – 30%                              30 – 40%               > 40%
HR               < 100                          > 100                                 > 120                  > 140
BP               Normal                         Normal mean,  systolic,                                   
                                                diastolic
PP                      Normal                                                                             Unobtainable
Mentation               Normal/slight           Mild anxiety                          Anxious and            Confused or
                        anxiety                                                       confused               lethargic
U/O                     Normal                  ~ 0.5 cc/kghr                         < 0.5 cc/kghr          Nil
Volume                  Often none              Crystalloid (3:1)                     Crystalloid &          Blood &
required                                                                              blood                  crystalloid




ICU DRUGS
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Drug       Mechan Dos                Therapeutic          Side    Indicati Uniq
           ism    e                  Effects              Effects ons      ue
                                                                           Featu
                                                                           re
Dobutami   1>2            2 – 20   Inotropic            Vasodilatio   CHF and         D/C by
ne         agonist          mcg/kg   Chronotropic         n             low             tapering
                            min                           Tachyarrhyt   cardiogenic     
                                                          hmias         shock when      afterload
                                                          Ischemia      there is
                                                                        myocardial
                                                                        ischemia
Dopamine   DA: 2 - 5        2 and    Inotropic            Tachyarryth   CO, BP in
           1: 5 – 10       up       Chronotropic         mias          cardiogenic
           : > 10          mcg/kg   vasoconstriction     ischemia      shock
                            min
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Ephedrine    Nonspecific    5 mg     Inotropic               Tachyphyla     Hypotension
             adrenergic &   q5min    Chronotropic            xis            during
              epi                   Vasoconstriction                       anesthesia
             release
Epinephri     and         1        Inotrope                Tachyarrhyt    Anaphylaxis    Hypergly
ne                          mcg/mi   Chronotrope             hmias          Cardiogenic    cemia
                            n        Vasoconstriction        Myocardial,    shock
                                                             mesenteric,    Cardiac
                                                             renal, &       arrest
                                                             extremity
                                                             ischemia,
                                                             hyperglyce
                                                             mia
Hydralazi    Arteriolar     1         BP                    Reflex         Severe HTN     Less
ne           vasodilation   mg/hr     afterload             tachycardia,   Afterload     cerebral
                            and up                            CO,         in CHF         vasodilati
                                                             plasma                        on
                                                             volume
Isoprotere   1,2>>>      1-30     Chronotrope             Tachyarrhyt    Life
nol                         mcg/mi   Inotrope                hmias          threatening
                            n        Vasodilation            MI             bradycardias
                                                             Hypotensio
                                                             n
Labetalol    / blocker    0.5-4     PVR                   Bronchospa     Mild to
                            mcg/mi   ↓HR                     sm             severe HTN
                            n                                CHF            emergencies
                                                             Heart block
Lidocaine    Blocks Na      1        Suppresses electrical   Hypotensio     Acute
             channels       mg/kg    activity of             n              treatment of
                            then 1   depolarized             Paraesthesi    V-
                            mg/mi    arrhythmogenic tissue   a              arrythmias
                            n                                Tremor         associated
                                                             Nausea         with MI,
                                                                            cardiac
                                                                            manipulatio
                                                                            n, and dig
                                                                            toxicity
Norepinep    , 1 > 2     1        Inotrope                Tachyarrhyt    Shock          Extravasa
hrine                       mcg/mi   Vasoconstriction        hmias                         tion
(levophed                   n and    Minimal chronotropic    Myocardial,                   causes
)                           up                               mesenteric,                   tissue
                                                             renal, &                      necrosis
                                                             extremity
                                                             ischemia
Nitropruss   Arterial and   ~3        BP                    Tachyphyla     HTN crisis
ide          venous         mcg/kg    afterload             xis            CHF
             vasodilator    min                              Metabolic
                                                             acidosis
                                                             Thiocyanat
                                                             e toxicity
Phenyleph     agonist      30-300   Vasoconstrictor         Reflex         Hypotension
rine                        mcg/mi                           bradycardia    (vascular
                            n                                HTN            failure in
                                                                            shock)
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ANTIBIOTICS
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Drug         Class      Mechanism                 Activity   Coverage   Toxicity             Notes
Penicillins     Beta-     Inhibits Pen binding    Cidal      Variable   Hypersensitivity,    Methicillin, oxacillin,
- Pen V/G       lactams   protein and prevents                          nephrotoxic.         cloxacillin, and nafcillin are
- -lactamase             cross linking of                              Amp causes C. diff   -lactamase resistant.
resistant                 peptidoglycan strands
- Aminopens               of cell wall
- Anti-pseud-
omonal
- Imi/Meropen
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1st gen. Ceph     Beta-         As for pen, prevents   Cidal    Pos (MSSA,        Hypersensitivity,
PO: Keflex        lactams       cross linking                   all strept, no    15% cross reactivity
IV: Ancef                                                       enterococci),     to pen, nephrotoxic,
                                                                easy neg          C diff
                                                                (Escherichia,
                                                                proteus,
                                                                klebsiella)
2nd gen Ceph      Beta-         As for pen, prevents   Cidal     neg but        Pen cross reactivity     Cefoxitin and cefotetan
PO: Ceclor        lactams       cross linking                   pos coverage      less than 1st gen,       cover anaerobes
IV: Cefuroxime                                                  compared to       nephrotoxic, C. diff
                                                                1st gen
3rd gen ceph      Beta-         As for pen, prevents   Cidal    Broad neg,        Pen cross reactivity     Crosses BBB, ceftazidime is
PO: Cefixime      lactams       cross linking                   less pos, anti-   less than 2nd gen,       best for Pseudomonas
IV: Ceftaz,                                                     pseudomonal.      nephrotoxic, C. diff     Ceftizoxime covers
Cefotax,                                                                                                   anaerobes
Ceftriax
4th gen ceph      Beta-         As for pen, prevents   Cidal    Broad neg,        Hypersensitivity, less
IV only:          lactams       cross linking                   good pos          pen cross reactivity
Cefepime                                                                          than 3rd gen,
                                                                                  nephrotoxic, C. diff
Vancomycin        Glycopepti    Blocks peptidoglycan   Cidal    Pos only          Red man syndrome,        Useful in those with true pen
                  de            polymerization                                    nephrotoxic,             allergy, resistant to
                                                                                  ototoxic,                penicillinase
                                                                                  thrombophleb
Chloramphenic     Protein       Binds ribosomal 50s,   Static   Excellent pos     Rev/irrev marrow
ol                synthesis     prevents tRNA                   and neg           suppression
                  inhibitor     association with                including
                                peptidyl transferase            anaerobes
Eryth, clarith,   Macrolide     Binds P site of 50s    Static   Pos,              Hepatotoxic              Staph & strept infections
azith             (protein      and prevents                    mycoplasma,                                when pen allergic
                  synthesis     translocation                   legionella,
                  inhibitor)                                    chlamydia
Clindamycin       Lincosamid    Binds 50s              Static   Pos,              Pseudomemb.
                  e (protein                                    anaerobes         Colitis/C. diff
                  synthesis
                  inhibitor)
Gent, tobra,      Aminoglyc     Binds 30sinhibits     Cidal    Neg aerobes       Nephrotoxic,             Synergistic with pens against
strept, amik,     osides        initiation & misread            &                 ototoxic, neurotoxic,    enterococci and
neomycin          (protein                                      mycobacteria      vestibulotoxic           pseudomonas
                  synthesis                                                       (vertigo)
                  inhibitors)
Tetra &           Tetracyclin   Binds 30sprevents     Static   Chlamydia,        Hepato,
doxycycline       e             AA-tRNA from                    mycoplasma,       photosensitizing
                                binding to A site of            rickettsia, pos
                                ribo                            cocci
TMP/SMX           Folic acid    TMP inhs DHFR,         Static   Broad pos and     Kernicterus, nephron,
                  inhs          SMX competes with               neg               photosensitizing
                                PABA for
                                incorporation into
                                folic acid
Cipro (2nd)       Quinolones    Inhs DNA gyrase        Cidal    GNR and           Seizures, dizziness.     Comparable tissue levels
Levo (3rd)                                                      GPC               Need to adjust dose      whether given iv or oral
Moxi (4th)                                                                        of phenytoin,            except norfloxacin. Tendon
Gati (4th)                                                                        theophyllines,           rupture in combo with roids.
                                                                                  coumadin,
                                                                                  cyclosporine
Rifampin                        Interacts with DNA-    Cidal    Pos cocci, neg    Induces p450
                                dep RNA polymerase              bacilli, most     (↓cyclosporine &
                                                                mycobacteriu      coumadin levels)
                                                                m
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Metronidazole   DNA          Intrabact activation   Cidal   Anaerobes       Disuslfiram reaction   C.diff treatment
                complexing   leads to release of            and some
                agent        metabolites that               protozoan
                             damage DNA
Imipenem,       Carbapene                                   GPC (except
meropenem       ms                                          MRSA and
                                                            enterococci),
                                                            GNR
                                                            including
                                                            most
                                                            pseudomonas
Linezolid       Oxazolidin                                  Nearly all GP
                ones                                        including
                                                            VRE



IMMUNOGLOBULINS
Immunoglobulin MW                     Polymeric Structure           Additional                 Functional Associations
               (kd)                                                 Chains
IgA            160                    Monomer, dimmer, or           J chain                    Mucosal Ab
                                      trimer
IgD                    184            Dimmer                                                   Membrane bound R
IgE                    188            Dimmer                                                   Immediate
                                                                                               hypersensitivity
IgG                    146 –          Dimmer                                                   Secondary Ab
                       170
IgM                    970            Pentamer                      J chains                   Primary Ab, membrane R

				
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