Master File 2003 - Body as a Whole

8/9/2019 Master File 2003 - Body as a Whole

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BODY AS A WHOLE - CLINICAL MANAGEMENT

PRE-OPERATIVE PREDICTION OF PERI-OPERATIVE CARDIAC

COMPLICATIONS

The single most important area in which preoperative evaluation and interventions may decrease peri-operative

morbidity involves the patients cardiac status because cardiac complications are the leading cause of death after

most operations. Peri-operative cardiac complications include Myocardial Infarction, Congestive eart !ailure,

and "eath.Pre-operative prediction of peri-operative cardiac complications depends on both patient-specific ris# factors

and surgery specific ris#s. The patient-specific ris# factors are usually ascertained with a thorough history and

physical e$amination and %C&. The 'merican College of Cardiology has identified patient specific clinical

predictors of increased peri-operative cardiac ris#. They have grouped these clinical predictors into ( ma)or

groups*

MAJOR*

+nstable coronary syndromes recent MI days /0month and unstable or severe angina1, decompensated

C!, 2ignificant 'rrhythmias high grade '3 bloc#, symptomatic ventricular arrhythmias or uncontrolled

23Ts1, and severe 3alvular "isease

INTERMEDIATE

Mild angina pectoris Canadian Class I or II1, Prior myocardial infarction by history or pathologic 4 waves,

Compensated or prior congestive heart failure, "iabetes Mellitus

MINOR

'dvanced 'ge, 'bnormal electrocardiogram 53, 5 666, 2T-T abnormalities1, 7hythm other than sinus

e.g. atrial fibrillation1, 5ow functional capacity, istory of 2tro#e, +ncontrolled ypertension

The surgery specific cardiac ris# for non-cardiac surgical procedures can be summari8ed as follows*

HIGH reported cardiac ris# often 9:1

%mergency ma)or operations, particularly in the elderly, aortic and other ma)or vascular, peripheral vascular,

or prolonged procedures associated with large fluid shifts ;rthopedic, Prostate

LOW reported cardiac ris# often /0:1

%ndoscopic Procedure, 2uperficial Procedure, 6reast, Cataract

GENERAL RECOMMENDATIONS:

-!or elective surgery, men or women older than ?@ should receive a 0A-lead electrocardiogram.

-Patients with an abnormal %C&, significant ris# factors for C'" e.g. previous MI or stro#e, "M, T=,

ypercholesterolemia, P3"1, preoperative evidence of cardiac ischemia e.g. angina1, or functional heart

disease should undergo a more formal cardiac evaluation depending on the clinical predictors and the inherent

surgical ris# of the operation.

Patients with ma)or clinical predictors should be evaluated by a provocative cardiac e$amination stress

test1 such as stress-%C&, thallium perfusion or dobutamine echocardiography irrespective of theinherent surgical ris# of the operation they are planning to undergo and irrespective of their functional

capacity. If the results of these tests are favorable, then the patient can proceed to the >7. If the results

of these tests are unfavorable, then there must be some consideration of delaying or canceling the

surgery and proceeding with coronary angiography with subseBuent care dictated by the findings and

treatment results.

Patients with intermediate clinical predictors planning to undergo a lowris# surgical procedure may

proceed to the >7. Those with intermediate clinical predictors and moderate to e$cellent functional

capacity planning to undergo an intermediate surgical ris# procedure may also proceed to the >7.

owever, patients with intermediate clinical predictors planning to undergo a highris# surgical

procedure or those with a poor functional capacity should undergo further cardiac evaluation which can


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include echocardiography and provocative cardiac e$amination stress %C&, adenosine-thallium,

dobutamine echo1 before proceeding to the >7.

Patients with minor or no clinical predictors can proceed to the >7 without further evaluation for a low

or intermediatesurgical ris# procedure. owever, even patients with minor or no clinical predictors that

have poor functional capacity should undergo non-invasive cardiac evaluation if they are planning to

undergo a highsurgical ris# procedure.

0. Cameron 5 Current 2urgical Therapy p0ADD-9

A. %agle E' 'CC


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Initial treatent !" #$inal #%!&'

Central neurogenic hypotension C=1 is treated by ameliorating vagal tone, ensuring adeBuate ventricular

filling, and increasing vascular resistance. In spinal cord lesions rostral to T0, cardiac vagal influences dominate,

and bradycardia is prominent. ypotension / F@ mm g systolic, or mean arterial pressure / @ mm g1

should first be treated with atropine to increase 7 and prevent sudden death. +nopposed vagal innervation

alters cardiac conduction and produces so-called dispersion of repolari8ation, manifested by a lengthened 4Tc,

which can be the substrate of tachydysrhythmias. More often, vagal stimulation during intubation leads to

sudden bradyasystolic arrest from unopposed atrioventricular nodal suppression.

Hith C=, atropine should be readily available in case it is needed during rapid seBuence induction to bloc# the

vagal discharge triggered by tracheal intubation. 'deBuate intravascular volume e$pansion should be confirmed

by C3P and 6P measurements. Hith spinal cord in)ury, 6P must be normali8ed, even if urine output indicates

adeBuate renal perfusion.

InadeBuate perfusion pressure can worsen ischemia in the region of a spinal cord contusion where vascular

dysregulation e$ists. ConseBuently, pharmacologic vasoconstriction should be instituted promptly to increase

spinal cord perfusion. The agents of choice are 0 -adrenergic specific, including phenylephrine and ephedrine.

In the setting of trauma resuscitation, ephedrine is especially usefulJ one 0@-mg bolus will increase vascularresistance for ( to ? hours.

Dia(n!#i# !" li)er le#i!n in a &irr%!ti& $atient

Cirrhosis of the liver of any etiology may be followed by hepatocellular carcinoma hepatoma1. In fact,

appro$imately 9: of patients with cirrhosis develop hepatocellular carcinoma and D@: of patients with

hepatocellular carcinoma have cirrhosis.

epatocellular carcinoma is endemic to parts of 'frica and 'sian in areas where 'flato$ins of the mold

aspergillus flavus are a contaminant in the diet or e$posure to epatitis 6 and C are common. >ther conditions

associated with hepatocellular carcinoma are hemochromatosis, schistosomiasis, and environmental e$posures.

Hor# up of a cirrhotic patient with a liver lesion should include*

01 ep 6 and C ab panels

A1 5!T2 although nonspecific1

(1 'lpha !eto Protein '!P1 elevated in appro$imately G@: of cases1?1 Imaging

a. 7ight +pper 4uadrant +ltrasound

b. CT-scan

c. M7I if needed to determine resectability.

"iagnosis can be confirmed by biopsy usually image-guided techniBues e.g. CT or ultrasound1.

2abiston. 09th%dition. p.0@@.

2chwart8. Principles of 2urgery. th%dition. p.0?@F.


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CNS EFFECTS OF HYPONATREMIA

yponatremia is defined as serum sodium of less than 0(Dm%B


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A. 'drogue et al H+$!natreiaNEJM v#$2no2%&%'(%)%'(*May A9,A@@@

De#&ri.e t%e treatent !" H+$er'aleia &a*#in( a.n!ral /RS 0a)e"!r

Treatment +or h,-er.alemia i/ devided into # 0ategorie/&

0. Minimi8e cardiac effects of hyper#alemia.

A. Induce E; upta#e by cells resulting in decrease in plasma E;.

(. 7emove E; from the body.

Antagoni1e memrane e++e0t/ and /taili1e memrane -otential&0. IV Cal&i*is cardioprotective and the most rapid way to treat hyper#alemia even in normocalcemic

patients1. It can be administered as calcium gluconate or calcium carbonate. Hhen hyper#alemia is

accompanied by evidence of circulatory comprimise, calcium chloride is preferredJ it may prove

beneficial in maintaining peripheral vascular tone. %ffects on the %C& are apparent in 0 K ( minutes

and last for (@ K D@ minutesJ if no %C& changes are evident after 9 K 0@ minutes an additional bolus of

calcium should be administered.

Care should be ta#en for patients ta#ing digo$in, as hypercalcemia can potentiate the

cardioto$icity of digitalis. Calcium should be administered over (@ minutes and not be used as liberally.

"igitalis is a relative contraindication to calcium administration.

A00elerate Cell3lar ota//i3m 4-ta.e&

0. In#*linrapidly stimulates hepatocytes and myocytes to ta#e-up potassium. It wor#s within 0@ K A@

minutes. Insulin 0@ +nits should be administered with 0 'mp of "9@.

A. Beta1-a(!ni#t#administered in nebuli8er form has an immediateonset of action and is ma$imi8ed at F@

K 0A@ minutes. The primary limitation of albuterol administration is tachycardia.

(. Bi&ar.!nateadministration is less effective than insulin and beta-agonists. It is most appropriate in

those patients e$hibiting acidosis associated with hyper#alemia. It is associated with a large sodium

load, and thus should be used for patients with hyper#alemia and academia who do not have a history of

congestive heart failure. 'lso, it should not be given after calcium is administered, as it binds calcium.

Enhan0e ota///i3m !emoval&

0. P!ta##i*-0a#tin( i*retiinclude either loop or thia8ide diuretics. These are usually notadeBuate

for cases of acute hyper#alemia, especially in patients with underlying renal insufficiency. They may

suffice as treatment for patients with chronic mild hyper#alemia.

A. S!i* P!l+#t+rene Re#in 23a+e4alate5e$changes =a for E in the &I tract. It can be administered

orally or per rectum as a retention enema. Hhen given orally, coadministration of sorbitol can inhibit

constipationJ however, sorbital should notbe given in con)unction with the enema form, as this has been

associated with rectal perforation.

(. Dial+#i#is the mo/tefficient way to reduce E;. This may reBuire a period of time to initiate, during

which methods described above should be instituted.

A&*te Mana(eent !" H+$er'aleia

Condition Treatment Comment

%E& changes or serum E

meBT give

bicarbonate after calcium.

%E& changes and circulatory

comprimise

Calcium Chloride Calcium chloride has ( $ more

Calcium than calcium

gluconate.

'3 bloc# refractory to calcium

treatment

0. Insulin

A. &lucose

This combination should drop

the serum E by 0m%BT use calcium for


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A. "igitalis-specific

antibodies if necessary

hyper#alemia associated with

digitalis to$icity.

'fter acute phase or when no

%E& changes

Eaye$alate with sorbitol. >ral and < or rectal.

0. 6renner L 7ectors* The Eidney, Dthedition., Copyright A@@@. H.6. 2aunders Company

A. The IC+ 6oo#. And%dition. Paul Marino. Copyright 0FFG. Hilliams L Hil#ens.

REFEEDING SYNDROME

The refeeding syndrome is an underappreciated entity characteri8ed by acute electrolyte derangements--notably

hypophosphatemia--that occur during nutritional repletion of patients with significant suboptimal caloric inta#e.

7efeeding syndrome occurs when previously malnourished patients are fed with high carbohydrate loads. The

result is a rapid fall in phosphate, magnesium and potassium, along with an increasing %C! volume, leading to a

variety of complications.

Patients who are malnourished develop a total body depletion of phosphorousJ serum phosphorous levels are

maintained by redistribution from the intracellular space. The body uses endogenous fuel stores as its main

source of energy. !at and protein from muscle1 are metaboli8ed.

The delivery of glucose, either enterally or parenterally, as part of a feeding strategy, can cause a huge increase

in the circulating insulin level. The patient struggles to cope with converting to e$ogenous fuel sources. There israpid upta#e of glucose, potassium, phosphate and magnesium into cells. The serum concentration of theseagents falls dramatically. In addition, for an une$plained reason, the body swiftly begins to retain fluid, and the

e$tracellular space e$pands.

The dramatic reduction in serum electrolytes and fluid retention leads to a number of systemic pathologies.

There is an increase in cardiac wor#load, with increased stro#e wor#, heart rate and o$ygen consumption. This

sudden increase in demand for nutrients and o$ygen may outstrip supply. Moreover, in patients with

cardiovascular disease, the sudden increase in cardiac wor# and circulating fluid can precipitate acute heart

failure.

The sudden administration of carbohydrates e$erts a considerable strain on the respiratory system, whose

musculature may well be atrophied due to starvation. There is an increase in C>A production and >A

consumption, and a resultant increase in the respiratory Buotient 741. The conseBuence of this is an increase in

minute ventilation, which may cause dyspnea and tachypnea, and ma#e weaning difficult.

The gut atrophies with starvation and the production of digestive en8ymes diminishes. Hith return of enteral

nutrition, the gut may be initially intolerant, reBuiring time to adapt, and many patients complain of nausea and

diarrhea.

The serum phosphorous level falls precipitously with refeeding, due to a shift of phosphate from the

e$tracellular to the intracellular compartment, due to the huge demands for this ion for synthesis of

phosphorylated compounds. The result of this sudden massive reduction in phorphorous levels is a multitude of

life threatening complications involving multiple organs* respiratory failure, cardiac failure, cardiac arrhythmias,

rhabdomyolysis, sei8ures, coma, red cell and leucocyte dysfunction.

The most effective way to treat refeeding is to be aware of it. >ne should start feeds slowly and aggressively

supplement magnesium, phosphate and potassium.


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C!$li&ati!n# a##!&iate 0it% &+&l!#$!rine *#e

6orels discovery in 0FA of the immunosuppressive properties of cyclosporine, a fungal metabolite e$tracted

from Tol,-o0ladi3m in+lat3m&ams, contributed enormously to the rapid and successful growth of the field ofclinical organ transplantation, especially of livers and hearts. It represented a completely new class of clinically

important immunosuppressive agents. Many of its selective, suppressive effects on T cells appear to be related

to its selective inhibition of TC7-mediated activation events. It inhibits cyto#ine production by T cells in vitro

and impairs the development of mature C"?;

and C"G;

T cells in the thymus. Cyclosporine is a cyclic peptide00 amino acids, molecular weight 0A@A daltons1.

Cyclosporine was discovered to be immunosuppressive by its ability to suppress antibody production in mice.

>ther in vivo properties include inhibition of antibody plaBue-forming cell production, graft-versus-host

disease, s#in graft re)ection, delayed solid organ allograft re)ection, and delayed-type hypersensitivity reactions.

'bsence of myelosuppression was a ma)or advance over other immunosuppressive agents and indicated that the

mechanism of action was relatively specific for lymphocytes. >ther inflammatory cells are much less sensitive

to its inhibitory effects. Clinically, prophylactic administration of cyclosporine suppresses allograft re)ection and&3 disease.

'nalyses of the effect of cyclosporine on T lymphocytes have shown 01 inhibition of both I5-A-producing T

lymphocytes and cytoto$ic T lymphocytes, A1 inhibition of I5-A gene e$pression by activated T lymphocytes,

(1 no inhibition of activated T lymphocytes in response to e$ogenous I5-A, ?1 inhibition of resting T-

lymphocyte activation in response to alloantigen and e$ogenous lympho#ine, 91 inhibition of I5-0 production,

and D1 inhibition of mitogen concanavalin '1 activation of I5-A-producing T lymphocytes. These T-

lymphocyte responses involve both C"? ;T 1 and C"G;T-cytoto$ic


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Ele&tr!l+te a.n!ralitie# a##!&iate 0it% (a#tri& !*tlet !.#tr*&ti!n7

Differential Diagnosis of Gastric Outlet Obstruction

Complication of peptic ulcer diseaseNfreBuency is significantly decreased due to treatment of .

Pylori, anti-secretory medications A bloc#ers and proton pump inhibitors1, and endoscopic dilation

Primary carcinoma of the gastric antrum

Pancreatic or biliary tract carcinoma

Symptoms of Gastric Outlet Obstruction

"elayed vomiting more than one hour after meal ingestion1 3omiting of partially digested food

=on-bilious vomiting versus bilious vomiting which is characteristic of small bowel obstruction1

%pigastric pain


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Treatent !" $!#t-tran#$lant &+t!e(al!)iral 2CMV5 in"e&ti!n

>rgan transplant recipients are susceptible to postoperative viral infections as a result of immunosuppression.

The most important of these infections is caused by Cytomegalovirus CM31, a "=' erpes virus that is

thought to afflict nearly one-third of solid-organ transplant recipients. Patients are especially susceptible during

the most intense period of immunosuppression, usually (@-0G@ days after transplant. CM3 is a ubiBuitous agent

which infects most people during their lives, and as with other herpesviruses, becomes latent in donor andrecipient tissues e.g., lymphocytes1. Post-transplant infection can range from an asymptomatic rise in anti-

CM3 titers to severe systemic disease with fever, leu#openia, lethargy, hypotension, respiratory failure,

hepatitis, pancreatitis, &I ulceration with hemorrhage, retinitis, multi-system organ failure, and death. '

common presentation of post-transplant CM3 infection is fever, leu#openia, cough, hypo$ia, and diffuse

interstitial pulmonary infiltrates on chest $-ray. CM3 seropositive recipients can e$perience reactivation disease

with immunosuppression, and this form tends to be of mild to moderate severity. Patients at increased ris# for

severe disease are those seronegative recipients who receive organs from seropositive donors. >thers at high

ris# are those who receive anti-re)ection therapy esp. antilymphocyte t$1, elderly patients, and those who

receive cadaveric organs. "iagnosis of CM3 infection can be clinical, but confirmatory evidence consists ofCM3 inclusion bodies in body fluid or tissue specimens. Prophylactic therapy with intravenous ganciclovir, an

acyclic guanosine analog that reBuires triphosphorylation for activation prior to inhibiting CM3 "='

polymerase, has been shown to decrease the incidence of symptomatic post-transplant CM3 disease. 'yclovir,anti-CM3 immunoglobulin, or various combinations of all three agents have also been effective

prophylactically. %stablished CM3 disease is most effectively treated with intravenous ganciclovir. !oscarnet,

an inorganic pyrophosphate compound that inhibits viral "=' and 7=' polymerases, is another agent that can

be used to treat CM3, although it can cause considerable neuro- and nephroto$icity.

7eferences* &reenfield 5. S3rger,& S0ienti+i0 rin0i-le/ and ra0ti0e5 #rdEd6pp 9?(-9??.


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Arenal In#*""i&ien&+9S%!&'%tiology

- primary insufficiency due to loss of adrenal function1

- in general, autoimmune disorders are most common cause

- in IC+, hemorrhage is most common cause

- other causes*

- Haterhouse-!riedrichsen syndrome* adrenal hemorrhage, meningococcal sepsis

- tuberculous infection of adrenal glands

- metastatic disease- secondary insufficiency secondary to disease or suppression of hypothalamic-pituitary a$is1

- surgery or trauma in setting of adrenal suppression is most common cause

- 2heehan syndrome postpartum pituitary infarction1

Presentation*

- two main flavors*

- low cardiac output with high vascular resistance if patient dry1

- high cardiac output with low vascular resistance if patient tan#ed1

- fluid


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Ne*r!l!(i& "inin(# a##!&iate 0it% .rain eat%Hidespread cortical destruction

+nresponsiveness to the environment

Midbrain damage

'bsent pupillary light reaction

Pontine "amage

'bsent oculovestibular

'bsent corneal refle$es

Medullary dysfunctionComplete 'pnea

>ther signs


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Inter$retati!n !" P*l!nar+ Arterial Cat%eter 2PAC5 Tra&in(#

Hhen Rfloating a swanS through a right internal )ugular vein puncture site, the P'C tip should reach the

right atrium at appro$imately A@ to A9cm C3P tracing still1, the right ventricle at (@ to (9cm, the pulmonary

artery at ?@ to ?9cm, and wedge position at ?9 to 99 cm. Hhen using the left I or right


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TABLE ;-;


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TABLE ;-;;-- %ffects of therapeutic measures on hemodynamic measurementsA

T%era$e*ti& Mea#*re CO SVR PCWP

, IncreasesJ U, decreasesJ CO5cardiac outputJN5no effectJC85pulmonary capillary wedge pressureJ S9!5

systemic vascular resistance.

;Miller: Ane#t%e#ia6 =t%e76 C%*r&%ill Li)in(#t!ne6 In&: 1


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6 > " Z ' 2 ' H > 5 % K 6 ' 2 I C

2 C I % = C %

Changes in caloric reBuirements in sepsis

arris 6enedict eBuation estimates basal metabolic rate* but 5ong Modification of 6% multiplies 6M7 by

various stress and activity factors*

5ong Modification of 6%*

6M7 for menO DD.? ;


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Grae i# !#t i$!rtant in 0%i&% t+$e# !" ne!$la##

Most neoplasm are staged using the T=M classification* T Tumor Characteristics K i.e. "epth of InvasionJ =

=odal 2tatus1J and M Metastatic 2tatus1.

2arcomas arise from mesodermal tissues and they are uniBue for two reasons* 01 histologic grade is the best

indicator of the biologic behavior of soft tissue sarcomas and plays a much greater role than si8e and A1dissemination occurs predominantly via the hematogenous route and not the lymphatic system.

istologic grading is mostly based on a three stage classification scheme*

&rade 0I < III 5ow istologic &rade1

&rade AII < III Intermediate istologic &rade1

&rade (III < III igh istologic &rade1

Criteria used to determine grades include 01 degree of differentiation, A1 cellularity, (1 mitotic inde$, and ?1

amount of spontaneous necrosis.

's sarcomas tend to disseminate via the hematogenous route, the lung is the principle site of metastasis for

e$tremity sarcomas and the liver is the principle site of metastasis for intraabdominal sarcomas. 5ymph node

metastases are rare. Preoperative evaluation for e$tremity sarcomas includes CQ7 for low grade lesions andchest CT for high-grade lesions. CT-scan of the abdomen liver1 should be performed for intraabdominal

sarcomas to r


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CHARACTERISTICS OF CALCITONIN

Structure&uman Calcitonin is a (A amino-acid hypocalcemic peptide hormone produced by the para-follicular

a.#.a. clear or C 1 cells of the thyroid gland, which in several mammalian species serves as the physiologic

antagonist of PT parathyroid hormone1.

Secretion Metabolism&2ecretion of calcitonin is increased when the thyroid gland is perfused with solutions

containing a high CaA;concentrationJ i.e. secretion is under direct control of blood calcium. Measurement of

circulating calcitonin by immunoassay indicates that it is not secreted until the plasma calcium level reachesappro$imately F.9mgther stimulators of calcitonin secretion include [-'drenergic agonists, dopamine, and estrogen. &astrin, CCE,

glucagons, and secretin have all been reported to stimulate calcitonin secretion.

Mechanism of Action& The main action of calcitonin is that it is a calcium-lowering hormone. 2erpentine

receptors for calcitonin are found in bones and the #idneys. Calcitonin lowers the circulating calcium and

phosphate levels and its calcium lowering effect is e$erted via two distinct mechanisms*

The hypocalcemic effect of calcitonin is accounted for primarily by its direct inhibition of osteoclast-

mediated bone resorption. This action is direct, and calcitonin inhibits the activity of osteoclasts in vivo.

'lso, calcitonin has the secondary effect of stimulating renal e$cretion of calcium.

Calcitonin also e$erts additional effects through receptors present in brain, gastrointestinal tract, and

immune system. !or e$ample, it e$erts analgesic effects directly on cells in the hypothalamus and

related structures, possibly by interacting with receptors for related peptide hormones, such as calcitonin

gene-related peptide C&7P1 or amylin.

!hysiological Significance of Calcitonin&The e$act physiologic role of calcitonin is uncertain, but it seems to

be of limited physiologic significance in humans, at least in calcium homeostasis, as contrasted with a clearly

definable role in calcium metabolism in many other mammalian species. In humans, changes in calcium and

phosphate metabolism are not seen despite e$treme variations in calcitonin production. The calcitonin content of

the human thyroid is low, and after thyroidectomy, bone density and plasma CaA;levels are normal as long as the

parathyroid glands are intact.

!urthermore, no definite effects are attributable to either calcitonin deficiency as seen in totally

thyroidectomi8ed patients receiving only replacement thyro$ine1 or e$cess as seen in patients with medullary

carcinoma of the thyroid, a calcitonin-secreting tumor1.

Clinical Significance of Calcitonin&"espite the fact that calcitonin does not seem to play any physiologicallysignificant role in calcium metabolism in humans, it does have some clinical significance and uses*

Calcitonin is useful in the treatment of Pagets disease, a condition in which increased osteoclastic

activity triggers compensatory formation of disorgani8ed new bone.

Calcitonin has also been useful as an ad)unctive treatment of severe hypercalcemia seen in such diseases

as humoral hypercalcemia of malignancy M1 and local osteolytic hypercalcemia 5>1, conditions

where serum calcium levels become e$tremely elevated secondary to osteoclast mediated bone

resorption. Calcitonin also has medical significance because of its role as a tumor mar#er in sporadic and hereditary

cases of medullary carcinoma of the thyroid.

&anong, H! Re)ie0 !" Mei&al P%+#i!l!(+- 1;#tE 21


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Li#t t%e &%ara&teri#ti !" &+&l!#$!rine

Cyclosporine !"' 'pproved 0FG( =ov1*

Indications* 'rthritis, rheumatoidJ Eeratocon)unctivitis siccaJ PsoriasisJ 7e)ection, heart transplant, prophyla$isJ

7e)ection, liver transplant, prophyla$isJ 7e)ection, renal transplant, prophyla$is

Pregnancy Category C Cyclosporine was not teratogenic in appropriate test systems1

The effectiveness of cyclosporine results from specific and reversible inhibition of immunocompetentlymphocytes in the &@- and &0-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T-helper

cell is the main target, although the T-suppressor cell may also be suppressed. Cyclosporine also inhibits

lympho#ine production and release including interleu#in-A. =o effects on phagocytic function changes in

en8yme secretions, chemotactic migration of granulocytes, macrophage migration, carbon clearance in vivo1

have been detected in animals. Cyclosporine does not cause bone marrow suppression in animal models or man.

The immunosuppressive activity of cyclosporine is primarily due to parent drug. !ollowing oral administration,

absorption of cyclosporine is incomplete. The e$tent of absorption of cyclosporine is dependent on the

individual patient, the patient population, and the formulation.

Cyclosporine is e$tensively metaboli8ed by the cytochrome P-?9@ (' en8yme system in the liver, and to a lesser

degree in the gastrointestinal tract, and the #idney. %limination of cyclosporine is primarily biliary with only

D: of the dose parent drug and metabolites1 e$creted in urine. The disposition of cyclosporine from blood is

generally biphasic, with a terminal half-life of appro$imately G.? hours range 9-0G hours1. !ollowing

intravenous I31 administration, the blood clearance of cyclosporine assay* P5C1 is appro$imately 9-

mlccasionally patients have developed a syndrome of thrombocytopenia and

microangiopathic hemolytic anemia, which may result in graft failure. ypertension is a common side effect of

cyclosporine therapy which may persist. 2ignificant hyper#alemia sometimes associated with hyperchloremic

metabolic acidosis1 and hyperuricemia have been seen occasionally in individual patients. Those patients

receiving cyclosporine are at increased ris# for development of lymphomas and other malignancies, particularly

those of the s#in. %ncephalopathy has been described both in post-mar#eting reports and in the literature.

Manifestations include impaired consciousness, convulsions, visual disturbances including blindness1, loss of

motor function, movement disorders and psychiatric disturbances.

5aboratory

=ephroto$icity 7e)ection

Cy' serum trough level A@@ ng


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Li#t t%e in%i.it!r# !" $latelet a((re(ati!n

Primary hemostasis* process of platelet plug formation at sites of in)ury

2econdary hemostasis* the reactions of the plasma coagulation system which result in fibrin formation

There are ( ma)or events in primary hemostasis*

01 Platelet adhesion* the interaction of platelets with nonplatelet surface such as vascular endothelium

A1 Platelet activation and secretion* the secretion of a variety of factors such as '"P, !actor 3a,Thrombospondin, von Hillebrands !actor, etc.

(1 Platelet a((re(ati!n:the binding of activated platelets to the adherent monolayer

PLETAL 2&il!#ta!l5:mechanism not fully understood. P5%T'5 and several of its metabolites are cyclic 'MP

c'MP1 phosphodiesterase III inhibitors, inhibiting phosphodiesterase activity and suppressing c'MP

degradation with a resultant increase in c'MP in platelets and blood vessels, leading to inhibition of platelet

aggregation and vasodilation mainly in the femoral vascular bed1, respectively.

PLAVI 2&l!$i!(rel5:'n inhibitor of '"P-induced platelet aggregation acting by direct inhibition ofadenosine diphosphate '"P1 binding to its receptor and of the subseBuent '"P-mediated activation of the

glycoprotein &PIIb


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Li#t t%e e&%ani# !" le*'!&+te a%e#i!n t! en!t%elial &ell#

It is now clear that leu#ocyte adhesion and transmigration are determined largely by the binding of

complementary adhesion molecules on the leu#ocyte and endothelial surfaces and that chemical mediators--

chemoattractants and certain cyto#ines-- affect these processes by modulating the surface e$pression or avidity

of such adhesion molecules. The adhesion receptors involved belong to four molecular families--the selectins,

the immunoglobulins, the integrins, and mucin-li#e glycoproteins. The most important of these are shown in

Table (-0.2electins consist of %-selectin C"DA%, previously #nown as %5'M-01, which is confined to endotheliumJ P-

selectin C"DAP, previously called &MP0?@ or P'"&%M1, present in endothelium and plateletsJ and 5-selectin

C"DA5, previously #nown by many names, including 5'M-01, which decorates most leu#ocyte types.

2electins bind, through their lectin domain, to sialylated forms of oligosaccharides e.g., sialylated 5ewis Q1,

which themselves are covalently bound to various mucin-li#e glycoproteins &lyC'M-0, P2&5-0, %25-0, and

C"(?1.

The immunoglobulin family molecules include two endothelial adhesion molecules* IC'M-0 intercellular

adhesion molecule 01 and 3C'M-0 vascular cell adhesion molecule 01. 6oth of these molecules interact with

integrins found on leu#ocytes.Integrins are transmembrane-adhesive heterodimeric glycoproteins, made up of alpha and beta chains that also

function as receptors for the e$tracellular matri$. The principal integrin receptors for IC'M-0 are the beta

integrins 5!'-0 and M'C-0 C"00aT%5I'5CZT% '"%2I>= M>5%C+5%2

En!t%elial M!le&*le Le*'!&+te Re&e$t!r Ma!r R!le

P-selectin 2ialyl-5ewis Q P2&5-0 7olling neutrophils,

monocytes, lymphocytes1

%-selectin 2ialyl-5ewis Q %25-0, P2&5-

0

7olling, adhesion to activated

endothelium neutrophils,

monocytes, T cells1

IC'M-0 C"00n stimulation by

mediators such as histamine, thrombin, and platelet-activating factor P'!1, P-selectin is rapidly redistributed to

the cell surface, where it can bind the leu#ocytes. 09This process occurs within minutes in flowing blood and

serves to deliver preformed adhesion molecules in short order to the surface. 2tudies suggest that this process

may be particularly important in early leu#ocyte rollingon endothelium.
http://home.mdconsult.com/das/book/body/227041660/891/#T003001http://home.mdconsult.com/das/book/body/227041660/891/#T003001http://home.mdconsult.com/das/book/body/227041660/891/28.html#R003010015http://home.mdconsult.com/das/book/body/227041660/891/28.html#R003010015http://home.mdconsult.com/das/book/body/227041660/891/28.html#R003010015http://home.mdconsult.com/das/book/body/227041660/891/#T003001http://home.mdconsult.com/das/book/body/227041660/891/28.html#R003010015


21/32

Ind30tion o+ adhe/ion mole03le/ on endotheli3m* 2ome inflammatory mediators, particularly cyto#ines I5-0

and T=!1, induce the synthesis and surface e$pression of endothelial adhesion molecules. This process reBuires

new protein synthesis and begins usually after a delay of some 0 or A hours. %-selectin, for e$ample, which is

not present on normal endothelium, is induced by I5-0 and T=! and mediates the adhesion of neutrophils,

monocytes, and certain lymphocytes by binding to its receptors. The same cyto#ines also increase the e$pression

of IC'M-0 and 3C'M-0, which are present at low levels in normal endothelium.

In0rea/ed avidit, o+ inding* This mechanism is most relevant to the binding of integrins. !or e$ample, 5!'-0 is

present on leu#ocytes--neutrophils, monocytes, and lymphocytes--but does not adhere to its ligand IC'M-0 on

endothelium. To become firmly adherent, the neutrophils need to be activated such that 5!'-0 is converted from

a state of low-affinity binding to high-affinity binding toward IC'M-0, owing to a conformational change in theintegrin molecule. The principal agents causing such leu#ocyte activation are chemotactic agents including thechemo#ines, discussed later1 made by endothelium or other cells emanating from the site of in)ury. "uring

inflammation, the increased affinity of 5!'-0 on the activated leu#ocyte, coupled with the increased IC'M-0

e$pression on endothelium induced by cyto#ines, sets the stage for strong 5!'-0


22/32

Li#t t%e n!ne$!lariin( ane#t%eti& a(ent 0%!#e eta.!li# i# *na""e&te .+

%e$ati& !r renal i#ea#e7

"ackground #nformation on Metabolism of Anesthetic Agents

2ystemic clearance of anesthetic drugs is usually via hepatic metabolism. The liver metaboli8es drugs

through o$idation and reduction via the cytochrome P?9@ system1, hydrolysis, and con)ugation transformation

of hydrophobic molecules into water-soluble molecules through addition of polar groups renders the

metabolite easier to e$crete via the #idneys1.

7enal clearance of anesthetic agents occurs via filtration at the level of the glomerulus with directtransport into the renal tubules. 6oth renal blood flow and creatinine clearance are inversely correlated with

age, so anesthetic agents must be dosed appropriately in elderly patients despite presence of normal creatinine

level. It is also important to note that inhalational anesthetics also decrease renal blood flow and therefore delay

renal e$cretion. !or e$ample, pancuronium is G9: eliminated via renal clearance.

Tissue clearance i.e. blood, muscle and lungs1 is another important mechanism of metabolism.

7emifentanil is cleared by nonspecific esterases located primarily in muscle and intestines.

2uccinylcholine depolari8ing muscle rela$ant1and mivacurium are all metaboli8ed by plasma

butyrylcholinesterases also #nown as pseudocholinesterases1.

Cisatracurium an isomer of atracurium1 is metaboli8ed completely by ofmann degradation a

spontaneous process in plasma at normal p and temperatureJ this process does =>T depend on

circulating esterases1J therefore cisatracurium metabolism is =>T affected by disease or genetic

variants of cholinesterase metabolism.

Comparison of Metabolism of Commonly $sed

%euromuscular "locking Drugs

DRG DRATION METABOLISM 25

2uccinylcholine

depolari8ing muscle

rela$ant1

+ltrashort Plasma cholinesterase

FG-FF:1

YYsynthesi8ed by liver

Mivacurium 2hort Plasma cholinesteraseF9-FF:1

YYsynthesi8ed by liver

'tracurium Intermediate ofmann elimination

and nonspecific esterhydrolysis D@-F@:1

3ecuronium Intermediate 5iver (@-?@:1

Pancuronium 5ong 5iver 0@-A@:1

Conclusions

'T7'C+7I+M metabolism is =>T affected by hepatic or renal dysfunction because it undergoes

spontaneous chemical degradation ofmann elimination1 and ester hydrolysis.

Re"eren&e#:

0. Miller. 'nesthesia. 9thedition, A@@@.

A. Eat8ung, 6& and Trevor '. %$amination and 6oard 7eview* Pharmacology, 9thedition, 0FFG


23/32

C%ara&terie an i*n!l!(i& &%iera

Chimerism is the e$istence in an individual of two or more cell lines, each of which has a different genetic

origin.

The most robust form of donor-specific tolerance is that associated with hematopoietic stem cell chimerism. T5I

plus donor bone marrow infusion of adult mice can cause tolerance induction. The first association between

chimerism and tolerance was observed in the 0F?@s when "r. >wen reported that !reemartin cattle were red

blood cell chimeras. The common placenta that they shared allowed e$change with hematopoietic stem cells.'lthough genetically disparate, these cattle accepted s#in grafts from the other twin. 6illingham and colleagues

demonstrated that this active transfer of tolerance to donor antigens was due to bone marrow hematopoietic stem

cells from the donor. 2ubseBuently, chimerism was demonstrated to be associated with tolerance in mice, pigs,

rats, primates, and humans. +ntil recently, the ris# of conventional bone marrow transplantation was too great to

tolerate in clinical attempts to induce tolerance. owever, a number of advances have been made in the clinical

application of hematopoietic stem cell chimerism to induce tolerance approach as clinical reality. 7econstitution

of mice with mi$tures of T-cell-depleted syngeneic and allogeneic bone marrow pioneered by Ildstad and

2achs1 produces mi$ed hematopoietic bone marrow chimerism and donor-specific tolerance to s#in grafts. Most

importantly, 0: donor chimerism is sufficient to provide robust deletional tolerance, opening the door to partialconditioning strategies to establish mi$ed chimerism. =onlethal preparative regimens, using anti-T-cell

monoclonal antibodies, cyclophosphamide, '5&, and tacrolimus, in addition to sublethal total body irradiation

plus donor bone marrow, have more recently been shown to induce tolerance in mice. 7ecent improvements in

marrow processing and graft engineering to decrease problems with &3 disease have increased interest in this

approach.


24/32

I*n(l!.*lin A

- ma)or role* mucosal immunity.

- humans produce more Ig' than any other class A@: of total serum immunoglobulins1

- Ig' found in serum and e$ternal secretions such as saliva, tracheobronchial secretions, colostrum, mil#, and

genitourinary secretions

- there are two Ig' subclasses and these differ only in AA of (D9 amino acids- Ig' e$ists both in monomeric G@: of total1 and polymeric forms AA1nor AA1nwhere n is AK9

- monomeric Ig' is synthesi8ed by plasma cells located in the interstitial space of e$ocrine glands

- the ma)or polymeric form is the Ig' dimer monomers combine with the chain, which is also synthesi8ed

by Ig' plasma cells, to form Ig'1A- dimers1

- Ig's are too large to cross tight )unctions, they are transported across the epithelium by an

active transport system

Se&ret!r+ I(A

- appear to be locally derived and not from serum, consists of four components*

0


25/32

T%e e""e&t !" 4ant%ine !4ia#e in i#&%eia-re$er"*#i!n in*r+

Cells lac#ing adeBuate vascular supply of nutrient o$ygen are ischemic and will progress to cellular death unless

blood flow is efficiently restored to these tissues. 7eperfusion of viable ischemic tissue, however, can actually

amplify cellular in)ury through a comple$ cascade of cellular and tissue changes. 7eperfusion in)ury is often far

more severe than the damage incurred during the period of ischemia, and it is characteri8ed by cellular edema,

intracellular calcium overload with activation of ccalcium-dependent autolytic en8ymes, disruption of lipid-

laden membranes, and alteration of mitochondrial structure and function. The first organ discovered to e$hibitreperfusion dysfunction was the heart, which e$periences arrhythmias and impaired ventricular contractile

function Rmyocardial stunningS1 with reperfusion after acute coronary events. 7eperfusion in)ury centers

around the re-introduction of o$ygen to ischemic cells, and highly reactive, unstable o$ygen metabolites

supero$ide anion >A1, hydrogen pero$ide A>A1, hydro$yl anion >1 are its ma)or mediators. These to$ic

o$ygen-derived metabolites subseBuently produce pero$idation of lipid membranes, protein degradation, nucleic

acid damage, hemoprotein


26/32

-s#in rash less freBuent, may be cause by histamine release1

-apnea, respiratory insufficiency

Re"eren&e#:

01 "rug Information for the ealth Care Professional. 0theditionJ p. A0A0, A0(0-A.

A1 Clinical Pharmacology Made 7idiculously 2imple, >lsen 0FF, p GA.

Mali(nant H+$ert%eria

Malignant hyperthermia is characteri8ed by paro$ysmal fulminant hypermetabolic crisis in s#eletal and heart

muscle. Massive heat generation overwhelms bodys ability to dissipate heat. 'ny anesthetic agent and musclerela$ants may trigger this condition. alothane and succinylcholine are the most common offenders. >f note,

malignant hyperthermia is a condition that can occur at any time perioperatively.

Malignant hyperthermia is genetically predisposed syndrome transmitted in autosomal dominant fashion with

reduced penetrance and variable e$pressivity. This condition results from sudden increase in intracellularcalcium in s#eletal muscle and possibly also cardiac muscle1 triggered by causative agents.

%$cessive myoplasmic calcium activates 'TPase and phosphorylase and cause muscle contracture. This results

in massive increase in o$ygen consumption, carbon dio$ide production and heat generation. Calcium within

mitochondria at to$ic concentration cause uncoupling of o$idative phosphorylation and lead to increasedanaerobic metabolism. This results in accelerated generation of lactic acid, carbon dio$ide and heat. Membrane

permeability increases when 'TP level eventually falls, leading to lea#age of potassium, magnesium andphosphates from myoplasm and flow of calcium into myoplasm. 2evere respiratory and metabolic acidosis

develops and dysrhythmias and cardiac arrest may ensue. Muscle damage manifest as rhadomyolysis,myoglobinuria and hyper#alemia.

Patients with malignant hyperthermia present with une$plained tachycardia FD:1 and tachypnea G9:1. They

may also present with profuse sweating, flushed s#in, mottling and cyanosis, arrythmias, hyper or hypotension.

Mar#ed fasciculations or sustained rigidity may also be present. 7apid rise in body temperature 0 degreecelcius per 9 minutes1 is classic finding, but this is a relatively late sign. "iagnosis of malignant hyperthermia is

made based on clinical findings* most commonly, clinical triad of history of e$posure to causative agent, muscle

rigidity and signs of hypermetabolic activity with hyperthermia. A@: of patients may not have any of these

signs. They may present instead with pulmonary edema, myoglobinuria, "IC or cardiovascular collapse.

'6& analysis classically reveals respiratory and metabolic acidosis in association with hypercapnia. 2udden,

mar#ed increase in end-tidal C>A is best early clue to the diagnosis. ypo$emia, hyper#alemia,

hypermagnesemia, myoglobinemia, hemoglobinemia, increase in lactate, pyruvate and creatine #inase may also

be observed.

%arly diagnosis, prompt dantrolene treatment and supportive and cooling measures are #ey to management of

patients with malignant hyperthermia. Clinician must promptly discontinue use of causative agent, intubate and

hyperventilate the patient with 0@@: o$ygen, cool down the patient with iv refrigerated saline, iced saline

lavage of &I tract and surface cooling with ice


27/32

De#&ri.e t%e &!$en#ati!n !" i#!)!lei& aneia

Isovolemic anemia is also #nown as acute hemodilution. This is sometimes used as a method to reduce

autologous p76C transfusion in the perioperative period. The patient will undergo the removal of blood and

replacement with cell-free fluid colloid or crystalloid1. The intent is that operative blood loss will be dilute and

the patient can be transfused autogenous blood instead of autologous blood, ideally after operative blood loss

has occurred. There are conflicting reports of the physiologic response of isovolemic anemia. Please see the

abstract below.

Tran#"*#i!n

3olume ?( Issue A Page A(9 - !ebruary A@@(

doi*[email protected]@?D


28/32

Deterine t%e #i(ni"i&an&e !" ran!ie trial#

7andomi8ation is a process in which patients are assigned to different arms of a trial without bias.

7andomi8ation allows for removal of selection biasNtreatment groups will be similar with respect to all

variables e.g. 'ge, se$, race, comorbidities, etc.1 e$cept for the one being tested e.g. drug vs. placebo1. This

effect of eliminating confounding variables increases with sample si8e. Hithout randomi8ation one could choose

to put those more li#ely to respond to treatment in the intervention group, and those less li#ely in the placebo

group. "ecisions regarding who will receive treatment are not made by a person in randomi8ed studies. 6y

removing all other variables one can be certain that differences between groups are due to treatment.

In studies that are not randomi8ed, for e$ample case control studies, great effort is reBuired to ensure that

comparisons are made between individuals that are as similar as possible. It is however, impossible to eliminate

all variation. These efforts are not necessary with randomi8ed trials. 'll that is reBuired is a system for

randomi8ation and a large enough group. 7andomi8ation does not eliminate all forms of bias. 6linding is

reBuired to eliminate observer bias and measurement bias.

7andomi8ed trials allow for causality to be determined. Hhile other study types may be able to determine that a

relationship e$ists, only randomi8ed controlled trials allow for determining the nature of that relationship.

2ources

!letcher 7, !letcher 2H, Hagner %. Clini0al E-idemiolog, The E//ential/. (rded. Hilliams and Hil#ins,

0FFD, p0?9.

De#&ri.e t%e in&rea#e &!lla(en &!ntent *rin( 0!*n %ealin(

There are ( phases to wound healing* In+lammator, ha/e5 roli+erative ha/e5 and Mat3rational ha/e6

In+lammator, ha/e # da,/?& =eutrophils arrive on the scene and attain large numbers by A? hours after

wound healing begins. =e$t, macrophages have the dominantrole in the inflammatory phaseJ they are recruited

and secrete many growth factors and cyto#ines which induce fibroblast proliferation source of collagen1,

endothelial cell proliferation, and e$tracellular matri$ production.

roli+erative ha/e # wee./?& The formation of a fibrin-fibronectin matri$ initiates the proliferative

phaseJ this becomes saturated with fibroblasts appro$imately ( days after the insult. !ibroblasts are the

dominantcell involved in the proliferative phase. Collagen accumulation in the wound reaches a ma$imum by

the end of this phase ( wee#s1. Type III collagen is predominant. The amount of collagen synthesi8ed dictates

the initialwound strength. 't appro$imately ( K ? wee#s, collagen synthesis declines and remodeling ta#es

place. Collagen crosslin#ing is dependent on hydro$ylation of lysine and proline. >$ygen, 3itamin C, and Iron

enhance hydro$ylation. Corticosteroids inhibit hydro$ylationJ their effect can be counterbalanced by 3itamin '.owever, steroid inhibition on wound contractionNa process dependent on myofibroblastsNis not reversedwith 3it. '1.

Mat3rational @ !emodeling ha/e& Type I collagen replaces Type III collagenJ the usual ?*0 ratio as in a normal

adult is restored. Ten/ilestrength is increased as random collagen fibrils are replaced with organi8ed fibrils with

more intermolecular bonds. Collagen is in a state of eBuilibrium* collagen degredation by collagenase and

other MMPs1 is balanced by new production of collagen. 't eBuilibrium, collagen fibrils align themselves in a

longitudinal manner as dictated by the stress on the wound. 2cars increase in ten/ile strength for appro$imately

D months after the initial insult and reach appro$imately @: of normal s#in tensile strength. +ltimate wound

strength is determined by the degree of collagen organi8ation and crosslin#ing.


29/32

Li#t t%e e&%ani# !" #'in ne&r!#i# *rin( &!*ain aini#trati!n

Coumadin induced s#in necrosis, associated with a diffuse thrombosis in small vessels usually involves full

thic#ness sloughing over fatty areas such as buttoc#s, abdomen, and breasts but can occur anywhere.

Coumadin bloc#s the essential vitamin E-dependent carbo$ylation of coagulation factors II, 3II, IQ, and Q

resulting in the formation of biologically inactive proteins and a decrease in the coagulation activity of these

factors in plasma. alf-life of 3it E dependent factors ranges from D-D@hours therefore the full effect of the

therapy is delayed for A-( days. 'lso, full restoration of normal coagulation after stopping coumadin reBuires atleast (-9 days.

The tissue necrosis is a##!&iate 0it% a $r!tein C e"i&ien&+. Pr!tein C i# n!rall+ an anti&!a(*lantby

inactivating !actor 3a and !actor 3IIIc. Pr!tein C an S are al#! Vitain 3 e$enent "a&t!r#7 Therefore,

the relatively rapid decay in already low protein C levels at a time when levels of coagulation factors are still

normal, results in a net procoagulant state. Treatment includes stopping Coumadin and starting eparin.

I=7* International =ormali8ed 7atio corrects for the differences of the various thromboplastins used in the

prothrombin assays.

0. 2urgery* 6asic 2cience and Clinical %vidence. =orton et alJ A@@0. p0A(-09@

A. &reenfield, And%dition. pF-FG.

C%ara&terie raiati!n in*r+ t! #!"t ti##*e#

7adiotherapy wor#s by releasing free radicals and pero$idases into cells. These intermediaries cause destruction

of rapidly dividing cells, such as neoplastic cells, by fracturing "=' molecules. These ioni8ing

rays also cause a nonspecific in)ury and therefore can damage surrounding normal tissue. %ndothelial cells in

blood vessels are particularly susceptible to in)ury, leading to arteritis and ischemic fibrosis. ence, poorly

vasculari8ed tissues such as bone and cartilage are very susceptible to radiation in)ury. ' wide spectrum ofin)uries has been reported, ranging from erythema of the s#in radiodermatitis1 to soft tissue ulceration with

osteoradionecrosis and chondroradionecrosis. 'lthough the severity of the in)uries is dose-dependent, standard

doses of ?9@@ to 9@@@ c&y given over ? to D wee#s appear to limit complications.

T'65% 0FG-0 -- T>5%7'=C% >! =>7M'5 TI22+%2 T> I77'"I'TI>=

TI22+% T>QIC %!!%CT 5IMITI=& ">2% &y1 Y6one marrow 'plasia A.9

5ung Pneumonitis, fibrosis 09.@

Eidney =ephrosclerosis A@.@

5iver epatitis A9.@2pinal cord Infarction, necrosis ?9.@

Intestine +lceration, fibrosis ?9.@eart Pericarditis, myocarditis ?9.@

6rain Infarction, necrosis 9@.@

2#in "ermatitis, sclerosis 99.@

Y7adiation in A.@-&y fractions to the whole organ for 9 days wee#ly

produces a 9: incidence of the listed to$icities at the limiting doses

listed.

2ource* Townsend* 2abiston Te$tboo# of 2urgery, 0Dth ed., Copyright ]

&oldman* Cecil Te$tboo# of Medicine, A0st ed., Copyright ] A@@@

H. 6. 2aunders Company pgs0@D0-0@DA


30/32

Li#t t%e #tati#ti&al e"initi!n !" Meian

The median is the number that divides the total distribution of ordered observations in half. If the number of

observations n1 is even, then the median is the mean of the n


31/32

Li#t t%e .i!l!(i& e""e&t# !" ta!4i"en'ntiestrogen compound

6inds directly to the estrogen receptor and functions as a wea#

agonist


32/32

2chwart8, th%dition

Fl*!r!8*in!l!ne anti.i!ti!luoroBuinolones are bactericidal antibiotic which acts intracellularly by inhibiting topoisomerase II "='

gyrase1 and

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