06 October 2009

Hyponatremia



Hyponatremia
By :
James Yost, MD, MS, MBA
Emory Family Medicine

Hyponatremia
* Definition
* Epidemiology
* Physiology
* Pathophysiology
* Types
* Clinical Manifestations
* Diagnosis
* Treatment

Hyponatremia
* Definition:
o Commonly defined as a serum sodium concentration 135 meq/L
o Hyponatremia represents a relative excess of water in relation to sodium.
* Epidemiology:
o Frequency
+ Hyponatremia is the most common electrolyte disorder
+ incidence of approximately 1%
+ prevalence of approximately 2.5%
+ surgical ward, approximately 4.4%
+ 30% of patients treated in the intensive care unit
o Mortality/Morbidity
+ Acute hyponatremia (developing over 48 h or less) are subject to more severe degrees of cerebral edema
# sodium level is less than 105 mEq/L, the mortality is over 50%
+ Chronic hyponatremia (developing over more than 48 h) experience milder degrees of cerebral edema
# Brainstem herniation has not been observed in patients with chronic hyponatremia
o Age
+ Infants
# fed tap water in an effort to treat symptoms of gastroenteritis
# Infants fed dilute formula in attempt to ration
+ Elderly patients with diminished sense of thirst, especially when physical infirmity limits independent access to food and drink
* Physiology
o Serum sodium concentration regulation:
+ stimulation of thirst
+ secretion of ADH
+ feedback mechanisms of the renin-angiotensin-aldosterone system
+ renal handling of filtered sodium
o Stimulation of thirst
+ Osmolality increases
# Main driving force
# Only requires an increase of 2% - 3%
+ Blood volume or pressure is reduced
# Requires a decrease of 10% - 15%
+ Thirst center is located in the anteriolateral center of the hypothalamus
# Respond to NaCL and angiotensin II
o Secretion of ADH
+ Synthesized by the neuroendocrine cells in the supraoptic and paraventricular nuclei of the hypothalamus
+ Triggeres:
# Osmolality of body fluids
* A change of about 1%
# Volume and pressure of the vascular system
+ Increases the permeability of the collecting duct to water and urea
o renin-angiotensin-aldosterone
+ Renin
# Stemuli are perfusion pressure, sympathetic activity, and NaCl delivery to the macula densa
# Increase in NaCl delivery to the macula decreases the GFR by decrease in the renin secretion
+ Aldosterone
# Reduces NaCl excretion by stimulating it’s resorption
* Ascending loop of Henle
* Distal tubule
* Collecting duct
o extracellular-fluid and intracellular-fluid compartments make up 40 percent and 60 percent of total body water
o renal handling of water is sufficient to excrete as much as 15-20 L of free water per day
o sodium is the predominant osmole in the extracellular fluid (ECF) compartment and serum

* Pathophysiology
o hyponatremia can only occur when some condition impairs normal free water excretion
o acute drop in the serum osmolality:
+ neuronal cell swelling occurs due to the water shift from the extracellular space to the intracellular space
+ Swelling of the brain cells elicits 2 responses for osmoregulation, as follows:
# It inhibits ADH secretion and hypothalamic thirst center
# immediate cellular adaptation
* Types
o Hypovolemic hyponatremia
o Euvolemic hyponatremia
o Hypervolemic hyponatremia
o Redistributive hyponatremia
o Pseudohyponatremia
Hypovolemic hyponatremia
* develops as sodium and free water are lost and/or replaced by inappropriately hypotonic fluids
* Sodium can be lost through renal or non-renal routes
* Nonrenal loss
o GI losses
+ Vomiting, Diarrhea, fistulas, pancreatitis
o Excessive sweating
o Third spacing of fluids
+ ascites, peritonitis, pancreatitis, and burns
o Cerebral salt-wasting syndrome
+ traumatic brain injury, aneurysmal subarachnoid hemorrhage, and intracranial surgery
+ Must distinguish from SIADH
* Renal Loss
o Acute or chronic renal insufficiency
o Diuretics

Euvolemic hyponatremia
* Normal sodium stores and a total body excess of free water
o Psychogenic polydipsia, often in psychiatric patients
o Administration of hypotonic intravenous or irrigation fluids in the immediate postoperative period
o administration of hypotonic maintenance intravenous fluids
o Infants who may have been given inappropriate amounts of free water
o bowel preparation before colonoscopy or colorectal surgery
* SIADH
o downward resetting of the osmostat
o Pulmonary Disease
+ Small cell, pneumonia, TB, sarcoidosis
o Cerebral Diseases
+ CVA, Temporal arteritis, meningitis, encephalitis
o Medications
+ SSRI, Antipsychotics, Opiates, Depakote, Tegratol

* Total body sodium increases, and TBW increases to a greater extent.
* Can be renal or non-renal
o acute or chronic renal failure
+ dysfunctional kidneys are unable to excrete the ingested sodium load
o cirrhosis, congestive heart failure, or nephrotic syndrome

Redistributive hyponatremia
o Water shifts from the intracellular to the extracellular compartment, with a resultant dilution of sodium. The TBW and total body sodium are unchanged.
+ This condition occurs with hyperglycemia
+ Administration of mannitol
* Pseudohyponatremia
o The aqueous phase is diluted by excessive proteins or lipids. The TBW and total body sodium are unchanged.
+ hypertriglyceridemia
+ multiple myeloma
* Clinical Manifestations
o most patients with a serum sodium concentration exceeding 125 mEq/L are asymptomatic
o Patients with acutely developing hyponatremia are typically symptomatic at a level of approximately 120 mEq/L
o Most abnormal findings on physical examination are characteristically neurologic in origin
o patients may exhibit signs of hypovolemia or hypervolemia
* Diagnosis
o CT head, EKG, CXR if symptomatic
o Repeat Na level
o Correct for hyperglycemia
o Laboratory tests provide important initial information in the differential diagnosis of hyponatremia
+ Plasma osmolality
+ Urine osmolality
+ Urine sodium concentration
+ Uric acid level
+ FeNa
o Plasma osmolality
+ normally ranges from 275 to 290 mosmol/kg
+ If >290 mosmol/kg :
# Hyperglycemia or administration of mannitol
+ If 275 – 290 mosmol/kg :
# hyperlipidemia or hyperproteinemia
+ If <275 mosmol/kg :
# Eval volume status
o Plasma osmolality < 275 mosmol/kg
+ Increased volume:
# CHF, cirrhosis, nephrotic syndrome
+ Euvolemic
# SIADH, hypothyroidism, psychogenic polydipsia, beer potomania, postoperative states
+ Decreased volume
# GI loss, skin, 3rd spacing, diuretics
o Urine osmolality
+ Normal value is > 100 mosmol/kg
+ Normal to high:
# Hyperlipidemia, hyperproteinemia, hyperglycemia, SIADH
+ < 100 mosmol/kg
# hypoosmolar hyponatremia
* Excessive sweating
* Burns
* Vomiting
* Diarrhea
* Urinary loss
o Urine Sodium
+ >20 mEq/L
# SIADH, diuretics
+ <20 mEq/L
# cirrhosis, nephrosis, congestive heart failure, GI loss, skin, 3rd spacing, psychogenic polydipsya
o Uric Acid Level
+ < 4 mg/dl consider SIADH
o FeNa
+ Help to determine pre-renal from renal causes
* Treatment
o four issues must be addressed
+ Asyptomatic vs. symptomatic
+ acute (within 48 hours)
+ chronic (>48 hours)
+ Volume status
o 1st step is to calculate the total body water
+ total body water (TBW) = 0.6 × body weight
o next decide what our desired correction rate should be
o Symptomatic
+ immediate increase in serum Na level by 8 to 10 meq/L in 4 to 6 hours with hypertonic saline is recommended
o acute hyponatremia
+ more rapid correction may be possible
# 8 to 10 meq/L in 4 to 8 hours
o chronic hyponatremia
+ slower rates of correction
# 12 meq/L in 24 hours

* Symptomatic or Acute
o Treatment Cont. - Here comes the Math!!!
+ estimate SNa change on the basis of the amount of Na in the infusate
+ ΔSNa = {[Na + K]inf − SNa} ÷ (TBW + 1)
# ΔSNa is a change in SNa
# [Na + K]inf is infusate Na and K concentration in 1 liter of solution
o OH MY GOD, what did he just say!!!!!!!!!!!!!!!!!!

* IV Fluids
o One liter of Lactated Ringer's Solution contains:
+ 130 mEq of sodium ion = 130 mmol/L
+ 109 mEq of chloride ion = 109 mmol/L
+ 28 mEq of lactate = 28 mmol/L
+ 4 mEq of potassium ion = 4 mmol/L
+ 3 mEq of calcium ion = 1.5 mmol/L
o One liter of Normal Saline contains:
+ 154 mEq/L of Na+ and Cl−
o One liter of 3% saline contains:
+ 514 mEq/L of Na+ and Cl−

* Example:
o a 60 kg women with a plasma sodium of 110 meq/L
o Formula:
+ ΔSNa = {[Na + K]inf − SNa} ÷ (TBW + 1)
o What is the TBW?
o How high will 1 liter of normal saline raise the plasma sodium?
* Answer:
o TBW is 30 L
o Serum sodium will increase by approximately 1.4 meq/L for a total SNa of 111.4 meq/L

* Example:
o a 90 kg man with a plasma sodium of 110 meq/L
o Formula:
+ ΔSNa = {[Na + K]inf − SNa} ÷ (TBW + 1)
o What is the TBW?
o How high will 1 liter of 3% saline raise the plasma sodium?
* Answer:
o TBW is 54 L
o Serum sodium will increase by approximately 7.3 meq/L for a total SNa of 117.3 meq/L

* Asymptomatic or Chronic
o SIADH
+ response to isotonic saline is different in the SIADH
+ In hypovolemia both the sodium and water are retained
+ sodium handling is intact in SIADH
+ administered sodium will be excreted in the urine, while some of the water may be retained
# possible worsening the hyponatremia

Hyponatremia

* Asypmtomatic or Chronic
o SIADH
+ Water restriction
# 0.5-1 liter/day
+ Salt tablets
+ Demeclocycline
# Inhibits the effects of ADH
# Onset of action may require up to one week

* Example:
+ 85 y/o male with weakness and head ache
+ SNa is 118 mEq/L
+ Plasma osmolality is 254 mosmol/kg
+ Urine osmolality is 130 mosmol/kg
+ Urine sodium >20 mEq/L
+ Uric acid is 3mg/dl
o What type of hyponatremia does this patient have?
o What additional labs/studies would you want?

* Example Cont.:
o Noncontrast CT Head:
* Tx
o Call Neurology and neurosurgery
o Free water restriction

* Example:
o 63 y/o female at 75 Kg with N/V/D for 4 days
o SNa is 108 mEq/L
o She has had one seizure in the ambulance
# Plasma osmolality is 251 mosmol/kg
# Urine osmolality is 47 mosmol/kg
# Uric acid is 6mg/dl
o What type of hyponatremia does this patient have?
o What additional labs/studies would you want?
* How will you Tx her?
o Calculate the total body water
+ 0.5 x weight = 37.5 L
o What rate of correction do you want?
+ 8 to 10 mEq/L in 6 to 8 hours
o What fluid will you use?
+ 3% Saline
o How will you calculate the amount of sodium to give her?
+ ΔSNa = {[Na + K]inf − SNa} ÷ (TBW + 1)
o How will her sodium increase after 1 liter of 3% saline?
+ By 10.8 mEq/L to 118.8 mEq/L

* What other medication will she need?
o Lasix and a foley
* Her sodium increases to 118.8 mEq/L over the next 8-10 hours. How will you continue to correct her hyponatremia?
o ΔSNa = {[Na + K]inf − SNa} ÷ (TBW + 1)
o ΔSNa = 154mEq/L – 118.8mEq/L ÷ 38.5L = 0.9 mEq/L
* So 2 liters of normal saline over the next 14 hours

Hyponatremia.ppt

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Fluid, Electrolyte & Acid-Base Balance



Fluid, Electrolyte & Acid-Base Balance

Body Fluids
* Your body is 66% water
* Not evenly distributed – separated into compartments
* Able to move back and forth thru the cell membranes to maintain an equilibrium

Fluid Compartments
* Intracellular fluid – fluid inside cells [ICF]
* Extracellular fluid – fluid outside cells and all other body fluids --- ž is plasma [intravascular fluid], remaining ū is interstitial fluid. Small amount is localized as CSF, serous fluid, synovial fluid, humors of eye & endo/perilymph of ears

Edema
* Condition in which fluid accumulates in the interstitial compartment. Sometimes due to blockage of lymphatic vessels or by a lack of plasma proteins or sodium retention

Fluid Balance
* Amount in = amount out
* Average daily intake is 2500 ml [ fluids, food and metabolic water]
* Average daily output is 2500 ml [ urine, feces, perspiration, insensible perspiration]
* What can throw off these numbers?

Electrolyte Balance
* Def: - concentration of individual electrolytes in the body fluid compartments is normal and remains relatively constant.
* Electrolytes are dissolved in body fluids
* Sodium predominant extracellular cation, and chloride is predominant extracellular anion. Bicarbonate also in extracellular spaces
* Potassium is the predominant intracellular cation and phosphates are the predominant intracellular anion
* Cations are actively reabsorbed, anions passively follow by electrochemical attraction
* Aldosterone works at kidney tubules to regulate sodium & potassium levels
* Because of sodium and potassium influence, water will move between compartments
* Example: if high [sodium], then water will move from intracellular space to extracellular space due to osmotic pressure

Balance of other Electrolytes
* Calcium – hypercalcemia / hypocalcemia
* Magnesium – hypermagnesemia/ hypomagnesemia
* Phosphate – hyperphosphatemia/ hypophosphatemia
* Chloride – hyperchloremia/ hypochloremia
Acid - Base Balance
* Blood - normal pH of 7.2 – 7.45
* < 7.2 = acidosis > 7.45 = alkalosis
* 3 buffer systems to maintain normal blood pH
* Buffers
* Removal of CO2 by lungs
* Removal of H+ ions by kidneys
Buffers
* Protein Buffer Systems
* Amino Acid buffers
* Hemoglobin buffers
* Plasma Protein buffers
* Phosphate Buffer Systems
* Carbonic Acid – Bicarbonate Buffer System
Maintenance of Acid-Base Balance
* Respiratory System: removal of CO2 by lungs – stabilizes the ECF, has direct effect on Carbonic Acid – Bicarbonate Buffer System

* Urinary System: removal of H+ ions by kidneys

Disturbances to Acid-Base Balance
* Respiratory Acidosis
* Respiratory Alkalosis
* Metabolic Acidosis [ lactic acidosis, ketoacidosis]
* Metabolic Alkalosis

Fluid, Electrolyte & Acid-Base Balance.ppt

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Evaluation of Laboratory Data in Nutrition Assessment



Evaluation of Laboratory Data in Nutrition Assessment
By:Cinda S. Chima, MS, RD

Laboratory Data and the NCP
* Used in nutrition assessment (a clinical sign supporting nutrition diagnosis)
* Used in Monitoring and Evaluation of the patient response to nutritional intervention

Specimen Types
* Serum: the fluid from blood after blood cells and clot removed
* Plasma: fluid from blood centrifuged with anticoagulants
* Erythrocytes: red blood cells
* Leukocytes: white blood cells
* Other tissues: scrapings and biopsy samples
* Urine: random samples or timed collections
* Feces: random samples or timed collections
* Less common: saliva, nails, hair, sweat

Interpretation of Routine Medical Laboratory Tests
* Clinical Chemistry Panels
o Basic metabolic panel
o Comprehensive metabolic panel
* Complete blood count
* Urinalysis
* Hydration status

Clinical Chemistry Panels: Basic Metabolic Panel (BMP)
Also called Chem 7
Includes
o Electrolytes: Na+, K+, Cl-, HCO3 or total CO2
o Glucose
o Creatinine
o BUN
Basic Metabolic Panel Charting Shorthand
Creatinine
CO2
K+
glucose
BUN
Cl
Na
BMP
Clinical Chemistry Panels: Comprehensive Metabolic Panel
Includes
* BMP except CO2
* Albumin
* Serum enzymes (alkaline phosphatase, AST [SGOT], ALT [SGPT]
* Total bilirubin
* Total calcium
Phosphorus, total cholesterol and triglycerides often ordered with the CMP

Clinical Chemistry Panels:
Complete Blood Count (CBC)
* Red blood cells
* Hemoglobin concentration
* Hematocrit
* Mean cell volume (MCV)
* Mean cell hemoglobin (MCH)
* Mean cell hemoglobin concentration (MCHC)
* White blood cell count (WBC)
* Differential: indicates percentages of different kinds of WBC

Clinical Chemistry Panels: Urinalysis
Negative
Leukocyte esterage
Negative
Nitrite
0.1-1 units/dl
Urobilinogen
Not detected
Bilirubin
Negative
Blood
Negative
Ketones
Not detected
Glucose
2-8 mg/dl
Protein
6-8 (normal diet)
pH
1.010-1.025 mg/ml
Specific gravity
Types of Assays
* Static assays: measures the actual level of the nutrient in the specimen (serum iron, white blood cell ascorbic acid)
* Functional Assays: measure a biochemical or physiological activity that depends on the nutrient of interest (serum ferritin, TIBC)
o (Functional assays are not always specific to the nutrient)

Assessment of Nutrient Pool
Assessment of Hydration Status
* Dehydration: a state of negative fluid balance caused by decreased intake, increased losses, or fluid shifts
* Overhydration or edema: increase in extracellular fluid volume; fluid shifts from extracellular compartment to interstitial tissues
o Caused by increase in capillary hydrostatic pressure or permeability
o Decrease in colloid osmotic pressure
o Physical inactivity
* Use laboratory and clinical data to evaluate pt

Hypovolemia
Isotonic fluid loss from the extracellular space caused by
* Fluid loss (bleeding, fistulas, nasogastric drainage, excessive diuresis, vomiting and diarrhea)
* Reduced fluid intake
* Third space fluid shift, when fluid moves out of the intravascular space but not into intracellular space (abdominal cavity, pleural cavity, pericardial sac) caused by increased permeability of the capillary membrane or decrease on plasma colloid osmotic pressure

Symptoms of Hypovolemia
* Orthostatic Hypotension (caused by change in position)
* Central venous and pulmonary pressures 
* Increased heart rate
* Rapid weight loss
* Decreased urinary output
* Patient cool, clammy
* Decreased cardiac output
* Ask the medical team!!
Treatment of Hypovolemia
* Replace lost fluids with fluids of similar concentration
* Restores blood volume and blood pressure
* Usually isotonic fluid like normal saline or lactated Ringer’s solution given IV
* Excess of isotonic fluid (water and sodium) in the extracellular compartment
* Osmolality is usually not affected since fluid and solutes are gained in equal proportion
* Elderly and those with renal and cardiac failure are at risk

Causes of Hypervolemia
* Results from retention or excessive intake of fluid or sodium or shift in fluid from interstitial space into the intravascular space
* Fluid retention: renal failure, CHF, cirrhosis of the liver, corticosteroid therapy, hyperaldosteronism
* Excessive intake: IV replacement tx using normal saline or Lactated Ringer’s, blood or plasma replacement, excessive salt intake
* Fluid shifts into vasculature caused by remobilization of fluids after burn tx, administration of hypertonic fluids, use of colloid oncotic fluids such as albumin

Symptoms of Hypervolemia
* No single diagnostic test, so signs and symptoms are key
* Cardiac output increases
* Pulse rapid and bounding
* BP, CVP, PAP and pulmonary artery wedge pressure rise
* As the heart fails, BP and cardiac output drop
* Distended veins in hands and neck
* Anasarca: severe, generalized edema
* Pitting edema: leaves depression in skin when touched
* Pulmonary edema: crackles on auscultation
* Patient SOB and tachypneic
* Labs: low hematocrit, normal serum sodium, lower K+ and BUN (or if high, may mean renal failure)
* ABG: low O2 level, PaCO2 may be low, causing drop in pH and respiratory alkalosis

Treatment of Hypervolemia
* Restriction of sodium and fluid intake
* Diuretics to promote fluid loss; morphine and nitroglycerine to relieve air hunger and dilate blood vessels; digoxin to strengthen heart
* Hemodialysis or CAVH

Dehydration
* Excessive loss of free water
* Loss of fluids causes an increase in the concentration of solutes in the blood (increased osmolality)
* Water shifts out of the cells into the blood
* Causes: prolonged fever, watery diarrhea, failure to respond to thirst, highly concentrated feedings, including TF

Symptoms of Dehydration
* Thirst
* Fever
* Dry skin and mucus membranes, poor skin turgor, sunken eyeballs
* Decreased urine output
* Increased heart rate with falling blood pressure
* Elevated serum osmolality; elevated serum sodium; high urine specific gravity
* Use hypotonic IV solutions such as D5W
* Offer oral fluids
* Rehydrate gradually

Laboratory Values and Hydration: BUN
Low: inadequate dietary protein, severe liver failure
High: prerenal failure; excessive protein intake, GI bleeding, catabolic state; glucocorticoid therapy
Creatinine will also rise in severe hypovolemia
Decreases
Increases
BUN
Normal: 10-20 mg/dl
Other factors influencing result
Hyper-volemia
Hypo-volemia
Lab Test
Adapted from Charney and Malone. ADA Pocket Guide to Nutrition Assessment, 2004.
Laboratory Values and Hydration Status: BUN:Creatinine Ratio
Low: inadequate dietary protein, severe liver failure
High: prerenal failure; excessive protein intake, GI bleeding, catabolic state; glucocorticoid therapy
Decreases
Increases
BUN: creatinine ratio
Normal: 10-15:1
Other factors influencing result
Hyper-volemia
Hypo-volemia
Lab Test
Laboratory Values and Hydration: HCT
Low: anemia, hemorrhage with subsequent hemodilution (occurring after approximately 12-24 hours)
High: chronic hypoxia (chronic pulmonary disease, living at high altitude, heavy smoking, recent transfusion)
Laboratory Values and Hydration: Alb, Na+
Serum sodium generally reflects fluid status and not sodium balance Serum albumin
Other factors influencing result
Hyper-volemia
Hypo-volemia
Lab Test
Laboratory Values and Hydration Status
Low: diuresis, hyponatremia, sickle cell anemia
High: SIADH, azotemia,
Urine osmolality (200-1200 mosm/kg)
Urine sp. Gravity
1.003-1.030
Serum osmolality
(285-295 mosm/kg)
Other factors influencing result
Serum sodium
Low: malnutrition; acute phase response, liver failure
High: rare except in hemoconcentration
Serum albumin
Other factors influencing result
Hyper-volemia
Hypo-volemia
Lab Test
Hypokalemia (K+< 3.5 mEq/L)
* ↑ renal losses (diuresis)
* ↑ GI losses (diarrhea, vomiting, fistula)
* K+ wasting meds (thiazide and loop diuretics, etc)
* Shift into cells (anabolism, refeeding, correction of glucosuria or DKA)
* Inadequate intake
Hyperkalemia (K+>5.0 mEq/L)
* Decreased renal excretion as in acute or chronic renal failure
* Medications, e.g. potassium sparing diuretics, beta blockers, ACE inhibitors
* Shift out of cells (acidosis, tissue necrosis, GI hemorrhage, hemolysis)

Serum Calcium
* Normal serum 9.0-10.5 mg/dL (includes ionized calcium and calcium bound to protein, primarily albumin, and ions)
* Ionized calcium: 4.5-5.6 mg/dL
* Normal levels maintained by hormonal regulation using skeletal reserves
* Ionized calcium is more accurate, especially in pt with hypoalbuminemia; evaluate before repleting Ca+
Hypocalcemia (serum calcium <9.0 mg/dL; ionized Ca+ <4.5 mg/dL)
* Hypoalbuminemia
* Hypoparathyroidism
* Hypomagnesemia
* Renal failure, renal tubular necrosis
* Vitamin D deficiency or impaired metabolism

Hypercalcemia (serum calcium >10.5 mg/dL; ionized Ca+ >5.6 mg/dL)
* Hyperparathyroidism
* Some malignancies, especially breast, lung, kidney; multiple myeloma, leukemia, lymphoma
* Medications: thiazide diuretics, lithium, vitamin A toxicity
* Immobilization
* Hyperthyroidism
Serum Phosphorus (normal 3.0-4.5 mg/dL)

* Serum phos a poor reflection of body stores because <1% is in ECF
* Bones serve as a reservoir
Hypophosphatemia (<3.0 mg/dL)

* Impaired absorption (diarrhea, Vitamin D deficiency, impaired metabolism)
* Medications: phosphate binding antacids, sucralfate, insulin, steroids)
* Alcoholism, especially during withdrawal
* Intracellular shifts in alkalosis, anabolism, neoplasms
* Refeeding syndrome
* Increased losses: hyperparathyroidism, renal tubular defects, DKA recovery, hypomagnesemia, diuretic phase of ATN




Charney and Malone, 2004, p. 93





Hyperphosphatemia (>4.5 mg/dL)

* Decreased renal excretion: acute or chronic renal failure (GFR<20-25 mL/min); hypoparathyroidism
* Increased cellular release: tissue necrosis, tumor lysis syndrome
* Increased exogenous phosphorus load or absorption, phosphorus containing laxatives or enemas, vitamin D excess
* Acidosis
Hypomagnesemia <1.3 mEq/L (normal 1.3-2.1 mEq/L)
* Decreased absorption: prolonged diarrhea, intestinal or biliary fistula, intestinal resection or bypass, steatorrhea, ulcerative colitis; upper GI fluid loss, gastric suctioning, vomiting
* Renal losses: osmotic diuresis, DM with glucosuria, correction of DKA, renal disease with magnesium wasting, hypophosphatemia, hypercalcemia, hyperthyroidism
* Alcoholism
* Inadequate intake: malnutrition
* Medications
* Intracellular shift: acute pancreatitis
* Refeeding syndrome
Hypermagnesemia (>2.1 mEq/L)
* Acute or chronic renal failure
Assessment for Protein-Calorie Malnutrition
* Hormonal and cell-mediated response
to stress
o Negative acute-phase respondents
o Positive acute-phase respondents
* Nitrogen balance
Assessment for Protein-Calorie Malnutrition–cont’d
* Hepatic transport proteins
o Albumin
o Transferrin
o Prealbumin
o Retinol-binding protein
o C-reactive protein
o Creatinine
* Immunocompetence
Hormonal and Cell-Mediated Response to Inflammatory Stress
* Acute illness or trauma causes inflammatory stress
* Cytokines (interleukin-1, interleukin-6 and tumor necrosis factor) reorient hepatic synthesis of plasma proteins
* Although protein-energy malnutrition can occur simultaneously, interpretation of plasma proteins is problematic

Hormonal and Cell-Mediated Response to Inflammatory Stress
* Negative acute-phase respondents (albumin, transthyretin or prealbumin, transferrin, retinol-binding protein) decrease
* Positive acute-phase reactants (C-reactive protein, orosomucoid, fibrinogen) increase
* The change in these proteins is proportional to the physiological insult

Nitrogen Balance Studies
* Oldest biochemical technique for assessment protein status
* Based on the fact that 16% of protein is nitrogen
* Nitrogen intake is compared to nitrogen output, adjusted for insensible losses (skin, hair loss, sweat)
* Nitrogen balance in healthy adults is 0
* Nitrogen balance is positive in growing children, pregnant women, adults gaining weight or recovering from illness or injury
* Nitrogen balance is negative during starvation, catabolism, PEM
* Nitrogen balance = nitrogen intake (g/24 hours) –(urinary nitrogen [g/24 hours) + 2 g/24 hours
* Use correction of 4 g/24 hours if urinary urea nitrogen is used
* Nitrogen intake = (grams protein/24 hours)/6.25
Nitrogen Balance Challenges
* Urea nitrogen is highly variable as a percent of total nitrogen excreted
* It is nearly impossible to capture an accurate nitrogen intake for patients taking food po
* Most useful in evaluating the appropriateness of defined feedings, e.g. enteral and parenteral feedings

Visceral Proteins:
Serum Albumin
* Reference range: 3.5-5.2 g/dl
* Abundant in serum, stable (half-life 3 weeks)
* Preserved in the presence of starvation (marasmus)
* Negative acute phase reactant (declines with the inflammatory process)
* Large extravascular pool (leaves and returns to the circulation, making levels difficult to interpret)
* Therefore, albumin is a mediocre indicator of nutritional status, but a very good predictor of morbidity and mortality
Visceral Proteins: Plasma Transferrin

* Reference range: 200-400 mg/dl
* Half-life: 1 week
* Negative acute phase respondent
* Increases when iron stores are depleted so affected by iron status as well as protein-energy status
* Responds too slowly to be useful in an acute setting
Visceral Proteins: Transthyretin (Prealbumin)
* Reference range: 19-43 mg/dl
* Half-life: 2 days
* Negative acute-phase reactant
* Zinc deficiency reduces levels
* Due to short half-life, it is useful in monitoring improvements in protein-energy status if baseline value is obtained near the nadir as inflammatory response wanes
Visceral Proteins: Retinol-Binding Protein
* Reference range: 2.1-6.4 mg/dl
* Half-life: 12 hours
* Negative acute-phase protein
* Unreliable when vitamin A (retinol) status is compromised
* Elevated in the presence of renal failure, regardless of PEM status

Visceral Proteins: C-Reactive Protein
* Positive acute-phase reactant
* Increases within 4-6 hours of injury or illness
* Can be used to monitor the progress of the stress reaction so aggressive nutrition support can be implemented when reaction is subsiding
* Mildly elevated CRP may be a marker for increased risk for cardiovascular disease
Inflammation
* hs-CRP
* Homocysteine

Urinary Creatinine
* Formed from creatine, produced in muscle tissue
* The body’s muscle protein pool is directly proportional to creatinine excretion
* Skeletal muscle mass (kg) = 4.1 = 18.9 x 24-hour creatinine excretion (g/day)
* Confounded by meat in diet
* Requires 24-hour urine collection, which is difficult
Markers of Malabsorption
* Fecal fat
* Fat-soluble vitamins
* Vitamin D
Lipid Indices of Cardiovascular Risk
* Total cholesterol
* LDL
* HDL: HDL2a, HDL2b, HDL2c, HDL3a, HDLdb
* IDL
* VLDL
* Lp(a)
Nutrition Diagnoses and Laboratory Indices
* Nutrition-related labs can be used either as diagnostic labels or a clinical sign
Examples of Nutrition Diagnostic Statements Related to Lab Values
* Altered nutrition-related lab values (NC-2.2) related to excessive intake of saturated fat and cholesterol and genetic factors as evidenced by diet history and client history.
* Inappropriate intake of food fats (saturated fat and cholesterol) (NI-5.6.3) related to frequent use of baked goods and fried foods as evidenced by diet history and elevated LDL and TC
Examples of Nutrition Diagnostic Statements Related to Lab Values

* Excessive carbohydrate intake related to evening visits to Coldstone Creamery as evidenced by HS blood glucose and diet history

Evaluation of Laboratory Data in Nutrition Assessment.ppt

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HIV/AIDS 2008 Update



HIV/AIDS 2008 Update
By:David H. Spach, MD
Clinical Director, NWAETC
Professor of Medicine
Division of Infectious Diseases
University of Washington, Seattle

* HIV Epidemiology
* HIV Rapid Testing
* 2008 DHHS ARV Therapy Guidelines
* Antiretroviral Therapy: New Information in 2008
* New Scientific Discoveries
DHS/PP
Epidemiology*
Question
* In August 2008, the CDC reported their use of new epidemiologic methods that has led to significant revisions in the estimates of HIV incidence in the United States.

DHS/PP
In this recent report, which one of the following statements is TRUE regarding HIV infections in the United States in 2006?

* The number of estimated new infections in 2006 has been revised to a lower number (now 32,000 instead of 40,000)
* The rate (per 100,000 persons) of new infections in blacks was 7x whites
* Heterosexual sex has replaced male-to-male sex as the leading transmission category for new infections
* The number of new infections in women was greater than men
* “Based on extrapolations from these data, the estimated number of new infections for the United States in 2006 was 56,300.”
* “... the level of new HIV infections in the United States is higher than had previously been known, in fact approximately 40% higher than early estimates…”
Kevin Fenton, MD, PhD
Centers for Disease Control & Prevention.
HIV Rapid Testing*
Rapid HIV Tests
* In the June 18, 2008 issue of the MMWR, the NY City Department of Health and the CDC reported a problem with the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test.

What was the reported problem with the OraQuick rapid HIV test?
* Contamination of test kits with mold
* Kits were shipped too close to the expiration date
* Failure of external Kit Controls to validate the assay
* Increased numbers of False-Positive results with oral fluid samples

Persons NOT Infected with HIV
OraQuick Rapid ORAL HIV Test
Confirmatory HIV Test (EIA/WB)
Preliminary
Positive
EIA
WB
Reactive
Oral Fluid
Oral
Possible Revised Approach: Rapid HIV Testing
OraQuick Rapid HIV Tests
Confirmatory HIV Test (EIA & WB)
Preliminary
Positive
Reactive
Oral
Oral Fluid
EXAMPLE: Specificity of HIV Antibody Test
Persons NOT Infected with HIV (N = 15)
EXAMPLE: Specificity of HIV Antibody Test
Antibody Test Result: Persons NOT Infected with HIV
EXAMPLE: Specificity of HIV Antibody Test
HIV Antibody Testing in Low Prevalence Setting
HIV Test Specificity
HIV Antibody Testing in Low Prevalence Setting
DHHS ARV Guidelines
Initiating Antiretroviral Therapy
* As a group, make a list of at least 5 recommendations regarding initiating antiretroviral therapy that are new/different in current 2008 guidelines when compared with guidelines that existed one year ago at this time (at that time October 2006 most recent updated version).
Initiating Antiretroviral Therapy
* NEW RECOMMENDATIONS
1. New CD4 threshold (350 cells/mm3 in 2008 instead of 200)
2. New indications for starting ARV (chronic HBV, HIVAN) in 2008
3. Less impact of HIV RNA level in 2008
4. Zidovudine-lamivudine removed from preferred list in 2008
5. Abacavir-lamivudine added to preferred list in 2008
6. Do HLA-B5701 testing if considering using abacavir
Initiating Antiretroviral Therapy January 2008 DHHS Guidelines
*Initiate Antiretroviral Therapy
Consider Antiretroviral Therapy
Construct Regimen by choosing one component from Column A and one component from Column B
Recent Concerns Regarding Abacavir
Antiretroviral Therapy New Information in 2008
Host Cellular Receptors
Extracellular Space
Intracellular Space
Entry Inhibitor: Maraviroc (Selzentry)
Host Cell Membrane
CD4 Receptor
Extracellular Space
Intracellular Space
R5 HIV
Maraviroc
CXCR4
CCR5
HIV Co-Receptor Tropism Assay Monogram Biosciences Trofile Assay
HIV-1 Tropism Assay
What is the major difference in the new ENHANCED Trofile assay when compared with the older Trofile assay?

* The new assay has a lower limit of detection of minor species (<1% compared with previous lower limit of 10%)
* Results can be obtained in 7 days with the new assay
* The new assay is accurate with very low HIV RNA levels (accurate down to 100 copies/ml)
* The new assay detects CCR5 mutants resistant to Maraviroc

HIV Co-Receptor Tropism Assay Monogram Biosciences ENHANCED Trofile Assay
Tenofovir + Lamivudine + Efavirenz (n = 38)
Eligibility
- HIV-infected
- Treatment Naive
- HIV RNA > 5,000 copies/ml
- CD4 count > 100 cells/mm3
- Randomized, double-blind
Tenofovir + Lamivudine +
Raltegravir* (n = 160)
Virologic Response: Week 24
INVESTIGATIONAL
* Background
- N = 368
- ARV-naīve
- HIV RNA > 5,000 copies/ml
- Randomized, double-blind
* Regimens (all include 2 NRTIs*)
- Efavirenz: 600 mg qd
- Rilpivirine: 25 mg qd
- Rilpivirine: 75 mg qd
- Rilpivirine: 150 mg qd
New Scientific Discoveries
A Cure for HIV?
* In July 2008, our patients starting coming in asking about the news reports regarding the newly discovered cure for HIV. The report that came out in July 2008 was related to HIV gp120 (envelope).

What new therapeutic strategy was discovered?

* A CD4 coating molecule that is an inhibitor of gp120-CD4 binding
* Use of Abzymes to destroy a critical region of gp120
* A new enzyme that cause gp120 to separate from gp41
* A new particle that destroys the human co-receptor CCR5 and thus prevents gp120-CCR5 binding

HIV: Basic Structure
DHS/PP
gp120
gp41
Envelope
HIV: Envelope
Abzymes
- Antibodies with enzymatic activity
- Can break down thousands of virus particles per molecule of abzyme

HIV: gp120
DHS/PP
HIV gp120: Abzyme Interaction .........

HIV/AIDS 2008 Update: Summary

* HIV Epidemiology
* HIV Rapid Testing
* 2008 DHHS ARV Therapy Guidelines
* Antiretroviral Therapy: New Information in 2008
* New Scientific Discoveries

HIV/AIDS 2008 Update.ppt

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05 October 2009

Update on Infections



Update on Infections
By:Mark A. Lassoff, MD, MBA, MPH
September 18, 2007

Malacoplakia
* “malako” – soft, “plakos” – plaque
* Rare granulomatous disease
* Michaelis – Gutmann bodies: basophilic lamellar inclusion bodies
* Associated with other autoimmune diseases
o Sarcoidosis, Chedak-Higashi syndrome
* Incidence: 1 in 10,000
* Female: Male – 4:1
* Peak incidence is in patients ≥ 50 yrs old
* 75% of cases occur in GU system, most commonly in the bladder (2nd – kidney)
* Predilection for those with immunodeficiency, systemic dz, carcinoma or chronic UTI with coliform organisms (E Coli – up to 75%, Enterobacter, Klebsiella, Proteus and Pseudomonas)
* Etiology – unknown
o Theory: acquired immunodeficiency interfering with normal intracellular function of the monocyte’s phagolysosome. Residual undigested bacterial components become mineralized by Ca++ & Fe
o Cause appears to be related to imbalance in the intracellular cGMP/cAMP
* Dx made by biopsy
o Lesion: large histiocytes  von Hansemann cells and small intracytoplasmic calculospherules  Michaelis-Gutmann bodies
o Immunohistochemical staining for α1-antitrypsin useful for early and accurate differential dx
* Clinical findings
o Bladder
+ Irritability and hematuria
+ Mucosal plaques or nodules  fungating, firm, sessile masses
o Renal
+ Bilaterality in up to 50%; multifocal is more common
+ Fever, flank pain or mass on PE
+ Cause loss of function via direct invasion or obstruction
+ E Coli infxn in up to 93%
+ Bilateral dz  mortality rate approaches 100% w/i 6 mos of dx w/o intervention
+ IVP: unifocal – may displace calyces vs. multifocal – nephromegaly and poor renal fxn; multiple filling defects
* Management
o Lower tract:
+ Initial treatment with medications
# Bethanecol (↑ cGMP), Ascorbic acid (↓ cAMP)
# Fluoroquinolones (DOC)
# Others: Bactrim, Rifampin, Cipro
+ TUR prn for plaque removal
o Upper tract:
+ Unilateral renal dz: most often requires nephrectomy
o In immunodeficient pts and those with multifocal dz, surgical tx is essential to survival

Sexually Transmitted Infections
Syphilis
* Treponema pallidum (spirochete)
* Spread: infectious lesions, body fluids, in utero, blood transfusions
* Primary
o Single painless, indurated ulcer appearing 3 wks after inoculation (@ site of inoculation) and remains for 4 – 6 wks
o Often with bilateral, non-tender inguinal or regional lymphadenopathy
o Can heal w/o treatment; often goes unnoticed
o Presence of chancres increases risk of HIV acquisition 2-5x
* Latent
o Seroreactivity w/o clinical evidence of dz
o Early: within the last year
o Late latent vs. latent syphilis of unknown duration
* Secondary
o Begins 4 – 10 wks after the appearance of the ulcer but may present up to 24 mos after initial infection
o Mucocutaneous, constitutional and parenchymal signs and symptoms
+ Maculopapular rash (trunk and arms)
+ Generalized non-tender lymphadenopathy
+ Papular rash (may accompany first rash)
# Becomes necrotic and pustular
# Affects palms and soles
# Intertriginous areas: enlarge and erode  condyloma lata (infectious)
+ Less commonly: hepatitis and immune-complexed glomerulonephritis
* Tertiary
o One third of untreated pts
o Rare in industrialized countries, except for pts w/ HIV
o Cardiovascular, skeletal, CNS, skin
+ Aortitis, meningitis, uveitis, optic neuritis, general paresis, tabe dorsalis, gummas of skin/skeleton
* Screening
o Rapid Plasma Reagin (RPR) & Venereal Disease Research Laboratory (VDRL)
+ Correlate with disease activity
+ Become negative one year after treatment
o T. pallidum particle agglutination (TP-PA) or Fluorescent Treponemal Antibody Absorbed (FTA-ABS)
+ Antibody tests remain positive for life; do not correlate w/ active disease
o HIV can cause FN results by treponemal & non-treponemal methods
* Treatment
o Benzthiazide penicillin G (2.4 million units IM x 1)
o Jarisch – Herxheimer rxn
+ Headaches, myalgia, fever, tachycardia, increased resp rate within first 24 hrs after tx w/ PCN
+ Managed with bed rest and NSAIDs
o PCN allergy: Doxycycline (100mg BID x 14d)
o Latent: PCN IM weekly x 3 doses or doxycycline for a total of 4 wks
o Tertiary: Aqueous crystalline PCN G (IV q4h) x 10-14 d or PCN G procaine IM + probenecid (po QID) x 10-14 d
o Pregnancy: desensitization to PCN

Herpes Simplex Virus
* Genital herpes: HSV-2 (85-90%), HSV-1 (10-15%)
* Silent infection may account for >75% of transmission
* Primary
o Painful ulcers of genitalia or anus
+ Group of vesicles on an erythematous base that does not follow a neural distribution is pathognomonic
o Bilateral painful inguinal adenopathy
o Often associated with constitutional flu-like symptoms
o Urethral lesions may cause transient urinary retention in women
o Asx viral shedding can happen up to 3 mos after clinical presentation
* Recurrent episodes are usually less severe
* Severe dz and complications:
o Pneumonitis, disseminated infxn, hepatitis, meningitis, encephalitis
* Dx: viral culture with subtyping (gold standard)
o Not on clinical suspicion alone, classic presentation occurs in a small percentage of pts
o Can see abrasions, fissures or itching
o Subtyping is important for prognosis and counseling
+ HSV-2: ave of 4 recurrences in 1st yr vs. 1 for HSV-1
o Sensitivity: 30 – 95% depending on stage of lesion and whether it is primary or recurrence
* Treatment
o Oral acyclovir, valacyclovir and famciclovir
o Topical meds are not effective
o Recurrences: episodic or suppressive approach
+ Suppressive: decreases frequency/duration and viral shedding
Chancroid
* Haemophilus ducreyi
* Men: Women – 3:1
* Painful, non-indurated ulcer on penis or vulvovaginal area
o Friable base covered with a gray or yellow purulent exudate and a shaggy border
* Inguinal adenopathy is typically unilateral and tender with tendency to become suppurative and fistulize
* Dx: culture media not widely available so gram stain often helpful (short, fine, GN streptobacilli in short, parallel chains)
* Approximately 10% are co-infected w/ HSV or syphilis
* Treatment
o Single dose
+ Azithromycin 1gm po or Ceftriaxone 250mg IM
o Other tx: Cipro x 3d or Erythromycin x 7d

Lymphogranuloma Venereum
* Chlamydia trachomatis – L1, L2, L3
* Single, painless ulcer on the penis, anus or vulvovaginal area that goes unnoticed
* Painful unilateral suppurative inguinal adenopathy and constitutional symptoms that occur 2 – 6 wks after resolution of ulcer
* Significant tissue injury and scarring can occur leading to labial fenestration, urethral destruction, anorectal fistulas and elephantiasis of penis, scrotum or labia
* Dx: mainly clinical
o Complement fixation or indirect fluorescence antibody titers can confirm
* Tx: Doxycycline BID or erythromycin QID x 3 wks

Genital Warts
* Condylomata acuminata
* Human papillomavirus (HPV) – DNA virus
* Types 6 and 11 are most often responsible for visible external genital warts
o Cervix, vagina, urethra, anus, mucous membranes
* Types 16, 18, 31, 33, 35, 39, 45 and 51: associated with cervical dysplasia and neoplasm in women and squamous intraepithelial neoplasia in men
o >99% of cervical cancers and 84% of anal cancers are associated with HPV (16 & 18)
o Cervical cancer is considered an AIDS defining illness
* Most are subclinical and asx
* In women HPV may be associated with nonspecific symptoms such as vulvodynia or pruritis; malodorous vaginal discharge
* Dx: usually inspection or palpation
* Bx: not routinely needed
o Atypical, pigmented, indurated, fixed or ulcerated
o Lesions persist/worsen after tx; immunocompromised pts
* Treatment
o Depends on size, number, location, and patient and physician preference
o Observation (spontaneously resolve with time)
o Patient applied (less expensive)
+ Podofilox 0.5% solution or gel (3d on, 4d off, may repeat x 4)
+ Imiquod 5% cream (3/wk qhs for up to 16 wks)
# Needs to be washed off, can cause ulceration
o Provider applied
+ Cryotherapy with liquid nitrogen
+ Electrosurgery
+ Laser therapy (CO2)
+ Podophyllin resin (20 – 25%)
+ Trichloracetic acid (TCA) or bichloracetic acid (BCA)
+ Surgical excision
* Lesions around the meatus may herald presence of urethral or bladder condyloma
* Urethral or bladder lesions should be cystoscopically excised
* Intraurethral 5% FU cream 2/wk
* Vaccine containing 8 of the most common HPV types associated with cancer could potentially prevent 95% of cervical cancer
* Topical BCG: promising preliminary results

Sexually Transmitted Infections
Chlamydia
* Chlamydia trachomatis: most common bacterial STD in the US and worldwide
* Majority of men and women are asx
* 50% of men experience LUTS attributed to urethritis, epididymitis or prostatitis; may see clear or white urethral discharge
* 75% of women are asx and 40% of those untreated will have PID
* May be transmitted during vaginal birth
o Ocular, oropharyngeal, respiratory, urogenital or rectal infxn
Chlamydia
* Women should be screened annually until 25 yo or if risk factors such as new sexual partner are present
o Nucleic acid amplification test (NAAT) on endocervical swab or urine specimen
o Unamplified nucleic acid hybridization test, enzyme immunoassay or direct fluorescence antibody test
o Culture
* Treatment
o Azithromycin 1gm po x 1 or Doxy BID x 7d
o Refrain from sex until treatment completed or 7d after single dose therapy
o Re-culture recommended 3 wks later if treated with erythromycin, in pregnant women or if symptoms persist
o Re-screened 3 – 4 mos after tx as are high risk for re-infxn

Gonorrhea
* Neisseria gonorrhoeae (GN diplococcus)
* Men usually experience LUTS attributed to urethritis, epididymitis, proctitis or prostatitis w/ associated mucopurulent urethral discharge
* Women may have vaginal and pelvic discomfort, dysuria or abnormal vaginal discharge but are usually asx
* Same screening recs as for Chlamydia
* Treatment
o Ceftriaxone 125mg IM x 1
o Single dose oral regimen
+ Cipro, Levaquin, Ofloxacin (growing resistance to FQs)
o Simultaneous treatment for Chlamydia






Trichomoniasis

* Trichomonas vaginalis (flagellated protozoan)
* Increased incidence in developing countries and those with multiple sexual partners
* Can inhabit the vagina, urethra, Bartholin glands, Skene’s glands and prostate (not rectum/mouth)
* Men: usually asx but can produce short-term urethral discharge, dysuria and urgency
* Women: asx in 50%, otherwise can see sudden onset of frothy white or green, foul-smelling vaginal discharge, pruritis, and erythema
o Dyspareunia, suprapubic discomfort, urgency
Trichomoniasis
* Examination: frothy discharge and “strawberry vulva” or “strawberry cervix”
* Vaginal discharge has increased pH
* Motile protozoa on vaginal wet-mount smear or microscopic examination of urine
* Men: urethral cx or microscopic exam of urine
* Treatment
o Metronidazole 2gm po x 1 (ok in 2nd trimester)
+ GI side effects common
o Abstain from Etoh consumption
o Prolonged Metronidazole for failure

Vaginitides / Urethritides
* Ureaplasma urealyticum, Mycoplasma hominis, Mycoplasma genitalium
o Implicated in chronic prostatitis and urgency frequency symptoms in women and in up to 40% of NGU
o Tx: Azithromycin po x 1 or doxycycline x 2 wks
* Bacterial vaginosis
o Gardnerella vaginalis, anaerobic orgs, Mycoplasma and/or inhibition of normal vaginal flora
o 10% KOH with vag secretions  fishy odor secondary to release of amines
o Microscopic exam (3 of 4 necessary): (1) thin, white vag d/c (2) vag pH >4.5 (3) clue cells (4) pos whiff test
o Tx: Metro po BID x 7d, Clinda cream x 7d, Metro gel x 5d
* Candida albicans
o Thick, cheesy vaginal discharge usually associated with vulvar irritation and itching
+ Vaginal discomfort, burning, dyspareunia and external dysuria
o Dx: yeast or pseudohyphae on wet prep or gram stain
o Tx: single oral dose of fluconazole (150mg) or OTC antifungal vaginal creams, tablets or suppositories x 1-7 days (butoconazole, clotrimazole, miconazole and terconazole)
References

Update on Infections .ppt

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HUMAN PAPILLOMA VIRUS (HPV)



HUMAN PAPILLOMA VIRUS (HPV)
By: Nathalia Cruz

What is a Virus?
* Exceptionally simple living microbes.
* Contain a single type of nucleic acid (DNA or RNA) and a protein coat.
* Obligatory intracellular parasites.
* Range from 20 to 14.000 nm in length.
* It’s classification is based on type of nucleic acid, strategy for replication, and morphology

HUMAN PAPILLOMA VIRUS
* HPV is the virus that causes warts.
* More than 100 different kinds, 30-some of this cause genital HPV.
* Spread by sexual contact or from mother to baby.
* Genital warts appear 6 weeks to 8 months after contact with an HPV infected person.
* The most common sexually transmitted disease worldwide.
* Certain types of HPV are linked with cervical cancer.
* Divided into 2 subcategories: Genital Warts and Cervical Dysplasia.
* Most people do not know they have it.
* There are high risk and low risk types of it.

HISTORY
* The papillomaviruses are part of the PAPOVAVIRIDAE family of DNA tumor viruses.
* First discovered in the early 40’s.
* Gained notoriety in the early 80’s when it was discovered that some types of HPV caused cervical cancer.

MORPHOLOGY
* Papilloma virus genome is circular covalently closed double stranded DNA of about 8 kbp.
* All PV genes are coded in one of the 2 DNA strands utilizing the alternative splicing for the individual expression of each gene.
* Papillomavirus expression is characterized by a large array of mRNAs cells coding for different genes.
* 55 nm in diameter.

MECHANISM OF INFECTION
* All PV exhibit extreme specificity for infection on epithelial cells.
* The papillomavirus epitheliotrophy resides in the interaction of specific transmission factors with the viral regulatory region LCR.
* The infection normally results in hyperproliferation of the host cell and may lead to transformation and immortalization.

GENITAL WARTS
* Sometimes called condylomata acuminata.
* Are soft, moist or flesh colored, and appear in the genital area within weeks or months after infection.
* Sometimes appear in clusters and are either raised or flat, small or large.
* Women: appear in the vulva, cervix, vagina and anus.
* Men: Can appear on the scrotum or penis.

LIFE CYCLE (HPV-16)
* Starts with the infection of the host cell.
* The virus DNA is released within the nucleus
* Numerous cellular transcription factors interact with the non-coding viral regulatory region (LCR), starting transcription of the two hpv-16 transforming early genes (E6 and E7).
* The transforming proteins interact with the cellular antioncogenic regulator p53 disrupting the cell cycle.

HPV TYPES
* Numbered in order of discovery.
* 30 HPV types primarily infect the squamous epithelium of the lower anogenital tracts of both males and females.
* HPV types 6, 11, 42, 43, or 44 present as papillary condylomas, may also present as flat lesions that may or may not be visible to the unaided eye are part of the “low-risk” HPV types.
* Types 16, 18, 31, 33, 35, 45, 51, 52, and 56 are considered “high-risk” types because they have been found in cervical and other lower genital tract cancers.

HPV GENOMIC ORGANIZATION
* Three main regions (early, late and the long control region)
* (E) resides the transformation and immortalization potential.
* (L) Two capsid genes.
* (LCR) contains all the cis-regulatory elements.

HOW HPV CAUSES CANCER
* HPV DNA integrates into the host genome.
* The proteins E6 and E7 are produced from the resultant DNA.
* E6 binds and degrades p53 (a tumor suppressor gene).
* If the DNA is altered, the cell keeps replicating. The mutation rate of the cell increases.
* E7 binds and degrades retinoblastoma (another tumor suppressor gene).
* Retinoblastoma normally keeps the cell from growing too fast or responding to growth stimulators. This inhibitory factor is now lost.
* without these two mechanisms to slow down cell growth and prevent mutation. . .
* Malignant Transformation Occurs.

HPV TREATMENT
* Genital warts can be treated by a doctor and by different methods.
* Podofilox gel: A patient-applied treatment for external genital warts.
* Imiquimod cream: A patient-applied treatment.
* Chemical treatments (including trichloracetic acid and podophyllin), which must be applied by a trained health care provider to destroy warts.
* Cryotherapy: Uses liquid nitrogen to freeze off the warts.
* Laser therapy: Uses a laser beam or intense lights to destroy the warts.
* Electrosurgery: Uses and electric current to burn off the warts.
* Surgery: Can cut away the wart in one office visit .
* Interferon: an antiviral drug, which can be injected directly into warts.

CURE
* There is currently no cure for human papillomavirus.
* Once an individual is infected, he or she carries the virus for life even if genital warts are removed.
* The development of a vaccine against HPV is under way, but is still not available.
* If left untreated, some genital warts may regress on their own.

HUMAN PAPILLOMA VIRUS.ppt

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Protect yourself and Protect others! During this Flu Season



Protect yourself and Protect others!
During this Flu Season…

This module has been designed to provide information to the Duke Employees on seasonal and H1N1 Flu. After completing this module, you will be able to:

* Identify important facts related to seasonal and H1N1 Flu
* Describe proper hygiene practices and control measures, including vaccination to prevent
o Seasonal Flu and
o H1N1 Flu

* Describe the impact of the seasonal flu and H1N1Flu on employees and on Duke as an organization

Why Should I Be Concerned?

+ Typically, the” Flu” comes around yearly during the fall and early winter. This is considered the “seasonal” Flu and a vaccine is developed each year to provide protection against the most common strains that are expected to cause the most illness.
* Seasonal Flu is a serious disease. In fact, 25,000 to 35,000 die annually in the U.S. due to the seasonal Flu. Those at the highest risk for developing complications are:
o The elderly
o The very young
o Those with chronic medical conditions, such as heart disease, lung disease, diabetes or conditions that effect the immune system

Why Is This Year’s Flu Season Different?

+ This year, there is a new and very different Flu virus spreading worldwide called the H1N1 Flu or formerly known as the “Swine Flu”. Though this new type of Flu is turning out to be milder than originally feared, it can lead to complications.
+ At this time, many are susceptible to the H1N1 and those infected experience symptoms similar to the seasonal Flu. Those at highest risk for complications seem to be:
# Pregnant women
# Children
# Youth and young adults up to age 24
# Those with chronic medical conditions between ages 24 and 64

What Does This Mean For DU/DUHS?

Based on the government’s current estimate, 30-50% of our employees could be infected with the Flu this season.

Since we work closely together in the Duke community, we have many opportunities for contact.

Duke is taking steps to slow the spread of illness in the workforce.

Protecting yourself, your co-workers and your patients is the best way to decrease the impact of either the seasonal Flu or the H1N1 Flu. You’ll find out how in the next slides.


Remember that we all are susceptible to BOTH kinds of Flu.

To Protect Yourself & Prevent Spread . . .

It is important to know that the Flu is highly contagious, and spreads when the virus is passed from one individual to another individual. This can happen when an infected individual:

o Coughs, sneezes, or has direct physical contact with another individual
o Indirectly contaminates objects such as door knobs, telephones or surfaces. This is not the most common route of infection.

Remember that the virus can spread from the hands to eyes, nose, and mouth; so good hand hygiene is critical.

Here’s What You Can Do To Prevent Spreading The Virus . . .

+ Wash your hands. Washing hands often with soap and water or an alcohol-based hand cleaner will help protect against germs.
+ Cover your nose and mouth with a tissue when you cough or sneeze. Throw the tissue in the trash immediately after use. Wash your hands immediately.
+ If a tissue is not available, cough or sneeze into your elbow or sleeve.
+ Avoid touching eyes, nose or mouth. Germs are often spread when you touch something contaminated with germs and then touch your eyes, nose or mouth.
+ Stay home and away from others when you’re sick. You will help prevent others from getting sick.

And Take The Time To Get Vaccinated

* Too many employees unwisely continue to work while sick with the Flu.
* Unvaccinated workers who are not yet feeling sick can spread the virus.
* Infected individuals may be infectious the day before they become sick as well as after their fever is gone.

YOU maybe the source of Flu transmission!

Get Vaccinated for Seasonal Flu
The Center for Disease Control recommends a seasonal flu vaccine as the first and foremost important step in protecting against seasonal flu. Vaccination for seasonal Flu is vital for:

* Individuals at high-risk for serious Flu complications:
o The elderly
o The very young
o Those with chronic medical conditions, such as heart disease, lung disease, diabetes or conditions that effect the immune system
* Health care workers
* Individuals who live with or care for high-risk individuals
* All persons wishing to prevent seasonal flu


For more information, go to www.cdc.gov
Remember That DU/DUHS Offers Free
Seasonal Flu Vaccination

* Duke offers free seasonal flu vaccination to all employees.
* Times and locations of flu vaccination sites will be posted online at www.duke.edu/flu.
* Bring your Duke ID to receive the vaccination.
* If you have a fever, postpone your flu shot.

And Remember To Get Vaccinated for H1N1

* The seasonal Flu vaccine will not protect you against the H1N1 Flu.
* A separate vaccine is being developed for H1N1. It is expected to be available in late fall.
* The H1N1 vaccine will be distributed based on criteria as defined by the Centers for Disease Control (CDC).

How Do I Know If I Have The Flu?

Symptoms for both the Seasonal Flu and H1N1 Flu are similar . . .

o Fever of 100 degrees or more and any of these symptoms:
+ Cough
+ Sore throat
+ Runny or stuffy nose/sneezing
+ Body ache
+ Headache
+ Chills
+ Unusual fatigue

How Should I Care for Myself?

* Get Extra Rest
* Increase Fluid Intake
* Take Fever Lowering Medication (no aspirin for children)
* If you have severe illness or you are at high risk for flu complications, contact your health care provider or seek medical care.

Seek Urgent Medical Attention If You Experience . . .

Any of these emergency warning signs . . .

* Difficulty breathing or shortness of breath
* Pain or pressure in the chest or abdomen
* Sudden dizziness
* Confusion
* Severe or persistent vomiting

Protect yourself and Protect others!.ppt

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03 October 2009

The Cardiovascular Examination



Valvular Heart Disease and the Cardiac Exam
By:Charlotte Bai, M.D.
Internal Medicine Board Review
May 28, 2009

Overview
* Clinical syndromes
* Overview of cardiac murmurs and maneuvers
* Left sided valvular lesions
o Aortic stenosis and sclerosis
o Mitral stenosis
+ Rheumatic fever prophylaxis
o Acute and chronic aortic regurgitation
o Acute and chronic mitral regurgitation
* Right sided valvular lesions
o Tricuspid valve disease
* Prosthetic valves
* Endocarditis prophylaxis
* Questions

General Appearance
* Marfan Syndrome
o Tall, long extremities
o Associated with: aortic root dilitation, MV prolapse
* Acromegaly
o Large stature, coarse facial features, “spade” hands
o Associated with: Cardiac hypertrophy
* Turner Syndrome
o Web neck, hypertelorism, short stature
o Associated with: Aortic coarctation, pulmonary stenosis
* Pickwickian Syndrome
o Severe obesity, somnolence
o Associated with: Pulmonary hypertension
* Fredreich ataxia
o Lurching gait, hammertoe, pes cavus
o Associated with: hypertrophic cardiomyopathy
* Duchenne type muscular dystrophy
o Pseudohypertrophy of the calves
o Cardiomyopathy
* Ankylosing spondylitis
o Straight back syndrome, stiff (“poker”) spine
o Associated with: AI, CHB (rare)
* Lentigines (LEOPARD syndrome)
o Brown skin macules that do not increase with sunlight
o Associated with: HOCM, PS
“Spade” hands in acromegaly
* Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu)
o Small capillary hemangiomas on the face or mouth
o Associated with: Pulmonary arteriovenous fistula
* Lupus
o Butterfly rash on face, Raynaud phenomenon- hands, Livedo reticularis
o Associated with: Verrucous endocarditis, Myocarditis, Pericarditis
* Pheochromocytoma
o Pale diaphoretic skin, neurofibromatosis- café-au-lait spots
o Associated with: Catecholamine-induced secondary dilated CM
* Sarcoidosis
o Cutaneous nodules, erythema nodosum
o Associated with: Secondary cardiomyopathy, heart block
* Tuberous Sclerosis
o Angiofibromas (face; adenoma sebaceum)
o Associated with: Rhabdomyoma
* Myxedema
o Coarse, dry skin, thinning of lateral eyebrows, hoarseness of voice
o Associated with: Pericardial effusion, LV dysfunction

Grading the Intensity of Cardiac Murmurs
* Grade 1
o Murmur heard with stethoscope, but not at first
* Grade 2
o Faint murmur heard with stethoscope on chest wall
* Grade 3
o Murmur hears with stethoscope on chest wall, louder than grade 2 but without a thrill
* Grade 4
o Murmur associated with a thrill
* Grade 5
o Murmur heard with just the rim held against the chest
* Grade 6
o Murmur heard with the stethoscope held away and in from the chest wall

Cardiac Murmurs


* Most mid systolic murmurs of grade 2/6 intensity or less are benign
o Associated with physiologic increases in blood velocity:
+ Pregnancy
+ Elderly
* In contrast, the following murmurs are usually pathologic:
o Systolic murmurs grade 3/6 or greater in intensity
o Continuous murmurs
o Any diastolic murmur

Diagnostic Testing
* ECHOCARDIOGRAM
Aortic Stenosis
Progression of Aortic Sclerosis
* Hemodynamic progression usually slow
o Average rate of increase in aortic jet velocity of 0.3 m/s per year
o Increase in mean transaortic gradient of 7 mmHg
o Decrease in AVA of 0.1 cm2 per year
* Severe AS
o Aortic jet velocity > 4 m/s
o Mean transvalvular pressure gradient > 50 mmHg
o AVA < 1.0 cm2

Pathophysiology of Aortic Stenosis
* Obstruction of LV outflow increases intracavitary systolic pressures and leads to LV pressure overload
* Initial compensatory mechanism is myocardial hypertrophy with preservation of systolic function
* Diastolic function impaired as a consequence of increased wall thickness and abnormal myocardial relaxation
* Increased wall stress and afterload causes eventual decrease in ejection fraction

Pseudostenosis
* Occurs in patients with impaired systolic function and aortic stenosis
o Unable to generate transvalvular gradient
* Careful diagnostic testing with dobutamine infusion protocols can aid in differentiating between true AS and pseudostenosis
* If the calculated AVA increases with augmentation of cardiac output, then pseudostenosis present
* If AVA does not increase with dobutamine, then obstruction fixed and true AS present

Clinical Presentation of Aortic Stenosis
* Cardinal symptoms:
o Angina
+ Occurs in >50% of patients, not sensitive due to prevalence of CAD
o Syncope
o CHF
* Sudden cardiac death rare, <1% per year
* In earlier stages, AS presentation more subtle
o Dyspnea
o Decreased exercise tolerance
* Rarely, AS diagnosed in the setting of GI bleeding
o Heyde’s syndrome
+ Bleeding caused by AVM
+ Concurrent AS occurs at prevalence rate of 15-25%
+ Associated with an acquired von Willebrand syndrome due to disruption of vW multimers through a diseased AV

Management of Aortic Stenosis
* Prognosis in asymptomatic disease excellent
* Conservative approach with monitoring for symptoms recommended
* When severe stenosis present-
o 38% of asymptomatic patients develop symptoms within 2 years
o 79% are symptomatic within 3 years
* Once symptoms occur, AVR needed
* LV dysfunction and severe AS have increased perioperative mortality with AVR
o But outcomes still favorable with surgery
* Nitroprusside may transiently improve cardiac function as a bridge to valve replacement
o Does not supplant AVR in symptomatic patients

Aortic Valve Replacement
* Prophylatic AVR in asymptomatic patients not routinely performed due to surgical risks
o Thromboembolism, bleeding associated with anticoagulation, prosthetic valve dysfunction, and endocarditis
o Occurs at a rate of 2-3% annually
o Only should be considered:
+ If other cardiac surgery (such as CABG) planned
+ Severe LVH or systolic dysfunction
+ Women contemplating pregnancy
+ Patients remote from health care
* Surgical valve replacement with operative morbidity and mortality of 10%
* Percutaneous balloon aortic valvotomy rarely used

Mitral Stenosis
* Usually associated with history of rheumatic fever
* >40% of cases of RHD result in mitral stenosis
o Women affected more than men (2:1)
* Presentation 20-40 years after the initial episode of rheumatic fever
o If infected at a young age, latent period is a few years

Clinical Presentation of Mitral Stenosis
* Significant MS leads to ↑LA pressure and pulm HTN
* Symptoms include dyspnea with ↑ cardiac demand
o Exercise
o Pregnancy
* Survival excellent with asymptomatic or minimally symptomatic patients
o >80% survival at 10 years
* Survival in symptomatic patients much worse
o 10 year survival drops to 15% or lower (if pulm HTN present)
* Findings consistent with severe MS:
o Transvalvular diastolic pressure gradient >10 mmHg
o MVA <1.0 cm2
o Severe pulmonary hypertension (>60 mmHg)

Management of Mitral Stenosis
* Atrial fibrillation
Mitral Valve Repair
* Percutaneous valvotomy
Rheumatic Fever Prophylaxis
* Primary prophylaxis
* Secondary prophylaxis
Acute Aortic Regurgitation
Acute Mitral Regurgitation
Chronic Valvular Regurgitation
Chronic Aortic Regurgitation
Chronic Mitral Regurgitation
Treatment of Chronic Mitral Regurgitation
Timing of Intervention for Left-Sided Valvular Conditions
OTHERWISE
Repeat TTE yearly, repeat clinical evaluation biannually
OTHERWISE
Repeat TTE at least yearly, repeat clinical evaluation at least biannually depending on the severity of the LV dilitiation
OTHERWISE
Clinical evaluation at least annually, depending on the severity of the mitral stenosis
OTHERWISE
Depending on the severity of AS, at least annual clinical evaluation with TTE to monitor for symptom onset
Intervention:
AVR
Chronic Severe MR
Chronic Severe AR
Mitral Stenosis
Aortic Stenosis
Tricuspid Valve Disease
* Tricuspid stenosis is rare
o Associated with rheumatic heart disease
* TR usually occurs secondary to:
o Pulmonary hypertension
o RV chamber enlargement with annular dilatation
o Endocarditis (associated with IV drug use)
o Injury following pacer lead placement
* Other secondary causes: carcinoid, radiation therapy, anorectic drug use, and trauma
* Primary causes: Marfan’s syndrome and congenital disorders such as Ebstein’s anomaly and AV canal malformation
* Echo is diagnostic in most cases
Tricuspid Regurgitation
* Severe tricuspid regurgitation is difficult to treat and carries a poor overall clinical outcome
* Symptoms are manifestations of systemic venous congestion
* Surgical intervention usually considered if other cardiac surgery planned
* Surgical options include valvular annuloplasty or replacement

Prosthetic Valves- Mechanical
* Three types:
o Ball-cage valve
o Single tilting disk valve
o Bileaflet valve
* Durable but require life long anticoagulation
* For operative procedures, warfarin typically is discontinued for 48-72 hours and restarted postop as soon as possible, except for:
o Mechanical mitral prosthesis
o Atrial fibrillation
o Prior thromboembolic events
Ball-cage valve
Single tilting disk valve
Bileaflet valve
Prosthetic Valves- Biological
* Biological Valves
o Composed of autologous or xenograft biological material mounted on stents and a sewing ring
o Warfarin therapy not required due to lower thromboembolic potential
o Valve durability less when compared to mechanical valves
o Newer stentless valves with increased longevity

Anticoagulation Guidelines for Mechanical Valves
Prosthetic Valve Complications
* Common complications include:
o Structural valve deterioration
o Valve thrombosis
o Embolism
o Bleeding
o Endocarditis
* Endocarditis prophylaxis required for patients with all types of prosthetic valves
* Suspect valve dehiscence or dysfunction in:
o Acute CHF in the immediate postop period
o New cardiac symptoms
o Embolic phenomena
o Hemolytic anemia
o New murmurs
* TEE is the diagnostic procedure of choice
* Postop TTE should be done 2-3 months after surgery

Valve Thrombosis
* Incidence with mechanical prosthesis of 2-4 % per year
* Suspect in patients with new murmur, change in cardiopulmonary symptoms, or an embolic event
* Diagnosis based on clinical presentation, TTE/TEE, and fluroscopy
* In small thrombus, treatment with heparin may be adequate
* Optimal treatment for left sided thrombosis is emergency surgery
* Consider thrombolytic therapy for right sided thrombosis or if surgery cannot be performed with left sided disease
Endocarditis Prophylaxis

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Heart Murmurs



Heart Murmurs
By: David Leder

Outline

I. Basic Pathophysiology
II. Describing murmurs
III. Systolic murmurs
IV. Diastolic murmurs
V. Continuous murmurs
VI. Summary

Basic Pathophysiology
Murmurs = Math
Describing a heart murmur

1. Timing
o murmurs are longer than heart sounds
o HS can distinguished by simultaneous palpation of the carotid arterial pulse
o systolic, diastolic, continuous
2. Shape
o crescendo (grows louder), decrescendo, crescendo-decrescendo, plateau

3. Location of maximum intensity
o is determined by the site where the murmur originates
o e.g. A, P, T, M listening areas
4. Radiation
o reflects the intensity of the murmur and the direction of blood flow

5. Intensity
o graded on a 6 point scale
+ Grade 1 = very faint
+ Grade 2 = quiet but heard immediately
+ Grade 3 = moderately loud
+ Grade 4 = loud
+ Grade 5 = heard with stethoscope partly off the chest
+ Grade 6 = no stethoscope needed

*Note: Thrills are assoc. with murmurs of grades 4 - 6

6. Pitch
o high, medium, low
7. Quality
o blowing, harsh, rumbling, and musical
8. Others:
i. Variation with respiration

+ Right sided murmurs change more than left sided

ii. Variation with position of the patient

iii. Variation with special maneuvers

+ Valsalva/Standing => Murmurs decrease in length and intensity

EXCEPT: Hypertrophic cardiomyopathy and Mitral valve prolapse

Systolic Murmurs
* Derived from increased turbulence associated with:

1. Increased flow across normal SL valve or into a dilated great vessel
2. Flow across an abnormal SL valve or narrowed ventricular outflow tract - e.g. aortic stenosis
3. Flow across an incompetent AV valve - e.g. mitral regurg.
4. Flow across the interventricular septum

Early Systolic murmurs
1. Acute severe mitral regurgitation
2. Congenital, small muscular septal defect
3. Tricuspid regurg. with normal PA pressures

Midsystolic (ejection) murmurs
* Are the most common kind of heart murmur
* Are usually crescendo-decrescendo
* They may be:
1. Innocent
2. Physiologic
3. Pathologic

Aortic stenosis
* Loudest in aortic area; radiates along the carotid arteries
* Intensity varies directly with CO
* A2 decreases as the stenosis worsens
* Other conditions which may mimic the murmur of aortic stenosis w/o obstructing flow:

1. Aortic sclerosis
2. Bicuspid aortic valve
3. Dilated aorta
4. Increased flow across the valve during systole

Hypertrophic cardiomyopathy
Pansystolic (Holosystolic) Murmurs
1. Mitral valve regurgitation
2. Tricuspid valve regurgitation
3. Ventricular septal defect
Diastolic Murmurs
* Almost always indicate heart disease
* Two basic types:

1. Early decrescendo diastolic murmurs
2. Rumbling diastolic murmurs in mid- or late diastole

Aortic Regurgitation
* Best heard in the 2nd ICS at the left sternal edge
* High pitched, decrescendo
* Blowing quality => may be mistaken for breath sounds
* Radiation:

Mitral Stenosis
* Two components:
1. Middiastolic - during rapid ventricular filling
2. Presystolic - during atrial contraction; therefore, it disappears if atrial fibrillation develops
Continuous Murmurs

1. Cervical venous hum
2. Mammary souffle
3. Patent Ductus Arteriosus
4. Pericardial friction rub
Back to the Basics
1. When does it occur - systole or diastole
2. Where is it loudest - A, P, T, M
I. Systolic Murmurs:
1. Aortic stenosis - ejection type
2. Mitral regurgitation - holosystolic
3. Mitral valve prolapse - late systole

II. Diastolic Murmurs:
1. Aortic regurgitation - early diastole
2. Mitral stenosis - mid to late diastole

Summary
A. Presystolic murmur
o Mitral/Tricuspid stenosis
B. Mitral/Tricuspid regurg.
C. Aortic ejection murmur
D. Pulmonic stenosis (spilling through S20
E. Aortic/Pulm. diastolic murmur
F. Mitral stenosis w/ Opening snap
G. Mid-diastolic inflow murmur
H. Continuous murmur of PDA

Heart Murmurs.ppt

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Valvular Heart Disease



Valvular Heart Disease

Medical Surgical I
Types
* Mitral Stenosis
* Mitral Regurgitation
* Mitral Valve Prolapse
* Aortic Stenosis
* Aortic regurgitation
* Tricuspid valve is affected infrequently
o Tricuspid stenosis – causes Rt HF
o Tricuspid regurgitation –causes venous overload

Tricuspid Valve
Rheumatic Heart Disease
* Inflammatory process that may affect the myocardium, pericardium and or endocardium
* Usually results in distortion and scarring of the valves
* Subjective symptoms
o Prior history of rheumatic fever
o General malaise
o Pain – may or may not be present
* Objective symptoms
o Temperature
o Murmurs
o Dyspnea
o polyarthritis
* Diagnosis
o H/P
o WBC and ESR
o C-reactive protein
o Cardiac enzymes
o EKG
o Chest x-ray
o Echo
o Cardiac cath
o Cardiac output
* Nursing Care
o Vital signs
o Rest and quiet environment
o Give antibiotics, digitalis, and diuretics
o Provide adequate nutrition
o Monitor I/O
o Explain treatment and home care

Mitral Stenosis
* Usually results from rheumatic carditis
* Is a thickening by fibrosis or calcification
* Can be caused by tumors, calcium and thrombus
* Valve leaflets fuse and become stiff and the cordae tendineae contract
* These narrows the opening and prevents normal blood flow from the LA to the LV
* LA pressure increases, left atrium dilates, PAP increases, and the RV hypertrophies
* Pulmonary congestion and right sided heart failure occurs
* Followed by decreased preload and CO decreases
* Mild – asymptomatic
* With progression – dyspnea, orthopneas, dry cough, hemoptysis, and pulmonary edema may appear as hypertension and congestion progresses
* Right sided heart failure symptoms occur later
* S/S
o Pulse may be normal to A-Fib
o Apical diastolic murmur is heard

Mitral Regurgitation
* Primarily caused by rheumatic heart disease, but may be caused by papillary muscle rupture form congenital, infective endocarditis or ischemic heart disease
* Abnormality prevents the valve from closing
* Blood flows back into the right atrium during systole
* During diastole the regurg output flows into the LV with the normal blood flow and increases the volume into the LV
* Progression is slowly – fatigue, chronic weakness, dyspnea, anxiety, palpitations
* May have A-fib and changes of LV failure
* May develop right sided failure as well

Mitral Valve Prolapse
* Cause is variable and may be associated with congenital defects
* More common in women
* Valvular leaflets enlarge and prolapse into the LA during systole
* Most are asymptomatic
* Some may report chest pain, palpitations or exercise intolerance
* May have dizziness, syncope and palpitations associated with dysrhythmias
* May have audible click and murmur

Aortic Stenosis
* Valve becomes stiff and fibrotic, impeding blood flow with LV contraction
* Results in LV hypertrophy, increased O2 demands, and pulmonary congestion
* Causes – rheumatic fever, congenital, arthrosclerosis
* Atherosclerosis and calcification is primary cause in the elderly
* Complications – right sided heart failure, pulmonary edema, and A-fib
* S/S – Early: dyspnea, angina, syncope

Aortic Regurgitation
* Aortic valve leaflets do not close properly during diastole
* The valve ring that attaches to the leaflets may be dilated, loose, or deformed
* The ventricle dilates to accommodate the ^ blood volume and hypertrophies
* Causes: infective endocarditis, congenital, hypertension, Marfan’s
* May remain asymptomatic for years
* Develop dyspnea, orthopnea, palpitations, ,and angina
* May have ^ systolic pressure with bounding pulse
* Have a high pitch, blowing, decrescendo diastolic murmur

Assessment for Valve Dysfunction
* Subjective symptoms
o Fatigue
o Weakness
o General malaise
o Dyspnea on exertion
o Dizziness
o Chest pain or discomfort
o Weight gain
o Prior history of rheumatic heart disease
* Objective symptoms
o Orthopnea
o Dyspnea, rales
o Pink-tinged sputum
o Murmurs
o Palpitations
o Cyanosis, capillary refill
o Edema
o Dysrhythmias
o Restlessness

Diagnosis
* History and physical findings
* EKG
* Chest x-ray
* Cardiac cath
* Echocardiogram

Medial Treatment
* Nonsurgical management focuses on drug therapy and rest
* Diuretic, beta blockers, digoxin, O2, vasodilators, prophylactic antibiotic therapy
* Manage A-fib, if develops, with conversion if possible, and use of anticoagulation

Interventions
* Assess vitals, heart sounds, adventitious breath sounds
* ^ HOB
* O2 as prescribed
* Emotional support
* Give medications
* I/O
* Weight
* Check for edema
* Explain disease process, provide for home care with O2, medications

Surgical Management of Valve Disease
* Mitral Valve
o Commissurotomy
o Mitral Valve Replacement
o Balloon Valvuloplasty
* Aortic Valve Replacement

Mechanical Valve
Porcine Valve
Tissue Valve

Valvular Heart Disease.ppt

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Developmental Toxicology



Developmental Toxicology

* Structural malformations
* Growth retardation
* Functional impairment
* Death of the organism
4 manifestations of developmental toxicity

Teratology
1. the study of malformations or serious deviations from the normal type in organisms

2. the branch of science concerned with the production, development, anatomy, and classification of malformed fetuses.

* Teratogen
o Any agent that causes a birth defect
o After Greek “monster creating”
* Environmental conditions (1200)
* Maternal nutritional deficiencies (1930)
* Rubella virus infection (1941)
* Thalidomide (1961)

Adverse Outcomes in Pregnancy
Cause of human birth defects
Chemical teratogenicity
Pregnancy Risk Categories
Therapeutic Drugs Teratogenic to Humans
* Anticonvulsants
o Phenytoin, primidone, trimethadione, valproic acid, carbamazepine
* Anticancer agents
o Alkylating agents –busulfan, cyclophosphamide, chlorambucil, mechlorethamine
o Antimetabolites-aminopterin, methotrexate, cytarabine
* Androgenic hormones-danazol
* Coumarin anticoagulants-warfarin
* Retinoids-accutane, isotretinoin, etretinate, acitretin
* Antihyperlipidemic agents-lovastatin, atorvastatin
* Other drugs-diethystilbestrol, thalidomide, penicillamine, lithium, fluconazole, misoprostol
Thalidomide
Diethylstilbesterol (DES)
Alcohol (Ethanol)
Fetal Alchohol Syndrome (FAS)
Fetal Alchohol Effects (FAE)
* Cranial facial dysmorphism
* Intrauterine and postnatal growth retadation
* Retarded psychomotor and intellectual development
* IQ 68

Tobacco smoke
* Spontaneous abortions
* Perinatal deaths
* Lower birth weight
* Increased risk of
o Sudden infant death syndrome
o Behavioral attention disorders
o Orofacial cleft (particular xenobiotic gene polymorphisms)
o Gastroschisis (with variant alleles N053, ICAM1, NPPA)
o Branching morphogenesis and maturation of the lung
* Nicotine-related adverse nerodevelopmental outcomes
Cocaine
* At risk for premature labor, spontaneous abortion, increased perinatal mortality and fetal death.
* intrauterine growth retardation, microcephaly, altered presencephalic development, decreased birth weight, a neonatal neurologic syndrome of abnormal sleep, tremor, poor feeding, irritability, and occasional seizures.
* Genitaouinary tract malformation
* Impaired uditory process

Retinoic Acid
Retinoic acid is the active ingredient in “Accutane”, a drug used to treat severe acne. Since its introduction in September of 1982, an estimated 160,000 women of child bearing age have ingested the drug. Between 1982 and 1987, approximately 900-1300 malformed children, 700-1000 spontaneous abortions and 5000-7000 elective abortions are due to Accutane exposure. Exposed children may have hydrocephaly, ear malformations, cardiovascular defects and decreased IQ. Accutane carries a pregnancy category X warning, meaning it is a known human teratogen.
c acid
Retinoids
* Malformations of the face, limbs, heart, CNS, and skeleton
* RXR α receptor
* Schizophrenia
Retinoid Therapies
Tretinoin/ATRA (Vesanoid)
Leukemia
Adapalene (Differin),
Tretinoin (Renova),
Isotretinoin (Accutane)
Acne
Tazartene (Zorac),
Etritinate (Tegison)
Psoriasis
Drugs
RAR and RXR (Simple Version)
* Nuclear Receptors (like ER, PPAR, VDR and others)
* RXR/RAR Heterodimer is functional unit
* Bind selectively to REs in genome
* Act as transcription factors
* Up-regulate or Repress the expression of particular genes

Valproic acid was released in 1967 in Europe and in 1978 in the United States to treat epilepsy. Approximately 11,500 epileptic women become pregnant each year, many of which use valproic acid. By 1980, publications began linking malformed children to in utero exposure to valproic acid (greater than 500 mg/day).

Valproic Acid
* spina bifida with menigomyelocele or menigocele
* The proposed mechanism of action is that valproic acid influences folate metabolism

Angiotensin Converting enzyme inhibitors and angiotensin antagonists
* 2-3 trimester
* related reduced amniotic fluid volume and impaired fetal renal function
o Oligohydromnios
o Fetal growth retardation
o Pulmonary hypoplasia
o Renal failure
o Hypotension
o Death
* First trimester
o Congenital malformation

Wilson’s General Principles of Teratology (Table 10-2)
* Susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this interacts with environmental factors.
* Susceptibility to teratogenic agents varies with the developmental stage at the time of exposure.
* Teratogenic agents act in specific ways (mechanisms) on developing cells and tissues to initiate abnormal embryogenesis (pathogenesis).
* The final manifestations of abnormal development are death, malformation, growth retardation, and functional disorder.
* The access of adverse environmental influences to developing tissue depends on the nature of the influences (agent).
* Manifestations of deviant development increase in degree as dosage increases from the no-effect to the totally lethal level.
Critical periods of susceptibility and endpoints of toxicity
* Gametogenesis and Fertilization

Mechanism unclear, may be related to imprinting
Cytosine methylation and change in chromatin conformation ethylene oxide, ethylmethane sulfonate, ethylnitrosourea→malformed fetus

DNA Methylation vs Genomic Imprinting
Mechanisms and pathologenesis of developmental toxicology

* Mutations
* Chromosomal breaks
* Altered mitosis
* Altered nucleic acid integrity or function
* Diminished supplies or precursors of substrates
* Decreased energy supplies
* Altered membrane characteristics
* Osmolar imbalance
* Enzyme inhibition
Example of cyclophosphamide (CP)
Single strand DNA break
A teratogenic chemotherapeutic agent
CP induces DNA damage
Advances in the Molecular basis of dysmorphogenesis
1.Using either singly or double gene knockout Retinoic acid receptor family (syndactyly)
2. Antisense oligonucleotide Wnt-1, Wnt-3a (mid and hindbrain malformation)
3. Reporter transgenes

Pharmacokinetics and metabolism in pregnancy
1.Changes in maternal physiology
hepatic metabolism, GI tract, cardiovascular system, excretory system, respiratory system
2.Overall decrease in hepatic xenobiotic transformation
3.Roles of placenta in influence embryonic exposure help to regulate blood flow
-offer a transport barrier-pH gradient, weak acid rapidly transfer
-metabolize chemicals
2-acetylaminofluorene (proteratogen)
7-hydroxyl metabolites(proximate teratogen)
4.Maternal metabolism of xenobiotics 2-methoxyethanol 2-methoxyacetic acid

Placental toxicity
* Metals, Cd, As, Hg, ethanol, cocaine, cigaratte, sodium salicylate
* Maternal injection vs fetal injection of Cd
* Production of metallothionein
* Interaction with Zn

Maternal toxicity-
* acetazolamide inhibits carbonic anhydrase forelimb ectrodactyly

* diflunsial results in anemia skeleton defects in rabbits
* phenytoin affects folate metabolism and heart rates
* metallothionein synthesis inducer-urathane, mercaptopurine, valproic acid Zn deficiency

Develpmental toxicity of endocrine-disrupting chemicals
Definition of endocrine-disrupting chemicals
“Exogenous agent that interferes with the production, release, transport, metabolism, binding, action, or elimination of natural hormones responsible for the maintenance of homeostasis and the regulation of developmental processes.”
Endocrine-disrupting chemicals
Four modes of action
1. Serving as steroid receptors ligands
2. Modifying steroid hormone metabolizing enzymes
3. Perturbing hypothalamic-pituitary release of trophic hormones
4. Uncharacterized proximate modes of action

Fetal Basis and Transgenerational Transmission of Reduced Fertility
Environmental Epigenetics
Decreased spermatogenic capacity and decreased fertility ..as well as increased prevalence of other diseases transferred via MALE germ line

Summary
* A transient embryonic exposure to endocrine disruptors at the time of gonadal sex determination can cause epigenetic transgenerational disease state of subfertility and spermatogenic defects in F1 through F4 generations
* Transgenerational disease phenotype was primarily transmitted through the male germ line
* Exposure appears to have caused an epigenetic reprogramming of the germ cell line that is “permanent” and transferred transgenerationally to subsequent generations

Modern safety assessment
* Regulatory guidelines for in vivo testing
* Multigeneration tests
* Children’s health and the food quality protection act
o Tenfold safety factor for children
* Alternative testing strategies
* Epidemiology
* Concordance of data (among species)
* Elements of risk assessment
use-in pregnancy rating: A, B, C, D, X

In Vivo Regulatory Protocol Guideline
The 17 intercellular signaling pathways by most metazoans
* Early development and later
* 1. Wnt pathway
* 2. Receptor serine/threonine kinase (TGFb) pathway
* 3. Hedgehog pathway
* 4. Receptor tyrosine kinase (small G proteins) pathway
* 5. Notch/Delta pathway
* Mid-development and later
* 6. Cytokine receptor (cytoplasmic tyrosine kinases)
* pathway
* 7. IL1/Toll NFkB pathway
* 8. Nuclear hormone receptor pathway
* 9. Apoptosis pathway
* 10. Receptor phosphotyrosine phosphatase pathway
* Larval/adult physiology
* 11. Receptor guanylate cyclase pathway
* 12. Nitric oxide receptor pathway
* 13. G-protein coupled receptor (large G proteins) pathway
* 14. Integrin pathway
* 15. Cadherin pathway
* 16. Gap junction pathway
* 17. Ligand-gated cation channel pathway

Sonic Hedge-hog signal pathway
cyclopamine
jervine
Holoprosencephaly
Cholesterol synthesis inhibitor
Consequences of Folate Deficiency
* Result of low dietary intake, genetic error of folate metabolism, lifestyle exposures
* DNA Hypomethylation
o Gene overexpression, uncontrolled cell growth, genomic instability
* Hyperhomocysteinemia
o Excessive accumulation of Hcy
* Base Misincorporation
o Decrease in thymine synthesis; replaced by uracil
o DNA strands prone to nicks, breaks and vulnerable to mutagen insertion
Homework

1. Describe the possible mechanisms for teratogenic effects of the following chemicals.
a. aminoglycosides
b. ethylene oxide
c. captopril
d. danazol
e. aminopterin
f. Accutane

Developmental Toxicology.ppt

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