Surgical Preparation and Instrument Care

Surgical Preparation and Instrument Care

Sanitation, Disinfection and Sterilization

Learning Outcomes
After this section is completed you should be able to:
List the classes of pathogenic organisms in order of their resistance to destruction
Differentiate between sanitation, disinfection and sterilization
List the different ways that microbial control methods destroy or inhibit pathogenic organisms

After this section is completed you should be able to:
List the five categories of physical methods of microbial control
Name and describe the physical methods of microbial control
Identify the level of microbial control achieved with each of the physical methods
State an example of the application of each of the physical methods of microbial control

List the properties of the “ideal chemical agent” for microbial control
Name and describe the classes of microbial control chemicals
Identify the level of microbial control achieved by the chemical classes

List the advantages and disadvantages of the autoclave in animal care facilities
Explain the function of the autoclave
Compare and contrast the different autoclaves

Describe the preparation of each of the following for processing in the autoclave: linen packs, pouch packs, hard goods, liquids and contaminated objects
List the guidelines for loading the autoclave chamber
Compare the three different autoclave cycles

List and define the five methods of quality control for sterilization
List and define the two methods of quality control for disinfection

Section Outline
Levels of microbial resistance
Degrees of microbial control
How microbial control methods work
Methods of microbial control
Autoclave
Quality control for sterilization and disinfection

Overarching Principle
The objective in sanitation, sterilization and disinfection is to control microorganisms, or pathogens, in the environment, thus protecting patients and staff from contamination and disease, and thereby promoting optimal healing and wellness.

The Ever Present Danger
Improper application of the methods of sanitation, sterilization and disinfection can lead to microbial resistance and increase the risk of nosocomial infection

Levels of Microbial Resistance
Pathogens
Microorganisms that cause disease
Viruses
Bacteria
Fungi
Protozoan
Prions
Different classes of pathogens vary in their resistance to destruction by chemical methods

Protozoan Cysts
Bacterial Spores
Non-enveloped virus
TB organisms
Enveloped viruses
Fungi
Vegetative bacteria


Most Resistant
Least Resistant
Levels of Microbial Resistance
Microbial control
Is achieved by using methods of sanitation, disinfection and sterilization
Microbial control
Done to a degree that is practical, efficient and cost effective

Levels of Microbial Resistance
Sterility is used only when necessary

In many situations sanitation and disinfection create acceptable levels of microbial control

Degrees of Microbial Control
Sterilization is the elimination of all life from an object
Complete microbial control
Asepsis is a condition in which no living organisms are present
Free of infection or infectious material

Degrees of Microbial Control
Sanitation: The state of being clean and conducive to health.

Disinfection: To cleanse so as to destroy or prevent the growth of disease-carrying microorganisms

Degrees of Microbial Control
Disinfection, sanitation and cleaning remove most microorganisms
Most disinfectants are microbiocidal
Microbes are killed
Some disinfectants are bacteriostatic
Microbial growth is inhibited

Degrees of Microbial Control
Disinfectants can be classified according to their spectrum of activity
Bacteriocidal
Bacteriostatic
Sporocidal
Virucidal
Fungicidal

How Microbial Control Methods Work
Mode of Action
Different physical and chemical methods destroy or inhibit microbes in several ways
Damage cell walls or membranes
Interfere with cell enzyme activity or metabolism
Destroy microbial cell contents through oxidation, hydrolysis, reduction, coagulation, protein denaturation or the formation of salts

Efficacy of Microbial Control
The effectiveness of all microbial control methods depends on the following factors:
Time
Most methods have minimum effective exposure times
Temperature
Most methods are more effective as temperature increases

Efficacy of Microbial Control
The effectiveness of all microbial control methods depends on the following factors:
Concentration and Preparation
Chemical methods require appropriate concentrations of agent
Disinfectants may be adversely affected by mixing with other chemicals
Organisms
Type, number and stage of growth of target organisms

Efficacy of Microbial Control
The effectiveness of all microbial control methods depends on the following factors:
Surface
Physical and chemical properties of the surface to be treated may interfere with the method’s activity
Some surfaces are damaged by some methods

Efficacy of Microbial Control
The effectiveness of all microbial control methods depends on the following factors:
Organic debris or other soils
Will dilute, render ineffective or interfere with many control methods
Method of application
Items may be sprayed, swabbed or immersed in disinfectants
Cotton and some synthetic materials may reduce chemical activity

Methods of Microbial Control
Physical Methods
Chemical Methods

Physical Methods
Dry Heat
Oxidation
Moist Heat
Denatures microbial protein
Radiation
Damages cell enzyme systems and DNA
Filtration
Traps organisms that are too large to pass through the filter
Ultrasonic Vibration
Coagulates proteins and damages cell walls

Dry Heat
Incineration
Material or object is exposed to a hot fire
Object must become red hot as in the inoculation loops used in microbiology
Used to dispose of tissue or carcasses
Efficacy: complete sterilization

Dry Heat
Hot Air Oven
Sterility requires 1 hour of exposure @ 170° C(340° F)
Powders and non-aqueous liquids like paraffin or Vaseline
Used in some animal care facilities and useful in domestic applications (e.g. the kitchen oven)
Efficacy: complete sterilization

Dry Heat
Drying
Most organisms require humidity to survive and grow
More commonly used to prevent spoiling and preserve foodstuffs (e.g. raisins)
Efficacy: incomplete sterilization

Moist Heat
Hot Water
Used to clean and sanitize surfaces
Addition of detergents increases efficacy by emulsifying oils and suspending soils so they are rinsed away
Efficacy: incomplete sterilization

Moist Heat
Boiling
Requires 3 hours of boiling to achieve complete sterilization
Boiling for 10 minutes will destroy vegetative bacteria and viruses but not spores
Addition of 2% calcium carbonate or sodium carbonate will inhibit rust and increase efficacy
Useful for field work
Efficacy: may be complete sterilization

Moist Heat
Steam
Similar to boiling because the temperature is the same
Exposure to steam for 90 minutes kills vegetative bacteria but not spores
Efficacy: incomplete sterilization

Moist Heat
Steam under pressure
Pressure increases the boiling point such that the temperature of the water becomes much higher that 100° C (212° F)
The autoclave utilizes steam under pressure to achieve sterilization
This is the most efficient and inexpensive method of sterilization for routine use
Efficacy: complete sterilization

Radiation
Ultraviolet (UV)
Low energy UV radiation is a sterilant when items are placed at a close range
UV radiation has no penetrating ability
Used to sterilize rooms
Very irritating to eyes
Efficacy: may be complete sterilization

Radiation
Gamma radiation
Ionizing radiation produced from a Cobalt 60 source
Good penetrating ability in solids and liquids
Used extensively in commercial preparation of pharmaceuticals, biological products and disposable plastics
Efficacy: complete sterilization

Filtration
Fluid filtration
Forced through a filter with either positive or negative pressure
Filter is most commonly a synthetic screen filter with micropore openings
Used to sterilize culture media, buffers and pharmaceuticals
Pore size of 0.45µm removes most bacteria
Microplasmas and viruses require 0.01µm to 0.1µm
May be used in conjunction with a pre-filter
Efficacy: can be complete sterilization

Filtration
Air filtration
Examples of usage: surgical masks, laboratory animal cages and air duct filters
Fibrous filters made of various paper products are effective for removing particles from air
Efficacy is influenced by air velocity, relative humidity and electrostatic charge
Efficacy: can be complete sterilization

Filtration
Air filtration
HEPA: high efficiency particle absorption filters are 99.97% to 99.997% effective in removing particles with diameters greater that 0.3µm

Filtration
Air filtration
Surgical masks
Designed to protect the patient from the surgeon, not the surgeon from the patient
Special masks are available that are designed to protect personnel from animal pathogens
Masks must fit snugly, stay dry and be changed every 3 to 4 hours to remain effective

Ultrasonic Vibration
Cavitation
High frequency sound waves passed through a solution create thousands of cavitation “bubbles”
Bubbles contain a vacuum; as they implode or collapse, debris is physically removed from objects
Effective as an instrument cleaner
Efficacy: incomplete sterility

Chemical Methods
Many chemicals are available to sterilize, disinfect or sanitize
None is the “ideal” agent
Chemicals penetrate cell walls and react with cell components in various ways to destroy or inhibit growth
Many chemicals are disinfectants with varying levels of efficacy
Some are sterilants

Chemical Methods

Bacteria Viruses

Level Vegetative Acid-fast Spores Lipophilic Hydrophilic

High + + + + +

Medium + + 0 + +/-

Low + 0 0 +/- 0

Examples:

High: Aldehydes, VPHP, Chlorine-dioxide

Medium: Alcohols, Phenols, 7th generation Quats

Low: Quats

Ethylene oxide

Aldehydes

Vapor phase H2O2

Halogens

Phenols

7th generation quaternary

Alcohols

Chlorhexidine

Old generation quaternary

High-cidal

Activity

Low-cidal

Activity

Chemical Methods
Ideal chemical agent
Broad spectrum of activity
Does not stain or damage surfaces
Stable after application
Effective in a short time
Nonirritating and nontoxic to surfaces and tissues
Inexpensive and easy to store and use
Not affected by organic debris or other soil
Effective at any temperature
Nontoxic, nonpyrogenic and nonantigenic
Possesses residual and cumulative action

Chemical Methods
Soaps
Detergents
Quaternary ammonium compounds
Phenols
Aldehydes
Halogens
Chlorine and chlorine releasing compounds
Alcohols
Peroxygen compounds
Ethylene Oxide

Chemical Methods
Soaps
Anionic cleaning agent made from natural oils
Ineffective in hard water
Does not mix well with quats and decreases the effectiveness of halogens
Is not antimicrobial
Minimal disinfectant activity

Chemical Methods
Detergents
Synthetic soaps
Anionic, cationic or nonionic; anionic combined with cationic will lead to neutralization of both
Most are basic; a few are acidic
Emulsify grease and suspend particles in solution
May contain wetting agents

Chemical Methods
Quaternary Ammonium Compounds
Quats: Centrimide, benzalkonium chloride, Zephiran, Quatsyl-D, Germiphene
Effective against gm+ and gm- microorganisms and enveloped viruses
Low toxicity and generally nonirritating
Prolonged contact irritates epithelial tissues

Chemical Methods
Quaternary Ammonium Compounds
Inactivated by organic material, soap, hard water and cellulose fibers
Reduced efficacy in presence of organic debris, soap, detergents and hard water
Ineffective sporocide and fungicide
Bacteria not destroyed may clump together; those inside the clump are protected
Dissolves lipids in cell walls and cell membranes

Chemical Methods
Quaternary Ammonium Compounds
Organically substituted ammonium compounds
More effective in basic pH
Cationic detergent
Deodorizes


Chemical Methods
Phenols
Active against gm+ bacteria and enveloped viruses
Developed from phenol or carbolic acid
Synthetic phenols are prepared in soap solutions that are nontoxic and nonirritating
Prolonged contact may lead to skin lesions

Chemical Methods
Phenols
Toxic to cats because cats lack the inherent enzymes needed to detoxify the compound
May be toxic to rodents and rabbits
Not inactivated by organic matter, soap or hard water
Activity decreased by quats

Chemical Methods
Aldehydes
Active against gm+ and gm-, most acid fast bacteria, bacterial spores, most viruses and fungi
Considered to be a sterilant but may require prolonged contact

Chemical Methods
Aldehydes
Gluteraldehyde (Cidex)
Noncorrosive
Supplied as an acid, activated by adding sodium bicarbonate
Good for plastics, rubber, lenses in “cold sterilization”
Not inactivated by organic material or hard water
Irritating to respiratory tract and skin

Chemical Methods
Aldehydes
Formaldehyde (Formicide)
Aqueous solution 37% to 40% (w/v) formaldehyde
May be diluted with water or alcohol
Irritating to tissues and respiratory tract
A vapor phase surface disinfectant that slowly yields formaldehyde

Chemical Methods
Aldehydes
Biguanide (e.g. chlorhexidine gluconate [Hibitane, Precyde])
Active against gm+, most gm-, some lipophilic viruses and fungi
Efficient disinfectant, used mostly as an antiseptic
Some reduction of activity in presence of hard water and organic material
Immediate, cumulative and residual activity
Precipitates to an inactive form when mixed with a saline solution
Used as a surgical scrub and hand wash
Low toxicity

Chemical Methods
Halogens
Chlorine, iodine, fluorine and bromine
Active against gm+ and gm-, acid fast, all viruses and fungi
Iodine most common
Chlorine and chlorine releasing compounds

Chemical Methods
Halogens
Iodine
Used in solution with water or alcohol
Iodophors: iodine plus carrier molecule that acts to release iodine over time
Surgical scrub (Betadine): iodophor plus detergent
Tinctures and solutions: iodines and iodophors w/o detergent
Nonstaining and nonirritating
Inactivated by organic material
Aqueous forms are staining, irritating and corrosive to metals, especially if used undiluted

Chemical Methods
Halogens
Chlorine and chlorine releasing compounds (e.g. chlorine gas, chlorine dioxide)
Commonly available as sodium hypochlorite
Least expensive and most effective chemical disinfectant
Available chlorine equals oxidizing ability
Damages fabrics, corrosive to metals
Inactivated by organic debris
May require several minutes of contact to be effective
Skin and mucous membrane irritant if not diluted properly or rinsed well

Chemical Methods
Alcohols
Ethyl alcohol, isopropyl alcohol, methyl alcohol
Active against gm+ and gm- bacteria and enveloped viruses
Most effective when diluted to 60% to 70% (isopropyl), 705 to 80% (ethyl)

Chemical Methods
Alcohols
Used as a solvent for other disinfectants and antiseptics
Most commonly used skin antiseptic
Low cost and low toxicity

Chemical Methods
Alcohols
Irritating to tissues and painful on open wounds
Repeated use dries skin
Forms coagulum in presence of tissue fluid
Consists of a layer of tissue fluid whose proteins have been denatured by alcohol
Facilitates survival of bacteria under the coagulum
Fogs lenses, hardens plastics and dissolves some cements

Chemical Methods
Alcohols
Inactivated by organic debris
Ineffective after evaporation
Defatting agent

Chemical Methods
Peroxygen compounds (e.g. Peracetic acid)
Active against gm+ and gm-, acid-fast, fungi.
No virucidal activity
Classified as a sterilant but may not kill pinworm eggs

Chemical Methods
Peroxygen compounds (e.g. Peracetic acid)
Oxidizing agent
Reacts with cellular debris to release oxygen
Kills anaerobes
Applied as a 2% solution for 30 minutes at 80% humidity
Explosive and can damage iron, steel and rubber
Irritating to healthy tissues

Chemical Methods
Ethylene Oxide
Active against gm+ and gm-, lipophilic and hydrophilic viruses, fungi and bacterial spores
Classified as a sterilant
Effective sterilant for heat labile objects

Chemical Methods
Ethylene Oxide
EO is a colorless nearly odorless gas that diffuses and penetrates rapidly
Flammable and explosive
Toxic, carcinogenic and irritating to tissue

Chemical Methods
Ethylene Oxide
Used in a chamber with a vacuum
May be mixed with CO2, ether or freon
Used at temperatures of 21° to 60° C (70° to 140° F)
Works quicker at higher temperatures
Exposure times of 1 to 18 hours
Requires minimum relative humidity of 30% (40% is optimum
Items must be clean and dry and can be wrapped muslin, polyethylene, polypropylene or polyvinyl
Sterilized items must be ventilated in a designated area for 24 to 48 hours to dissipate residual EO

Autoclave
Advantages
Consistently achieves complete sterility
Inexpensive and easy to operate
Safe for most surgical instruments and equipment, drapes and gowns, suture materials, sponges and some plastics and rubbers
Safe for patients and personnel
Established protocols and quality control indicators are easy to access

Autoclave
Disadvantages
Staff may overestimate the ability of the autoclave
Sterility depends on saturated steam of the appropriate temperature having contact with all objects within the unit for a sufficient length of time
Requires a thorough understanding of techniques to ensure that the above occurs

Autoclave
Function
Heat is the killing agent
Steam is the vector that supplies the heat and promotes penetration of the heat
Pressure is the means to create adequately heated steam

Autoclave
Function
Complete sterilization of most items is achieved after 9 to 15 minutes exposure to 121° C (250° F)
Steam at sea level is 100° C (212° F) as pressure is increased the temperature of the steam increases
The minimum effective pressure of the autoclave is 15 pounds per square inch which provides steam at 121° C (250° F)
Many autoclaves attain 35 psi which creates steam temperature of 135° C (275° F)

Autoclave
Function
Exposure times must allow penetration and exposure of all surfaces to 121°C (250° F) steam
Exposure time is decreased by increasing pressure, which increases steam temperature

Steam Sterilization Temperature/
Pressure Chart

Temperature

Pressure(psi) °C °F Time(mins)

0 100 212 360

15 121 250 9-15

20 125 257 6.5

25 130 266 2.5

35 133 272 1

Autoclave
Types
Gravity displacement autoclave
Prevacuum autoclave

Autoclave
Types
Gravity displacement
Water is heated in a chamber
Continued heating creates pressure
Steam displaces air within the chamber forcing it out through a vent
Cycle timing begins when the temperature reaches at least 121°C

Autoclave
Types
Gravity displacement
After sufficient exposure time, steam is exhausted through a vent back into a reservoir
Air that has been sterilized within the jacket and then filtered is admitted back into the chamber to replace the exhausting steam
If the chamber is loaded improperly or there is insufficient steam, there will be air pockets remaining in the chamber that will interfere with steam penetration and result in non-sterile areas
The load must be dried within the autoclave

Autoclave
Types
Prevacuum
Usually a much larger and more costly machine
Equipped with a boiler to generate steam and a vacuum system
Air is taken out of the loaded chamber by means of the vacuum system
Steam at 121°C or more is introduced into the chamber
The steam immediately fills the chamber to eliminate the vacuum
Exposure time begins immediately
At completion of the cycle steam is vacuumed and replaced by hot, dry sterile air
Air pockets are eliminated and processing times are reduced due to the vacuum

Autoclave
Operation
Preparation of the load
Loading the chamber
Autoclave cycles

Autoclave
Operation
Preparation of the load
Linen packs
Pouch packs
Hard goods
Liquids
Contaminated objects

Autoclave
Linen packs
All instruments in packs are scrupulously cleaned and rinsed in de-ionized water
Instruments are disassembled and ratchets are left closed and unlocked
Appropriate lines are in good repair and freshly laundered
Disposable linens are not reused

Autoclave
Linen packs
A chemical sterilization indicator is included in every pack
Chemical sterilization indicators provide verification that the inside of the pack was exposed to appropriate sterilization temperatures for the appropriate length of time

Autoclave
Linen packs
The pack is wrapped using at least two layers of material
The shelf life of the sterilized pack varies with the type of the outer wrapping
Pack is sealed with autoclave tape and labeled with the date, contents and operator
Autoclave tape provides verification that the outside of the pack was exposed to appropriate sterilization temperatures

Autoclave

SHELF LIFE

Wrapper Shelf-life

Dbl wrapped two layer muslin 4 wk

Dbl wrapped two layer muslin 6 mo

heat sealed in dust covers

after sterilization

Dbl wrapped two layer muslin 2 mo

tape sealed in dust covers

after sterilization

Dbl wrapped non-woven barrier 6 mo

materials (paper)

Paper/plastic peel pouches, heat sealed 1 year

Plastic-peel pouches, heat sealed 1 year

Autoclave
Linen packs
Pack should not exceed 30 X 30 X 50 cm (12 X 12 X 20 inches) in size
Pack should not exceed 5.5 kg (12 lb) in weight
Pack should not exceed 115 kg/m3 in density

Autoclave
Pouch packs
Used for single instruments, sponges, etc.
Previous guidelines apply
Pouches are heat sealed or ends are rolled and securely taped with autoclave tape
Labeled as above

Autoclave
Hard goods
Stainless steel or other hard instruments, trays, bowls, laboratory cages and other equipment may be autoclaved without wrapping
Must be physically clean and rinsed in de-ionized water
Syringes and plungers are separated before autoclaving

Autoclave
Liquids
Contained in Pyrex flasks 3 times larger than contents require
Cover loosely with applied lid or paraffin film, or place a needle through the stopper to allow air exchange
Sterility of liquids processed in the autoclave is in question
Removing liquids from the chamber is hazardous to personnel

Autoclave
Contaminated objects
Used before disposal to decontaminate syringes, culture plates, etc., that contain biohazardous waste
Place objects in a container appropriate for disposal
Special autoclavable biohazard bags are available

Autoclave
Chamber loading
Must allow free circulation of steam
Use perforated or wire mesh shelves
Linen packs have 2.5cm to 7.5cm space between
Place multiple packs on edge instead of stacking
Paper/plastic pouches are placed in specially designed baskets that support them on edge with the paper side of each package facing the plastic side of the adjacent package
Solid bowls or basins are placed upside down or on edge
Mixed loads (hard goods and wrapped goods) have wrapped goods on upper shelf

Autoclave
Autoclave cycles
Wrapped goods
Hard goods
Liquids

Autoclave
Autoclave cycles
Wrapped goods
Has “dry” cycle that allows wrapped packs to dry
Used for most surgical packs

Autoclave
Autoclave cycles
Hard goods
Has no dry cycle
Used for trays, bowls, cages, etc. that will not be maintained in a sterile condition
Also used for flash autoclaving to quickly sterilize instruments that are needed immediately

Autoclave
Autoclave cycles
Liquids
Exhausts steam more slowly than other cycles
Used for liquids that would be forced from containers during a faster exhaust cycle

Quality Control
The effectiveness of any method of microbial control must be monitored regularly
Verification of the effectiveness of microbial control should be performed at least monthly

Quality Control
Methods
Recording thermometer
Thermocouple
Chemical indicator
Biological testing
Bowie Dick test
Surface sampling
Serology

Quality Control
Methods
Recording thermometer
Displays the temperature of the autoclave chamber
Operator observes for correct temperature during cycle
Some autoclaves are equipped with printed tape of chamber temperatures during cycle

Quality Control
Methods
Thermocouple
Used in steam and dry heat sterilization chambers
Temperature sensors are placed in the part of a test pack that is most inaccessible to steam penetration

Quality Control
Methods
Chemical indicator
Paper strips impregnated with sensitive chemicals change color when conditions of sterility are met
Used with autoclaves and ethylene oxide systems
Placed deep inside packs before sterilization

Quality Control
Methods
Biological testing
Bacterial spores are exposed to autoclave or ethylene oxide and then cultured
Recommended method for verification of proper autoclave operation in veterinary clinics

Quality Control
Methods
Bowie Dick test
Tests pre-vacuumed autoclaves for complete removal of air and uniform steam penetration
Uses a pack of uniform dimensions with a cross of autoclave tape in the center

Quality Control
Methods
Surface sampling
Surface to be tested is swabbed with a sterile applicator and transferred to a suitable media plate for growth
Surface or item is rinsed with a sterile solution, which is examined for contamination
“Contact plate” of media is touched to the surface and incubated
Recommended method for ensuring proper disinfection of surgical suites in veterinary clinics

Quality Control
Methods
Serology
The presence of viruses in the environment is monitored by serological testing of animals to determine the presence of antibodies
Animals maintained for this purpose are referred to as sentinel animals

Surgical Preparation and Instrument Care.ppt

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The Randomized Controlled Trial

The Randomized Controlled Trial
By: Rakhi Naik, MD

Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C

STUDY OUTLINE
* Hypothesis: Eltrombopag can increase platelet counts in patient with hepatitis C cirrhosis.
* Design: Randomized controlled trial
* Setting: Multicenter trial in US & Europe
* Participants: 74 patients w/Hepatitis C cirrhosis
* Data Collection: Measurement of platelet counts before and after eltrombopag administration for 4 weeks; measurement of platelet counts after standard hepatitis C treatment with peg-interferon/ribavirin
* Outcome: Platelet counts, safety

BACKGROUND
* Chronic liver disease secondary to hepatitis C cirrhosis is often associated with significant thrombocytopenia.
* Thrombocytopenia in chronic hepatitis C infection is multifactorial in origin & is thought to be caused by:
o splenic sequestration (2/2 portal hypertension/hypersplenism)
o decreased thrombopoetin production (2/2 impaired hepatic synthetic function)
o bone marrow suppression (2/2 direct toxic effect of the hepatitis virus itself).

* Platelet counts below 75,000 are often not eligible for treatment with pegylated interferon & ribavirin because treatment itself leads to cytopenias in almost 100% of cases.

BACKGROUND
* Eltrombopag is an oral thrombopoetin receptor agonist that increases megakaryocyte proliferation and differentiation in animal models.

* Research questions:
o Can eltrombopag increase platelet levels in patients with untreated chronic hepatitis C cirrhosis?
o Can continued use of eltrombopag during hepatitis C treatment reduce treatment-related thrombocytopenia?
o What dose of eltrombopag is most effective for achieving these goals?

METHODS

* 22 centers in the United States & Europe were involved in recruitment.
* Inclusion criteria:
o 18 years of age or older
o Presence of serum HCV antibody levels
o Detectable serum HCV RNA levels
o Compensated liver disease (which is not defined explicitly)
o Thrombocytopenia with platelet levels between 20,000-70,000.
o Evidence of cirrhosis defined as: liver biopsy c/w cirrhosis, radiographic evidence of cirrhosis, or endoscopic evidence of varices

* Exclusion criteria:
o Pregnancy
o History of thrombosis
o HIV co-infection
o Hepatitis B co-infection

METHODS
Patients randomly assigned to placebo or eltrombopag (30mg, 50mg, 75mg daily) x 4 weeks
Any patient with plt count >70k or >100k was eligible for treatment with peg-interferon α-2a or peg-interferon α-2b, respectively. The decision to treat was left to the physician & patient.
Patients continued with their previous dose of eltrombopag during treatment.
Study designed by GlaxoSmithKline & academic principal investigator.
Daily eltrombopag doses were held if platelet count rose >200,000 and would be resumed when counts dropped to around 100,000

RESULTS
Approximate bilirubin (converted) 1.5+/- 1mg/dL. INR and creatinine not reported.
5 of total 74 patient listed here were excluded for baseline plt counts >75k but were ultimately eligible for the treatment phase.
Uneven number of patients in each arm because this was a mulicenter trial & not all sites contributed to all 4 arms.

RESULTS
Only 18 patients completed treatment. Only 1 placebo patient completed tx even though 7 were eligible.
Median platelet values prior to inferon treatment and % responders had significant p values compared to placebo

RESULTS
Pre-treatment platelet values, especially in the 50mg and 75mg eltrombopag arms, were statistically significant.
Platelet levels decreased with hep C treatment in all arms. P values for the eltrombopag groups vs. placebo were not statistically significant.
More patients in the eltrombopag arms completed treatment.

CONCLUSIONS/ IMPLICATIONS
* Eltrombopag increases platelet counts in a dose-dependent manner in patients with untreated chronic hepatitis C cirrhosis.
* Eltrombopag can be used to boost platelet counts in patients being considered for peg-interferon & ribavirin treatment.

STRENGTHS
* Clinical relevance: Thrombocytopenia is a very common complication of hepatitis C infection and ineligibility for treatment is a significant public health concern.
* Efficacy: Eltrombopag is extremely effective in increasing pre-interferon platelet counts (i.e. the study was able to demonstrate efficacy even though the sample size was low).
* Ease of use: Eltrombopag can be taken orally and has an easy daily dosing schedule.
* Safety: Eltrombopag has minimal side effects, which do not seem to be dose-dependent, and are not associated with significant morbidity.

WEAKNESSES
* Small sample size, especially in interferon treatment group (underpowered)
* Failed to standardize the protocol for initiation and cessation of interferon treatment phase.

* Lack of generalizability
o The investigators may have referred only patients with cirrhosis without portal hypertension to the study in order to select for a group who was more likely to benefit from treatment.
o Similarly, HCV viral loads were not taken into account.
* ? Clinical utility
o Could not ultimately answer question of whether pre-treatment with eltrombopag resulted in successful clearance of hepatitis C with treatment (i.e. whether the fact that more patients can receive interferon treatment actually leads to more patients who benefit from treatment).

The Randomized Controlled Trial.ppt

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From mice To Men

From mice To Men

Jumpstarting A Laboratory Research Career
December 6, 2007
By: Elizabeth M. Jaffee, M.D.
The Dana and Albert “Cubby” Broccoli Professor of Oncology


Issues to Consider
* Stay where you trained or go elsewhere
* Identifying mentors
* Deciding on a research focus
* Leveraging small grants, getting the big one
* Building a team to work for you
* Balancing the work versus home life

Should you stay where you trained or should you take your first job at another institution?
* Pros for staying
o Implies you have a supportive mentor
o Implies you have a project of interest to others in your institution
o Experience with the institutional systems
o Experience with who might be good colleagues
* Start Up Time Is Shorter
* Pros for leaving
o Cuts the apron strings so that you are not in competition with your mentor at same place
o Likely to get more space and resources due to negotiations
o Likely able to get good students with less competition in your field
* No Identity Complex

Identify a mentor(s) for the most difficult stage in your career

* Cheer leader, promoter, encourager
* Sounding board for fine tuning ideas
* Devil’s advocate whose not afraid to give you the opposite view
* Editor of paper’s, grants, and presentations
* Guidance counselor to help you navigate through tough issues
* Referral Agent who sends you qualified student/postdoctoral fellow applicants
* Introduces you to leaders in your field
Your parent in the workplace

Develop A Five-Year Plan
Time interval goal between Assistant and Associate Professor
* What research questions do you want to focus on?
* What do you need to get you to where you want to be at 5-years
* Is it feasible now? At 1, 2, 3, and 4 years later?
* Revisit each year with your mentor to make sure you are on track
* How many grants and papers do you plan to submit?

Considerations in choosing how to focus your research
* Choose areas that make you want to come to work
o Desire, Desire, Desire!
* Choose a 5-year plan that will help you develop an identity separate from your mentor’s
* Consider several related areas - one high risk and and one or more low risk
* Choose areas that have more than one funding source

Grants: If only it were the 1990’s Again!
* Apply for more than one
o Can submit same grant to several funding agencies or similar ones that overlap
* Apply for career development grants first
* Pursue institutional grants and foundations if appropriate
* Spend 3 or more months writing your first grant
o Have a draft available 1-2 months before due date
o Ask mentor and other colleagues to review
o Have a scientist in a related but different field read the grant for clarity of presentation of ideas
* Go for the R01 by the end of the 5-year plan

Building a Team That Works For You, Literally!
* Learn to lead
o You will make mistakes - learn from them
o Take leadership development courses
o Listen to your team
o Show trust and faith in your team members!
o Mistakes are made by all of us. Be forgiving and continue to trust.
o Don’t let emotions or sense of insecurity get in the way of doing the right thing for your team (we all have this starting at all stages of our career).
* Lead by example
* Identify individuals you can influence
o Make sure they have the personality to take direction from you
o Make sure they have qualities you value
o Make sure you can lead them to be the best they can be

Get the right people on the bus!
Key Point
* There are no special deals when it comes to people resources. Make sure they have the right experience to contribute to your team

* People resources are the single most important ingredient to success
* Develop a healthy work environment
* If you can’t do it on your own, hire someone to be your lab ambassador
* Get as many references as possible
* Ask everyone in your group and others with successful labs to interview candidates
* Reward valued team members with lunches, meetings, etc.
* Provide career development to your valued team members.

Healthy environments attract more good people to help you build and maintain a productive team!
Develop a reputation for leadership and fairness early!
You Are Your Best Advocate
* Promote yourself
o Discuss ideas with others
o Let colleagues know about your successes
o Offer to participate in meetings, etc
o Let colleagues know you are willing and available
* Let your boss know of your important successes
o Grant awards
o Accepted papers
o Abstract acceptances of high impact
* Develop a national reputation
o Get invited to national meetings by telling colleagues of interesting work
o Offer to present locally and at national meetings for visibility
o Get introduced to prominent individuals in your field

Senior scientists delight in interacting with enthusiastic, intelligient, honest, and creative young scientists who are the next leaders!

Women still have special issues (I can tell some stories!)
* My graduate student’s experience
* Women in science (am I the only one?)
* Postdoctoral fellows and junior faculty I know who get taken in by charming individuals disguised as mentors
* Our generation of men and women are making a difference

Pearls of Advise On How To Succeed in A Man’s World (from The Godfather)
* Just when I thought I was out, they pulled me back in!!!
* Keep your friends close, and your enemies closer!!!
* It ain’t personal, just business!!!

If you are going to fight for something, pick the right battles!
You can’t possible win them all!
If you don’t like someone, nominate them for something important!
If someone does something bad to you, don’t allow your emotions
to get in the way of how you deal with the situation!

HARDWORK
FOCUS
DETERMINATION
Don’t forget about a home life!
Physician-Scientist, Wife, and Mom
* Roadmap to successful

Inspiration
Role Models or Mentors
Hardwork
Focus
Determination
A balancing act!
Integrating a successful career with a home life
The road to success in anything is easier when you have a supportive partner!
Kids are the ultimate reminders of what is important in life!
Animals can be less demanding but loving substitutes!

Jumpstarting A Laboratory Research Career.ppt

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Insect Sting Allergy and Venom Immunotherapy

Insect Sting Allergy and Venom Immunotherapy
By: David B.K. Golden, M.D.
Johns Hopkins University, Baltimore


History of Reaction to Insect Stings (Skin Test Positive Patients)

No reaction
Large Local
Cutaneous Systemic
Anaphylaxis

Severe swelling 24 hrs after a sting should be treated with:
A. Antibiotics C. Antihistamine E. Epinephrine
B. Prednisone D. Venom immunotherapy

Venom immunotherapy:
A. Is not necessary (“He’ll outgrow it”) B. Is dangerous
C. is only partially effective D. Is forever E. None of the above

Diagnosis of Insect Sting Allergy (Indications for Venom Immunotherapy)
Symptoms and Signs of Insect Sting Anaphylaxis in Adults and Children
Symptoms or Sign
Cutaneous only
Urticaria/angioedema
Dizziness/hypotension
Dyspnea/wheezing
Throat tightness/
Hoarseness
Loss of consciousness

Epidemiology of Venom Allergy
* History of systemic reaction in 0.5%-3.0% of the population
* Positive venom skin test or RAST in 15%-25% of the population.
* Transient positive skin test or RAST may occur after uneventful sting.
* Presence of IgE venom antibody not necessarily predictive of clinical reactivity.

Correlation of Yellow Jacket Venom
RAST and Skin Tests
History Positive Patients with Negative Venom Skin Tests
Possible explanations:
Not true allergic reaction (no objective signs)
Allergy “outgrown”
Mastocytosis (~1 % of insect allergic patients)
Not detected:
Diagnostic Venom Test Reactivity after Systemic Sting Reaction
Venom Skin Test / RAST in History Positive Patients
Total history positive patients screened:
Diagnosis of Insect Allergy in Patients With Positive History (Systemic)
Skin test positive
ST negative /
Low Risk Sub-Groups of Patients With Positive Venom Skin Tests
Insect Sting Allergy in Children
Summary Of Sting Reactions
Natural History of Large Local Reactions
Repeat Systemic Reaction In Sting Allergic Patients
Risk of Systemic Reaction in
Untreated Skin Test Positive Patients
Controlled Trial of Venom Immunotherapy
Venom Immunotherapy Treatment Protocols
Dose Response of Venom Immunotherapy
Premedication During Venom Immunotherapy
Venom-IgE and Skin Test During
and After Venom Immunotherapy
Discontinuing Venom Immunotherapy:
Reported Studies and Criteria
Discontinuing Venom Immunotherapy

Insect Sting Allergy and Venom Immunotherapy.ppt

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Allergy Grand Rounds

Allergy Grand Rounds
By:Sarbjit S. Saini, M.D.
JHAAC

Chief complaint
* 13 yr old male referred in June 2004 for evaluation of severe chronic urticaria
* Referred by pediatric allergist in VA
* Significant illnesses:
o include Type I DM for 2.5 yrs
o ADHD
o mood disorder

History of Present Illness-I
History of Present Illness-II
History of Present Illness-III
Other atopic history
* No history of eczema or food allergy
* Allergic rhinitis symptoms
* Exercise-related asthma age 9 treated with prn albuterol prior to activity
* Reported qhs cough, but denied wheezing
Medications
* Zoloft, 50 mg qd**
* Oxcadazepine (Trileptal) 300 mg/600 mg **
* Adderall 30 mg bid
* Quetiapine (Seroquel) 200 mg qd
* Fexofenadine 180 mg qd ( off 1 wk)
* Cetirizine 10 mg qd ( off 1 week)
* Cyclosporine 100 mg bid (off 1 wk)
* Humulin 7 U/4 U, Humulin R 5 U/ 4 U
* Epipen, Albuterol

Past Medical History
* Type I DM for 2.5 yrs
* ADHD
* Mood disorder, possible bipolar
o exacerbated by steroids
o suicidal ideation due to urticaria
* Chicken pox as child
* Salivary gland surgery
* Normal birth history, negative history of other infections
Family History
* Younger Sister with eczema
* PGM with asthma
* Paternal cousins with asthma
Environmental Hx
* Apt dweller x 5 yrs
* Dog since 1999
* 3 hamsters

Social Hx
* 7th grader
* Lives with mom and sister
Physical Exam
* T-99.7, HR-121, BP-109/75, HT-5, WT-125,RR-22
* General: no obvious pubertal signs,central obesity, moon facies
* HEENT: “allergic shiners”,erythematous nasal mucosa, prominent turbinates
o Normal TMs, oropharynx, neck
* Resp: CTA, normal I:E ratio, CV: nl S1, S2 tachy
* Abdomen: benign Ext: no joint swelling
* Skin: urticaria on face, arms, feet, back, chest; no pigmentation

Recent labs
* CBC-WBC 7.3 HCT-41.2, Plts-331
* HbA1C-8.6 (4-6) Jan 2004
* Negative studies: ANA, H. Pylori Ab,anti-thyroid peroxidase antibodies, WESR
* Normal C3, C4, CH50; TSH, thyroxine, T3 and T4
* RASTS- negative for crab, lobster, fish garlic and insulin

Cyclosporine related labs
* Jan 2004 reduced Hct-12.1 HB- 37.2
o CsA: 37 ng/ml trough
* March 2004 Normal studies
* June 2004
o CsA: 46 ng/ml trough
o CBC, Mg, Cr, K normal
Impression/ Recommendations
* Severe CIU/angioedema h/o significant steroids requirements
o No clear drug (insulin), food or systemic etiology
o Avoiding NSAIDs
* Consider alternate diagnoses:
o Hx of autoimmunity with Type I DM
o Rheumatologic?-joint symptoms, bruising
o Obtain a skin Biopsy to verify urticaria vs. other
+ Consider immunofluorescence

Follow-up on Recommendations
* Rheum evaluation: Repeated ANA, RF, dsDNA, ANCA, Urine and SPEP- all normal
o showed IgA of < 20, no other etiology for joints
* October 04 -Csa 100 mg qd and fexofenadine with good control
* Prednisone used only single day since 6/2004
* No skin biopsy to date- attempted
* Glucose under better control
CU in children : association with thyroid autoimmunity
* 187 CU pts (6- 18 yr) followed 7.5 yrs
* Tests: CBC, sed, Chem, Antibodies to Hep B, HSV, EBV,CMV, mycoplasma, ASO, ANA, C3, C4, Thyroid function and antibodies,Ua, chest and sinus X-rays, food skin tests, ice cube test
* Results: 8/187 antithyroid Ab (4.3%), all girls
o 3x -1.27% rate seen in pediatric population
o Much less than 14 to 33% range in adults
o 5 +ANA, 4 + family Hx of autoimmunity
Cyclosporine in Urticaria
* CBC, Mg, K, renal function q 2 wks for first 3 months, CsA levels
* Gingival hypertrophy
* BP monitoring
* Dose: 2-6 mg/kg/d similar to RA and psoriasis (2.5 mg/kg/day)
* Tx dose 8 mg/kg/d; trough levels 100 ng/ml

CsA and Urticaria-RDBCT
* 30 subjects, severe CIU unresponsive to H1 tx and positive ASST ( +HRA)
o 4mg/kg CsA (n=20) or placebo (n=10) for 4 wks
o All subjects followed for up to 20 wks, all on daily 20 mg cetirizine
* Outcome: +< 25% of baseline UAS, relapse > 75% of UAS
* Results: 8/19 + at week 4, 6 relapse wk 6
o Noted reductions in HRA and ASST

CsA in CIU:Adults
* Open trial in 35 CIU with 3(0-3)
o Low dose CsA 3 mos, 68% response (13/19) with few SEs1
* DB trial :40 pts CsA 5 mg/kg x 8 wks, then 4 mg/kg x 8 wks vs. cetirizine 10 mg/d2
o All cetirizine crossed to active CsA
o 3 pts reduced CsA for Cr rise
o On tx- 22 had relapse, 10 resolved spon 12 with H1
o Off tx- 16/40 in remission at 9 mos

Immunosuppression in Adolescents: Cyclosporin
* 80% of liver, kidney, cardiac Tx > 5 yr survivors on CsA
* Nephrotoxicity: 4-5 % in cardiac and liver
o 10% in RA dosed > 4 mg/kg avg 19 mos
* HTN (20-30%)
* Hyperlipedemia (10% of cardiac)
* Post-tx lymphoproliferative disease:5-17%
* Cosmetic-Gingival hyperplasia, hirsutism

Allergy Grand Rounds.ppt

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A case of refractory, severe,steroid-dependent asthma

A case of refractory, severe,steroid-dependent asthma
By: Bruce S. Bochner, M.D.

* 24 y/o AA female referred in 2/99 from southern Maryland for evaluation and management of uncontrolled asthma
* At the time, 20 weeks pregnant (G5, P4)
* Last two pregnancies were complicated by uncontrolled asthma and oral steroid use throughout the pregnancy
* H/O asthma since age 12, frequent episodes of wheezing & cough without any obvious triggers or seasonal pattern
* Review of accompanying records revealed that her FEV1 can range from 30% to 80% predicted on any given visit

* Early on, exacerbations 1x/yr, necessitating ER visits
* Initially treated with Cromolyn, Vanceril and Albuterol
* Since 1992, worsening asthma, increased ER visits and for 1998 at least 6 hospitalizations
* In 1992, found to have multiple positive skin tests, tried on ImTx w/o improvement; in fact, exacerbations of wheezing with most shots
* Frequent courses of antibiotics for bronchitis or sinusitis

* At the time of her 2/99 visit:
o Daily nocturnal symptoms
o Wheezing with minimal activity
o Normal CXR
o managed with Prednisone 30 mg qAM, Flovent 110 2 puffs BID, Serevent 2 puffs BID, Alupent 2 puffs q3h and nebs PRN, Atrovent 4 puffs BID, Accolate 20 mg BID, and Cromolyn q3h

* Drug allergy Hx: acute rashes from Penicillin, Codeine, Ceclor; Erythromycin caused GI upset
* Environ. Hx: Born and raised in MD, lives in a separate home, no pets
* Family Hx: All of her four kids (two different fathers) have asthma; current pregnancy is with a third father

* PE:
o Vitals: BP 105/66, P 112, RR 18, Wt 168 lbs, peak flow best effort 130 liters/min
o GEN: Mild Cushingoid facies, no rashes
o HEENT: Nasal exam normal, no lymphadenopathy or thyromegaly
o LUNGS: Diffuse expiratory wheezing and prolonged expiratory phase; sounds were in chest but not neck
o HEART: Normal S1, S2.
o EXTREMITIES: No peripheral edema

* SPIROMETRY
o FEV1: 1.1 liters (36% predicted), FVC: 1.62 liters (42% predicted), ratio 0.68. Post-bronchodilator FEV1 1.89 liters (79% increase), FVC 2.34 liters (44% increase)

* TREATMENT CHANGES
o At this visit, patient was switched from Flovent to Pulmicort 4 puffs bid
o The rest of her medications were continued
o Inhaler technique was observed to be correct
o Husband verified medication adherence.

* Delivered the baby on continuous nebs. Baby and Mom did fine. 5 weeks postpartum admitted to Hopkins Bayview for 5 days for worsening SOB, wheezing and leg pain
* On admission, wheezing; PEF 100 liters/min
* V/Q scan and leg dopplers normal
* FEV1 28% predicted; flow-volume loops normal
* CT scan of sinuses revealed pan-sinusitis
* 24-hr pH probe documented significant GERD
* Discharged on 24-day steroid taper with markedly improved lung function at discharge; started on antibiotics and Prilosec

* Since 2000, multiple ER visits
o two prolonged intubations in 2000 and 2001
+ 2000: complicated by full respiratory arrest and persistent doll’s eyes
+ 2001: complicated by bilateral pneumothoraces requiring chest tubes and a DVT; s/p IVC filter
* Multiple meds tried in 2000-2001 included Advair, Pulmicort respules, Theophylline, and Methotrexate. None had a significant impact on our ability to taper oral steroids.

* In 10/01, sent for an outpatient evaluation by me to National Jewish (made possible through philanthropic help from NJC, AAFA and her local church) with dx of severe, labile steroid-dependent asthma
* Diagnosis quickly confirmed when she required admission for worsening SOB and wheezing

* Skin tests positive to dust mites, grasses, alternaria
* Alpha-1 antitrypsin: normal
* CF genotyping: normal
* No peripheral blood eosinophilia
* Total IgE: 123 IU/ml
* Chest CT: no interstitial disease
* Bone densitometry: normal
* Sinus CT: mild sinusitis
* Oral steroid kinetics normal

* Seen by Drs. Barry Make and Sally Wenzel
* After stabilization with IV steroids and nebs, underwent bronchoscopy
* Found to have some collapsibility of her larynx with exhalation which they felt would be helped with CPAP
* Sleep study found sleep apnea for which CPAP was also recommended

* Bronchoscopy (on IV steroids) revealed prominent basal lamina thickening and a mild inflammatory infiltrate, primarily lymphocytic

* After 3 weeks, sent back to Baltimore on the following regimen:
o Serevent 3 puffs q12
o QVAR 6 puffs bid
o Atrovent 4 puffs qid
o Uniphyl 400 mg qhs
o Singulair 10 mg qhs
o Zyflo 600 mg qid
o Prilosec 40 mg qd
o Supplemental Calcium
o Prednisone 40 mg q am, 20 mg q afternoon
o Nasonex 1 spray bid
o CPAP

* Within 2 months, back to pre-Denver management
* 2002 to 2003
o Managed primarily with Prednisone (40-80 mg/day), Prilosec and Albuterol
o Extremely Cushingoid; now weighs 240 lbs
o Tried Xopenex w/o any additional benefit
* September 2003
o Started Xolair one vial q month (completely covered by her insurer)
o Still had ER visits but no hospitalizations while on Xolair
o Despite this, after seven months, Prenisone, q3h albuteral requirements and FEV1 remained unchanged
o She became frustrated, so we discussed other options (Enbrel) and stopped Xolair

Pathophysiology of allergic airway inflammation
Model of IgE-dependent acute and chronic allergic inflammatory reactions
Leukocyte recruitment in allergic disease
Soluble Tumour Necrosis Factor Alpha (TNF-a) Receptor (Enbrel) as an Effective Therapeutic Strategy in Chronic Severe Asthma
Respiratory Cell & Molecular Biology
Study design
* Open label, single center study
* Subjects with chronic severe asthma on oral corticosteroids, high dose inhaled corticosteroids, salmeterol, and/or theophylline
* 25 mg of Enbrel administered subcutaneous twice a week for 12 weeks
* Subjects aged 18-65 years
* FEV1 of at least 50% predicted
* Demonstrated a reversibility of at least 9%
* Lung function, methacholine response performed before and after treatment
* Asthma control symptom questionnaire completed before and after the trial
* Diary cards issued to assess peak flows and use of rescue medication

Results

* 15 subjects enrolled in the trial
* 11 female, 4 male
* Mean age of the patients: 41 yrs
* Mean duration of asthma: 24 years
* Mean dose of oral prednisolone: 12.1mg/day
* Mean dose of inhaled corticosteroids
o 2500 ľg/day of beclomethasone or equivalent
* Mean dose of nebulised albuterol: 8 mg/day

Changes in FEV1 with Enbrel

WEEK 1 WEEK 12
Changes in Symptom Scores with Enbrel
Symptom score (Juniper Scale)
Adverse effects
* Skin rashes (4)
* Injection site reactions (4)
* Respiratory tract infections (7)
* Weakly positive ANA (3)

Conclusions
Treatment with Enbrel in patients with chronic severe asthma:

* Improves lung function (FEV1, FEV1/FVC, morning and evening PEF)
* Markedly improves asthma control
* Markedly improves airway hyperresponsiveness
* Markedly reduces the need for rescue medications as all the subjects completely withdrew from their nebulised albuterol by the end of the study

* April - early June 2004
o Started Enbrel 25 mg sq twice weekly (completely covered by her insurer) after PPD was negative; husband trained on administration technique
o Two weeks later, she was admitted for an asthma exacerbation associated with nausea, fatigue, myalgias and unexplained fevers to 102° despite Enbrel and prednisone; discovered Prilosec had been stopped
o Infectious workup unrevealing; IV steroids given
o Enbrel dosing held for 2 weeks, fever resolved
o Enbrel restarted and 1 week later she was admitted for another asthma exacerbation
o Enbrel discontinued

* June 21: planned to restart Xolair but got admitted again
* Discharged June 22
* Seen June 23
o FEV1 60%; FVC 93%
o Diffuse wheezing on Prednisone 80 mg
o Restarted Xolair 300 mg q 4 weeks
o Restarted Serevent diskus 1 puff BID
* What next????

Our ongoing work on TNFa and allergic inflammation

* There is a tissue-specific pattern of chemokines/cytokines/adhesion molecules involved in human allergic inflammation
* This pattern is TNF- dependent
* The primary source of TNF- released in human allergic inflammation is the mast cell

Etanercept in late phase cutaneous allergic inflammation: study overview

* Randomized DBPC Trial
* To evaluate effects of etanercept (Enbrel) on cutaneous allergen LPR in 10 perennial allergic rhinitis/dust mite sensitive patients
* 15 visits to JHAAC over 8.5 wks
* Lead investigators: Lisa Beck, Ed Conner, Bruce Bochner

Study Purpose

* To evaluate the clinical effects of etanercept on cutaneous allergen challenge late phase responses
* To evaluate the effects of etanercept on the allergen dose response
* To characterize a variety of biomarkers in the cutaneous late phase responses
* To assess limited pharmacokinetic data of etanercept in the serum and nasal washings

DBRPC Crossover Study Design
A case of refractory, severe,steroid-dependent asthma.ppt

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Occupational Exposures to Bloodborne Pathogens

Occupational Exposures to Bloodborne Pathogens
By:Arjun Srinivasan
Johns Hopkins Hospital

Outline
* What’s an exposure?
* 1st step in all exposures - Clean the site!!
* Specific pathogens
o Hepatitis C
o Hepatitis B
o HIV

Scope of the Problem
Impossible to measure the psychological stress that an exposure places on a health care worker
At Risk Exposures
1. Percutaneous injury
Hollow needle > Solid sharp
Visible blood
Deep injury
Device in patient’s artery or vein
2. Splash on non-intact skin
3. Splash on mucous membrane

Risks From Body Fluids
* Known to be infectious:
o Blood
o Any fluid visibly contaminated with blood
o Semen
o Vaginal secretions
o Concentrated virus (used in labs)
* Potentially infectious
o CSF
o Pleural fluid
o Pericardial fluid
o Peritoneal fluid
o Amniotic fluid
o Synovial fluid
o Tissue samples
* Not Infectious (if not visibly bloody)
o Tears
o Saliva
o Urine
o Feces
o Sweat
o Emesis

The Solution to Pollution . . .
* Exposure site should be cleaned IMMEDIATELY! This may be the most important part of PEP
* Skin wounds should be washed with soap and water
* No evidence that antiseptics are useful and caustic agents (bleach) may do more harm than good
* Mucous membranes should be flushed thoroughly with water
* Eyes should be irrigated with a liter of saline

A word from our lawyers . . .
* ALL exposures should be reported to the proper people (Occupational health, Employee health etc.)
* Disability claims can be denied if follow up reporting was not done right

Hepatitis C
Hepatitis C: Risk of Exposure
Hepatitis C: Risk of Disease
Post Exposure Recommendations
* Clean the site immediately
* Hepatitis B immune globulin has NOT been effective
* Interferon is NOT recommended at this time
Hepatitis C: Follow Up
* Enzyme linked immunoassay (EIA) is screening test of choice
* ALL exposed HCWs should have LFTs monitored
* Average interval between exposure and seroconversion with EIA is 8-10 weeks
* Follow up guidelines vary - CDC recommends follow up at 4-6 months
Hepatitis C: Follow up issues
* EIA is falsely positive in up to 50% of HCW and falsely negative in 5% - results must be confirmed by RIBA or VL
* PCR may catch infection earlier but detection is highly variable
* Immediate referral for treatment if HCW seroconverts
Hepatitis C: Counseling
* Risk of transmission to infants and partners is thought to be low
* Exposed HCW do not need to modify sexual practices, stop breast feeding or refrain from becoming pregnant
* Should not donate blood

Hepatitis B
Hepatitis B: Risk of Exposure
Hepatits B: Outcome of Infection
* In patients who are infected with Hep B:
o 25% get jaundice
o 5% require hospitilization
o 6-10% become chronically infected
o .125% die of fulminant hepatitis

Hepatitis B: Good News
* Most HCWs have been vaccinated and vaccine offers virtually complete protection to responders
Hepatitis B: Bad News
* Some employees are NOT vaccinated
* 6-10% of vaccinees do NOT develop antibody
* Really bad news:
CDC estimates that 50-75 HCW die from Hep B each year
Hepatitis B: Post Exposure
* Clean the site immediately
* Determine the vaccine status of the HCW
* Determine the surface antigen status of the source patient

Hep B: HCW Never Vaccinated
* HCW should receive vaccine ASAP
1. Source patient is sAg positive:
HCW should also receive one dose of Hep B immune globulin (HBIG) .06ml/kg (1 vial=5 ml) ASAP and absolutely within 7 days of exposure
2. Source patient sAg neg or unknown
Vaccine alone
Hep B: HCW Vaccinated (one or more doses)
* Source patient should be tested for sAg AND HCW should be tested for sAb
* If HCW has adequate Ab >10 IU/mL (now or at any time) then no additional treatment
* IF HCW has inadequate Ab:
1. If pt is sAg negative:
HCW should get booster dose of vaccine (or complete series)
2. If pt is sAg positive:
HCW should receive HBIG AND a booster dose of vaccine at different sites (complete series if necessary)
If HCW has inadequate Ab:
3. Unknown source:
Give vaccine booster or complete series
Vaccine non-responders
* If HCW has inadequate Ab after 3 dose series they should get another series: 30-50% chance of responding to 2nd series
* If no response to 2nd series HCW should be considered susceptible
* PEP for known non-responders exposed to Hep B positive or high risk unknown sources: 2 doses of HBIG- 1 at exposure then 4 weeks later
Hep B: Follow Up Testing
* Hepatitis B sAg is the test of choice as it rises in about 6 weeks
* LFTs should be monitored at regular intervals
Post Exposure Counseling
* Risk of transmission to infants and partners is thought to be low
* Exposed HCW do not need to modify sexual practices, stop breast feeding or refrain from becoming pregnant
* Should not donate blood
HIV
HIV: Risk of Exposure
* Risk of transmission from percutaneous expsosures involving HIV positive pts estimated at 0.3%
* Risk from mucous membrane exposure estimated at 0.1%
* As of 2000 there were 56 confirmed and 138 possible cases of occupational transmission in the US
Rationale for PEP
* HIV infects dendritic cells and then regional lymph nodes before becoming systemic
* AZT blocks infectivity of HIV infected dendritic cells
* Goal of PEP is to halt viral replication before systemic infection is established

Does It Work?
* Several animal studies showing efficacy
* Peri-natal prophylaxis has been effective
* Retrospective study showed that risk of seroconversion after exposure was 81% lower in HCWs who took AZT PEP.
Time is Virus
What To Use?
* Before: AZT+3TC +/- IDV or NFV
* Now: Becoming more difficult to answer!
* Regimens may need to be tailored based on the treatment history of the source patient -Surveillance study from 1998-1999 found that 39% of virus from source patients had some NRTI resistance and 10% had some PI resistance.

Nucleoside Reverse Transcriptase Inhibitors (NRTI)
* Still form the backbone of most regimens
* AZT has been formally studied thus it should be included if possible
* Addition of 3TC is recommended because:
1. It appears non-toxic
2. It has some synergistic effect with AZT with respect to mutations
* If source patient’s virus is felt to be resistant to AZT or 3TC alternatives include:
* d4T + 3TC
* d4T + ddI
* Role of abacavir?
* Role of tenofovir?
Protease Inhibitors (PI)
* Are very potent anti-virals and work very well in patients
* BUT they have significant side effects and can cause HCW to stop PEP altogether
* PI should be recommended primarily when the exposure is high risk
* Any PI can be used but indinavir and nelfinavir have been used the most
Non Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
* Not much experience using these for PEP
* Use should be reserved for situations when source patient’s virus is thought to be resistant to all PIs
* Nevirapine should probably be avoided as PEP: from 1997-2000 there were 22 reports of serious toxicity in HCW taking it for PEP

Toxicity of PEP
Side Effects of PEP
PEP Counseling
* Clean the site immediately
* Determine the HIV status of the source
* Determine the extent of the exposure
PEP management: Source Patient Testing
* Crucial 1st step as most exposures do NOT involve HIV positive patients
* Rapid test kit (SUDS) is available and yields an answer in about 30 minutes
* Rapid test is an EIA that is >99.9% sensitive
* Testing of blood on sharps is NOT recommended
* Patient consent is required in Maryland
HIV RNA Testing of Source
* No official recommendations and test is not approved for this indication
* Should be reserved for cases where there is a suspicion of acute retroviral conversion

Source Patient
1. Patient HIV negative - No PEP
2. Patient HIV positive
Low viral load / high CD4 = class 1
High viral load / low CD4 = class 2
3. Patient HIV positive, unknown CD4, VL
Use best judgement - err towards class 2
4. Unknown source
Exposure Types
1. Non-infectious fluids - No PEP
2. Mucous membrane, non-intact skin
Small volume
Large volume
3. Percutaneous injury
Less severe
More severe
HIV PEP Recommendations
Percutaneous injuries
Less severe
* Source pt HIV negative - No PEP
* Source pt class 1 - Recommend 2 drugs
* Source pt class 2 - Recommend 3 drugs
* Source of unknown status- Consider 2 drugs in setting where exposure to HIV positive pt likely or if pt has HIV risk factors

HIV PEP
More severe injury
* Source pt HIV negative - No PEP
* Source pt HIV class 1 or 2 - Recommend expanded 3-drug regimen
* Source of unknown status - Consider 2 drugs in setting where exposure to HIV positive pt likely or if pt has HIV risk factors
HIV PEP
Mucous membrane exposures
Small Volume
* Source pt HIV negative - No PEP
* Source pt class 1 - Consider 2 drugs
* Source pt class 2 - Recommend 2 drugs
* Source of unknown status- Consider 2 drugs in setting where exposure to HIV positive pt likely or if pt has HIV risk factors
Large volume
* Source pt HIV negative - No PEP
* Source pt class 1 - Recommend 2 drugs
* Source pt class 2 - Recommend 3 drugs
* Source of unknown status- Consider 2 drugs in setting where exposure to HIV positive pt likely or if pt has HIV risk factors
Duration of Treatment
* Current recommendation is 4 weeks but this is an arbitrary selection
* Animal studies suggest 10 days is too short but 28 days conferred protection
Resistance
* Becoming a significant problem now that so many patients are getting treated
* Treatment history can be helpful in the acute setting
* Recent history may be more important than remote
Resistance Issues
* Full medical history often not available when the exposure occurs - PEP should NOT be delayed
* Data from maternal transmission studies shows viral resistance does not preclude benefit
* Consultation with someone experienced in HIV treatment is recommended in cases where HIV resistance is possible
* PEP may need to be modified once more history is available
* Resistance testing is too slow to be of use right now

PEP and Pregnancy
* Women of child bearing age should be offered a pregnancy test before starting PEP
* BUT, recommendations on starting PEP should NOT change just because HCW is pregnant

HIV medications to avoid in Pregnant HCW
* d4T, ddI: have been associated with severe lactic acidosis in pregnant women
* Efavirenz: is teratogenic in primates
* Indinavir: causes hyperbilirubinemia in newborns if given near time of delivery

Post Exposure Testing
* Testing should be done at regular intervals (eg 6,12 weeks and 6 months)
* Testing should continue for 12 months if the HCW contracts HCV from the exposure
* Unclear if testing should be prolonged in exposures to pts with HIV and HCV or in HCW who have history of impaired Ab responses
* EIA is test of choice
* Viral loads and p24 assays should be reserved for suspected cases of acute seroconversion given high false pos rate
Counseling
* For 3 months following exposure HCW should avoid:
-unprotected sex
-donating blood
-sharing razors, toothbrushes
* HCW should consider stopping breast feeding (risk of perinatal transmission and drugs may get into breast milk)

Time to Seroconversion
* Most HCW seroconvert in 6-12 weeks with median time of 46 days
* 95% seroconvert within 6 months
* 100% seroconvert in one year
* Co-infection with HCV may delay HIV seroconversion

Acute Retroviral Conversion
* Symptomatic seroconversion develops in 50-90% of cases
* Average time from exposure to symptoms is 2-6 weeks
* ANY HCW who develops a flu-like illness in the follow up period should be encouraged to get HIV RNA testing

Resources
Conclusion

* People react very differently to exposures - be prepared for anything!
* The psychological impact of an exposure can be enormous
* Your patience and understanding may be the best PEP of all

Occupational Exposures to Bloodborne Pathogens.ppt

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Prenatal Testing And Screening

Prenatal Testing And Screening
By:Adel D. Gilbert, MS, CGC
Genetic Medicine Education Coordinator
Institute of Genetic Medicine
Johns Hopkins University

Genetics Board Review Lecture
Lecture Outline
* Definitions
* Age related risks
* Etiology and phenotype of chromosome anomalies
* Risks, phenotype and testing options of ONTD
* 1st and 2nd Trimester Prenatal Testing Options
* 1st and 2nd Trimester MS Screening Options
* New approaches to combining these tools
* Ultrasound as a screening tool

Testing Defined
Screening Defined
* Identify those at increased risk who are not be perceived to be at risk
* Does not dx definitively
* Follow-up options available for definitive information
* Sensitivity=True positives/all affected
* Specificity=True negatives/all unaffected
Baseline Risk for Having a Child With a Serious Birth Defect
Phenotype
* Moderate mental retardation
* Characteristic facies
o upslanting palpebral fissures
o epicanthic folds,
o midface hypoplasia,
o macroglossia
* Congenital malformations
o heart (30-40%), atrioventricular canal
o gastrointestinal tract, such as duodenal stenosis or atresia, imperforate anus, and Hirschsprung disease
o Leukemia (both ALL and AML) 10-20x
o acute megakaryocytic leukemia occurs 200 to 400 times more frequently in the Down syndrome
o 90% have significant hearing loss, usually of the conductive type
Facial
* microcephaly with prominent occiput
* narrow bifrontal diameter
* short palpabral fissures
* low-set malformed ears
* cleft lip +/- palate
* narrow palatal arch
* micrognathia

Skeletal
* neck
* webbed
* chest
* short sternum
* widely spaced nipples
* hips:
* small pelvis, congenital dislocation of the hips, limited hip abduction
* extremities:
* phocomelia
* rockerbottom feet or equinovarus short dorsiflexed big toes fixed flexion deformity of the fingers (overlapping of the 2nd and 5th fingers over the 3rd and 4th fingers)simple arch pattern of the fingers and toes

hypoplasia of fingernails single crease of 5th finger or all fingers (absence of interphalangeal flexion creases)
Trisomy 18
Kleinfelter syndrome
Miscarriage
Turner syndrome
Neural Tube Defects
* Second most common major congenital defect (1-2/1000)
* Not a chromosome anomaly
* Routinely tested and screened for in pregnancy
* Failure neural tube to close at 28 days gestation
* 20% are closed lesions and difficult to detect prenatally

Open Neural Tube Defects
Closed lesions
Open lesions
INDICATIONS FOR PRENATAL DIAGNOSIS
PRENATAL DIAGNOSTIC PROCEDURES
* AMNIOCENTESIS
* CHORIONIC VILLUS SAMPLING
* PERCUTANEOUS UMBILICAL CORD SAMPLING

AMNIOCENTESIS
ULTRASOUND GUIDED
AMNIOCENTESIS
Amniocentesis Testing
* Chromosome analysis
* AF-AFP levels
* Acetylcholinesterase
* Risk of miscarriage associated with procedure 1/100-1/400
Advantages
* Highly reliable results 99+%
* Familiar
* Long standing reputation
* NTD detection
Disadvantages
* Late in gestation
o Decision making
o Privacy
o Mom feels movement
* Fear of needles
* Needle invades the sac

Fetus: 12 weeks gestation
Transcervical
Chorionic Villus Sampling
Transabdominal
Performed >10 wks-13 weeks
Chromosome analysis
Risk 1/100-1/200
* trophoblastic shell cells
* Syncitiotrophoblasts – poly-proliferate tissue type=directs
* cytotrophoblasts
* Mesodermal core=tissue culture
* frorm finger-like extensions

Disadvantages
* Placental mosaicism 1% of CVS is confirmed in the fetus ~ 10-40%
* Second trimester amniocentesis mosaicism ~ 0.1-0.3% & confirmed in a fetus up to 70% of the time.
* ?LRD risk prior to 70 days gestation (10 weeks)
* Higher loss rate
* Less access to procedure
* Higher chance of insufficient sample
* Early test=risk of sampling a fetus potentially destined to miscarry
* No ONTD testing
* More risk of vaginal bleeding
* Speculum

Benefits
* Earlier in gestation
* rapidly growing cell cultures practically free of maternal cell contamination
* an efficient direct method to obtain high quality metaphases from the of the syncitiotrophoblasts tissue which the fetal karyotype is defined within a few hours of chorionic villi sampling (specialty cyto techinque)
* is suitable for a rapid, direct diagnosis of the related metabolic diseases.
* placental mosaicism (trisomic rescue in fetus) can increase the risks of genetic abnormalities such as uniparental disomy

Fetal Blood Sampling
Percutaneous Umbilical Cord Sampling
(PUBS) or Cordocentesis
* ~2% risk of loss
* Technically difficult prior to 20 weeks
* Blood disorders such as hemophilia and anemia
o Useful for detection of Rh isoimmunization of the fetus (blood cell count and oxygen level)→erythroblastosis fetalis (HDN)
* Chromosomal abnormalities Fetal karyotype in 48 hours
* Infections such as toxoplasmosis and rubella.
* The procedure is also used to perform blood transfusions to the fetus and to administer medication directly into the fetal blood supply.

Reproductive Decision Making
RISK Fetal Aneuploidy
Procedure Related RISK
TO TEST OR NOT TO TEST
* I want to know
* The benefits outweigh the risks
* Options are desirable
* Because my doctor says so…..
* Not sure I want to know
* Risks are a big worry
* Options stink
* Because my doctor says so….

SECOND TRIMESTER
MATERNAL ANALYTES FOR ANEUPLOID
SCREENING
FETAL
Alpha-fetoprotein- AFP
Estriol- uE3
PLACENTAL
Estriol- uE3
Human chorionic gonadotrophin- hCG
Inhibin-A

2nd Trimester MSS Overview
Used for detection of:
+ ONTD
+ Down syndrome
+ trisomy 18
+ Smith-Lemli-Opitz syndrome
Serum Marker
Smith Lemli Opitz Syndrome
* Defect enzyme in the conversion of 7-dehydrocholesterol to cholesterol.
* Affects 1 in 20,000 to 40,000 births
* Autosomal Recessive
* Mental Retardation
* Slow growth
* Heart defects
* Facial cleft
* Screen positive women have uE3 < 0.4 MoM
* ~2% baby affected
* Testing AF for 7-8- dehydrocholesterol (7/8-DHC) levels

Turner T13 Triploidy Pregnancy complications
ONTD screening
Detection Rates
MSAFP
Add Ultrasound
Screening for DS
2nd Trimester 1/270 Cut-off
First Trimester Integrated Screening For Trisomies =FIRST
Nuchal Translucency (NT)
First Trimester Screening
Down syndrome DR ~1:270 Cut-off
Nasal bone
Recommendations 1st Trimester Nuchal >3.5
* CVS
* Targeted ultrasound evaluation 18-20
* Echocardiogram
* Residual 5-6% risk neonate may have a yet undefined genetic syndrome…
Fetal Nasal Bone
* 65% DS have absent nasal bone
* General population 1%
o African Americans 8%-10%
* Secondary screen
* Difficult to obtain
* Higher false positive in 1st

Integrated Screening
PAPP-A and Nuchal
Quad Screen
Screen Positive
Screen Negative
Timeline weeks
Decision Making
Advantages
* Increases detection rate
* Decreases false positive rate (fewer tests and fewer procedure related losses)
Disadvantages
* Long wait time for result
* Unable to utilize CVS and early detection
* Late GA by the time amnio results final
Contingent

First Trimester Screening
High risk
Low Risk
Intermediate
Triple Screening Integration
Offer CVS
High risk
Low Risk
US and Amnio
Stop
Advantages
* Increase detection rate 90%
* Decrease FPR 2%
* Reduce the number of amnios performed in low risk pregnancies
Disadvantages
* New (limited data)
* Hard to determine uptake
* Offered at few institutions
RISK OF ANEUPLOIDY BASED ON GA AND ANOMALY

3D Ultrasound
Fetal Face
24 weeks Gestation
Fetal MRI
FETOSCOPY
Amnion (stuck twin)
Umbilical cord

Prenatal Testing And Screening.ppt

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Neurobiology of autism

Neurobiology of autism
By:Christopher Gillberg, MD, PhD
Professor of Child and Adolescent Psychiatry
University of Göteborg (Queen Silvia´s Hospital)
University of London (St George´s Hospital Medical School)


Autism spectrum disorders: neurobiology

* Overview
* Acquired brain lesions
* Genetics
* Where in the brain is autism?
* Psychosocial interactions
* Intervention implications
* Outcome implications
* The future

Overview
* At least four clinical presentations of autism (autism/autistic spectrum disorder)
* Autistic disorder (Kanner syndrome)
* Asperger’s disorder (Asperger syndrome)
* Childhood disintegrative disorder (Heller syndrome)
* PDD NOS (atypical autism, other autistic-like condition, other autism spectrum disorder)
* Prevalence much higher than believed in the past: ASD in 1% of population, AD in 0.2%
* Associated with learning disability 15% (80% in autistic disorder/AD)
* Associated with epilepsy 5-10% (35% in AD)
* Medical disorder in 5% (25% in AD)
* Skewed male:female ratio 2-4:1
* High rate of visual, hearing and motor impairments (including at birth)
* Sibling rate raised; identical twin conocordance rate much raised in classic autism

”Acquired” brain lesions
* Tuberous sclerosis, Fragile X syndrome, Partial tetrasomy 15, Down syndrome, XYY, XO, Hypomelanosis of Ito, Rett complex variants, Angelman syndrome, Williams syndrome, CHARGE association, Smith-Magenis syndrome, Smith-Lemli-Opitz syndrome, 22q11 deletion, Silver-Russell syndrome, Fetal alcohol syndrome, Retinopathy of prematurity, Thalidomide embryopathy, Moebius syndrome, Herpes and rubella infection
* Known medical disorders 25% in autistic disorder ”proper” (unselected samples) and 2-5% in Asperger syndrome
* These are either genetic in their own right, affect autism susceptibility gene areas, or cause brain lesions through direct/indirect insults
* High rate of pre- and perinatal risk factors
* Tuberous sclerosis
o 3-9% of all autism cases, more common in those with epilepsy
o chromosome 16p involved in one variant (autism susceptibility genetic area? ADHD susceptibility genetic area)
o dopamine genes on chromosome 9 affected in other TS variant
o autism likely if TS lesions in temporofrontal regions and if there are many lesions

* Herpes encephalitis
o affects temporofrontal areas more often than other brain structures
o can lead to classic symptoms of autism even in previously unaffected individuals who are 14 and 31 years of age
* Thalidomide embryopathy
o 5% of all have (classic) autism
o Brainstem lesions
o Day 20-24 postconceptionally

Genetics
* Sibs affected in 3%: core syndrome
* Sibs affected in 10-20%: spectrum disorder
* Identical twins affected in 60-90%
* Non-identical twins affected in 0-3%
* All of these findings refer to probands with autism proper, not spectrum disorders
* First-degree relatives increased rates of affective disorders (depression, bipolar), social phobia, obsessive-compulsive phenomena, and ”broader phenotype symptoms”, ADHD?, Tourette syndrome?
* First-degree relatives also show possibly increased rates of learning disorders including MR, dyslexia and SLI
* Genes on certain chromosomes (e.g. 2, 6, 7, 16, 18, 22, and X) may be important (genome scan studies of sib-pairs)
* Clinical findings in particular syndromes such as partial tetrasomy 15 (15q), Angelman (15q), tuberous sclerosis (9q, 16p), fragile X (X), Rett syndrome (X), Turner syndrome (X)

* Neuroligin genes on X-chromosome mutated in some cases
o (Jamain, Bourgeron, Gillberg et al 2003. Laumonnier et al 2004)
* Neuroligin genes on other chromosomes, including chromosome 17
o (Jamain et al 2003)
* Other neurodevelopmental genes according to microarray study
o (Larsson, Dahl, Gillberg et al 2003)

Where in the brain is autism?

* Clinical finding: macrocephalus common
o (Bayley et al 1997, Gillberg & deSouza 2002)
* Acquired brain lesions implicate temporal, frontal, fronto-temporal and bilateral dysfunction in core syndrome; right or left dysfunction in spectrum disorder
o (Gillberg & Coleman 2000)
* Autopsy data suggest: amygdala, pons and cerebellum
o (Bauman 1988)
* Brainstem damage suggested by
o Thalidomide
+ (Strömland, Gillberg et al 1994)
o Moebius syndrome association
+ (Gillberg & Steffenburg 1997)
o CHARGE association
+ Johansson et al 2004
o Auditory brainstem responses
+ (Rosenhall, Gillberg et al 2003)
o Decrease in/lack of postrotatory nystagmus
+ (Ornitz, Ritvo 1967)
o Aberrant muscle tone and concomitant squint
+ (Gillberg & Coleman 2000)
* Cerebellar dysfunction suggested by
o Autopsy studies
+ (Bauman et al 1992, Bayley et al 1999, Oldfors, Gillberg et al 2000, Weidenheim, Rapin, Gillberg et al 2001)
o Imaging studies
+ (Courchesne 1988)
o Relationship to ataxia
+ (Åhsgren, Gillberg et al 2003)
* Frontotemporal brain dysfunction suggested by
o Autopsy studies
o Functional imaging studies
o Neuropsychological studies
o Combined neuropsychological-neuroimaging studies
o Clinical picture
* Neuropsychological studies show
o Metarepresentation problems
o Central coherence problems
o Non-verbal learning disability in AS
o Verbal learning disability in AD
o Executive function deficits
o Procedural (complex) learning deficits
o Superior fact learning
o Aberrant reading of facial expression

* At least four biological variants of autism?
o Early brainstem/cerebellar associated with severe secondary problems
o Midtrimester bitemporal lobe damage
o Uni- or bilateral frontotemporal dysfunction in high-functioning cases
o Multi-damage autism

* Likely that several functional neural loops are implicated and that all impinge on neurocognitive/social cognitive functions that are crucially (but possibly not specifically) impaired in autism

Where in the brain is autism?
* Dopamine
o (Gillberg et al 1987)
* Serotonin (in LD also)
o (Coleman 1976)
* Noradrenaline dysfunction
o (Gillberg et al 1987)
* Neuroligins
o (Jamain et al 2003)
* GFA-protein
o (Ahlsén et al 1993)
* Gangliosides
o (Nordin et al 1998)
* Endorphines
o (Gillberg et al 1985)
* Immune system
o (Plioplys 1989)
* Glycine, GABA, Ach, glutamate?

Psychopharmacology of autism
* Only dopamine antagonists (neuroleptics) have been convincingly shown to affect core symptoms of autism
o (van Buitelaar 2000)
* SRIs?
* Antiepileptics??
* Peptides?? And peptide-targeted drugs

The pathogenetic chain
* Genetic or environmental insult
* Damage or neurochemical dysfunction
* Neurocognitive and social cognitive functions restricted (metarepresentations, central coherence, executive functions, procedural learning, )
* The ”syndrome” (or, sometimes, the ”arbitrary” symptom constellation) of autism
* The dyad of social impairment plus the monad of restricted behaviour pattern as a common comorbidity? (rather than the triad?)

Psychosocial interactions
* Not associated with social class
* Not associated with psychosocial disadvantage; however, “pseudoautism” described in children exposed to extreme psychosocial deprivation
* Temporally restricted major improvement in good psychoeducational setting
* Immigration links? Indirect link with genetic factors?
* Abnormal child triggers unusual interactions
* Some parents have autism spectrum disorders themselves
* Anxiety, violent behaviours, self-injury and hyperactivity reduced in autism-know-how-millieu

Implications for treatment
* All people are individuals first and foremost; at least as true in autism as in “neurotypicality”
* People WITH autism; not autistic people!
* Change attitudes
* Respect for people in the autism spectrum
* Focus on changing environment and
* Foster adaptive skills
* If known underlying disorder: treat this (and be aware of syndrome-specific symptoms such as gaze avoidance in fragile X)
* If epilepsy: treat this (however, there are major caveats here)
* If hearing, vision, or motor impaired: treat this
* Psychoeducational measures
* Symptomatic biological treatments
* No medication for majority
* Atypical neuroleptics, antiepileptics, SSRIs, stimulants, lithium (and other drugs) for some
* Diets??
* Physical exercise!!
* “Sensory awareness” environment (reduce noise, certain sounds, smell etc.)
* Concrete, visual (not always), straight-forward
* Minimize ambiguities and symbolic interpretation

Outcome
* Very variable
* Better with early diagnosis
* Majority probably live to be old, but increased mortality in subgroup
* Basic problems remain, albeit modified
* High rate of secondary psychiatric problems (personality disorder, affective, social, catatonia)

Outcome
* Better but also very restricted in Asperger syndrome
+ Cederlund et al 2004
* If autism and no language at age 7, classic autism in adulthood
* If autism and no language at age 3, some classic, some Asperger in adulthood
* If autism and some language at age 3, most will be Asperger in adulthood


The future
* Specific knowledge (including genetic) and treatment for subgroups (new diagnostic criteria)
* Symptomatic treatments
* Psychoeducation
* Acceptance and attitude change!
* People with autism, not autists or autistic people! Cannot be stressed enough
* Respect!

Neurobiology of autism .ppt

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SGA and IUGR

SGA and IUGR
By Tina Burleson Stewart, MD

What is the difference between SGA and IUGR?
Can these terms be used interchangeably?
SGA - small for gestational age infants
* an infant whose weight is lower than the population norms
* defined as weight below 10th percentile for gestational age or greater than 2 standard deviations below the mean
* cause may be pathologic or nonpathologic

IUGR - intrauterine growth retardation
* defined as failure of normal fetal growth
* caused by multiple adverse effects on fetus
* due to process that inhibits normal growth potential of fetus


So what is the difference between SGA and IUGR?
* These terms are related but not synonomous.
* Not all IUGR infants are small enough to fit the qualifications for SGA.
* Not all SGA infants are small because of a growth-restrictive process, and therefore, do not meet criteria for IUGR.

Incidence
* 3-10% of all pregnancies
* 20% of stillborn infants
* perinatal mortality 4-8 times higher
* half have serious or long-term morbidity

Epidemiology
* more common in low socioeconomic class
* more common in those of African-American race
* leading cause in third world countries is inadequate nutrition of mother
* leading cause in US is uteroplacental insufficieny

Causes of IUGR
* maternal factors
* fetal factors
* placental factors
* environmental factors

Maternal causes of IUGR
* inadequate nutrition of mother
* multiple gestation
* uteroplacental insufficiency
* hypoxia
* drugs

Mother’s Malnutrition
* lack of adequate food supply
* poor weight gain
* chronic illness
* malabsorption

Multiple Gestation
* difficult to provide optimal nutrition for greater than one fetus
* uterine capacity limitations

Uteroplacental Insufficiency
* preeclampsia
* chronic HTN
* renovascular disease
* vasculopathy from diabetes
* drugs

Hypoxia
* maternal hemoglobinopathies - sickle cell
* maternal anemia
* maternal cyanotic heart disease
* mom living at high altitudes

Maternal Drug Use and Toxin Exposure
* cigarettes
* cocaine
* amphetamines
* antimetabolites - MTX
* bromides
* heroin
* hydantoin
* isoretinoin (Accutane)
* methadone
* alcohol
* methyl mercury
* phencyclidine
* phenytoin (Dilantin)
* polychlorinated biphenyls
* propanolol
* steroids - prednisone
* toluene
* trimethadione
* warfarin (Coumadin)

Fetal Causes of IUGR
* genetics
* congenital infection
* inborn errors of metabolism

Chromosome Disorders associated with IUGR

* trisomies 8, 13, 18, 21
* 4p- syndrome
* 5p syndrome
* 13q, 18p, 18q syndromes
* triploidy
* XO - Turner’s syndrome
* XXY, XXXY, XXXXY
* XXXXX

Syndromes associated with low birth weight
* Aarskog-Scott syndrome
* anencephaly
* Bloom syndrome
* Cornelia de Lange syndrome
* Dubowitz syndrome
* Dwarfism (achondrogenesis, achondroplasia)
* Ellis-van Creveld syndrome
* Familial dysautonomia
* Fanconi pancytopenia
* Hallerman-Streiff syndrome
* Meckel-Gruber syndrome
* Microcephaly
* Mobius syndrome
* Multiple congenital anomalads
* Osteogenesis imperfecta
* Potter syndrome
* Prader-Willi syndrome
* Progeria
* Prune-belly syndrome
* Radial aplasia; thrombocytopenia
* Robert syndrome
* Robinow syndrome
* Rubinstein-Taybi syndrome
* Silver syndrome
* Seckel syndrome
* Smith-Lemli-Opitz syndrome
* VATER and VACTERL
* Williams syndrome

Congenital Infections associated with IUGR
* rubella
* cytomegalovirus
* toxoplasmosis
* herpes
* syphilis
* varicella
* hepatitis B
* coxsackie
* Epstein-Barr
* parvovirus
* Chagas disease
* malaria

Metabolic disorders associated with low birth weight
* agenesis of pancreas
* congenital absence of islets of Langerhans
* congenital lipodystrophy
* galactosemia
* generalized gangliosidosis type I
* hypophosphatasia
* I cell disease
* leprechaunism
* maternal and fetal phenylketonuria
* maternal renal insufficiency
* maternal Gaucher disease
* Menke syndrome
* transient neonatal diabetes mellitus

Placental Causes of IUGR
* placental insufficency
o very important in the 3rd trimester
* anatomic problems
o infarcts
o aberrant cord insertions
o umbilical vascular thrombosis
o hemangiomas
o premature placental separation
o double vessel cord
* microscopic changes
o villous necrosis
o fibrinosis

Environmental Causes of IUGR
* high altitude - lower environmental oxygen saturation
* toxins

IUGR classification
* SYMMETRIC
* height, weight, head circ proportional
* early pregnancy insult: commonly due to congenital infection, genetic disorder, or extrinsic factors
* normal ponderal index
* low risk of perinatal asphyxia
* low risk of hypoglycemia
* ASYMMETRIC
* head=height, both > weight
* brain growth spared
* later in pregnancy: commonly due to uteroplacental insufficiency, maternal malnutrition, hypoxia, or extrinsic factors
* low ponderal index
* increased risk of asphyxia
* increased risk of hypoglycemia

Ponderal Index
* The ponderal index is used determine those infants whose soft tissue mass is below normal for their stage of skeletal development. Those who have a ponderal index below the 10th % can be classified as SGA.
* Ponderal Index = birth weight x 100 crown-heel length

Diagnosis
Prior to delivery, it is necessary to determine the correct gestational age.
* last menstrual period - most precise
* size of uterus
* time of quickening (detection of fetal movements)
* early ultrasound - the earlier the better accuracy
o biparietal diameter
o abdominal circumference - best sensitivity
o ratio of head to abdominal circumference
o femur length
o placental morphology and amniotic fluid

Diagnosis after delivery (OUR JOB!)
* low birth weight - this parameter alone misses big IUGR infants and overdiagnoses constitutionally small infants
* appearance - thin with loose, peeling skin; scaphoid abdomen; disproportionately large head; may be dysmorphic
* ponderal index
* Ballard/Dubowitz - accurate within 2 weeks of gestation if birth weight >999g, most accurate within 30-42 hrs of age
* birth/weight curves

Complications
* hypoxia
o perinatal asphyxia
o PPHN
* hematologic - polycythemia
* meconium aspiration
* metabolic
o hypoglycemia
o hypocalcemia
o acidosis
* hypothermia
* neurological
o more tremulous
o more easily startled
o less visual fixation
o less activity
o less oriented to visual and auditory stimuli

Management in utero
* serologic testing if desired by parents
* decrease mother’s activity
* stop or decrease risk factors if possible
* closely monitor with biophysical profile or nonstress testing or amniotic fluid measurements
* ultrasound every 10-21 days
* teach mom fetal kick counting
* deliver if reaches 36 weeks

Management after birth
* obtain history of risk factors
* appropriate resuscitation
* prevent heat loss
* watch for hypoglycemia
o check glucoses
o early feeding
o parenteral dextrose
* check hematocrit
* screen for congenital infections
* screen for genetic abnormalities
* check calcium

Outcome

* depends on cause of IUGR/SGA and neonatal course
* symmetric IUGR - poor outcome because early insult
* asymmetric IUGR - better outcome because brain spared
* very bad if brain growth failure starts at < 26 weeks
* school performance influenced by social class
* 25-50% likelihood of neurodevelopmental problems


SGA and IUGR.ppt

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Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz Syndrome (SLOS)
By: Suraj Gathani

Description and Occurrence
* Autosomal recessive disorder
o Cholesterol metabolism effected.
* Common characteristics:
o Multiple malformations at birth.
o Mental retardation later.
* Occurrence:
o 1 in 20,000 people of central European decedents.
o Rare in Africans and Asians.

Clinical Features
* Clinical anomalies:
o Mental retardation (100% affected)
o Small brain at birth (microcephaly) >90%
o Second and third toe fusion (synadactyly) ~98%
o Genital abnormalities in males >50%
o Muscle weakness (hypotonia) ~50%
o Polydactyly
o Abnormalities of heart, lung, kidneys, and liver.

Smith-Lemli-Opitz Syndrome
* Distinctive facial features:
o High, broad forehead
o Narrow temples
o Upward pointing nostrils
o Drooping eyelids and a broad nasal bridge
* Behavioral characteristics:
o Repeated self injury
o Prolonged temper tantrums & violent outbursts
o Hyperactivity

Molecular Defects
* Caused from mutation in the DHCR7 gene
o Located at 11q12-13
o Encodes for sterol-Δ7-reductase
* Defects in sterol-Δ7-reductase
o Build up of 7-dehydrocholesterol
o Deficiency of cholesterol
* Importance of cholesterol
o Important component in cell membrane and myelin sheaths
o Precursor for steroid hormones such as progesterone
o Precursor for bile salts

Cholesterol Metabolism
Diagnosis and Treatment
* Diagnosis:
o Detection of an elevated level of 7-dehydrocholesterol in plasma
* Treatment:
o Individuals with SLOS need support and care
o Congenital abnormalities can be corrected with surgery.
o Dietary cholesterol supplementation is beneficial.

Reference

Smith-Lemli-Opitz Syndrome.ppt

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Management Considerations for Patients on Anticoagulants

Management Considerations for Patients on Anticoagulants

Dental Management of Patients on Anticoagulant and Antiplatelet Drugs
By:Donald A. Falace, DMD
Professor and Division Chief
Oral Diagnosis and Oral Medicine
University of Kentucky College of Dentistry


Normal Hemostasis

Following injury to a blood vessel:
* Vascular retraction (vasoconstriction) to slow blood loss

2. Adherence of platelets to the vessel wall (endothelium) and then to each other to form a platelet plug

3. Initiation of the coagulation cascade resulting in the formation and deposition of fibrin to form a clot

Coagulation Cascade
* Extrinsic pathway: Factor VII is activated by tissue factor (phospholipid) that is released by injured perivascular or vascular tissues; very rapid reaction
* Intrinsic pathway: Factor XII is activated by exposure to collagen from vessel wall (endothelium) or blood cell membrane; slower reaction

* Anticoagulants:
o Inhibit the production of clotting factors
* Antiplatelet Agents:
o Interfere with the functioning of platelets, thus inhibiting platelet aggregation

Anticoagulants
Coumarin Derivitives (dicoumarol, warfarin: Coumadin, Panwarfin)
Coumadin antagonizes the production of vitamin K
Vitamin K is necessary for the synthesis of four of the coagulation factors (VII, IX, X and prothrombin)

Pharmacologic Properties (warfarin: Coumadin)
* Taken orally
* Metabolized in the liver
* Half-life: 1.5-2.5 days
* Duration of action: 2-5 days (it takes several days for dosage changes to take effect)
* Increased anticoagulant effect when combined with:
o Antibiotics
o Aspirin
o NSAIDs
o Antifungals
o Tramadol
o Tricyclic antidepressants
o Certain herbals (gingko, ginsing, ginger, garlic)

Co-morbid Conditions That Can Contribute to Increased Bleeding
* Liver disease
* Kidney disease
* Tumor
* Bone marrow failure
* Chemotherapy
* Autoimmune diseases

Conditions for which Coumadin is prescribed to prevent unwanted blood clotting
* Prophylaxis/Treatment of:
o Venous thrombosis (DVT)
o Pulmonary embolism
o Atrial fibrillation
o Myocardial infarction
o Mechanical prosthetic heart valves
o Recurrent systemic embolism

Laboratory Tests to Monitor the Activity of Coumadin
* Prothrombin Time (PT): time for fibrin formation via the extrinsic pathway-factor VII
o Test performed by taking a sample of the Pt’s blood and adding a reagent (thromboplastin) and calculating the time required to form a clot; expressed in seconds
* PT Ratio: Pt’s PT/Normal PT
* Normal PT ration = 1
* Problem: There is variation among thromboplastin reagents, therefore the results from lab to lab are not comparable

Same patient- Same blood
5 different laboratories - 5 different PT Ratios!
Solution: International Normalized Ratio (INR)
o A mathematical “correction” that corrects for the differences in the sensitivity of thromboplastin reagents
o Each thromboplastin is assigned an ISI number which is a sensitivity index
o This correction makes INR values comparable from lab to lab
o Normal INR = 1 (an INR of 2 means that their INR is 2 times higher than normal)

Same Patient-Same Blood
Reported by INR

Recommended Therapeutic Range for Oral Anticoagulant Therapy
(American College of Chest Physicians: Chest 1998; 114(suppl): 439-769s)

INR: 2.0-3.0
Prophylaxis or treatment of venous thrombosis
Treatment of pulmonary embolus
Prevention of systemic embolism
Tissue heart valves
Acute MI
Atrial fibrillation

Recommended Therapeutic Range for Oral Anticoagulant Therapy
(American College of Chest Physicians: Chest 1998; 114(suppl): 439-769s)
* INR: 2.5-3.5
o Mechanical prosthetic valves (high risk)
o Acute MI (to prevent recurrent MI)
o Certain patients with thrombosis and the antiphospholipid antibody syndrome (antibodies that interfere with the assembly of phospholipid complexes and thus inhibit coagulation)


Dental Management Guidelines
* There are no uniformly accepted guidelines for managing anticoagulated patients during dental treatment
* Previous AMA/ADA recommendation was that it was safe to perform surgery on a patient if the PT was 1.5-2.5x normal. This, however, is equivalent to an INR of 2.6-5.0 depending on the sensitivity of the various thromboplastins; an average PT of 1.6 = INR of 3!

* This clinical problem is not amenable to a “cookbook” approach
* Each patient must be considered individually and you must take into consideration the risk-benefit of stopping vs continuing anticoagulation (they are on anticoagulants because they are at risk for thromboembolism)
* Your decision depends upon:
o Medical condition/stability
o Degree of anticoagulation
o Magnitude of planned surgery
o Scientific evidence
* If questionable, decision should be a shared with physician

What does the scientific literature tell us?

* Updated a previous study (Wahl,MJ: Dental surgery in anticoagulated patients. Arch Int Med. 1998;158:1610-1616) and added more cases (26 studies)
* A review of more than 2400 cases of dentoalveolar surgery on more than 950 patients undergoing multiple extractions, full mouth exts, alveoloplasties whose anticoagulant was continued (many with INR > than therapeutic levels)
o 12 cases (0.5%) experienced bleeding that was uncontrollable by local measures alone
o Of these 12, 7 had an INR> than therapeutic levels & 3 were on antibiotics
o 3 required vitamin K administration to stop the bleeding

* Reviewed case reports of 493 patients whose anticoagulant had been discontinued prior to dental extractions and other dental procedures
* 5 pts (1%) suffered significant adverse outcomes
o 4 patients had fatal embolisms
o 1 patient had a non-fatal embolism

Devani,P: Dental extractions in patients on warfarin: Is alteration of anticoagulant regime necessary?
Brit JOMFS 1998;36;107-111

* Compared 2 groups of extraction patients undergoing an average of 2 extractions (range of 1-9 teeth)
o 32 pts with anticoagulant discontinued prior to surg with INR 1.5-2.1, and
o 33 pts with anticoagulant continued with INR of 2.3-3.4. Local measures only for hemostasis (atraumatic technique, sutures, gauze, etc)
* None in either group had significant post-op bleeding; 1 pt in each group required additional local measures to control delayed oozing
* Compared blood loss of 3 groups of dentoalveolar surgery pts
o 12 pts who continued anticoagulant with INR 1.2-2.9
o 13 pts who discontinued anticoagulant 3-4 days with INR 1.1-3.0
o 10 pts who were never on anticoagulant (INR not tested)
* No significant difference in blood loss among groups and no serious postoperative bleeding requiring intervention

* Conducted a systematic review and synthesis of the English language literature from 1966-2001 examining the perioperative management and outcomes of patients receiving long term oral anticoagulant therapy; included a comprehensive review of 26 case reports and studies examining bleeding and thromboembolism after dental procedures (minor ext, fmx, alveolectomies)
* Conclusion: Most patients undergoing dental procedures can undergo the procedure without alteration of the OAC regimen. The current literature suggests that the perioperative stroke rate for patients who have OAC withheld may be substantially greater than would be normally predicted

Conclusions
* It would thus appear that most patients who are on anticoagulant therapy (Coumadin) can undergo minor dentoalveolar surgery without discontinuance of anticoagulant using local/topical measures if:
o INR is within the therapeutic range (<3.5)
o No assoc aggravating conditions (e.g. antibiotics, liver or kidney disease)
o Planned surgery is “minor” (extractions, alveoloplasty, biopsy)
* If anticoagulant needs to be adjusted (INR>3.5), this is the responsibility of the physician

Antiplatelet Agents Normal Platelet Function

Platelets adhere to the area of injured endothelium (mediated by von Willebrand factor)
Platelets adhere to each other and form a scaffolding for fibrin deposition (von Willebrand
factor is a carrier protein for factor VIII)

Uses for Antiplatelet Drugs
* Prevention of heart disease
* During heart attack
* Unstable angina
* Following heart attack
* During or following angioplasty and stenting
* Prevention of stroke or TIA
* Atrial fibrillation (low risk patient)
* Peripheral vascular disease

Antiplatelet Drugs
* Aspirin (irreversible effect for life of the platelet ~ 7-10 days)
* NSAIDs (reversible effect; limited to duration of drug)
o Cox-1 (renal blood flow, fluid/electrolyte transport, stomach mucosal integrity, vasomotor tone, platelet aggregation)
o Cox-2 (inflammation)
* Clopidogrel (Plavix)
* Ticlopidine (Ticlid)
* Dipyridamole (Persantine)

Action of Antiplatelet Drugs
*The life of a platelet is about 7-10 days
Laboratory Tests to Monitor the Effects of Antiplatelet Drugs
* Ivy Bleeding time: measures the length of time a patient bleeds after a standardized incision.
o low reproducibility
o questionable sensitivity
o poor correlation to clinical bleeding tendency
o normal: 1-6 or 7 minutes
o conventionally, a bleeding time >20 minutes has been considered likely to result in clinically significant bleeding
* Platelet Function Analyzer (PFA-100)
o currently the most widely used autoanalyzer
o not yet available in all laboratories
o measures the time it takes to form a platelet plug across the aperature of a capillary tube
o normals: 60-120 seconds
o guidelines not currently available for application of PFA-100 results to clinical bleeding probability
Antiplatelet Drugs and Postoperative Bleeding?

* Very limited literature on this topic
* Most of the studies deal with aspirin
* Little information available on the other antiplatelet drugs
* Most of the recommendations are based upon clinical experience, case reports and expert opinion

Aspirin and Bleeding
* In all studies, aspirin was continued
* All three studies found no significant difference in perioperative or postoperative blood loss between patients taking aspirin and controls
* Medline review and analysis of all articles from 1966-2002 on surgery and bleeding complications due to aspirin
* No clinically relevant bleeding complications were reported for cardiovascular, vascular, or orthopedic surgery, or epidural anesthesia; there was an increase in clinically non-relevant bleeding induced by aspirin
* Conclusion: There is no scientific evidence to support the withdrawal of aspirin in patients prior to surgery
Current Practice in Great Britain
* The general consensus of opinion from this survey suggests that most vascular surgeons do not stop antiplatelet drugs preoperatively
Expert Opinion Canada
* Conclusion: Aspirin should not be withdrawn in most cases
o If pt is on aspirin, clopidogrel or ticlopidine and intraoperative bleeding is feared, a short-acting NSAID can be temporarily substituted

Summary: Antiplatelet Agents
* Clinical experience, expert opinion, anecdotal reports and available studies suggest that for most patients undergoing dentoalveolar surgery, it is not necessary to discontinue the use of aspirin or other antiplatelet agents if used alone. The use of these agents is not usually associated with significant (serious) operative or postoperative bleeding.
* If two agents are used together (e.g. aspirin and clopidogrel), the risk for bleeding is likely increased, and depending upon the extent of the surgery, should be discussed with the physician

Local Measures to Control Postoperative Bleeding
* Careful, atraumatic surgical technique
* Use of absobable hemostatic agent in socket (e.g. Gelfoam,Avitene,Surgicel)
* Careful suturing; primary closure over sockets not essential
* Post-operative pressure pack (damp gauze for 30-60 minutes); especially important for flap compression
* May use antifibrinolytic agents: tranexamic acid [Cyklokapron Oral] or epsilon amino caproic acid [Amicar] as a mouthwash or to soak pressure gauzes

Antifibrinolytic Mouthrinses
* Epsilon amino caproic acid (Amicar)
o Syrup (1.25 gm/5cc) , 5-10 mL QID X 7 days
o Use either as mouthwash or as a soak for the pressure gauze
* Tranexamic acid (Cyklokapron)
o Used topically as 10 mL of a 4.8% -5% weight/volume solution as a mouthwash for 2 minutes, QID, for 7 days
o Unfortunately, the 4.8% elixir is not FDA approved for use in the USA market

Additional Postoperative Measures

Management Considerations for Patients on Anticoagulants.ppt

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