Clinical Trials Design

Clinical Trials Design
By:Martha A. Feldman, RAC
Drug & Device Development Co., Inc.

Purposes of conducting clinical studies
Types of clinical studies
Ethical considerations
Regulatory requirements
Monitoring
Database management issues
Statistical considerations
Reports for submissions or papers

Purposes of Clinical Studies
Further scientific knowledge
Prove concept
Evaluation of product features, capabilities
Obtain initial safety data
Substantiate claim/indication for use
Establish degree of efficacy or effectiveness
Compare with competitor product; marketing evaluation

Types of Clinical Studies
Prospective or retrospective
Blinded/masked or open label
Randomized or not
Active control or placebo
Normal subjects or patients
Actual or surrogate clinical endpoints
Statistically significant or “anecdotal”

Ethical Considerations
Human Subject Review: IRB, Declaration of Helsinki
Informed consent, community consent, waiver of consent
Use of placebos versus positive control
Use of normal subjects
Use of investigational material in addition to standard care
Vulnerable populations

Regulatory Considerations
Drug/Therapeutic Biologic Studies

Overall investigation Plan
Phase 1 - Normal subjects: usually < 50 subjects, at one facility, safety parameters
Phase 2 - Patients: about 50 - 100 subjects; at two sites; may do some dose-range assessment; safety and some initial efficacy
Phase 3 - Patients: few hundred to several thousand; multiple sites; main support study
Phase 4 - Patients (post-marketing): varies


Phase 1 Clinical Study
Normal subjects; occasionally use patients
See if/how pharmacokinetics data from animal studies extrapolates to human data
Document pharmacodynamic effects
Usually open label with ascending doses; establish dose-range
Build safety profile: monitor adverse effects

Phase 2 Clinical Study
Patients or people with clinical condition
Confirm dose range is similar in such people; if not, re-define range
Blinding, randomization, controls used
Strict entry criteria
Initial efficacy determination

Phase 3 Clinical Study
Few hundred to few thousand patients
Multiple sites
Blinding, randomization, controls, prospective
May have slightly broader entry criteria - age, severity of disease,
Continue developing safety and efficacy profiles

Post-marketing Study
Surveillance or study
Numbers to be negotiated
Parameters determined as a result of Phase 3 study
May involve labeling issues

Device Clinical Studies
“It Depends”
Steps in Investigation Plan
Proof of concept/Feasibility: < 5 subjects or patients; one site, safety and some effectiveness
Pilot study: 20-50 subjects; “test drive” protocol, case report forms, initial effectiveness and safety; two sites
Pivotal study: 50 - 500 subjects; multiple sites; main supporting study for claims

Proof of Concept/Feasibility Study
few patients (<5)
limited to one site
usually investigator-sponsored study
goal: prove concept, check instructions for use; early safety and effectiveness assessments


Pilot Study
More rigorous protocol
May be up to 50, but usually around 20 subjects
One or two sites
Company-sponsored study
“Test drive” protocol, comparison of use at two sites, safety and some effectiveness data; finalize training plan
Adjust final protocol for pivotal trial

Pivotal Study
The main study to support the submission
Subject number could be from around 100 to several hundred
Multicenter study; each site should enroll sufficient subjects for separate analyses
Should demonstrate device is independent of inventors


IVD Studies
May be done in two parts: collection of samples (may take > 1 year) and use of IVD (may take < 1month); separate protocols
Collection of samples may involve dozens of sites; testing phase may be at minimum of three sites
Study size may range for 100 (for some monitoring studies) to several thousand (for screening indication)
May enrich samples with stored, known, positive samples: special IRB and consent issues

Monitoring
At least one a year on-site
Between visits: by telephone, e-mail, FAX and courier services

Prestudy Activities
Investigator selection and qualification
Site qualification:
additional staff
sufficient number of subjects
laboratories, pharmacies
special needs
Conduct Pre-study site visit

Prestudy Site Visit
Meet investigator, coordinators, other staff
Review protocol, case report forms
Emphasize consent procedure, requirements
Review adverse event procedures
Review investigator documentation
Review Regulatory Notebook
Visit, as needed, labs, pharmacy, etc.
“Build” study team

Routine, Interim Visit
Review regulatory notebook
Verify consent procedures followed
Ensure study eligibility criteria met
Compare data entries on CRFs and source data
Check investigational product accountability
Check for unreported adverse events
Resolve queries

“For Cause” Visit
Possible reasons
too little/too much enrollment
much greater number adverse events
badly completed case report forms
new coordinator/investigator needing training
results “too good”
Monitor has concerns about investigator or coordinator compliance with regulations

Close-Out Visit
Regulatory Notebook is complete
Supplies accountability checks out
All queries resolved
No unreported, unresolved adverse events
All patient follow-up completed
Investigator’s report done
Files prepared for FDA inspections and for storage

Database Management Issues
Programming for the case report entries
Developing a data entry plan; data entry verification plan
Generating queries for the monitors to have coordinators resolve
Entering amended data; database clean-up
Data editing plan
Closing database; data validation plan; send to statistician
Developing tables for the reports, submissions, etc.

Statistical Considerations
Developing hypotheses
Calculating sample size requirements
Developing plan for interim analysis, if needed, and for final analysis (including sub-analyses)
Determining how interim analysis results impact sample size
Perform analysis and data evaluation
Write statistical report

Sponsor Reports - Submissions
Adverse event reports
Use of investigational product without consent
IRB withdrawal of approval
Annual reports
Updating submissions with each advance in the investigational plan (e.g., study completion or termination)

Investigator Reports
Withdrawal of IRB approval
Use of product without consent
Adverse events - to sponsor and IRB
Study status reports; study close-out report
For device studies: malfunction, repair or replacement

Other Reports
Publications, posters, presentations
can review manuscript for proprietary information
cannot stop the publication of negative results
off-label use: company may not promote it, but can distribute articles written by health care practitioners
References

Code of Federal Regulations, Title 21
Part 50 - Informed Consent
Part 56 Institutional Review Boards
Part 312 - Investigational New Drug, antibiotic, Biotechnology-Derived Product regulations
Part 812 - Investigational New Device regulations
FDA Guidance Document on Good Clinical Practices, January 1988
ICH Guidance Document E6 - Good Clinical Practices
More References

Clinical Trials Design.ppt

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Increasing Complexity of Clinical Trials

Increasing Complexity of Clinical Trials

Definitions:
Procedures: include lab & blood work, routine exams, x-rays & imaging, questionnaire & subjective assessments, invasive procedures, heart assessment, etc.

Protocol: the clinical-trial design plan
Enrollment rate: the percentage of volunteers meeting the increasing number of protocol eligibility criteria (percentage screened who were then enrolled)

Retention rates: the percentage of volunteers enrolled who then completed the study; declining retention rates mean that firms must enroll more patients initially and/or recruit more patients during the trial.

Increasing Complexity of Clinical Trials
During the last decade clinical trial designs and procedures have become much more complex, demanding more staff time and effort, and discouraging patient-enrollment and retention

Unique Procedures per Trial Protocol (Median)
Total Procedures per Trial Protocol (Median)
Clinical-Trial Staff Work Burden (Measured in Work-effort Units)
Length of Clinical Trial (Days)
Clinical-Trial-Participant Enrollment Rate
Clinical-Trial-Participant Retention Rate

Increasing Complexity of Clinical Trials.ppt

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Clinical Protocol Development

CLINICAL PROTOCOL DEVELOPMENT

What’s The Question?
What is the study hypothesis?

What’s The Question?
* What’s the outcome?
* What’s the intervention?
* When and for how long?
* For whom?
* How many participants are needed?
* How can we optimize potential benefit (and what we learn) while minimizing potential harm?

Answering the Question
* Response variable selection and measurement
* Defining the intervention
* Study design
* Eligibility criteria
* Sample size estimate
* Patient management procedures
* Monitoring for safety and benefit
* Data analysis approaches
Response Variable Selection
* “Dose ranging”
* Biologic activity
* Biomarker
o Understand mechanism
o Surrogate outcome
* Toxicity
* Condition/vector/gene interaction
* Feasibility for larger study
* Clinical outcome

Response Variable Criteria
* Well defined
* Stable
* Reproducible
* Unbiased
* Ascertainable in all participants
* Adequately address study hypothesis

Defining the Intervention
* Dose/dosing schedule
* Vector
* Route of delivery
* Method of preparation

Study Design
* Uncontrolled
* Controlled
o Before/after
o Historical
o Concurrent, not randomized
o Randomized

Comparing Treatments
* Fundamental principle
o Groups must be alike in all important aspects and only differ in the intervention each group receives
o In practical terms, “comparable treatment groups” means
“alike on the average”
* Randomization
o Each participant has the same chance of receiving any of the
interventions under study
o Allocation is carried out using a chance mechanism so that neither the participant nor the investigator will know in advance which will be assigned
* Blinding
o Avoidance of conscious or subconscious influence
o Fair evaluation of outcomes

Non-randomized Trials May Be Appropriate
* Early studies of new and untried therapies
* Uncontrolled early phase studies where the standard is relatively ineffective
* Investigations which cannot be done within the current climate of controversy (no “clinical equipoise”)
* Truly dramatic response

Advantages of Randomized Control Clinical Trial
1. Randomization "tends" to produce comparable groups
2. Randomization produces valid statistical tests

Disadvantages of Randomized Control Clinical Trial

1. Generalizable Results?
o Participants studied may not represent general study population.
2. Recruitment
o Hard
3. Acceptability of Randomization Process
o Some physicians will refuse
o Some participants will refuse
4. Administrative Complexity
Study Population
Subset of the general population determined by the eligibility criteria
General population
Eligibility criteria
Enrollment
Study sample
Eligibility Criteria
* State in advance
* Consider
o Potential for effect of intervention
o Ability to detect that effect
o Safety
o Ability for true informed consent

Sample Size (1)
* The study is an experiment in people
* Need enough participants to answer the question
* Should not enroll more than needed to answer the question
* Sample size is an estimate, using guidelines and assumptions

Sample Size (2)
* Approaches for early phase studies
o Dose escalation schemes
o Decision that intervention is unlikely to be effective in ?x% of participants
o Decision that intervention could be effective in ?x% of participants
* Standard ways of estimating for phase III
Sample Size (3)
* Assumptions depend on
o Nature of condition
o Desired precision of answer
o Availability of alternative treatments
o Knowledge of intervention being studied
o Availability of participants

Regular Follow-up
* Routine Procedures (report forms)
o Interviews
o Examinations
o Laboratory Tests
* Adverse Event Detection/Reporting
* Quality Assurance
Contingency Plans
* Patient management
* Evaluation and reporting to all relevant persons and groups
* Data monitoring plans
* Protocol amendment or study termination
Data Analysis (1)
* Occurrence of event
* Time to event
* Mean level of response
* Duration of response
Data Analysis (2)
* Intention-to-treat
* Explanatory
* Subgroups
* Adjusted vs. Unadjusted

Data Analysis (3)
* Specify in advance
o Primary
o Secondary
o Other
o Statistical approach
* Exploratory

Clinical Protocol (1)
* Background/Justification
--Where we are in the field
--What the study will add that is important
* Objectives
--Primary hypothesis
--Secondary hypotheses
--Other
Clinical Protocol (2)
* Study Design and Methods
--Type of study, comparison
--Inclusion and exclusion criteria
--Description of intervention (what, how)
--Concomitant therapy
--Examination procedures (baseline, follow-up, outcome assessment)
--Intervention assignment procedure

Clinical Protocol (3)
* Monitoring and Management
--Data and safety monitoring
--Adverse event assessment, reporting
--Contingency procedures
--Withdrawal criteria

Clinical Protocol (4)
* Statistics
--Sample size
--Stopping guidelines
--Analysis plans
* Participant protection issues
Summary
* Protocol lays out who, what, why, when, where, how
* Safeguards participants
* Safeguards study integrity
* Midcourse changes are often appropriate (even necessary)

Clinical Protocol Development.ppt

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Introduction to Clinical Trials

Introduction to Clinical Trials

Issues in Analysis of Randomized Clinical Trials
Sources of Bias
1. Patient selection
2. Treatment assignment
3. Patient Evaluation
4. Data Analysis

Minimize Bias
1. Randomized Controls
2. Double blind (masked)
3. Analyze what is randomized

What Data Should Be Analyzed?
* Basic Intention-to-Treat (ITT) Procedure
o Analyze what is randomized!
* Randomized control trial “gold” standard
o Beware of lookalikes
* Definitions
Exclusions
o Screened but not randomized
o Affects generalizability
o Validity OK
Withdrawals from Analysis
o Randomized, but not included in data analysis
o Possible to introduce bias!

Patient Closeout
* ICH E9 Glossary
o “Intention-to-treat principle - …It has the consequence that subjects allocated to a treatment group should be followed up, assessed, and analyzed as members of that group irrespective of their compliance with the planned course of treatment.”

Patient Withdrawn in Analysis
* Common Practice - 1980s
o Over 3 years, 37/109 trials in New England Journal of Medicine

* Typical Reasons Given
a. Patient ineligible (in retrospect)
b. Noncompliance
c. Competing events
d. Missing data

I. Patient Withdrawn in Analysis
A. Patient INELIGIBLE
o After randomization, discover some patients did not in fact meet entry criteria
o Concern ineligible patients may dilute treatment effect
o Temptation to withdraw ineligibles
o Withdrawl of ineligible patients, post hoc, may introduce bias

Betablocker Heart Attack Trial
* 3837 post MI patients randomized
* 341 patients found by Central Review to be ineligible
* Results

Anturane Reinfarction Trial (1980) NEJM
* Randomized, double blind, placebo controlled
Anturane Reinfarction Trial (1980)
* 1629 patients randomized
o 1631 entered, but two patients randomized twice
o Need to delete 03013, 17008
o Use first randomization!

* Declared post hoc 71 “ineligible” patients

Analyzable Deaths - Within 7 days of being off drug

1980 Anturane Mortality Results
Total Mortality
Anturane Reinfarction Trial (1980)
Total Mortality
Anturane Sudden Death (SD)
for Total Follow-up
Anturane Analysis
Acceptable Policies For Ineligible Subjects

1. Delay randomization, confirm eligibility and allow no withdrawals (e.g. AMIS) (Chronic Studies)
2. Accept ineligibles, allow no withdrawals
(e.g. BHAT, MILIS) (Acute Studies)
3. Allow withdrawals if:
a. Procedures defined in advance
b. Decision made early (before event)
c. Decision independent and blinded
d. Use baseline covariates only (two subgroups)
e. Analysis done with and without

B. WITHDRAWL FOR NON-COMPLIANCE
References: Sackett & Gent (1979) NEJM, p. 1410

Coronary Drug Project (1980) NEJM, p. 1038
* Two Types of Trials
1. Management
- "Intent to Treat" Principle
- Compare all subjects, regardless of compliance

2. Explanatory
- Estimate optimum effect, understand mechanism
- Analyze subjects who fully comply
WITHDRAWALS FOR NON-COMPLIANCE MAY LEAD TO BIAS!

Breast Cancer Adjuvant Therapy Probability of Disease Free Survival for Years Post Mastectomy (Method I)
Breast Cancer Adjuvant Therapy
Probability of Disease Free Survival for
Years Post Mastectomy (Method II)
Redmond et al (1983) Cancer Treatment Report
Example: Coronary Drug Project 5-Year Mortality
Comments

* Higher % of estrogens patients did not comply
* Beneficial to be randomized to estrogen & not take it
* (6.1% vs. 9.9%)
* Best to be randomized to placebo & comply (4.8%)
Aspirin Myocardial Infarction Study (AMIS)
Summary of Compliance
* No consistent pattern
Example Non-compliance Did Worse
CDP Clofibrate, AMIS Both Treatment & Control
CDP Estrogen Control Only
Beta-blocker, Wilcox Two Treatments, Not Control
* Compliance an outcome, not always independent of treatment
* Withdrawal of non-compliers can lead to bias
* Non-compliers dilute treatment
* Try hard not to randomize non-compliers

II. Competing Events
* Subject may be censored from primary event by some other event (e.g. cancer vs. heart disease)
* Must assume independence
* If cause specific mortality used, should also look at total death
* If non-fatal event is primary, should also look at total death and non-fatal event
* Problem for some response measures

Problem of Definitions
Classification Anturane Placebo P-value
Anturane Reinfarction Trial Sudden Death
Category Source Placebo Anturane P-value

III. "Wrong", Inconsistent, Outlying Data
* "Wrong" or "outlying" data may in fact be real
* Decisions must be made blind of group assignment
* All modifications or withdrawals must be documented
IV. Missing Outcome Data
* Design with zero
o missingness may be associated with treatment
+ for analysis, data are not missing at random
+ even if same number missing, missing may be for different reason in each treatment group
* Implement with minimum possible
* Analyze exploring different approaches
o if all, or most, agree, then more persuasive

“Best” and “Worst” Case Analyses
VI. Poor Clinic Performance in a Multicenter Study

* If randomization was stratified by clinic, then withdrawal of a clinic is theoretically valid
* Withdrawal must be done independent of the outcome at that clinic
VIII. Fishing or Dichotomizing Outcomes
* Common practice to define a response (S,F) from a non-dichotomous variable
* By changing our definition, we can alter results
* Thus, definitions stated in advance
* Definitions should be based on external data

Dichotomizing Outcomes
Example
IX. Time Dependent Covariate Adjustment
* Classic covariate adjustment uses baseline prognostic factors only
o Adjust for Imbalance
o Gain Efficiency

* Adjustment by time dependent variates not recommended in clinical trials (despite Cox time dependent regression model)

* Habit from epidemiology studies
Intent To Treat (ITT) Principle

* Analyze all patients randomized, regardless of compliance to assigned intervention
* Analyze all events in the follow-up, regardless of compliance


Introduction to Clinical Trials.ppt

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Blood

BLOOD

CIRCULATORY SYSTEM
* BLOOD
* HEART
* BLOOD VESSELS

FUNCTIONS OF BLOOD
* TRANSPORT
* PROTECTION
* REGULATION

TRANSPORT
* OXYGEN (O2)
* CARBON DIOXIDE (CO2)
* NUTRIENTS
* WASTES
* HORMONES
PROTECTION
* IMMUNE SYSTEM
o WHITE BLOOD CELLS
o ANTIBODIES
* CLOTTING SYSTEM
o PLATELETS
o FIBRINOGEN / FIBRIN

REGULATION
* BODY TEMPERATURE
* pH
* WATER BALANCE
* ELECTROLYTE BALANCE

BLOOD COMPOSITION
BLOOD IS COMPRISED OF TWO MAIN COMPONENTS:
* PLASMA
* FORMED ELEMENTS
THESE COMPONENTS CAN BE SEPARATED BY CENTRIFUGATION
THE FRACTION OF THE BLOOD VOLUME COMPRISED OF RED BLOOD CELLS IS TERMED THE HEMATOCRIT

PLASMA COMPOSITION
* WATER (~90%)
* SOLUTES (~10%)
o PROTEINS (~8%)
o OTHER COMPOUNDS (~2%)
+ NUTRIENTS
+ GASES
+ WASTES
+ HORMONES
+ ELECTROLYTES

PLASMA PROTEINS
* MOST ABUNDANT PLASMA SOLUTE
* LIVER CAN PRODUCE 4 GRAMS OF PLASMA PROTEINS PER HOUR
* THREE MAJOR CATEGORIES
o ALBUMINS
o GLOBULINS
o FIBRINOGEN
ALBUMINS
* ~60% OF PLASMA PROTEINS
* SMALL
* TRANSPORT LIPIDS, HORMONES, CALCIUM, ETC.
* BUFFER BLOOD pH
* CONTRIBUTE TO VISCOSITY & OSMOLARITY
* INFLUENCE BLOOD PRESSURE, BLOOD FLOW, AND FLUID BALANCE

GLOBULINS
* ~36% OF PLASMA PROTEINS
* THREE SUBCLASSES
o ALPHA (a)
o BETA (b)
o GAMMA (g)
* ALPHA (a)
o VARIOUS FUNCTIONS, ESPECIALLY TRANSPORT
* BETA (b)
o VARIOUS FUNCTIONS, ESPECIALLY TRANSPORT
* GAMMA (g)
o COMPONENTS OF IMMUNE SYSTEM
o PRODUCED BY PLASMA CELLS, WHICH ARE DESCENDED FROM WHITE BLOOD CELLS

FIBRINOGEN
* ~4% OF PLASMA PROTEINS
* PRECURSOR OF FIBRIN
* INVOLVED IN BLOOD CLOTTING

PLASMA: NUTRIENTS
* SUGARS
* AMINO ACIDS
* FATS
* CHOLESTEROL
* PHOSPHOLIPIDS
* VITAMINS
* MINERALS

PLASMA: GASES
* OXYGEN (O2)
o REQUIRED FOR CELLULAR RESPIRATION
* CARBON DIOXIDE (CO2)
o PRODUCT OF CELLULAR RESPIRATION
* NITROGEN (N2)
o USUALLY PHYSIOLOGICALLY UNIMPORTANT
o WHY DO YOU THINK IT IS THERE?

PLASMA: WASTES
NITROGENOUS WASTES
* PRODUCTS OF CATABOLISM
o (ESP: AMINO ACID CATABOLISM)
* MOST ABUNDANT IS UREA
* REMOVED FROM BLOOD BY KIDNEYS
* EXCRETED THROUGH URINE
* RATE OF REMOVAL BALANCES RATE OF PRODUCTION

PLASMA: ELECTROLYTES
* SODIUM (Na+)
* CALCIUM (Ca2+)
* POTASSIUM (K+)
* MAGNESIUM (Mg2+)
* CHLORIDE (Cl-)
* BICARBONATE (HCO3-)
* PHOSPHATE (HPO42-)
* SULFATE (SO42-)
* VARIOUS IONS
* SODIUM IS THE MOST PREVALENT
* INCREASE BLOOD OSMOLARITY
o AFFECT BLOOD VOLUME
o AFFECT BLOOD PRESSURE

FORMED ELEMENTS
* ERYTHROCYTES (RED BLOOD CELLS)
* LEUKOCYTES (WHITE BLOOD CELLS)
* PLATELETS (CELL FRAGMENTS)

ERYTHROCYTE FUNCTIONS
* CARRY O2 FROM LUNGS TO CELLS
* CARRY CO2 FROM CELLS TO LUNGS
* HOW DO O2 AND CO2 RELATE TO THE FUNCTIONS OF A CELL?

ERYTHROCYTE QUANTITIES
* MEN: 4.6 – 6.2 MILLION/mL IN
o HEMATOCRIT 42 – 52 (% RBCs)
* WOMEN: 4.2 – 5.4 MILLION/mL
o HEMATOCRIT 37 – 48 (% RBCs)
* GENDER DIFFERENCES BASED ON:
o ANDROGENS INCREASE NUMBER
o MENSTRUAL LOSS DECREASES NUMBER
o BODY FAT (INVERSE RELATIONSHIP)
o FASTER CLOTTING IN MEN

ERYTHROCYTE STRUCTURE
* DISC SHAPED
* BICONCAVE
* 7.5 MICROMETER (mm) DIAMETER
* 2 MICROMETERS (mm) THICK

ERYTHROCYTE STRUCTURE
PLASMA MEMBRANE
* PHOSPHOLIPID BILAYER
* GLYCOPROTEINS, GLYCOLIPIDS
o DETERMINE BLOOD TYPE
* ACTIN AND SPECTRIN ON INNER SURFACE
o RESILIENCE / DURABILITY / PLIABILITY
* HIGH SURFACE AREA:VOLUME RATIO
o RESULT OF BICONCAVE SHAPE
o INCREASES RATE OF GAS DIFFUSION INTO AND OUT OF CELLS

ERYTHROCYTE STRUCTURE
CYTOPLASM
* LACKS ORGANELLES
o ESP: LACKS MITOCHONDRIA, NUCLEUS
o WHY IS THIS IMPORTANT?
o CANNOT REPAIR
o LIMITED LIFESPAN (~120 DAYS)
o CANNOT DIVIDE
o NEW CELLS FORMED IN BONE MARROW
* HEMOGLOBIN
o RED PIGMENT
o HIGH CONCENTRATION (33%)
o 280 MILLION MOLECULES PER CELL
o CARRIES MOST OF THE O2
o CARRIES SOME OF THE CO2
o PROTEIN & NON-PROTEIN COMPONENTS

HEMOGLOBIN
PROTEIN COMPONENT
* 4 POLYPEPTIDES (HETEROTETRAMER)
o 2 a-GLOBIN PROTEINS
o 2 b-GLOBIN PROTEINS
NON-PROTEIN COMPONENT
* 4 HEME GROUPS
o PORPHYRIN RING AND IRON ION
o IRON ION WITHIN HEME BINDS TO O2

ABO BLOOD TYPES
* DETERMINED BY SURFACE ANTIGENS
o GLYCOLIPIDS AND GLCOPROTEINS
+ (SUGARS ON CELL SURFACE)
o GENETICALLY DETERMINED
o RECOGNIZED BY ANTIBODIES
o INDIVIDUALS POSSESS ANTIBODIES TO ANTIGENS THEY THEMSELVES DO NOT POSSESS
o RECOGNITION OF THESE ANTIGENS BY ANTIBODIES CAUSES CELL CLUMPING
* DETERMINED BY GENE “I”
* THREE ALLELES
o IA
o IB
o i
* IA AND IB ARE CODOMINANT
* i IS RECESSIVE TO IA AND IB
* THREE ALLELES OF “I” GENE
* INDIVIDUALS POSSESS TWO COPIES
* FOUR BLOOD TYPES
o A GENOTYPE IAIA OR IAi
o B GENOTYPE IBIB OR IBi
o AB GENOTYPE IAIB
o O GENOTYPE ii

ANTIBODIES TO A AND B ANTIGENS
* APPEAR SHORTLY AFTER BIRTH
* PRESENT FOR ENTIRE LIFE
* PRODUCED IN RESPONSE TO SIMILAR ANTIGENS ON INTESTINAL BACTERIA
* CROSS-REACT WITH A AND B ANTIGENS
* TERMED “ANTI-A” AND “ANTI-B”
* CAUSE OF TRANSFUSION REACTIONS

Rh BLOOD TYPES
* DETERMINED BY SURFACE ANTIGENS
* UNRELATED TO ABO BLOOD TYPE
* GENETICALLY DETERMINED
* ALLELES OF THREE GENES
o C, c, D, d, E, e
o DD, Dd ARE Rh+
o dd MAY BE Rh-, DEPENDING ON ALLELES OF OTHER GENES
* ANTI-D ANTIBODIES NOT NORMALLY PRESENT
o PRESENT ONLY IN Rh- EXPOSED TO Rh+
o FIRST EXPOSURE NOT PROBLEMATIC
o SECOND EXPOSURE PROBLEMATIC
o TRANSFUSION / PREGNANCY
* IMMUNE RESPONSE PREVENTABLE
o RhoGAM (Rh IMMUNE GLOBULIN)

OTHER BLOOD GROUPS
* > 100 OTHER BLOOD GROUPS
* USEFUL IN GENETIC / BIOCHEMICAL TESTING
* RARELY CAUSE TRANSFUSION REACTIONS

ERYTHROCYTE DISORDERS
ANEMIA
* ERYTHROCYTE DEFICIENCY, OR
* HEMOGLOBIN DEFICIENCY
* THREE CLASSES
o INADEQUATE SYNTHESIS
o BLEEDING
o RBC DESTRUCTION
* CONSEQUENCES
o OXYGEN DEPRIVATION (HYPOXIA)
+ SHORTNESS OF BREATH
o REDUCED BLOOD OSMOLARITY
+ WATER RETENTION IN TISSUES (EDEMA)
o REDUCED BLOOD VISCOSITY
+ HEART BEATS FASTER
+ CARDIAC FAILURE
SICKLE-CELL ANEMIA
* ~0.25% OF AFRICAN AMERICANS
* GENETICALLY DETERMINED
* ABERRANT b-GLOBIN ALLELE (HbS)
o SINGLE AMINO ACID SUBSTITUTION
o GLUTAMIC ACID (HbA)  VALINE (HbS)
* CELLS SICKLE UNDER LOW OXYGEN
* MULTIPLE DELETERIOUS EFFECTS

* WHY IS THE FREQUENCY SO HIGH?
o MALARIA PREVALENT IN AFRICA
o Plasmodium PARASITE LIVES IN RBCs
o SURVIVES POORLY IN CELLS WITH HbS
o INDIVIDUALS WITH HbS LESS LIKELY TO DIE (HETEROZYGOTES MOST FIT)
o THUS, HbS PROVIDES PROTECTION

LEUKOCYTES
* 5,000 – 10,000 CELLS/mL
* FIVE TYPES:
o NEUTROPHILS 60 – 70 % 9 – 12 mM
o LYMPHOCYTES 25 – 33% 5 – 8 mM (most)
o MONOCYTES 3 – 8 % 12 – 15 mM
o EOSINOPHILS 2 – 4% 10 – 14 mM
o BASOPHILS <0.5 – 1% 8 – 10 mM
* GRANULOCYTES
o NEUTROPHILS
o EOSINOPHILS
o BASOPHILS
* AGRANULOCYTES
o LYMPHOCYTES
o MONOCYTES
LEUKOCYTES
NEUTROPHILS
* HIGHLY MOBILE
* INCREASE IN RESPONSE TO BACTERIAL INFECTIONS
* KILLS BACTERIA
o PHAGOCYTOSIS
o CHEMICALLY (BURST LYSOSOMES)

EOSINOPHILS
* INCREASE WITH ALLERGIES
* INCREASE WITH PARASITIC INFECTIONS
* PHAGOCYTOSIS
o ANTIGEN / ANTIBODY COMPLEXES
o ALLERGENS
* HYDROLYTIC ENZYME RELEASE
o RESPONSE TO HOOKWORM, TAPEWORM, ETC.
o TOO LARGE TO PHAGOCYTIZE
BASOPHILS
* GENERALLY NOT PHAGOCYTIC
* AID OTHER LEUKOCYTES
o RELEASE HISTAMINE
+ INCREASE BLOOD FLOW TO AREA
o RELEASE HEPARIN
+ INHIBIT CLOTTING
LYMPHOCYTES
* INCREASE IN IMMUNE RESPONSE
* SEVERAL SUBCLASSES
* VARIOUS IMMUNE FUNCTIONS
o ESP: SECRETE ANTIBODIES

MONOCYTES
* DIFFERENTIATE INTO MACROPHAGES
* PHAGOCYTOSIS OF PATHOGENS
* PHAGOCYTOSIS OF DEBRIS
* PRESENT ANTIGENS TO OTHER CELLS OF IMMUNE SYSTEM
PLATELETS
* 130,000 – 400,000 / mL
* NOT CELLS
o FRAGMENTS OF MEGAKARYOCYTES
o SMALL (2 – 4 mM DIAMETER)
* POSSESS VARIOUS ORGANELLES
* PSEUDOPODS
o AMOEBOID MOVEMENT
o PHAGOCYTOSIS
PLATELET FUNCTIONS
* SECRETE CLOTTING FACTORS
* SECRETE VASOCONSTRICTORS
* FORM TEMPORARY PLATELET PLUGS
* DISSOLVE OLD BLOOD CLOTS
* PHAGOCYTOSIS OF BACTERIA
* SECRETE CHEMICALS TO ATTRACT LEUKOCYTES TO SITES OF INFLAMMATION
* SECRETE GROWTH FACTORS

CONTROL OF BLEEDING
HEMOSTASIS
* VASCULAR SPASM
* PLATELET PLUG FORMATION
* COAGULATION
VASCULAR SPASM
* CONSTRICTION OF BROKEN VESSEL
* IMMEDIATE PROTECTION AGAINST BLEEDING
* MULTIPLE TRIGGERS
TRIGGERS OF VASCULAR SPASM
* PAIN RECEPTORS  NERVES  BLOOD VESSELS CONSTRICT
* SMOOTH MUSCLE OF BLOOD VESSELS CONSTRICT
* PLATELETS RELEASE SEROTONIN (CHEMICAL VASOCONSTRICTOR)
PLATELET PLUG FORMATION
* BLOOD VESSEL BROKEN
* COLLAGEN FIBERS EXPOSED
* PLATELETS BIND TO COLLAGE FIBERS
o FORM PSEUDOPODS
o ATTACH TO VESSEL AND OTHER PLATELETS
o CONTRACT AND PULL WALLS TOGETHER
o DEGRANULATION
PLATELET PLUG FORMATION
* DEGRANULATION
o RELEASE OF COMPOUNDS TO
+ VASOCONSTRICT
+ ATTRACT PLATELETS
+ STIMULATE DEGRANULATION
+ PROMOTE AGGREGATION
o POSITIVE FEEDBACK
CONTROL OF BLEEDING
* COAGULATION (CLOTTING)
* MOST EFFECTIVE DEFENSE
* FIBRINOGEN  FIBRIN  POLYMER
* TWO REACTION PATHWAYS
o EXTRINSIC MECHANISM
+ CLOTTING FACTORS FROM DAMAGED BLOOD VESSEL
o INTRINSIC MECHANISM
+ CLOTTING FACTORS FROM BLOOD
CLOTTING FACTORS
* PROCOAGULANTS
* PROTEINS PRODUCED IN LIVER
* INACTIVE  ACTIVE
o EACH ACTIVATES THE NEXT
o REACTION CASCADE
o AMPLIFICATION AT EACH STEP
o POSITIVE FEEDBACK INVOLVED
* CLOT RETRACTION
o CLOT FORMED
o PLATELETS ADHERE TO FIBRIN
o PLATELETS CONTRACT
o PULLS EDGES OF BROKEN VESSEL TOGETHER
* PLATELETS SECRETE PDGF
o PLATELET-DERIVED GROWTH FACTOR
o STIMULATES MITOSIS
* FIBROBLASTS INVADE AND PRODUCE CONNECTIVE TISSUE

CLOT DISSOLUTION
* FIBRINOLYSIS
* MULTIPLE STEPS
* POSITIVE FEEDBACK
* SIMILAR, IN REVERSE
PREVENTION OF COAGULATION
* PLATELET REPULSION
* DILUTION AND BLOOD MOVEMENT
* ANTICOAGULANTS
o ANTITHROMBIN (LIVER)
o HEPARIN (BASOPHILS)

COAGULATION DISORDERS
HEMOPHILIA

* DEFICIENCY IN A CLOTTING FACTOR
* CASCADE DISRUPTED
* CLOTTING DEFICIENCY
COAGULATION DISORDERS
HEMOPHILIA A
COAGULATION DISORDERS
HEMOPHILIA B
BLOOD CELL PRODUCTION
STEM CELLS
* PLURIPOTENT CELLS
o UNDIFFERENTIATED CELLS
o ABLE TO DIVIDE AND DIFFERENTIATE INTO MULTIPLE TYPES OF CELLS
o NOT ALL ARE “TOTIPOTENT”
o (NOT FULLY DIFFERENTIATED)
o E.G., HEMOCYTOBLASTS (BLOOD)
o E.G., EMBRYONIC STEM CELLS
* YOLK SAC
o EARLIEST HEMOPOIETIC TISSUE
o PRODUCES STEM CELLS
o COLONIZE OTHER ORGANS
+ BONE, LIVER, SPLEEN, THYMUS, ETC
o LIVER STOPS HEMOPOIESIS AT BIRTH
o SPLEEN STOPS ERYTHROPOIESIS SHORTLY AFTER BIRTH
* MYELOID HEMOPOIESIS
o OCCURS IN BONE MARROW
o FORMS ALL SEVEN FORMED ELEMENTS
* LYMPHOID HEMOPOIESIS
o OCCURS IN SEVERAL ORGANS
+ THYMUS, TONSILS, LYMPH NODES, SPLEEN, INTESTINES, ETC.
o PRODUCES LYMPHOCYTES
HEMOCYTOBLASTS
* STEM CELLS
* PLURIPOTENT
* DIFFERENTIATE INTO ALL FORMED ELEMENTS
o ERYTHROPOIESIS
o LEUKOPOIESIS
o THROMBOPOIESIS

ERYTHROCYTE PRODUCTION
ERYTHROPOIESIS
ERYTHROCYTE PRODUCTION
ERYTHROPOIESIS
ERYTHROCYTE HOMEOSTASIS
IRON METABOLISM
ERYTHROCYTE DEATH
HEMOLYSIS
* IRON
* PORPHYRIN RING
LEUKOCYTE PRODUCTION
LEUKOPOIESIS
PLATELET PRODUCTION
THROMBOPOIESIS
PLATELET PRODUCTION

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Venous Thromboembolic Disease

VENOUS THROMBOEMBOLIC DISEASE
by:R. Duncan Hite, MD
Section on Pulmonary and Critical Care Medicine

Venous Thromboembolic Disease

* Venous thrombosis - ~ 5 million pts yearly
+ Most caused by inadequate prophylaxis in hospitalized pts
* 10 % suffer pulmonary embolism ~ 500,000
* ~ 1% of all hospitalized pts have PE
* Contributes to 6 % of all hospital deaths
* ~ 125,000 deaths annually from PE
+ 3rd most common cardiovascular cause of death (MI, CVA)
+ Most deaths occur early – PREVENTION IS KEY!!
* Diagnosis of PE made in < 30% when contributes to death; < 10% if incidental

Case studies
Venous Thromboembolic Disease
Epidemiology

* 85 - 90% of PE pts have DVT risk factors
* 90-95% of PEs arise from lower ext. DVT
* Defined DVT Risk Factors: (Virchow’s Triad)
o Venous stasis - CHF, Immobility, Age > 70, Travel, Obesity, Recent surgery (4 weeks) or hospitalization (6 mos)
o Venous Injury - Prior DVT/PE, LE Trauma/Surgery
# LE trauma or surgery - Very high (50+%)
# Major surgery - (5 - 8%)
o Hypercoaguability - Cancer, Pregnancy, Nephrotic Syndrome, Hyperhomocysteinemia, Factor V Leyden mutation, Deficiency of Protein C/S or ATIII, Anti Phospholipid Ab, HITTS, Smoking

Pulmonary Hypertension Hemodynamic Effects
Deep Venous Thrombosis
Diagnosis
* Venography - remains the “gold standard”
+ Pitfalls: Difficult to perform, expensive, contrast load, DVT
* Compression Ultrasound (Sonography, Duplex and Color Doppler)
+ Criteria: echogenicity, noncompressibility, distension, free floating thrombus, absence of Doppler waveform, Abnormal color image
+ Accuracy:
# Symptomatic Patients: Sensitivity = 90-100%, Specificity = 95-100%
# High Risk Asymptomatic: Sensitivity = 50-80%, Specificity = 95-100%
* Impedance Plethysmography
* Radionuclide Venography (Indium-111)
* MRI - increasing popularity and utilization, includes deep pelvic veins

Deep Venous Thrombosis Prevention
* Orthopedic Surgery
o LMWH or Coumadin (INR 2.0 - 3.0) beginning preoperatively or immediately postoperatively. Adjusted dose SQ Heparin is an acceptable alternative but more complex.
o Adjuvant use of mechanical devices may add additional benefit. May be sufficient as primary prophylaxis for TKR if used optimally.
o Low dose SQ Hep, Aspirin, IPC alone are not recommended (less effective).
o Duration:
+ minimum of 7-10 days
+ Post Discharge Prophylaxis: 4-6 weeks for high risk patients
* General Surgery (including Urologic)
o Prophylaxis with SQHep, LMWH, ES or IPC
+ Moderate Risk - minor procedure with a risk factor or 40-60 yo, major procedures and <40
+ High Risk - minor procedure with risk factors or >60, major procedures with risk factors or age >40.
+ Increased Risk of Bleeding - use ES or IPC
o Combination therapy: very high risk - multiple risk factors
o Postdischarge Prophylaxis: selected very high risk pts
* Gynecologic Surgery
o Major surgery for benign disease
# SQ Hep BID, LMWH, IPC, continue for several days post op
o Major surgery for malignancy
# SQ Hep TID, Combination AC/Mech, high dose LMWH
* Neurosurgery
o Intracranial Surgery
# IPC or ES, Low dose SQHep or LMWH may be acceptable
# Combination IPC or ES with SQHep or LMWH in high risk

Deep Venous Thrombosis Prevention
* Trauma
o LMWH as soon as possible
o IPC or ES until LMWH started
* Acute Spinal Cord Injury
o LMWH recommended
o Low dose SQHep, ES or IPC are less effective
o Combination Mechanical/anticoagulant may be acceptable
o Continue throughout rehabilatation
* Medical (Cancer, CHF, Bedrest, MI, CVA…)
o Low dose SQ Hep or LMWH
o IPC if anticoagulation contraindicated

PE SIGNS AND SYMPTOMS
Symptoms
* Dyspnea - 80%
* Chest pain - 70%
* Cough - 50%
* Apprehension - 50%
* Hemoptysis - 30%

Signs
* Tachycardia - 60%
* Tachypnea - 70%
* Fever - 60%
* Clinical DVT - 30%

Pulmonary Embolism Diagnosis
* Chest x-ray - nonspecific abnormalities in most; normal early
+ Westermark's sign and Hampton's hump uncommon
* Arterial blood gas – hypoxemia is common
+ 15 - 20% will not manifest hypoxemia (i.e. normal A-a gradient)
* ECG – nonspecific changes typically
+ S1Q3T3 pattern in massive PE with RV strain
+ helpful in evaluating other causes of chest pain

PE – V/Q LUNG SCAN
* Radiolabeled Xenon inhaled for ventilation and radiolabeled Technetium for perfusion
* Safe
* Not very specific
* Not very useful if pre-existing lung disease

Pulmonary Embolism Diagnosis - V/Q Scan
Pulmonary Embolism
Diagnosis - Pulmonary Arteriogram
* Remains “gold standard” for Dx of PE
* Expensive
* Low morbidity and mortality
o Mortality < 0.1%
o Major morbidity < 0.5%
o Pulmonary Hypertension not a contraindication
Pulmonary Embolism
Diagnosis - Pulmonary Arteriogram
Lobar Defect
Segmental Defect
Pulmonary Embolism
Diagnosis - Chest CT
* Accurate for segmental or larger PE
+ Sensitivity 85 - 95% (Overall 50-60%)
+ Specificity 90 - 100%
* Accuracy depends on interpreter
+ Large Inter-interpreter variability
+ Reduced accuracy with less experience
* Significant contrast load ~ 65% of PA gram
* Similar expense to Pulmonary Arteriogram
* Can identify other pulmonary etiologies
Pulmonary Emboli Diagnosis - MRA
Venous Thromboembolism Treatment
Continuous IV Heparin:
Heparin-Induced Antibodies
Venous Thromboembolism Treatment
Low Molecular Weight Heparins:
Venous Thromboembolism Outpatient LMWH
Enoxaparin sodium
Unfractionated heparin
Venous Thromboembolism
Treatment
Synthetic Heparins:
Fondaparinux (Arixtra)
Oral anticoagulation (Coumadin)
Inferior Vena Cava Filter

VENOUS THROMBOEMBOLIC DISEASE.ppt

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Approach to the Jaundiced Patient

Approach to the Jaundiced Patient
Internal Medicine Survivor Series
By:Joel Bruggen, MD

New Onset Jaundice
* Viral hepatitis
* Alcoholic liver disease
* Autoimmune hepatitis
* Medication-induced liver disease
* Common bile duct stones
* Pancreatic cancer
* Primary Biliary Cirrhosis (PBC)
* Primary Sclerosing Cholangitis (PSC)

Jaundiced Emergencies
* Acetaminophen Toxicity
* Fulminant Hepatic Failure
* Ascending Cholangitis

Jaundice Unrelated to Intrinsic Liver Disease
* Hemolysis (usually T. bili < 4)
* Massive Transfusion
* Resorption of Hematoma
* Ineffective Erythropoesis
* Disorders of Conjugation
o Gilbert’s syndrome
* Intrahepatic Cholestasis
o Sepsis, TPN, Post-operation

New Onset Jaundice
* Viral hepatitis
* Alcoholic liver disease
* Autoimmune hepatitis
* Medication-induced liver disease
* Common bile duct stones
* Pancreatic cancer
* Primary Biliary Cirrhosis (PBC)
* Primary Sclerosing Cholangitis (PSC)

HBV Serology
Resolved HBV
HBV vaccinated
Chronic HBV
Acute HBV
HBSAb
HBcAb
IgG
HBcAb
IgM
Acute Hepatitis C
HCV RNA
Anti-HCV
Infection Day 0
HCV RNA Day 12
HCV Antibody Day 70
Plateau phase = 57 days

Alcoholic Liver Disease
* The history is the key – 60 grams/day
* Gynecomastia, parotids, Dupuytren’s
* Lab clues: AST/ALT > 2, MCV > 94

AST < 300
* Alcoholic hepatitis:
o Anorexia, fever, jaundice, hepatomegaly
o Treatment:
+ Abstinence
+ Nutrition
+ Consider prednisolone or pentoxifylline

Alcoholic Liver Disease
Discriminant Function Formula:
DF = [4.6 x (PT – control)] + bilirubin
Consider treatment for DF > 32
* Prednisolone 40 mg/day x 28 days
o contraindications: infection, renal failure, GIB
* Pentoxifylline 400 mg PO tid x 28 days

Autoimmune Hepatitis
* Widely variable clinical presentations
o Asymptomatic LFT abnormality (ALT and AST)
o Severe hepatitis with jaundice
o Cirrhosis and complications of portal HTN
* Often associated with other autoimmune dz
* Diagnosis:
o Compatible clinical presentation
o ANA or ASMA with titer 1:80 or greater
o IgG > 1.5 upper limits of normal
o Liver biopsy: portal lymphocytes + plasma cells

Drug-induced Liver Disease
* Hepatocellular
o acetaminophen, INH, methyldopa, MTX
* Cholestatic
o chlorpromazine, estradiol, antibiotics
* Chronic Hepatitis
o methyldopa, phenytoin, macrodantin, PTU
* Hypersensitivity Reaction
o Phenytoin, Augmentin, allopurinol
* Microvesicular Steatosis
o amiodarone, IV tetracycline, AZT, ddI, stavudine

Acetaminophen Toxicity
* Danger dosages (70 kg patient)
o Toxicity possible > 10 gm
o Severe toxicity certain > 25 gm
o Lower doses potentially hepatotoxic in:
+ Chronic alcoholics
+ Malnutrition or fasting
+ Dilantin, Tegretol, phenobarbital, INH, rifampin
+ NOT in acute EtOH ingestion
+ NOT in non-alcoholic chronic liver disease

Acetaminophen Toxicity
* Day 1:
o Nausea, vomiting, malaise, or asymptomatic
* Day 2 – 3:
o Initial symptoms resolve
o AST and ALT begin to rise by 36 hours
o RUQ pain, tender enlarged liver on exam
* Day 4
o AST and ALT peak > 3000
o Liver dysfunction: PT, encephalopathy, jaundice
o Acute renal failure (ATN)

Acetaminophen Toxicity Treatment
Indications for NAC therapy:
Fulminant Hepatic Failure
* Definition:
o Rapid development of hepatic dysfunction
o Hepatic encephalopathy
o No prior history of liver disease
* Most common causes:
o Acetaminophen
o Unknown
o Idiosyncratic drug reaction
o Acute HAV or HBV (or HDV or HEV)

Fulminant Hepatic Failure
* Close glucose monitoring IV glucose
* Avoid sedatives - give PO lactulose
* Avoid nephrotoxins and hypovolemia
* Vitamin K SQ
o Do not give FFP unless active bleeding, since INR is an important prognostic factor
* GI bleed prophylaxis with PPI
* Transfer all patients with FHF who are candidates to a liver transplant center

Indications:
* Hepatitis C 29%
* Alcoholic Liver Disease 15%
* Cirrhosis of unknown etiology 8%
* Hepatocellular Carcinoma 7%
* Fulminant Hepatic Failure 6%
* Primary Sclerosing Cholangitis 5%
* Primary Biliary Cirrhosis 4%
* Metabolic Liver Disease 4%
* Autoimmune Hepatitis 3%
* Hepatitis B 3%

Liver Transplantation:
Contraindications
* ABSOLUTE
o active alcohol or drug abuse
o HIV positivity
o extrahepatic malignancy
o uncontrolled extrahepatic infection
o advanced cardiopulmonary disease
* RELATIVE
o Age over 65
o poor social support
o poorly controlled mental illness

Obstructive Jaundice
CBD stones (choledocholithiasis) vs. tumor
* Clinical features favoring CBD stones:
o Age < 45
o Biliary colic
o Fever
o Transient spike in AST or amylase
* Clinical features favoring cancer:
o Painless jaundice
o Weight loss
o Palpable gallbladder
o Bilirubin > 10

Ascending Cholangitis
* Pus under pressure
* Charcot’s triad: fever, jaundice, RUQ pain
o All 3 present in 70% of patients, but fever > 95%
o May also present as confusion or hypotension
* Most frequent causative organisms:
o E. Coli, Klebsiella, Enterobacter, Enterococcus
o anaerobes are rare and usually post-surgical
* Treatment:
o Antibiotics: Levaquin, Zosyn, meropenem
o ERCP with biliary drainage

Ascending Cholangitis
Indications for Urgent ERCP
* Persistent abdominal pain
* Hypotension despite adequate IVF
* Fever > 102
* Mental confusion
* Failure to improve after 12 hours of antibiotics and supportive care

Obstructive Jaundice Malignant Causes
* Cancer of the Pancreas
* Cancer of the Bile Ducts (Cholangiocarcinoma)
* Ampullary Tumors
* Portal Lymphadenopathy

Primary Biliary Cirrhosis
* Cholestatic liver disease (ALP)
o Most common symptoms: pruritus and fatigue
o Many patients asx, and dx by abnormal LFT
* Female:male ratio 9:1
* Diagnosis:
o Compatible clinical presentation
o AMA titer 1:80 or greater (95% sens/spec)
o IgM > 1.5 upper limits of normal
o Liver biopsy: bile duct destruction
* Treatment: Ursodeoxycholic acid 15 mg/kg

Primary Sclerosing Cholangitis
* Cholestatic liver disease (ALP)
* Inflammation of large bile ducts
* 90% associated with IBD
o but only 5% of IBD patients get PSC
* Diagnosis: ERCP (now MRCP)
o No autoantibodies, no elevated globulins
o Biopsy: concentric fibrosis around bile ducts
* Cholangiocarcinoma: 10-15% lifetime risk
* Treatment: Liver Transplantation

Diagnosis of Immune-Mediated Liver Disease
Periductal concentric fibrosis
Unusual Causes of Jaundice
* Ischemic hepatitis
* Congestive hepatopathy
* Wilson’s disease
* AIDS cholangiopathy
* Amanita phalloides (mushrooms)
* Jamaican bush tea
* Infiltrative diseases of the liver
o Amyloidosis
o Sarcoidosis
o Malignancy: lymphoma, metastatic dz

Wilson’s Disease
* Autosomal recessive – copper metabolism
* Chronic hepatitis or fulminant hepatitis
* Associated clinical features:
o Neuropsychiatric disease
o Hemolytic anemia
* Physical exam: Kayser-Fleischer rings
* Diagnosis: ceruloplasmin, urinary Cu
* Treatment: d-penicillamine

Critical Questions in the Evaluation of the Jaundiced Patient
* Acute vs. Chronic Liver Disease
* Hepatocellular vs. Cholestatic
o Biliary Obstruction vs. Intrahepatic Cholestasis
* Fever
o Could the patient have ascending cholangitis?
* Encephalopathy
o Could the patient have fulminant hepatic failure?

Evaluation of the Jaundiced Patient HISTORY

* Pain
* Fever
* Confusion
* Weight loss
* Sex, drugs, R&R
* Alcohol
* Medications
* pruritus
* malaise, myalgias
* dark urine
* abdominal girth
* edema
* other autoimmune dz
* HIV status
* prior biliary surgery
* family history liver dz

Evaluation of the Jaundiced Patient PHYSICAL EXAM
* BP/HR/Temp
* Mental status
* Asterixis
* Abd tenderness
* Liver size
* Splenomegaly
* Ascites
* Edema
* Spider angiomata
* Hyperpigmentation
* Kayser-Fleischer rings
* Xanthomas
* Gynecomastia
* Left supraclavicular adenopathy (Virchow’s node)

Evaluation of the Jaundiced Patient LAB EVALUATION
* AST-ALT-ALP
* Bilirubin – total/indirect
* Albumin
* INR
* Glucose
* Na-K-PO4, acid-base
* Acetaminophen level
* CBC/plt
* Ammonia
* Viral serologies
* ANA-ASMA-AMA
* Quantitative Ig
* Ceruloplasmin
* Iron profile
* Blood cultures

Evaluation of the Jaundiced Patient
* Ultrasound:
o More sensitive than CT for gallbladder stones
o Equally sensitive for dilated ducts
o Portable, cheap, no radiation, no IV contrast
* CT:
o Better imaging of the pancreas and abdomen
* MRCP:
o Imaging of biliary tree comparable to ERCP
* ERCP:
o Therapeutic intervention for stones
o Brushing and biopsy for malignancy

Case studies

Approach to the Jaundiced Patient.ppt

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Managing Low Birth Weight and Sick Newborns

Managing Low Birth Weight and Sick Newborns

Advances in Maternal and Neonatal Health

Session Objectives
* To define essential elements of the care of sick newborns, including neonatal resuscitation
* To discuss best practices and technologies

Management of Newborn Illness

* Education of mothers to recognize danger signals
* Working with families to develop complication plan for newborns
* Early recognition and appropriate management of newborn illness

Minimum Preparation for ANY Birth
The following should be available and in working order:
* Heat source
* Mucus extractor
* Self-inflating bag of newborn size
* 2 masks (for normal and small newborns)
* 1 clock
* At least one person skilled in newborn resuscitation present at birth

Essential Care for All Newborns
Most newborns breathe as soon as they are born and only need:
* A clean and warm welcome
* Vigilant observation
* Warmth
* To be observed for breathing
* To be given to the mother for warmth and breastfeeding

Immediate Care of the Newborn: Warmth
* Lay newborn on mother’s abdomen or other warm surface
* Immediately dry newborn with clean (warm) cloth or towel
* Remove wet towel and wrap/cover newborn, except for face and upper chest, with a second towel/cloth

* Blood on newborn is not a risk to newborn, but is a risk to caregiver
* Bathe after 24 hours
* In areas with high HIV prevalence, consider bathing earlier to reduce risk of maternal-fetal transmission, and to reduce risk to caregiver and to other newborns

Immediate Care of the Newborn
* Assess breathing
* Keep head in a neutral position
* IMMEDIATELY assess respirations and need for resuscitation

Signs of Good Health at Birth
Objective measures
* Breathing
* Heart rate above 100 beats/minute
Subjective measures
* Vigorous cry
* Pink skin
* Good muscular tone
* Good reactions to stimulus
* Most important measure is whether newborn is breathing
* Assessing all of above delays resuscitation, if it is necessary.

Birth Asphyxia
* Definition: Failure to initiate and sustain breathing at birth
* Magnitude:
o 3% of 120 million newborns each year in developing countries develop birth asphyxia and require resuscitation
o An estimated 900,000 of these newborns die as a result of asphyxia

Steps in Resuscitation
* Anticipate need for resuscitation at every birth, be prepared with equipment in good condition
* Prevent of heat loss (dry newborn and remove wet clothes)
* Assess breathing
* Resuscitate:
o Open airway
+ Position newborn
+ Clear airway
o Ventilate
o Evaluate

Assess Breathing
Newborn crying?
Provide routine care
* Chest is rising symmetrically
* Frequency >30 breaths/min.
* Not breathing/ gasping
* Breathing < 30 or > 60 breaths/ min.

Immediately start resuscitation
Provide routine care
Open Airway
* Position newborn on its back
* Place head in slightly extend position
* Suction mouth then nostrils

Ventilate
* Select appropriate mask size to cover chin, mouth and nose with a good seal
* Squeeze bag with two fingers or whole hand, look for chest to rise
* If chest not rising:
o Reposition head and mask
o Increase ventilation
o Repeat suctioning

Evaluate
After ventilating for about 1 minute, stop and look for spontaneous breathing
If no breathing, breathing is slow (< 30 breaths/ min.) or is weak with severe indrawing
If newborn starts crying/breathing spontaneously
Continue ventilating until spontaneous cry/ breathing begins

* Stop ventilating
* Do not leave newborn
* Observe breathing
* Put newborn skin-to-skin with mother and cover them both

Harmful and Ineffective Resuscitation Practices
Practices to be avoided include:
* Routine aspiration of the newborn’s mouth and nose as soon as the head is born
* Routine aspiration of the newborn’s stomach at birth
* Stimulation of the newborn by slapping or flicking the soles of her/his feet: only enough stimulation for mildly depressed-delays resuscitation
* Postural drainage and slapping the back: dangerous
* Squeezing the chest to remove secretions from the airway
* Routine giving of sodium bicarbonate to newborns who are not breathing
* Intubation by an unskilled person
* Some traditional practices:
o Putting alcohol in newborn’s nose
o Sprinkling or soaking newborn with cold water
o Stimulating anus
o Slapping newborn

Infection Prevention for Resuscitation
* Handwashing
* Use of gloves
* Careful suctioning if using a mucus extractor operated by mouth
* Careful cleaning and disinfection of equipment and supplies
o Do not reuse bulb—difficult to clean, poses risk of cross infection
* Correct disposal of secretions

Documentation
Details of the re
Post-Resuscitation Tasks: Successful Resuscitation
Post-Resuscitation Tasks: Unsuccessful Resuscitation
Policy Decisions for Resuscitation
Principles of Success
Care of the Low Birth Weight Newborn
Care of the Preterm Newborn
Principles of Management for Low Birth Weight and Preterm Newborns
* Warmth
* Feeding
* Detection and management of complications (e.g., resuscitation, assisted respiration)

As for all newborns:
* Lay newborn on mother’s abdomen or other warm surface
* Dry newborn with clean (warm) cloth or towel
* Remove wet towel and wrap/cover with a second dry towel
* Bathe after temperature is stable

Warmth: Problem with Incubators
* Potential source of infection
* Often temperature controls malfunction
* Often share incubator for more than one newborn

Need alternative method: kangaroo care
Feeding
Early and exclusive breastfeeding
* Breastmilk = best nourishment
* Already warm temperature
* Facilitated by kangaroo care

Definition of Kangaroo Care
* Early, prolonged and continuous skin-to-skin contact between a mother and her newborn
* Could be in hospital or after early discharge

How to Use Kangaroo Care
* Newborn’s position:
o Held upright (or diagonally) and prone against skin of mother, between her breasts
o Head is on its side under mother’s chin, and head, neck and trunk are well extended to avoid obstruction to airways
* Newborn’s clothing:
o Usually naked except for nappy and cap
o May be dressed in light clothing
o Mother covers newborn with her own clothes and added blanket or shawl
* Newborn should be:
o Breastfed on demand
o Supervised closely and temperature monitored regularly
* Mother needs lots of support because kangaroo care:
o Is very tiring for her
o Restricts her freedom
o Requires commitment to continue

Effectiveness of Kangaroo Care
* Randomized controlled trial
* Conducted in three tertiary and teaching hospitals in Ethiopia, Indonesia and Mexico
* Study effectiveness, feasibility, acceptability and cost of kangaroo mother care when compared to conventional methods of care
Benefits of Kangaroo Care
* Is efficient way of keeping newborn warm
* Helps breathing of newborn to be more regular; reduce frequency of apneic spells
* Promotes breastfeeding, growth and extra-uterine adaptation
* Increases the mother’s confidence, ability and involvement in the care of her small newborn
* Seems to be acceptable in different cultures and environments
* Contributes to containment of cost— salaries, running costs (electricity, etc.)

Summary

* Skilled attendant
* Equipment available and working
* Begin resuscitation immediately
o Ventilate
o Reassess frequently
o Kangaroo care once successful

References

Managing Low Birth Weight and Sick Newborns.ppt

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Normal Newborn Care

Normal Newborn Care - Advances in Maternal and Neonatal Health

Normal Newborn Care
Session Objective
* Define essential elements of early newborn care
* Discuss best practices and technologies for promoting newborn health
* Use relevant data and information to develop appropriate essential newborn recommendations

Newborn Deaths
Essential Newborn Care Interventions
* Clean childbirth and cord care
o Prevent newborn infection
* Thermal protection
o Prevent and manage newborn hypo/hyperthermia
* Early and exclusive breastfeeding
o Started within 1 hour after childbirth
* Initiation of breathing and resuscitation
o Early asphyxia identification and management
* Eye care
o Prevent and manage ophthalmia neonatorum
* Immunization
o At birth: bacille Calmette-Guerin (BCG) vaccine, oral poliovirus vaccine (OPV) and hepatitis B virus (HBV) vaccine (WHO)
* Identification and management of sick newborn
* Care of preterm and/or low birth weight newborn

Cleanliness to Prevent Infection
* Principles of cleanliness essential in both home and health facilities childbirths
* Principles of cleanliness at childbirth
o Clean hands
o Clean perineum
o Nothing unclean introduced vaginally
o Clean delivery surface
o Cleanliness in cord clamping and cutting
o Cleanliness for cord care
* Infection prevention/control measures at healthcare facilities

Thermal Protection
* Newborn physiology
o Normal temperature: 36.5–37.5°C
o Hypothermia: < 36.5°C
o Stabilization period: 1st 6–12 hours after birth
+ Large surface area
+ Poor thermal insulation
+ Small body mass to produce and conserve heat
+ Inability to change posture or adjust clothing to respond to thermal stress
* Increase hypothermia
o Newborn left wet while waiting for delivery of placenta
o Early bathing of newborn (within 24 hours)

Hypothermia Prevention
* Deliver in a warm room
* Dry newborn thoroughly and wrap in dry, warm cloth
* Keep out of draft and place on a warm surface
* Give to mother as soon as possible
o Skin-to-skin contact first few hours after childbirth
o Promotes bonding
o Enables early breastfeeding
* Check warmth by feeling newborn’s feet every 15 minutes
* Bathe when temperature is stable (after 24 hours)

Early and Exclusive Breastfeeding
* Early contact between mother and newborn
o Enables breastfeeding
o Rooming-in policies in health facilities prevents nosocomial infection
* Best practices
o No prelacteal feeds or other supplement
o Giving first breastfeed within one hour of birth
o Correct positioning to enable good attachment of the newborn
o Breastfeeding on demand
o Psycho-social support to breastfeeding mother

Breathing Initiation and Resuscitation
* Spontaneous breathing (> 30 breaths/min.) in most newborns
o Gentle stimulation, if at all
* Effectiveness of routine oro-nasal suctioning is unknown
o Biologically plausible advantages – clear airway
o Potentially real disadvantages – cardiac arrhythmia
o Bulb suctioning preferred
* Newborn resuscitation may be needed
o Fetal distress
o Thick meconium staining
o Vaginal breech deliveries
o Preterm

Eye Care To Prevent or Manage Ophthalmia Neonatorum
* Ophthalmia neonatorum
o Conjunctivitis with discharge during first 2 weeks of life
o Appears usually 2–5 days after birth
o Corneal damage if untreated
o Systemic progression if not managed
* Etiology
o N. gonorrhea
+ More severe and rapid development of complications
+ 30–50% mother-newborn transmission rate
o C. trachomatis

Eye Care To Prevent or Manage Ophthalmia Neonatorum (continued)
* Prophylaxis
o Clean eyes immediately
o 1% Silver nitrate solution
+ Not effective for chlamydia
o 2.5% Povidone-iodine solution
o 1% Tetracycline ointment
+ Not effective vs. some N. gonorrhea strains
* Common causes of prophylaxis failure
o Giving prophylaxis after first hour
o Flushing of eyes after silver nitrate application
o Using old prophylactic solutions

Efficacy of Prophylaxis for Conjunctivitis in China
* Objective: To assess etiology of newborn conjunctivitis and evaluate the efficacy of regimens in China
* Design: November 1989 to October 1991 rotated regimens monthly: tetracycline, erythromycin, silver nitrate
* 302 (6.7%) infants developed conjunctivitis, most S. aureus (26.2%) and chlamydia (22.5%)
* Silver nitrate, tetracycline: fewer cases than no prophylaxis (p < 0.05), erythromycin: not significant

Prophylaxis for Conjunctivitis: Objective and Design
* Objective: To compare efficacy in prevention of nongonococcal conjunctivitis
* Design: Randomized control trial to compare erythromycin, silver nitrate, no prophylaxis
o Examined with test for leukocyte esterase and chlamydia trachomatis antibody probe 30–48 hours postpartum, 13–15 days later, and telephone contact up to 60 days of life
* Main outcome measured: conjunctivitis within 60 days of life and nasolacrimal duct patency

Prophylaxis for Conjunctivitis: Results and Conclusion

* Results: 630 infants
* 109 with conjunctivitis
o Silver nitrate vs. no prophylaxis: Hazard ratio 0.61 (0.39-0.97)
+ Chemical conjunctivitis with silver nitrate resolves within 48 hours
o Erythromycin vs. no prophylaxis: Hazard ratio 0.69 (not significant)
* Conclusion: Parental choice of prophylaxis, including no prophylaxis, is reasonable IF antenatal care and STD screening

Povidone-Iodine for Conjunctivitis: Objective and Design

* Objective: To determine incidence and type of conjunctivitis after povidone-iodine in Kenya
* Design: Rotate regimen weekly: erythromycin, silver nitrate, povidone iodine
* Results:
o Conjunctivitis:
+ Chlamydia in 50.5%
+ S. aureus in 39.7%
o More infections in silver nitrate than povidone-iodine, OR 1.76, p < 0.001
o More infections in erythromycin OR 1.38, p=0.001

Povidone-Iodine for Conjunctivitis: Conclusion
Povidone-iodine:
o Is good prophylaxis
o Has wider antibacterial spectrum
o Causes greater reduction in colony-forming units and number of bacterial species
o Is active against viruses
o Is inexpensive

Immunization
* BCG vaccinations in all population at high risk of tuberculosis infection
* Single dose of OPV at birth or in the two weeks after birth
* HBV vaccination as soon as possible where perinatal infections are common

Summary
The essential components of normal newborn care include:

* Clean delivery and cord care
* Thermal protection
* Early and exclusive breastfeeding
* Monitoring
* Eye care
* Immunization
References

Normal Newborn Care.ppt

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Infant Lung Disease and Associated Complications

Infant Lung Disease and Associated Complications
By:Mary P. Martinasek, BS, RRT
Director of Clinical Education
Hillsborough Community College

Respiratory Distress Syndrome
* RDS , formerly called Hyaline Membrane disease (HMD)
* Primary cause of respiratory disorders
* 70% preterm deaths, 30% neonatal deaths
* Etiology - deficiency in surfactant
o Premature pulmonary system

Risk Factors associated with RDS
* Less than 35 weeks gestation
* Maternal diabetes
* Hx of RDS in sibling
* White male
* PFC (Persistent Fetal Circulation)
* Prenatal maternal complication
* Abnormal placental conditions
* Umbilical cord disorders

Pathophysiology of RDS
Decreased surfactant
Surface Tension
Compliance
Stiffer Lungs
Wide spread atelectasis
Worsening V/Q
FRC
WOB
PaO2& __ PaCO2
Respiratory Acidosis
Capillary damage
Alveolar Necrosis
Clinical Signs of RDS
* Respiratory Rate > 60 bpm
* Grunting
* Retracting
* Nasal flaring
* Cyanosis
* Hypothermia
* CXR = underaeration, opaque, ground glass appearance

Treatment of RDS
* Maternal steroids
* Artificial surfactant therapy
* Adequate hydration
* Thermoregulation
* Goal = support the patient’s respiratory system while minimizing complications

Complication of RDS
* ICH occurs in 40% of < 1500 grams
* Barotrauma = pulmonary air leaks
* Infection
* PDA

Airleak Identification
Clinical Scenario
BPD
Pathophysiology of BPD
CXR in BPD
* Stage I
o First 3 days of life
o Ground glass appearance on x-ray
* Stage II
o 3 - 10 days
o Opaque, obscure cardiac markings
* Stage III
o 10 - 20 days
o Cyst formations
* Stage IV
o 28 days
o Increased lung density, larger cysts
Treatment of BPD
* Avoidance of factors that lead to development
* Adequate ventilatory humidification
* CPT and bronchodilators
* Fluid management
* Nutrition

Persistent Pulmonary Hypertension
Treatment of PPHN
* Nitric Oxide (NO)
* Hyperventilation
* Tolazoline
* Dopamine
* ECMO (extracorporeal membrane oxygenation
* High frequency ventilation
Reverse Jeopardy
* What color tank is NO?
* What color tank is NO2?

Transient Tachypnea of the Newborn
* TTN
* Aka RDS II
* Term infants delivered via cesarean section
* Signs of RDS
* CXR - streaky infiltrates
* R/O pneumonia
* Treatment

TTN x-ray
Meconium Aspiration Syndrome
* Term and Postterm infan
Diagnosis and Treatment
* Aspiration of meconium
* Classic sign of RDS
* Irregular densities on CXR
* Treatment
o Suction meconium
o Peep
o Low peak pressures
o Antibiotics
o amnioinfusion

MAS x-ray
Asphyxia
* Major complication is hypoxic-ischemic encephalopathy
o Periventricular leukomalacia
* Tubular necrosis of kidneys and GI effects
* Liver damage
* Lung damage
PVL
Wilson- Mikity Syndrome
* AKA - Pulmonary dysmaturity
* BPD lung changes in unventilated infant
* Signs
o Hyperpnea, cyanosis, retractions, hypercarbia, respiratory acidosis
* Treatment
o Supportive
o Ventilated to treat apnea
o O2 to treat hypoxemia
Air leak syndrome
PIE x-ray
Apnea
Central or Nonobstructive Apnea
* Apnea of prematurity
* Chemoreceptor sensitivity
* Arousal response
* Stimulation of airway reflexes
* Dysfunction of the respiratory centers
* Dysfunction of the ventilatory muscles
* Dysfunction of the peripheral nervous system
* Treatment = caffeine or theophylline
Obstructive apnea
* Anatomic abnormalities
* Pierre Robin Syndrome (micronathia)
* choanal atresia, laryngeal webs, vocal cord paralysis, enlarged tonsils and adenoids
* Treatment = pharmacologic agents, surgery

What is choanal atresia and what is the classic sign?
Pierre Robin Syndrome
What is this x-ray terminology for this condition?
Retinopathy of Prematurity
Pathophysiology
Treatment of ROP
Intracranial/Intraventricular
Hemorrhage
* ICH and IVH
* Majority of hemorrhages in neonate are periventricular/ Intraventricular (IVH)
* Preterm and Infants <1500 grams high risk
* Germinal matrix most common

IVH
Signs of germinal matrix bleeding
IVH Classifications
Complications/ Treatment of IVH

Infant Lung Disease and Associated Complications.ppt

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Neonatal Resuscitation

Neonatal Resuscitation
By:Mary P. Martinasek, BS, RRT
Director of Clinical Education
Hillsborough Community College

Asphyxia
* Hypoxia + Hypercapnia + Acidosis
* May lead to irreversible brain damage
* The necessity to resuscitate is related to the degree of asphyxia

Causes of fetal asphyxia
* Maternal hypoxia
* Insufficient placental blood flow
* Blockage of umbilical blood flow
* Fetal disorders

Primary vs. Secondary Apnea
* Primary
o Initial asphyxia
o Signs
+ Initial period of rapid breathing
+ Respiratory movements cease
+ Heart rate and bp drop
+ Neuromuscular tone diminishes

Secondary Apnea
* If no resuscitation and apnea continues
* Signs
o Deep gasping respirations
o Heart rate continues to decrease
o Blood pressure begins to fall
o Infant flaccid

* Primary
o Stimulation and oxygen will usually induce respirations

* Secondary
o Infant unresponsive to stimulation – must be resuscitated

Effects of asphyxia on the lungs
* Ineffective respirations cannot open alveoli
* Pulmonary Hypertension
* Pulmonary vasoconstriction
o Hypoxia, hypercarbia, acidosis

Persistent Fetal Circulation
known as PPHN

* Leads to further asphyxia
* Blood shunted
* CO2 remains high despite ventilation
o Indocin
o Ligation of PDA

Preparation for Resuscitation

* Anticipation of high risk delivery
* Proper equipment
* Trained personnel

Purpose of Resuscitation

* Reverse asphyxia before irreparable damage has occurred

ABC’s of Resuscitation

* A – Establish an open airway
o Position infant
o Suction mouth then nose
* B – initiate breathing
o Use tactile stimulation
o Use PPV if necessary

Resuscitation

* C – Maintain circulation
o Stimulate and maintain circulation
+ Chest compressions
+ drugs

Initial steps
* Dry the infant
* Warm the infant
* Position the infant
* Suction the infant
* Stimulate the infant

Next step
* Evaluate respirations
o If none or gasping , provide PPV with 100% O2 for 15-30 seconds
o If spontaneous respirations then evaluate HR
* After 15-30 seconds of PPV or evaluation of spontaneous respirations then:
* EVALUATE HEART RATE
* If HR is above 100 then reevaluate respirations and color
* If HR is less than 60 continue/start PPV and start compressions

Reassess
* After 30 seconds reassess
* HR greater than 60 stop compressions
* HR greater than 100 and breathing stop PPV
* Evaluate infant’s color
o Peripheral vs. central cyanosis
o What is acrocyanosis?

Thermoregulation
* Maintain a neutral thermal environment
* Possible causes of heat loss
o Radiant
o Evaporative
o Convective
o Conductive

Neonatal Resuscitation.ppt

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Global trends of neonatal, infant and child mortality

Global trends of neonatal, infant and child mortality: implications for child survival
By:Dr KANUPRIYA CHATURVEDI & Dr S.K CHATURVEDI

When are child deaths occurring?

What are under-fives dying of?
(excluding neonatal causes of death)

* Pneumonia
* Diarrhoea
* Malaria
* Measles
* HIV/AIDS

Malnutrition contributes to more than half of all under-five deaths
What are neonates dying of?
* Preterm births
* Severe infection
* Asphyxia
* Congenital anomalies
* Tetanus

INDIA’S SHARE OF GLOBAL BURDEN
SOLUTIONS EXIST

* A mix of community and facility-based interventions
* A mix of integrated child health approaches
* Integrated management of neonatal and child hood illnesses is proven tool

Goals of IMNCI
* Standardized case management of sick newborns and children
* Focus on the most common causes of mortality
* Nutrition assessment and counselling for all sick infants and children
* Home care for newborns to
o promote exclusive breastfeeding
o prevent hypothermia
o improve illness recognition & timely care seeking

Essential components of IMNCI
* Improve health and nutrition workers’ skills
* Improve health systems
* Improve family and community practices
Home visits for young infants: Schedule
Colour Coded Case Management Strategy
Other innovations in case
Innovations in therapy
* Single daily dose gentamycin
* How to treat at home when hospital admission is not feasible
* Counselling the mother to give oral drugs at home
* Clear recommendations for follow up
* Negotiated feeding counselling
What does IMNCI not provide at all or fully
* Antenatal care
* Skilled birth attendance
* Birth asphyxia management
* Improved health system management
* What can be rapidly added to IMNCI
* Inpatient care modules for first level referral hospitals
IMNCI Experience--Milestones
* Early 2002, GOI constituted an Adaptation Group
* In joint GOI-UNICEF review meeting in April 2002 GOI requested to experiment IMNCI in BDCS districts
* July 2002, First national 2 days planning meeting
* December 2002, pre-tested 8-days physician course material
* Early 2003 - adaptation of H&N workers module
* May 2003 – First field testing in Osmanabad followed by one in Shivpuri & content & methodology frozen
* Implementation started in Andoor PHC, Osmanabad in June 03 followed by Valsad district
* Follow-up training of supervisors in April 04 in Osmanabad
* Field trial for case registers initiated in late 2004
* Physicians courses from 2005 included community visit, facilitation technique and briefing on Health workers’ course
* First Facilitation technique course in Orissa in June 2005

Training Flow
Training: Strengths -- Contents Doable
Training Limitations: Contents
Key messages

* Maternal and newborn care and support is essential to achieve a substantial reduction in neonatal mortality
* Improving child survival requires coordinated action between maternal and child health, and other programme areas (e.g. EPI, NUT, RBM, HIV)
* IMCI is an effective delivery strategy for multiple child survival interventions (India has already incorporated newborn care)
* For substantive impact, strong community component must accompany the health system strengthening

Global trends of neonatal, infant and child mortality.ppt

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Angioedema

Angioedema

Overview
* Self-Limited, subcutaneous edema resulting from increased vascular permeability
* Generally resolves over 24-48 hours
* Mast Cell / Kinin related etiologies
* Involvement of the lips, pharynx and bowel common (potentially life-threatening)
* Treated with CCS and H1/H2 blockers

Etiology
* Immunologic / IgE mediated
* Hereditary and Acquired (non-mast cell)
Ace-Inhibitors
* ACE (Kininase II) degrades bradykinin
* ACE-I results in inc levels bradykinin
* Pts with genetic deficiencies in bradykinin degradation could be at higher risk
* 0.1-0.7% of patients tx with ACE-I
* Intestinal edema may develop

ACE-I
Hereditary/Acquired
* Kinin-mediated angioedema that may be unmasked with use of ACE-I
* C1-Inh deficiency (level or fx) - Inc BKinin
Summary

* Angioedema is potentially life-threatening
* Associated pruritis and hives points to anaphylaxis
* Absence of pruritis and hives think ACE-I and/or C1-Inh deficiency
* Use caution when switching from an ACE-I to an ARB

Angioedema

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Congestive Heart Failure

Congestive Heart Failure
By:Chris Hague, PhD
Technical Advisor: Seth Goldenberg, PhD

Outline

1. What is congestive heart failure?
2. Cardiac Glycosides
3. Phosphodiesterase inhibitors
4. Beta-adrenergic receptor antagonists
5. Sympathomimetics
6. ACE inhibitors/angiotensin receptor antagonists
7. Vasodilators
8. Diuretics
9. Aldosterone antagonists

Congestive Heart Failure
Patient Classification
* Class I (asymptomatic)
* Class II (mild)
* Class III (moderate)
* Class IV (severe)

Factors contributing to CHF
* Ischemic Heart Disease: most prevalent
* CAD: less blood flow to heart, increased damage
* Myocardial Infarct: damaged tissue
* Hypertension: “overworked” heart
* Diabetes
* Lung Disease
* Cardiomyopathies: heart muscle disease
o dilated - enlarged chambers (ventricle/atria)
o hypertrophic - thickened ventricle walls
* Abnormal heart valves: inefficient pumping
o causes are genetic, infection or disease
* Congenital heart defects: present at birth
* Severe Anemia
* Hyperthyroidism
* Cardiac Arrhythmia

Effect on Cardiac Output
Overall decrease in Frank-Starling curve with CHF
Examples of CHF factors
Hypertrophic Cardiomyopathy
Congenital Heart Defects
Types of Heart Failure

* include left, right or both sides
* left ventricular heart failure
* right ventricular heart failure
Onset of disease

* chronic disease: can take years to develop
* endogenous compensatory mechanisms

Compensatory Mechanisms
Symptoms of CHF
* shortness of breath
* persistent coughing/wheezing
* edema (or excess fluid buildup in body tissues)

Symptoms of CHF
* tiredness/fatigue
* lack of appetite/nausea
* confusion/impaired thinking
* increased heart rate

Problems
* Reduced force of contraction
* Decreased cardiac output
* Increased TPR
* Inadequate organ perfusion
* Development of edema
* Decreased exercise tolerance
* Ischemic heart disease
* Sudden death

Therapeutic Overview
Goals
* alleviate symptoms
* improve quality of life
* arrest cardiac remodeling
* prevent sudden death
Drug
* Chronic heart failure
o ACE inhibitors
o Beta-blockers
o ATII antagonists
o aldosterone antagonists
o digoxin
o diuretics
* Acute heart failure
o diuretics
o PDE inhibitors
o vasodilators

Therapies
Non-drug
* Reduce cardiac work
* Rest
* Weight loss
* low Na+ diet
Cardiac Glycosides
* discovered by William Withering
* published “An Account of Foxglove and some of Its Medical Uses” in 1785
* Foxglove plant
Cardiac Glycosides
* derived from plants
o Strophanus - Ouabain
o Digitalis lanata - Digoxin, Digitoxin
* increase force of myocardial contraction
* alters electrophysiological properties
* toxic side-effects
* Digoxin most common used in USA

Digitalis lanata
Mechanism of Action
* inhibitor of Na+/K+ ATPase pump
* increased [Na+]i
* increased Ca2+ influx through Na+/Ca2+ exchanger
* new Ca2+ steady-state: increased Ca2+ release during cardiac action potential
Electrophysiological Effects
* Direct effects
o spontaneous depolarization of atrial cardiomyocytes at high doses

Electrophysiological Effects
Overall Effect on Cardiac Function

Foxglove
Therapeutic Uses
* only orally effective inotropic agent approved in US
* also for CHF secondary to ischemic heart disease
* contraindicated in patients with Wolff-Parkinson-White syndrome
* does not stop disease progression or prolong life in CHF patients

Pharmacokinetics
* long half-life (24-36 h): once daily dosing
* high bioavailability from oral dosing
* large volume of distribution
* digoxin excreted in kidneys
* digitoxin metabolized in liver, active metabolites
* intestinal flora cause variations in toxicity

Side Effects
* extremely low therapeutic index (~2)
* most effects caused by inhibition of Na+/K+ ATPase in extracardiac tissues
* CNS: malaise, confusion, depression, vertigo, vision
* GI: anorexia, nausea, intestinal cramping, diarrhea
* Cardiac: bradycardia, arrhythmias
* anti-digoxin antibody in toxic emergencies

Serum Electrolytes affect Toxicity
* Ca2+
* hypercalcemia: increases toxicity
* K+
* digitalis competes for K+ binding site on Na+/K+ ATPase
* contraindicated with K+ depleting diuretics or patients with hypo/hyperkalemia
* hypokalemia: increased toxicity
* hyperkalemia: decrease toxicity

Example of cardiac side effects
* action potential recordings from purkinje fiber cells
* toxic doses produce oscillatory after depolorizations
* leads to ventricular tachycardia (C)

Vision Effects
* yellow-tinted vision or yellow corona-like spots

Phosphodiesterase Inhibitors
* primarily used for management of acute heart failure
* positive inotropic effects
* increase rate of myocardial relaxation
* decrease total peripheral resistance and afterload

Mechanism of Action
* inhibitor of type III cAMP phosphodiesterase
* increased [cAMP]
* increased PKA phosphorylation of Ca2+ channels in cardiac muscle
* increased cardiac contraction
* relaxes vascular smooth muscle

Therapeutic Use
* Amrinone (Inocor) and Milrinone (Primacor)
* administered IV
* milrinone is ~1o fold more potent
* T 1/2 = 2.5 h for amrinone and 30-60 min for milrinone
* effective in patients taking Beta-blockers
* does not stop disease progression or prolong life in CHF patients
* prescribed to patients non-responsive to other therapies

Side Effects
* sudden death secondary to ventricular arrhythmia
* hypotension
* thrombocytopenia
* long term clinical trials associated with increased adverse effects and increased mortality
* now only prescribed for acute cardiac decompensation in patients non-responsive to diuretics or digoxin

β-adrenergic receptor antagonists
* “β-blockers”
* standard therapy for treatment of CHF
* cheap!
* reduce sudden death caused by other drugs
* Propranolol: prototype
* Carvedilol: combination effects

Propranolol
Carvedilol
Mechanism of Action
* mechanism still unclear
* antagonizes β-adrenergic receptors on cardiac myocytes
* counterbalances increased SNS activity in CHF
* prevents development of arrhythmias
* reduces cardiac remodeling
* prevents renin release

Therapeutic Use
* administered orally
* usually given in conjunction with other therapy
* effective in patients with chronic systolic heart failure in Class II (mild) to Class III (moderate)
* prevents remodeling and cardiac damage

Side Effects
* cardiac decompensation
* bradycardia
* hypoglycemia
* cold extremeties
* fluid retention
* fatigue

Direct acting sympathomimetics
* cause immediate increases in cardiac inotropy
* goal: to increase cardiac output but not effect total peripheral resistance
* used in treatment of acute life-threatening CHF

Dopamine
Dobutamine
Mechanism of Action
* Norepinephrine/epinephrine: increase CO, increase TPR
* Dopamine:
* Dobutamine:

Therapeutic Use
* administered IV, very short T 1/2
* Dopamine
o used in cardiogenic, traumatic or hypovolemic shock
o used with furosemide in diuretic resistant patients (volume overload)
* Dobutamine
o used in patients with low cardiac output and increased left ventricular end-diastolic pressure
o not for use in hypotensive patients

Side Effects
* restlessness
* tremor
* headache
* cerebral hemorrhage
* cardiac arrhythmias
* used with caution in patients taking β-blockers
* can develop dobutamine tolerance

ACE inhibitors/AT1 receptor antagonists
* Goal: to reduce afterload/preload, reduce workload on heart
* generates positive cardiac inotropy
* used in treatment of chronic CHF

ACE inhibitors/AT1 receptor antagonists
* orally active
* ACE inhibitors
* Captopril
* Enalopril
* AT1 antagonists
* Losartan
* Valsartan

Mechanism of Action
* ACE inhibitors
* AT1 receptor antagonists
* selectively inhibits ATI receptor activation
* decreased preload
* decreased afterload
* decreased cardiac remodeling
* decreased SNS effects

Therapeutic Uses
* drugs of choice in heart failure
* increase survival in long term CHF
* ACE inhibitors
* AT1 receptor antagonists
Side Effects
* ACE inhibitors
+ cough
+ angioneurotic edema
+ hypotension
+ hyperkalemia
* ACE inhibitors and ATI receptor antagonists are both teratogenic

Vasodilators
* Goal: reduce TPR without causing large decrease in BP
* reduce preload
* reduce afterload
* relieves symptoms
* increase exercise tolerance

Drugs Used
* NO Donors
o Nitroglycerin
+ acute ischemia or acute heart failure
+ orally active
+ also administered I.V. for peripheral vasodilation
+ quick onset for acute relief
o Isosorbide dinitrate/hydralazine
+ chronic administration for long-term symptom relief
+ administered I.V.

Drugs Used
* Nesiritide
o recombinant brain-natriuretic peptide (BNP)
o BNP is secreted from ventricular myocytes in response to stretch
o vasodilator: increases cGMP in SMCs
+ decrease afterload/preload
o inhibits cardiac remodelling
o suppresses aldosterone secretion
o administered IV for acute decompensated CHF
o adverse effects: hypotension, renal failure (?)

Diuretics
* used in CHF to reduce extracellular fluid volume
* primarily used in patients with acute CHF with volume overload
* IV infusion causes immediate and predictable diuresis for immediate relief
* Goal: reduce preload/afterload
* overdosing can result in excessive reduction in preload, overreduction in stroke volume
* thiazide and loop diuretics (i.e. Furosemide) commonly used as adjunct therapies in CHF

Aldosterone Antagonists

* elevated AngII levels increase production of aldosterone in the adrenal cortex (~20X increase)
* aldosterone activates mineralocorticoid receptors in renal epithelial cells in kidney
* aldosterone promotes
o Na+ retention, Mg2+ and K+ loss
o increased SNS activity
o decreased PSNS activity
o myocardial/vascular fibrosis

Therapeutic Use
* Goal: inhibit aldosterone negative effects in CHF
* aldosterone receptor antagonists
o spironolactone
o eplerenone
* both antagonists reduce mortality in patients with moderate to severe CHF
* only use in patients with normal renal function and K+ levels
* use with K+ sparing diuretic

Side Effects
* hyperkalemia
* agranulocytosis
* anaphylaxis
* hepatoxicity
* renal failure
* Spironolactone: gynecomastia, sexual dysfunction
* Eplerenone: arrhythmia, myocardial infarct/ischemia

Congestive Heart Failure

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