Unraveling the Paclitaxel Mystery
Pathophysiology of Type I
Hypersensitivity Reactions
Carrie Bilicki, RN, BSN, OCN
Carrie.bilicki@aurora.org
MSN 621 Spring
Alverno College, Milwaukee Wisconsin
Learning Objectives
• Explain the pathophysiology of a Type I
hypersensitivity reaction
• Relate humoral immunity to the body’s
response during a hypersensitivity reaction
to paclitaxel
• Identify and prevent adverse events to
improve patient outcomes
• Describe the rationale for rechallenging
patients with paclitaxel
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2
Overall Tutorial Outcome
The primary goal of this tutorial is to educate
nurses who administer Paclitaxel on the
pathophysiology of a type I reaction to this
chemotherapy. Additionally, learners will be
able to verbalize the principles in preventing a
reaction, understanding an evidenced based
approach in the management of an
anaphylactic reaction.
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3
Directions for Using the Tutorial
• When you see a link, click on it for more
information on that topic, or to be directed back
to a definition of that term
• Use the Navigation buttons on the bottom of
each page to move to the next page or previous
page
– Clicking on
will move you ahead one slide
– Clicking on
will move you back one slide
– Clicking on
will take you to the main
menu
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4
You can proceed
on with the tutorial by
moving forward
or come to the main menu
to review a
Specific section!
Main Menu
• Definitions
• Pathophysiology of
Type I reaction
• Relating Type I reaction
to Paclitaxel
• Genetics
• Nursing Sensitive
outcomes
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5
In order to break this down and understand the
pathophysiology of what is happening to the body
with a hypersensitivity/anaphylaxis reaction we
need to first understand the language used.
These Next Slides will review & define common
terms In describing hypersensitivity
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Microsoft Image Clip Art, 2007
6
Normal Immune
Response
Our Immune system is the body’s natural defense
against infections and diseases. Antibodies are
produced and part of a healthy immune system.
Adaptive (acquired) immunity is the antigen-specific
defense mechanisms, taking days to become effective
and developed though out the life span.
Humoral
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Cell
Mediated
Microsoft Image Clip Art, 2007
7
B-LYMPHOCYTE
B-lymphocytes are white blood cells that play a
large role in humoral immunity. Lymphocytes
manufacture antibodies, proteins which possess
Grabs
the ability to recognize and bind to foreign
and
holds
substances. The antibodies may be either
onto
secreted or bound to the lymphocyte
IgE
membrane. Plasma cells are differentiated
lymphocytes which are specialized to
manufacture and secrete relatively large amounts
of antibody. Their principal function is to make
I’ll
antibodies against antigens. They recognize
remember
antigens via B-cell receptors (BCRs) .
you
antigen!
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8
ANTIGEN
A substance that reacts
with antibody molecules
and antigen receptors on
lymphocytes. An
immunogen is an antigen
that is recognized by the
body as nonself and
stimulates an adaptive
immune response.
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10
Mast Cells
Secretory
alarm
cells in
our tissue
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Cells, which synthesize and
store histamines, found in most
body tissues, particularly just
below the epithelial surfaces,
serous cavities, and around
blood vessels. In an allergic
response, an allergen
stimulates the release of IgE
antibodies, which attach
themselves to mast cells.
Microsoft Image Clip Art, 2007
Trigger the
process of
inflammation
IgE
binds to
the mast
cell
11
BASOPHILS
In the
blood
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Leukocytes that
promote inflammation
by releasing or
synthesizing such
inflammatory mediators
as histamine,
leukotrienes, and
prostaglandins.
13
HISTAMINE
A chemical naturally produced
in cells of the body.
Overproduction in response to
allergens is released by
basophils, mast cells, and
platelets which promotes
inflammation by causing
vasodilatation and increased
capillary permeability. An
allergic reaction indicates an
excessive release of
histamines.
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Microsoft Image Clip Art, 2007
14
INFLAMMATION
A process in which blood
vessels dilate and become more
permeable, thus enabling body
defense cells and defense
chemicals to leave the blood
and enter the tissues. Acute
inflammation is usually a
localized, protective response to
tissue injury. Excessive or
chronic inflammation, however,
may lead to tissue destruction.
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Paclitaxel
ALLERGEN:
An antigen causing an
allergic reaction.
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Antibodies or
Immunoglobulins
Specific proteins
produced by Blymphocytes and plasma
cells in response to a
specific antigen and
capable of reacting with
that antigen. For this
tutorial we are focusing
on the antibody IgE.
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Antibody Structure
Constantly
circulating in our
system these
antibodies are
shaped like the
letter Y. These
antibodies bind to
antigens triggering
a cascade of events
causing the
hypersensitivity
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There are 5 classes of
human antibodies:
immunoglobulin G (IgG),
immunoglobulin M (IgM),
immunoglobulin A (IgA),
immunoglobulin D (IgD),
immunoglobulin E (IgE).
Microsoft Image Clip Art, 2007
Hypersensitivity
Reaction
21
Normal Immune
Response
The difference between a
normal immune response
and a type I hypersensitive
response is that plasma
cells secrete IgE, resulting in
a systemic inflammatory
response that can result in
symptoms as benign as a
runny nose, to lifethreatening anaphylactic
shock and death.
22
Humoral Immunity
Immediate Hypersensitivities
Humoral immunity involves
the production of antibody
molecules in response to an
antigen and is mediated by
B-lymphocytes.
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24
Cell-Mediated Immunity
Delayed Hypersensitivites
Type IV
Production of cytotoxic T-ymphocytes,
activated macrophages, activated
Natural Killer (NK) cells, and cytokines in
response to an antigen.
Mediated by T-Lymphocytes
26
Review of Hematopoiesis &
Pluripotent
Immunity Stem
Cell
Myeloid
stem cell
CFU-GEMM
Lymphoid stem cell
BFU-E
CFU-Meg
CFU-GM
CFUMast
Neutrophil
Platelets
NK
precursor
CFU-G
monocyte
RBC
Pre- PreBcell TCell
Monoblast
Megakaryocyte
Reticulocyte
CFUEO
B
Eosinophil
Macrophage
Tissue
Mast
Cell
T
Natural
killer
cell
Plasma
Cell
27
Review of Hematopoiesis &
Immunity
CFUMast
Humoral
Immunity
PreBcell
Cell Mediated
Immunity
PreTCell
lymphocytes
lymphocytes
B
Tissue
Mast
Cell
NK
precursor
T
Natural
killer
cell
Plasma
Cell
28
Role of Lymphocytes in the
Immune System
Lymphocytes are responsible for specific immune recognition
of pathogens. They circulate freely throughout the body
moving from blood stream to tissue and back. There role is to
act as scouts & destroy pathogens entering the body
B-Cells are genetically programmed to encode a surface
receptor specific for a particular antigen. Once the B cell
recognizes an antigen, the B cell multiplies and differentiates
into antibody producing Plasma Cells
T-cells release cytokines and have direct cell-cell interactions
T-helper cells interact with B cells and phagocytes
Cytotoxic T cells destroy host cells infected by viruses or other
Intracellular pathogens
29
Lets check our understanding!
These concepts can be confusing!
Humoral immunity can cause harm to the body by
antigen/antibody interactions and our body’s systemic
reaction is termed a hypersensitivity.
True or False
Microsoft Image Clip Art, 2007
30
TYPE I HYPERSENSITIVITY
Humoral Immunity
Most common type of
hypersensitivity due to excessive
production of the class of
antibody known as IgE. IgE is
made in response to an allergen.
For this tutorial we are focusing
on the allergen Paclitaxel and the
Type I hypersensitivity that is
seen.
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Here is a visual
of what is
happening.
Lets break down
these concepts!
IgE mediated
Reaction=Type I
Second exposure!
Allergen specific IgE antibody
to attach to IgE receptors on
Mast & Bashophils
Immediate
and
delayed
Release of Mast Cells or
Basophil Mediators
Histamine
Prostaglandins Cascade of
leukotrienes
Cellular
events
Eosinophil’s
called upon,
more cellular
inflammation
& injury
Neutrophils
come too!
Microsoft Image Clip Art, 2007
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Chinen, Fleisher, Shearer, 2008
34
Anaphylaxis
“Anaphylaxis is caused by the interaction
of a foreign antigen with specific
immunoglobulin E (IgE) antibodies found
on the tissue of mast cells and peripheral
blood basophils. The subsequent release
of bioactive mediators from these cellular
components results in smooth muscle
spasm, mucosal edema and inflammation,
and increased capillary permeability.”
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Timoney, J.P et al 2003
35
Anaphylaxis
Anaphylaxis is the most severe form of an IgE
mediated hypersensitivity and may occur within
minutes of an exposure. Acute & life-threating
characterized by respiratory distress, laryngeal
edema, severe bronchospasm and usually is
accompanied by cutaneous (pruritus, flush,
urticaria, angioedema) and GI symptoms.
**Anaphylaxis is directly related to the release of
IgE, whereas an Anaphylactoid reaction is not
caused by IgE. Clinical presentations are the
same. The jury is still out…is a Paclitaxel reaction
from IgE release or not?
(Timoney, et. al 2003)
(Lieberman et. al 2005)
36
Really? In English Please
Anaphylaxis is a severe, lifethreatening, generalized or
systematic hypersensitivity
reaction. Characterized by
breathing and circulatory problems,
usually associated with skin and
mucosal changes.
IgE
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IgE is made in response
to the allergen!
Microsoft Image Clip Art, 2007
37
Hypersensitivity vs. Anaphylaxis!
With
Taxol
Same word? Different meaning?
Infusion
related
side
effects
General
term for
allergic
reaction
Anaphylaxis
is the severity of
the hypersensitivity
Magnified
immune
response
Local tissue injury or change t.o. body in
response to antigen or foreign substance
Non immune mediated vs . immune?
Release
of
histamine
Release
of
cytokines
Same outcome regardless of mechanism
Adverse
Event
Carrie Bilicki, 2009
“There is no universally
accepted clinical definition
of anaphylaxis”.
Lieberman et. al, 2005, p.500
38
Genetic Link to Allergies?
Studies have looked at
the receptor site for IL4.
Variation’s in the genes
were found in patients
who had a history of
various allergies, this
variant occurred at a
low frequency with
patients with no
allergies.
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Interleukin 4
(IL4) is a
protein that
induces
immune cells
to make IgE
Genetic
alteration
at the end
of the IL4
receptor
Patient
outcome: With
this genetic
mutation
patients have
an exaggerated
response to
allergens
39
Pre-disposed to Allergies?
Children of allergic parents are
more likely to develop allergies
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Chinen, Fleisher, Shearer , 2008
40
CYTOCHROMES P450 (CYP)
(big fancy word for enzymes that work in the liver to break
down the drug)
CYP =
DNA
Codes our
proteins
RNA
What’s in your
Genes!
DNA missing
parts=altered
metabolism
Detoxification
& elimination
of drug &
Activation of
prodrug
We all metabolize differently! Ever wonder why
some patients have every side effect and others
experience few or none? Think P450!
TAXOL
METABOLIZED
BY CYP
pathway
CYP2C8
CYP3A4
Poor metabolizers have
trouble breaking down
the drug, increased side
effects!
Also effects the
transport of the
drug
Marsh, et. al, 2007
41
Let’s Review!
Answer the following questions True or False to the following questions
1.
2.
3.
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True or False - The main cause of a
hypersensitivity is plasma cells secreting
IgG.
True or False – An Allergen is an antigen
causing an allergic reaction
True or False – Histamine release causes
vessels to constrict and blood pressure to
rise
Microsoft Image Clip Art, 2007
42
What are the effects of a Type I
hypersensitivity, and how are they
linked to Paclitaxel?
Let’s Find Out!
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Microsoft Image Clip Art, 2007
43
What are Taxanes?
• Taxanes are a category of highly effective chemotherapeutic
agents, and standard of care for numerous cancer diseases
• Taxanes are in the class of microtubule stabilizing agents, to
review these medications, indications, and side effects click
on the links below
 Paclitaxel (Taxol) FDA approved in 1994 revolutionalized how we
treat patients.
 Docetaxel (Taxotere) FDA approved 1996 the “cousin” to Paclitaxel.
Lost some of the anaphylactic properties, gained bone marrow
suppression
 Nab-paclitaxel (Abraxane) Bound to protein, nanoparticle formulation
of paclitaxel
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Immune System
Type I
reaction
related to
Paclitaxel
What does
this really
mean?
First
exposure
Sensitizes
the Mast
cells
Cutaneous
& mucosal
surfaces
Circulating
basophils
The allergen (the chemotherapy or drug formulation in our case) enters
the body and is recognized by the surface immunoglobulin (the IgE) on a
B-lymphocyte. The B-lymphocyte then proliferates and differentiates into
plasma cells.
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Copyright © Gary E. Kaiser
The Grapes of Staph
http://student.ccbcmd.edu/~gkaiser/goshp.html
Used with permission.
45
Immune System
The plasma cells produce and secrete IgE which binds to
receptors on mast cells and basophils. Initial exposure does
not trigger symptoms!
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Copyright © Gary E. Kaiser
The Grapes of Staph
http://student.ccbcmd.edu/~gkaiser/goshp.html
Used with permission.
46
An antigen
causing an
allergic
reaction
Immune System
IgE antibody
produced in
response to
the allergen
Mast cell
synthesizes
and stores
histamine
BasophilsLeukocytes
Allergen cross reacting with IgE on mast
cell. IgE also promotes inflammation to
recruit phagocytes.
3/15/2016
Copyright © Gary E. Kaiser
The Grapes of Staph
http://student.ccbcmd.edu/~gkaiser/goshp.html
Used with permission.
47
HYPERSENSITIVITY
Histamine!
Immune System
Proinflammatory
mediators
also released
with
histamine!
Leukotrienes
Prostaglandins
•Uticaria
•Rash
•Angioedema
•Bronchospasm
•hypotention
The next time the allergen enters the body, it cross-links to the IgE bound to the mast
cells. This triggers the mast cell to release its histamine and other inflammatory
mediators. The inflammatory mediators are now able to bind to receptors on target
cells which leads to smooth muscle contraction, vascular permeability , dilation of
blood vessels, constriction of bronchioles, excessive mucus secretion.
3/15/2016
Copyright © Gary E. Kaiser
The Grapes of Staph
http://student.ccbcmd.edu/~gkaiser/goshp.html
Used with permission.
48
Adverse Effects of Taxanes
•
•
•
•
•
•
•
•
•
•
•
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Common
Peripheral neuropathies
Alopecia
Asthenia
Diarrhea
Hypersensitivity Reaction
Hypotension
Anemia
Mucositis
Myalgias
Nausea/Vomiting
Neutropenia
Rare
•
•
•
•
•
Cardiopyopathy
Dysrhytmias
Thrombocytopenia
Interstitial pneumonitis
Edema
51
Quick Check!
• To make sure we are understanding!
Microsoft Image Clip
Art, 2007
3/15/2016
If a patient has known
allergies the levels of IgE may
be thousands of times higher
than those without allergies?
True or False
54
What does this really mean?
Allergen!
Paclitaxel
given
Body says wowzers!!
Histamine
B-lymphocytes
say never fear
“B-lymphs here!”
The plasma
cells
differentiated
from the Blymphocytes
secreting IgE
which binds to
the mast cells
thoughout our
body tissue
So now
what…
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(Carrie Bilicki, 2009) Microsoft Image Clip Art, 2007
60
What’s the body doing!?
Remember histamine promotes
inflammation causing vasodilation and
increased capillary permeability
Resulting
in
How
do
we
stop
this!
Dilatation of Blood Vessels, flushing to skin, drop in blood
pressure, worst case scenario shock
Increased capillary permeability causing swelling of tissues
(edema), if severe untreated reaction decreased blood volume,
shock
Constricted bronchial airways, wheezing & difficulty breathing,
stimulation of mucous secretion causing congestion
Stimulation of nerve endings, causing itching & pain to skin
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If we think about preventing reactions
in Paclitaxel this all starts to make
Minimize
sense!
the risk
Can
you
guess
what
“H”
stands
for?
please!
Histamine!
H2
antagonist
Antihistamine
H1 receptor
antagonist
steroids
Routinely given by intravenous route, however studies have
shown safe protection against hypersensitivity reactions when
given orally
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(Zidan et. al, 2008) Microsoft Image Clip Art, 2007
62
Steroids, not only to build muscles!
Decadron is given as a
premedication to stabilize mast
cell membranes and prevent
mast cell degranulation.
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Microsoft Image Clip Art, 2007
63
Antagonist is an agent which serves to
inhibit the release or action
• Antihistamines are reversible competitive antagonists of
histamine at H1 receptor sites. They do not prevent
histamine release or bind to the histamine that has
already been released. The H1 receptor blockade results
in decreased vascular permeability, reduction of pruritus
and relaxation of smooth muscle in the respiratory and
gastrointestinal tracts.
• H2 Antagonist Inhibits histamine action at parietal cell H2
receptors
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H1 antagonist
Diphenhydramine 50 mg IV 30
minutes prior to hanging
Paclitaxel
Blocks the binding of histamine
to H1 receptors on target cells
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Microsoft Image Clip Art, 2007
66
H2 Antagonist
Cimetidine 300mg IV
Famotidine 20mg IV
Ranitidine 150mg IV
One of these
agents to be
used as a
premedication
Reducing mucus
secretion and
vascular smooth
relaxation
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(Greenberger, 2002) Microsoft Image Clip Art, 2007
67
How does the H2 antagonist
work?
Histamine is a chemical naturally
produced by certain cells in the body
including cells in the lining of the
stomach called the enterochromaffinlike cells (ECL cells). Histamine
released from ECL cells then
stimulate the acid making cells
(parietal cells) in the lining of the
stomach to release acid. What H2
blockers do is stop the acid making
cells in the stomach lining from
responding to histamine. This reduces
the amount of acid produced by your
stomach.
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Diagram copyright EMIS and PiP 2009, as distributed on
http://www.patient.co.uk
68
What is the incidence of a
hypersensivity to Paclitaxel?
Despite premedication
there is estimated 44%
minor reactions occuring
in patients and
approximately 1.5-3% of
patients experiencing
major anaphylactic
reactions
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(Zuylen, Verweij, Sparreboom, 2001) Microsoft Image ClipArt, 2007
69
Allergic Drug Reaction (ADR)
(Hypersensitivity)
These reactions are mediated by our immune
system that share similar characteristics
Involve
previous
exposure to
this drug or
a similar
agent
Small
number of
patients
Clinical
presentation
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(Timoney, Eagan, sklarin, 2003)
Reaction
develops
rapidly with
reexposure
70
Poor Reporting of ADR
Reporting of ADR is voluntary by
health care professionals. True
statistics on the frequency of a
hypersensitivity are not
available.
Do you know your institution’s guidelines?
Are you reporting ADRs? When would you need
to report a reaction to the Us Food and Drug
Administration (FDA)?
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Microsoft Image Clip Art, 2007
71
Keys to successful outcomes!
• Premedication's! Critical, critical!
• Patients prior allergic reaction
• Educate patient and family on
potential and actual side effects
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Microsoft Image Clip Art, 2007
72
What’s the deal with Paclitaxel?
Ovarian
Breast
Endometrial
Less
common
tumors/off
label
Head &
Neck
Taxol
saving
lives
Bladder
Testicular
Esophageal
Lung
3/15/2016
Presently one of the
most widely used
chemotherapeutic
agents today due to its
potent tumor
cytotoxcity in
numerous cancer
diagnoses
(Price, Mariana, Castells, 2002) Microsoft Image Clip Art, 2007
73
What’s the deal with Paclitaxel?
The Great Mystery…Is it the drug or the solution?
Countless studies have evaluated what causes the hypersensitivity and
anaphylaxis in patients. Remember an anaphylaxis reaction is the release of
histamine in response to the allergen, an anaphylactoid reaction is unrelated
to histamine release but the same clinical presentation.
Paclitaxel (Taxol) was developed from the bark of the Pacific yew tree (Taxus
brevifolia) How creative in picking the name!
In early phase I studies in the late 1980’s this chemotherapy agent it almost
never made it to be one of the most standard chemotherapy agents to date!
This was due to severe hypersensitivity reactions in patients and many
deaths. Over the years it is a known reaction potential and hence the
guidelines for pre-medications and slow titration to reduce the reaction
potential of our patients.
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74
What’s the deal with Paclitaxel and
Cremophor EL (CrEL)?
Made from
castor oil
So needs
50% CrEL&
50%
dehydrated
ethanol
Poorly
soluble in
water
Axonal degeneration
& demyelination
CrEL linked to
the main
cause of
neurotoxicity
Why we
need special
tubing!
Known to leach
plasticizers
from standard
IV bags and
tubing sets
Otherwise
toxins could
cause
hepatic
toxicity
Approximately 25% of
patients with
neuropathies
Flu like symptoms, loss of
circulation, imbalance,
memory problems
Damage
occurs to the
brain and/or
peripheral
nervous
system
Careful
assessment
of your
patients is
needed with
each cycle
In order for this chemotherapy to be administered it needs this “vehicle”
Paclitaxel alone is insoluble in water. Think of it like oil and water, without the
Cremophor EL the paclitaxel would remain in suspension unable to be
delivered.
(Zuylen, Verweij, Sparreboom, 2001)
Carrie Bilicki, 2009
75
The great mystery continues…
But wait? How can this be? From what we
know about a type I reaction it is the first
exposure that “primes” the IgE.
Then the next time the allergen enters the
body, it triggers the mast cell to release its
histamine and other inflammatory mediators.
Patients usually react on the first exposure
to paclitaxel!
76
Reaction mystery
Continues….IgE or not!
Is the
Cremophor
EL a direct
NON IgE
histamine
releaser?
And other
studies have
reported it’s
the paclitaxel
alone that
caused
histamine
release
There are a few theories on what is
occurring.
No clinical
studies have
measured
serum tryptase
after reactions
Cremophor EL is
used in
anesthetics,
vitamins, sedatives
and found in
cosmetics,
perfumes, creams
This could be
the “priming”
IgE exposure!
Are we not mixing
the Paclitaxel and
Cremophor well
enough prior to
administration?
Tryptase is a mediator along with histamine that is released from
mast cells into circulation when an allergic reaction or inflammation
occurs. This level can be measured in the blood serum of patients
to determine if an anaphylactic reaction had occurred. Histamine
metabolites can be measured in urine studies.
Cremophor EL
is 50% alcohol,
animal studies
have shown a
possible link of
the histamine
release to the
components of
Cremophor EL
“The mechanism(s) underlying paclitaxel hypersensitivity-like
reactions is skill unknown, and clinical data on probable complement
and mast cell activation are lacking” (Price et. al, 2002, p. 205)
(Zuylen, Verweij, Sparreboom, (2001)
(Price, Castells, 2002)
77
Cremophor EL
Microsoft Image Clip
To give you an idea the concentration Art, 2007
used in Paclitaxel it is 25.8 ml administered
(in an average adult) compared to 1.5 ml in
a dose of diazepam or 3.5 ml in
Cyclosporin A.
This may help you understand slowing the
infusion will lessen the volume of
concentration delivered & the importance
to ensure your infusion bag is gently mixed
prior to hanging Paclitaxel.
Gelderblom, et. al. 2001
78
Known Risk…
whatever the cause
In the early days of administering Paclitaxel it was given in the Intensive
Care Unit because of the high incidence of reactions. We now know a lot
more on the management of hypersensitivity to this chemotherapy.
A hypersensitivity reaction will most likely occur within minutes of
administration or shortly after you increase the rate. This is why it is so
important to follow all the steps when administering Paclitaxel. Missing
one step in premedication, length of time between premedication's, and
titration of paclitaxel can be detrimental to your patient.
We never know who is going to react.
Being prepared is key!
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Microsoft Image Clip Art, 2007
79
Know your patient
The number one preventative measure you can do to stop a
reaction is to know your patient and their history!
Assess your patient for previous Type I (IgE mediated) allergic reactions.
Genetic predisposition for sensitization to antigens.
seminal
fluid
food
vaccines
antibiotics
exercise
induced
other
medications
idiopathic
anesthesia
blood
transfusions
latex
Lieberman et. al, 2005
bee
stings
80
Did you know?
Microsoft Image Clip
Art, 2007
The more rapidly anaphylaxis occurs during
an infusion the more likely it is to be severe and
potentially life threatening
Most reactions will occur within minutes, but
some patients may have a delayed reaction such
as 30 minutes into the infusion
Some patients may have a delayed reaction
called “Late Phase” or “Biphasic reactions,
which may occur 8-12 hours after the patient is
home
Once a patient is reacting despite the best
interventions and aggressive treatment patients
may experience protracted and severe
anaphylaxis up to 32 hours
Lieberman et. al, 2005
81
Did you Know?
Microsoft Image Clip
Art, 2007
“Increased vascular permeability, a characteristic
feature of anaphylaxis, allows transfer of as
much as 50% of the intravascular fluid into the
extravascular space within 10 minutes. As a
result, hemodynamic collapse might occur
rapidly with little or no cutaneous or respiratory
manifestations”. That means our patients may
not complain of any shortness of breath, itching,
or any forewarning!
Good to Know!
Lieberman et. al, 2005
82
Ready, Set, Go!
Microsoft Image Clip
Art, 2007
3/15/2016
Established protocol to deal with
any event, equipment and emergent
medication readily available
Patient teaching completed
Patient history obtained
Premedication's administered as
ordered
You follow your established clinical
guidelines for the administration of
Paclitaxel
Stay with your patient for the first
15 minutes, monitoring vital signs
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Let’s review!
Mrs. Smith is in for her first infusion of Paclitaxel, 10 minutes into her
infusion she complains of itchy hands. What do you do?
A. Assure her this is a common side effect, to be expected and continue
on with the titration of Paclitaxel
B. Call a code, rushing to the patient asking if she would like “last rights”
C. Remain calm, assess all symptoms and (1) stop the infusion, infuse
Normal Saline and continue to monitor the patient, or (2) slow the
infusion an monitor for symptoms to alleviate.
D. Offer the patient hand lotion and tell her this may help her dry, itchy
hands.
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Keys to successful management
You know the
risks!
What’s your
patient’s
baseline?
Know
what you
should
monitor
for!
PROACTIVE
Ongoing monitoring and early interventions are the key to safe
administration & intervention if needed to a anaphylaxis reaction
Level of consciousness, acute confusion or gazed appearance may
indicate decreased oxygen saturation
Monitor airway, watch for shortness of breath, cough, wheezing
Cardiovascular system, ongoing evaluation of blood pressure and
pulse
Skin changes, flushing to face, itching, facial edema
GI symptoms, nausea, vomiting, diarrhea
Neurological changes, lightheadedness, headaches, feeling of
impending doom
Lieberman et. al, 2005
89
Slow and steady wins the race
Reactions are very frightening for
you, the patient and their family!
We know how beneficial Paclitaxel is
for our patients lets learn why it is
important to go slow, monitor for
reactions, and understand the
process of safely rechallenging
patients.
Microsoft Image Clip
Art, 2007
90
Slow Down!
What’s
the rush?
Keep your
Patient safe
Concentration & Rate Dependant
Microsoft Image Clip
Art, 2007
• Theory behind binding of anti-cholesterol antibodies to the oil
rich Cremophor El causes heightened hypersensitivity
• We now realize that histamine is released in response to the
antigen, give the body time to recognize and process, slower
concentration, less callout of the immune response
• For patients showing EARLY clinical signs, slowing the
infusion rate can alleviate hypersensitivity symptoms . STAY
with your patient and monitor closely for the first 15 minutes.
Safe delivery by a
knowledgeable nurse!
Tije, Verweij, Loos, Sparreboom, 2003
Improved
Patient
outcomes!
91
Slow Down!
What’s
the rush?
Keep your
Patient safe
Concentration & Rate Dependant
Microsoft Image Clip
Art, 2007
Up to 44% of patients receiving Paclitaxel will still react with minor
symptoms of itching hands or skin flushing, despite adequate
premedications. Important to start slow, and reduce the rate if your patient
starts to complain of symptoms. Stay close to your patient, and monitor.
Your strong assessment skills will allow patients to complete their infusions
without experiencing a “full blown” reaction!
Safe delivery by a
knowledgeable nurse!
Tije, Verweij, Loos, Sparreboom, 2003
Improved
Patient
outcomes!
92
Your patient reacts! Now what?
First Step--Stay in CONTROL
Stop Infusion
Recline your patient, elevating legs to slow progression of
hemodynamic compromise, prevent hypotension, & encourage
blood flow to the head, heart, and kidneys
I’m in control??!!
Microsoft Image Clip Art, 2007
**Some physicians may
administer corticosteroids
to block late allergic
symptoms (no effect on
initial reaction)
Maintain Airway, monitor pulse oximetry, administer oxygen to
patient
Bolus Normal Saline to replace fluids, goal to keep systolic
blood pressure greater than 90 mm
Possible re-dosing of diphenhydramine, and antihistamines
Give Epinephrine to control symptoms and increase Blood
Pressure
If patients fails to show response to the above interventions,
transport patient to an emergency room for further interventions
and monitoring
(Albanell, Baselga, 2000),
Lieberman et. al, 2005
93
Did you Know??
“
“Lactated
Ringers
solution might potentially
contribute to metabolic
acidosis, and dextrose is
rapidly extravased from
the intravascular
circulation to the
interstitial tissues”.
Lieberman, et al p. 493
Main message!
Use Normal
Saline, and up
to 7 liters might
be needed!
One to two
liters at a rate
of 5-10ml/kg in
the first 5
minutes!
Who Knew!
Microsoft Image Clip
Art, 2007
Lieberman et. al, 2005
94
Knowledge is POWER!
Desensitization
Protocols…
used to scare you…not anymore!
When patients are given a desensitization protocol, the goal is to give
small dilute amounts of Paclitaxel over an extended period of time.
What is believed to happen is stimulation of the production of IgG and
IgA. These antibodies, then, act as blocking antibodies to bind to and
neutralize as much of the allergen BEFORE it can bind to the deeper
cell-bound IgE on the mast cells and connective tissue.
Remember IgE is the culprit in producing histamine release.
So, No histamine, No allergic reaction!
Most
Up to 90% of patients
Can successfully be
rechallenged
patients can
tolerate
retreatment
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Knowledge is POWER!
Desensitization
Protocols…
used to scare you…not anymore!
Most institutions have established rechallenge protocols
Some institutions have found benefit in using the model of a
rechallenge protocol on ALL patients starting with cycle 1 of Paclitaxel
to minimize reactions. The next slide is an example used by an
outpatient infusion center in York, Pennsylvania.
This change in practice was due to NURSES questioning infusion
reactions (27% of patients) and collaborating with physicians piloting
their established rechallenge protocol on all Paclitaxel patients.
Outcome=less than 1% of patients show infusion reactions, virtually
eliminating any reactions in their clinic.
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Knowledge is POWER!
Apple Hill Infusion Center
York, Pennsylvania
Paclitaxel Rechallenge Protocol
1.
2.
3.
4.
5.
6.
Premedications: Decadron 20mg po, Cimetidine 300mg IV & Benadryl 50mg IV
40ml/hr for 15 minutes
60 ml/hr for 30 minutes
80 ml/hr for 30 minutes
90 ml/hr for 30 minutes
100 ml/hr until completed
Based on 135 mg/m² dose in 205 ml of D5W, given every 3 weeks
Vital signs are taken every 15 minutes for the first hour, including apical pulse
then hourly for the remainder of the infusion
(Huddleston et. al, 2005)
97
Knowledge is POWER!
The decision to rechallenge is evaluated individually
with each patient after careful consideration by the
treating physician and patient.
Nursing Sensitive Outcomes
1. Safety (preventable adverse events)
2. Psychological distress related to anxiety of the patient
3. Physiological outcomes related to interventions to control systemic
response to Taxane therapy
Your role is to be knowledgeable, supportive, and manage your patient
with nursing sensitive outcomes!
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Case Study! Lets Apply this!
Mrs. Smith, new ovarian cancer diagnosis arrives to your clinic for her
first time Carboplatin/Taxol regimen. She is anxious, already has had
chemotherapy/side effect teaching. You reassure her you will be by her
side and will monitor her closely over the next hour, and through the
duration of the infusion.. You know how important it is to monitor her
closely especially for the first 15 minutes.
1. Pre-medicaitons hung as ordered and given 30 minutes prior to the
initiation of Taxol.
2. 5 minutes into the infusion she complains of being SOB, her blood
pressure has dropped to 82/50 and her pulse ox is reading at 88%.
Her pulse is at 102 and respirations are 20 a minute.
Your keen assessment skills and knowledge that Taxol can
cause a hypersensitivity reaction you are aware these are
signs of a systemic reaction caused by IgE antibodies reacting
with the infusion; subsequent release of histamine is causing
these cascade of events and you need to act fast!
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Case Study! Lets Apply this!
Swiftly you stop the infusion and place O2 on your
patient monitoring her response to oxygen, titrating the
oxygen to maintain a saturation above 92%. Normal
Saline is now infusing while you are consistently
assessing her vital signs, with the goal to maintain her
systolic blood pressure above 90 mm. You have
already reclined your patient, elevating legs to slow
progression of hemodynamic compromise, prevent
hypotension, & encourage blood flow to the head,
heart, and kidneys You were so prepared and in control
prior to hanging the Taxol you have your standard
hypersensitivity reaction orders next to the patient
“just in case” and have all necessary rescue
medications available.
100
Case Study! Lets Apply this!
Great news! She responds to your interventions within
minutes of removing the Taxol. Seems the Taxol was the
allergen reacting with the antibodies IgE. These antibodies
attached to mast cells and basophils to release histamine.
That dang histamine caused the blood pressure to drop;
constricted bronchial airways, wheezing & difficulty
breathing, stimulation of mucous secretion causing
congestion and drop in pulse ox.
Your skills as an informed, knowledgeable oncology nurse
enabled this patient to have a potentially severe outcome,
be manageable and safe! Your patient also was spared
unnecessary frantic response because you remained in
control & you were aware this was a potential. NICE JOB!
101
You
did
it!
Conclusions!
Did we unravel the Mystery a little?
Microsoft Image Clip
Art, 2007
•Pathophysiology: of humoral immunity- Type I
hypersensitivity reactions (antibody IgE) related
to the immune system response
•Evaluating other possible reasoning behind
Paclitaxel hypersensitivity reactions
•Anaphylaxis vs. anaphylactoid reactions
•Developing strategies for preventing and
managing hypersensitivity reactions
•Understand the rationale for rechallenging
patients
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References
•
•
•
•
•
•
•
•
Albanell, J., Basselga, J., (2000) Systemic Therapy Emergencies. Seminars In Oncology, 27(3)
347-361.
Bristol-Myers Squibb Company. (2007). Taxol® (paclitaxell) injection [Package insert]. Princeton,
NJ: Author.
Chinen, J., Fleiser, T. A., Shearer, W. T.,(2008). The immune system: An overview. In Adkinson:
Middleton’s Allergy: Principles and Practice. Retrieved February 27, 2009 from Ovid database.
Chung, C. (2008). Managing Premedicaitons and the risk for reactions to infusional monoclonal
antibody therapy. The Oncologist, 13(6) 725-732.
Gelderblom, H., Verweij, J., Nooter, K., Spareboom, A. (2001) Cremophor EL: the drawbacks and
advantages of vehicle selection for drug formulation. European Journal of Cancer, 37, 1590-1598.’
Greenberger, P. A., (2002). Anaphylaxis. In Manual of Allergy & Immunology (10). Retrieved
February 27, 2009 from Ovid database.
Heinz-Josef, L.,(2007) Management and preparedness for infusion and hypersensitivity reactions.
The Oncologist, 12, 601-609. Retrieved February 20t, 2009 at www.TheOncologistcom.
Huddleston, R., Berkheimer, C., Landis, S., Houck, D., Proctor, A., & Whiteford, J. (2005).
Improving patient outcomes in an ambulatory infusion setting decreasing infusion reactions of
patients receiving paclitaxel and carboplatin. Journal of Infusion Nursing, 28(3), 170-172.
3/15/2016
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References cont.
•
•
•
•
•
•
Lieberman, P., Kemp, S. F., Oppenheimer, J., Lang, D. M., Berstein, I. L., & Nicklas, R. A.,(2005).
The Diagnosis and management of anaphylaxis: An updated practice parameter. The Journal of
Allergy and Clinical Immunology, 115(3), 483-523.
Markman, M., Kennedy, A., Webster, K., Kulp, B., Peterson, G., Belinson, Jerome. (2000).
Paclitaxel-associated hypersensitivity reactions: Experience of the Gynecologic Oncology
Program of the Cleveland Clinic Cancer Center. Journal of Clinical Oncology, 18(1) 102-105.
Retrieved February 20, 2009, from Ovid database.
Marsh, S., Somlo, G., Frankel, Pl, King, C. R., Shannon, W. D., McLeod, H., L. et al. (2007).
Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer. The
Pharmacogenics Journal, 7, 362-365. doi: 10.1038/sj.spj.65oo434.
Microsoft. (2007). Clipart. Retrieved April 15, 2009 from http://office.microsoft.com/enus/clipart/default.
Myers, J. S., (2000). Hypersensitivity reactions to paclitaxel: Nursing interventions. Clinical
Journal of Oncology Nursing, 4(4), 161-163.
Myers, J. S., (2000). Emergency: Chemotherapy-induced hypersensitivity reaction. American of
Nursing, 10(4), 53-54.
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References cont.
•
•
•
•
•
•
Price, K., S., & Castells, M. C. (2002). Taxol reactions. Allergy and Asthma Proc, 43(3), 205-208.
Tije, A., J., Verweij, J., Loos, W., Sparreboom, A. (2003) Pharmacological effects of formulation
vehicles implications for cancer chemotherapy. Clin Pharmocokinet, 42(7), 665-680.
Timoney, J., P., Eagan, M., M., Sklarin, N. T., Establishing clinical guidelines for the management
of acute hypersensitivity reactions secondary to the administration of chemotherapy/biologic
therapy. Journal of Nursing Care Quality, 18(1) 80-86.
Slater J., W., Zechnich AD, Haxby DG. Second-generation antihistamines. A comparative review.
Drugs 1999;57(1):31-47.
Zidan, J., Hussein, O., Abzah, A., Tamam, Sl, & Farraj, Z. (2008). Oral premedication for the
prevention of hypersensitivity reactions to paclitaxel. Med Oncology, 25, 274-278.
Zuylen, L,.V., Verweij, J., Sparreboom, A. (2001) Role of formulation vehicles in taxane
pharmacology. Investigational New Drugs, (19) , 125-141.
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Thank YOU!
Thank you for taking the time to view this tutorial.
My hopes are patient outcomes are improved through
increased nursing knowledge in understanding the great
reaction mystery’s of Paclitaxel!
If you would like to contact me with questions or comments
I can be reached at:
Carrie.bilicki@aurora.org
414-587-1860
3/15/2016
Template copyright 2005 www.brainybetty.com
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