Infusion reactions
Dr. Erika Möller
Objectives:
Understanding key definitions and physiology:
Anaphylactic reactions vs. Anaphylactoid reactions.
Recognizing patients who are experiencing infusion
reaction.
Appropriately managing these patients.
Anaphylactic (Allergic reaction - IgE)
Infusion reactions
Anaphylactoid ( NonAllergenic - cytokine release)
Clinical Manifestations are the same.
Physiology:
Immune response: Adaptive, innate or both.
Innate immunity: present prior to exposure.
Adaptive immunity: acquired response (involves
memory) and continued exposure increases defensive
response.
Adaptive immunity:
Response directed by lymphocytes.
B-lymphocytes (extra-cellular) and T-lymphocytes
(intracellular)
B-lymphocytes
unique antibody to an antigen
immune response e.g. phagocytosis, disruption of cell
membrane or NK cells. IgA, IgD, IgE, IgG and IgM.
IgE = allergic reactions.
T-lymphocytes
release cytokines (messengers
that co-ordinate immune & inflammatory responses)
e.g. TNF, Interleukins, interferon.
Inflammatory response
cytokine release = fever,
chills, nausea, fatigue, headache and hypo-tension.
Classification of allergic reactions.
( Gell PGH, Coombs RRA, eds. Clinical Aspects of Immunology. 1st ed. Oxford, England: Blackwell; 1963.)
Type I: Mast cells bind IgE via receptors. If subsequently an allergen, by binding to two IgE molecules cross-links the Fc(ε) receptors, the mast
cell degranulates and releases mediators that produce allergic reactions. Hypersensitivity usually appears on repeated contact with the
allergen.
Examples of type I allergic reactions
◦Anaphylaxis
◦Atopic asthma
◦Atopic eczema
◦Drug allergy
◦Hay fever
Type II: Antibody (IgG or IgM) is directed against antigen on an individual's own cells, or against foreign antibody, such as that acquired after
blood transfusion. This may lead to cytotoxic action by killer cells, or to lysis mediated by the complement system.
Diseases manifesting type II hypersensitivity
◦Autoimmune hemolytic anemia
◦Goodpasture's syndrome
◦Haemolytic disease of the newborn
◦Myasthenia gravis
◦Pemphigus
Type III: Immune complexes (antigen and usually IgG or IgM) are deposited in the tissue. Complement is activated and polymorphonuclear cells
(to a lesser extent monocytes) are attracted, causing local tissue damage and inflammation. The types of disease encountered are classified into
acute and chronic serum sickness.
Examples of human immune complex diseases
◦Polyarteritis nodosa
◦Post-streptococcal glomerulonephritis
◦Systemic lupus erythematosus
Type IV: T cells, sensitized to antigen, release lymphokines following secondary contact with the antigen. Cytokines induce an inflammatory
response, they also activate and attract macrophages, which release inflammatory mediators. Antibodies produced against fixed cellular or
tissue antigens are usually autoantibodies; less frequently they are produced against extrinsic antigens. Various forms of type IV hypersensitivity
(also called delayed hypersensitivity) are recognized: contact hypersensitivity, tuberculin-type hypersensitivity, and granulomatous
hypersensitivity.
Diseases manifesting type IV granulomatous hypersensitivity
◦Crohn's disease
◦Leprosy
◦Tuberculosis
◦Sarcoidosis
◦Schistosomiasis
Infusion reactions:
Are common.
Most common: Carboplatin (2%),Cetuximab (1520%), Docetaxel (15-33%), Oxaliplatin (5-12%)
Paclitaxel (41%), Rituximab (77% first infusion,
30% fourth infusion, 14% in eight infusion),
Trastuzumab (40% first infusion)
Signs and symptoms IR:
CVS: Chest pain, palpitations, hypotension,
hypertension, tachycardia, bradycardia, arrhythmia,
ischemia, cardiac arrest.
CNS: Throbbing headache, dizziness, confusion,
LOC.
Dermatologic: rash, pruritis, urticaria, flushing, local or
diffuse erythema, conjuntival erythema and tearing,
angioedema.
www.aic.cuhk.edu.hk/web8/Anaphylaxis%20pic.htm
© Janet Fong 2009
Endocrine, rigors, diaphoresis, “fever”.
GI: Nausea, vomiting, metallic taste, diarrhoea,
abdominal cramping and bloating.
GU: Incontinence, uterine cramping or pelvic pain,
renal impairment.
MSK: Arthralgias, myalgias, fatigue, tumour pain,
hypotonia.
Psychiatric: anxiety, sense of impending doom.
Respiratory: cough, wheeze, dyspnea, nasal
congestion: rhinitis, sneezing, hoarseness, tachypnea,
chest tightness, hypoxemia, bronchospasm,
oropharyngeal and laryngeal edema, stridor,
pulmonary infiltrates, cyanosis, acute respiratory
distress syndrome.
Criteria for diagnosing anaphylaxis
•
The
following diagnostic criteria are likely to capture more than 95% of cases of anaphylaxis.
•
Anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled:
•
Because the majority of anaphylactic reactions (>80%) include skin symptoms, it was judged that at
least 80% of anaphylactic reactions should be identified by criterion 1 — even when the allergic status of
the patient and potential cause of the reaction is unknown. However, cutaneous symptoms might be
absent in up to 20% of anaphylactic reactions in children with food or insect sting allergy.
•
Criterion 1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal
tissue, or both (e.g., generalized hives, pruritis or flushing, swollen lips-tongue-uvula)
•
AND AT LEAST ONE OF THE FOLLOWING:
1. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory
function [PEF], hypoxemia)
2. Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g., hypotonia
[collapse], syncope, incontinence)
•
In patients with a known allergic history and possible exposure, criterion 2 should provide ample
evidence that an anaphylactic reaction is occurring.
Criterion 2. Two or more of the following that occur rapidly after exposure to a likely allergen
for that patient (minutes to several hours):
1. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lipstongue-uvula)
2. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF,
hypoxemia)
3. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence)
4. Persistent GI symptoms (e.g., cramping abdominal pain, vomiting)
•
Criterion 3 should identify the rare patients who experience an acute hypotensive episode
after exposure to a known allergen.
•
Criterion 3. Reduced BP after exposure to known allergen for that patient
(minutes to several hours):
• Infants and children: low systolic BP* (age specific) or greater than 30% decrease
in systolic BP
• Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that
person’s baseline
* Low systolic BP for children is defined as <70 mm Hg from 1 month to 1 year; <
(70 mm Hg + [2 X age]) from 1 to 10 years; and <90 mm Hg from 11 to 17
years
Risk factors for
hypersensitivity reactions:
Asthma
Atopic patients
Circulating lymphocyte counts of 25 000m³ or higher
Concurrent autoimmune disease
female
Higher than standard doses
Iodine or seafood allergies
Newly diagnosed or untreated patients.
Older age.
Haematological malignancies e.g.. mantle cell
lymphoma or CLL.
Previous exposure to the drug.
Personal history of drug allergy or previous immediate
reaction to a medication.
Discussion:
Cytokine release syndrome e.g. Monoclonal antibody
binds with antigen (on targeted cell) then chemokines(
specialized cytokines) recruit immune effector cells
(monocytes, macrophages, cytotoxic T-cells, NK
cells)- this causes cell destruction of targeted cell
which causes cytokine release into circulation.
This looks the same as Type I HSR.
Mild to moderate reaction
Reactions related to monoclonal antibodies are
caused by cytokine release. Reactions are usually
mild to moderate, 1st infusion in first couple of hours.
Symptoms subside with subsequent doses ( tumour
burden)
Hypersensitivity reactions (Type I) occurs after
multiple exposures e.g. Carboplatin highest risk cycle
#6 & Oxaliplatin peaks at #5. Pre-medication may not
prevent HRS to platinum agents, unlike Taxanes.
Taxanes: clinically similar reactions to type I but
believed to be anaphylactoid. Almost all reactions are
early and progress rapidly. (1st or 2nd infusion)
Prophylactic management
of reactions:
Rapid recognition of patients at increased risk will
improve outcomes.
HISTORY important - previous allergies.
Note route, rate, form of drug administered.
Patient knowledge - what to look for and report
reactions promptly.
Pre-medication: make sure patient took oral drugs.
IV Access e.g. Monoclonal antibodies: never bolus,
piggy-back into distal port of main IV line, use an
infusion pump. First hour most likely for reactions to
occur.
Regular vitals and patient assessments prior and
during infusions. Delay in recognition of signs of
anaphylaxis can compromise patient’s outcome.
Emergency equipment: nearby and in order.
Emergency staff readily available.
Emergency plan.
Standing orders for emergent meds - do not wait for
clinician order to treat infusion reaction.
Staff must have training in basic life support.
Managing an infusion
reaction:
STOP infusion.
Keep Vascular access NaCl 0.9%
A B C’s
Emergency equipment + Meds
O2 if needed - cardiac or pulmonary problems.
Document time, type of reaction, watch for
progression - can be rapid.
Vital signs repeat 2-5 min intervals.
Recumbent position, elevate legs if low BP.
Observe for skin manifestations: 80% of anaphylactic
reactions has some sort of cutaneous symptoms e.g.
urticaria, angioedema, erythema (locally or diffuse).
Lung exam: wheezing, stridor, dysphonia, cough,
SOB.
Note other symptoms e.g. headache, dizziness,
nausea, vomiting abd pain.
Histamine blocker and consider corticosteroid.
If symptoms resolve (usually within 30 minutes) then
infusion can be restarted at infusion rate and titrated
to tolerance.
Treatment of severe SIR
and anaphylaxis.
NO ABSOLUTE CONTRAINDICATIONS TO
EPINEPHRINE IN SETTING OF ANAPHYLAXIS.
Epinephrine: 0.2 - 0.5 mg IM at 1 to 1000 aqueous
solution. Often under used, under dosed and delayed
in HSR. Repeat every 3-5 minutes prn.
Airway - immediate intubation if indication of
impending airway obstruction. Cricothyrotomy in
difficult intubation.
O2 6-8 l per face mask.
O2 in prolonged reactions, pt’s with myocardial
dysfunction, pt’s who need multiple doses of
epinephrine
Dopamine in hypotension unresponsive to
epinephrine.
Glucagon infusion (1-5mg) over 5 minutes if patient
taking B-adrenergic blocking agent.
Nacl 0.9% 5-10 ml/kg over first 5 minutes (max 50
ml/kg over first 30 minutes). Watch for fluid overload a
CHF or CRF patients. Massive fluid shifts with severe
loss of of IV volume can occur.
H1 and H2 antagonists -given in supportive Mx but
inferior to epinephrine. Do not give alone in treatment
of true anaphylaxis. Diphenhydramine 25-50 mg
slowly IV - oral doses in mild reactions. Benadryl
50mg + Ranitidine 50mg given together are better
than Benadryl alone in anaphylaxis.
Bronchodilators for bronchospasm. Persistent stridor continuous nebulised epinephrine in addition to IV
epinephrine.
Albuterol: bronchospasm resistant to IM Epinephrine.
(2.5-5mg in 3ml saline via nebulizer) Repeat prn.
Continuous pulse oximetry or blood gasses to asses
O therapy.
Corticosteroids do not work in acute Mx of anaphylaxis
but decrease duration of reaction or prevent recurrent
reaction. PO doses if reactions less severe.
Methylprednisolone 125mg IV.
Follow up after stability.
Once stable: Vitals every 15 min. Watch for
recurrence - half life of oncologic agent vs. rescue
meds. Inform emergency personnel.
Observe at least 4 hours after symptom resolution.
Severe reactions: 24 hours close observation.
Recurrent/biphasic reactions occur in 1-20% of
anaphylactic cases. Happens 8-72 hours after
resolution of initial phase - watch 24 hours - consider
comorbid factors, distance to ER. Epipen +
Instructions.
Grading and
documentation.
VERY important- help with decision whether to re
challenge.
Pre-infusion assessment ( Drugs administered, doses
previous infusions of agent and rates.)
Note initial symptoms and course of progression.
Timing of symptom onset.
Time of symptom resolution.
Discharge instructions or transfer to ER.
Re challenge.
Depend on nature of reaction, severity, treatment
goals, comfort level of patient and clinician.
Not to be attempted with true and severe anaphylaxis.
Pre treat antihistamines and steroids, increasing
infusion duration.
Desensitization - varying success.
Case by case basis - depends on treatment goals,
possible alternatives, risk vs. benefit.
Questions?