Neutropenic Fever

(Sepsis)
Dr. Sumayya Latif
 Definition of Fever in Febrile
Neutropenia
A single oral temp  38.3  C (101  F)

OR

A sustained temperature >38ºC (100.4ºF) on two

occasions separated by one hour
•
 Definition of Neutropenia
Ø ANC  500/mm3

OR
•
Ø  1000/mm3 and predicted nadir of 
500/mm3
•
 Absolute Neutrophil Count
(ANC)

(Total # of WBC) x (% of Neutrophils) x 10 = ANC

•
 Neutropenia
ØNormal ANC: 1500 to 8000 cells/mm³
ØNeutropenia: ANC < 1500 cells / mm3
ØMild Neutropenia: 1000-1500 cells / mm3
ØModerate Neutropenia: 500-999 cells / mm3
ØSevere Neutropenia: < 500 cells / mm3
ØProfound Neutropenia: <100 cells/ mm³
When Does Neutropenia Occur ?

Ø Most chemotherapy agents/protocols cause

neutropenia nadir at 10-14 days

Ø But can see anytime from a few days after

chemotherapy to up to 4-6 weeks later
depending on the agents used
 Risk Factors
The risk factors for developing neutropenic sepsis
include:
• Age (greater than 65 yrs)
• Poor performance status
• Previous episodes of febrile neutropenia
• Combined chemotherapy and radiotherapy
• Poor nutrition
• Advanced disease
• Comorbidities
• Open wounds or active infections
 Presentation
• A raised temperature
• A history of recent cytotoxic chemotherapy
• A low neutrophil cell count
• Signs of sepsis include a temperature of < 36°C or
>38°C, tachycardia, tachypnoea, an altered mental
state, hyperglycemia (in the absence of diabetes)
or a white cell count (WCC) >12 or < 4 × 109/L
 Risk of Complications
• Stratified into 2 groups according to their MASCC
score (Multinational Association for Supportive
Care in Cancer)
• A well, low-risk patient such as with a MASCC score
of ≥ 21:
Early discharge on oral antibiotics
•
 History & Examination
• When last chemo induction?
• Hx of diarrhoea
• Any Hx of hematemesis, hemoptysis, hematuria
• Temperature
• Pulse, B.P., Respiratory rate
• Look for oral thrush
• Sub-conjunctival hemorrhages
 Investigations
ØComplete Blood Count (with Differential)
-White cells, haemoglobin, platelets
ØBiochemistry
-Electrolytes, urea, creatinine, Liver function, Blood sugar
ØCoagulation Screen
Øc-reactive protein (CRP)
ØMicrobiology
-Blood cultures (peripheral and all central line lumens)
-Oral ulcers or sores –send swabs
-Exit site swabs
-Wound swabs
-Urine Cultures (Foley Catheter)
-Stool Cultures and Cl. Diff Toxin/PCR
ØRadiology
-C XR
Management (Neutropenic sepsis)
• For high-risk patients I/V antibiotics within an hours
acc. to local protocol
• For patients without an allergy to penicillin:
Meropenem 1 g I/V TDS
• For patients with a penicillin allergy:
Vancomycin 1 g I/V BD &
Gentamicin 6 mg/kg I/V OD
• For those with specific localizing sign:
Additional antibiotics: Clarithromycin for chest infection
If the fever settles within 48–72 hrs:
• Continue I/V antibiotics for additional 24 hrs
• Oral antibiotics for next 5 days (similar to low risk
protocol)
If the fever persists beyond 48–72 hours:
Advice should be sought from the microbiologist
 Low Risk patients
Low-risk patients who are well ANC > 500/mm:
§ Oral antibiotics according to hospital guidelines
§ Consider for early discharge

Low-risk patients with ANC < 500/mm3:

§ Admit and observe for 24 hrs
§ Start Ciprofloxacin 750 mg BD & Co-amoxiclav 625 mg
TDS
§ If penicillin allergy: Levofloxacin 500 mg BD
§ Discharge with information sheet
 Antifungals
Consider I/V antifungals if:
• Oral thrush is seen on examination
• Non-infectious cause of fever
üAmphotericin B –drug of choice
üFluconazole
üItraconazole
 Use of granulocyte-colony
stimulating factor (G-CSF)
• Not used routinely in patients with neutropenic sepsis
• Considered in those with a high risk of complications Such
patients include those with the following:
• profound neutropenia (ANC < 100/mm3)
• prolonged neutropenia (> 10 days)
• pneumonia
• hypotension
• multiorgan dysfunction
• uncontrolled primary disease
• invasive fungal infections
• age > 65 years
• hospital inpatients at the time of developing the fever
 Prophylaxis of neutropenic
sepsis
For patients on very myelosuppressive regimens, use of G-CSF
from cycle 1 as greater than 20% risk of neutropenic sepsis in
the first cycle
üFilgrastim (Leukokine)
Start one day after cemotherpay, S/C, 300 mcg
üPegfilgrastim (Neulasta)
Just 1 injection needed

• Prophylactic antibiotics
üFlouroquinolones:
Levofloxacin/ ciprofloxacin
Anaphylaxis ass. with
Anti-cancer drugs
 Drugs causing anaphylaxis
Ass particularly with:
• Paclitaxel
• Carboplatin
• Docetaxel
• L-asparaginase
 Presentation
• Agitation
• Hypotension
• Chest tightness
• Bronchospasm
• Laryngeal edema
• Rash
• Angioedema
• Urticaria
• Abdominal pain
• Tongue swelling
 Prevention
Prophylactic steroids and antihistamines reduce the
incidence of hypersensitivity reactions to taxanes and
carboplatin
 Management
• Stop the drug infusion
• Secure ABC
• Give O2
• Lie the patient flat and elevate the legs if hypotensive
• If there is stridor, wheeze, respiratory distress or clinical
signs of shock:
Adrenaline (epinephrine; 1:1000 solution) 0.5 ml I/M and
repeat the dose after 5 minutes if there is no improvement
• Chlorphenamine 10 mg I/V
• For all severe or recurrent reactions: Hydrocortisone
200 mg I/V
• If shock fails to respond to drug measures, give 1–2 L of
I/V crystalloid
Tumor Lysis Syndrome
 Etiology
• Caused by sudden tumour necrosis either due to
treatment or occurring spontaneously
TLS is associated with:
• Chemosensitive, bulky tumours such as high-grade
lymphoma, acute leukaemia and Burkitt lymphoma. It is
rarely seen in low-grade lymphomas or solid tumours
• Pre-existing renal failure---contributory factor
• Patients with lymphoma who have a raised lactate
dehydrogenase (LDH) (> 1500 IU/L) are likely to have
a high tumour burden and are at increased risk
 Presentation
• Non-specific symptoms:
weakness, nausea, vomiting, myalgia and dark urine

• Electrolyte imbalance:
K+ uric acid PO4 Ca++
which can result in arrhythmias, neuromuscular
irritability, seizure and death

• Renal failure: secondary to hyperuricaemia

 Investigations
• Serum electrolytes, phosphate and calcium
• Uric acid
• Acid/base balance
• Renal function
• Monitor ECG
 Prevention
In patients at particular risk:
• Routine acid and electrolyte measurements
• Correct any pre-existing electrolyte abnormalities
• Hydrate the patient
v3 L of normal saline / 24 hours to
vMaintain urine output: > than 100 mL / hour
v+/- Loop diuretic to maintain urate clearance
• Oral sodium bicarbonate:
To alkalise the urine and prevent urate nephropathy in
acidic conditions
• If low-risk:
Allopurinol 100 mg/m2 every 8 hours to prevent
hyperuricaemia
• If high-risk (pre-existing hyperuricemia or renal
impairment, high tumour burden, high sensitivity
to chemotherapy)
Rasburicase 200 μg/kg OD

ØUnfortunately, despite these treatments, 14% of

patients will still develop renal problems
•
 Treatment
• Aggressive hydration
• Therapy for hyperkalaemia:
ØCation exchange resins binding potassium (sodium
polystyrene sulphonate), calcium gluconate
ØSodium bicarbonate to correct acidosis
ØDextrose/insulin injection.
• Therapy for hyperphosphataemia and hypocalcaemia
Oral phosphate binders
ØAluminium hydroxide 30 mL QDS
ØCalcium gluconate (10 mL I/V injection)
• Therapy for hyperuricaemia
ØSodium bicarbonate: to maintain urine pH > 7.0
ØAllopurinol 600–800 mg/day
ØRasburicase 200 μg/kg OD
Ø
• Renal dialysis is required if hyperphosphataemia,
symptomatic hypocalcaemia, persistent
hyperkalaemia, hyperuricaemia and anuria/
oligouria, acidosis or volume overload develops
Extravasation of
chemotherapy
Flare Reaction:
• 3% of cytotoxic agent infusions
• Pruritus and patchy erythema along the course of the vein
• Disappears within 30 minutes without sequelae, does not
indicate extravasation.
Subcutaneous infiltration of irritant drugs:
• Burning pain and sometimes erythema at the injection site,
but without necrosis
• Application of cold or heat and elevation of the affected
extremity usually relieve symptoms without the need for
further therapy
 Extravasation
• Extravasation is leakage of intravenous drugs from a
vein into the surrounding tissue
• Extravasation may present during the
administration of chemotherapy or later
• Severity of an extravasation will depend on:
üInfusion site
üConcentration & volume of the chemotherapy drug
üTreatment given for the extravasation
 Vesicants
• Anthracyclines
• Vinca alkaloids
• Paclitaxel
• Streptozocin
• Mechlorethamine
• Oxaliplatin
• Mitomycin
 Risk factors

● Factors ● Description
Radiotherapeutic Previous local radiotherapy, radiation
recall reactions
Mechanical Needle insertion technique, multiple
venepuncture sites
Vein physiology Fragile, small, sclerosed
Pharmacological Duration and chemotherapy dosage
exposure to tissue
Physiological SVCO, lymphoedema, peripheral
neuropathy, phlebitis
 Presentation
• Pain and swelling at the site of the I/V cannula
More seriously, it can result in:
• Ulceration, necrosis, sloughing of the skin, damage
to underlying structures and permanent disability
 Management
• Stop infusion, disconnect tubing, but leave I/V cannula
in situ
• Aspiration of vesicant
• Administer antidote
• Keep limb elevated---24-48 hrs
• Cold or warm compression as indicated:
üFor 30 to 60 minutes and then 15 minutes off and on for 1
day
üAvoid applying pressure
• Adequate Analgesia
• Estimate the amount of extravasated drug
 Antidotes

● Drug ● Antidote
● Anthracyclines / Mitomycin • Topical DMSO (dimethyl sulfoxide) 50%
• Topical hydrocortisone cream 1%
● Vinca Alkaloids / Platins/ • Infiltrate the site with hyaluronidase (1500 units
Taxanes of hyaluronidase in 1 mL of water for injection)
using 0.2 mL injections over and around the
affected area
• Topical NSAID cream
● Anti-metabolites • Topical hydrocortisone cream
 Surgical debridement
Consultation:
• Lesions that are large
• Lesions on the hand or wrist

Clinical indicators for subsequent surgery:

• Significant worsening of the condition after 48
hours
• Pain at the extravasation site 1 to 2 weeks after the
event
• Painful necrosis—surgical debridement and skin
grafting