MANAGEMENT OF THE NEUTROPENIC PATIENT

 BASILDON AND THURROCK HOSPITAL GUIDELINES (revised Feb 2001)

INTRODUCTION: The following guidelines apply to all adult haematology patients who are neutropenic (absolute neutrophil count <1.0 x 10⁹/l) in Basildon + Thurrock Hospitals NHS Trust.  Neutropenic patients are uniquely susceptible to infection, principally arising from endogenous spread from the mouth, colon and skin.  The lack of neutrophils can results in a rapid deterioration to septicaemia, shock and death (within hours).  In addition, there may be little manifestation of septicaemia or infection, as the lack of neutrophils will result in a failure to localize the infection and the usual signs of inflammation will be absent.  NORMALLY THE ONLY SIGN OF SEPSIS IS AN EXPLAINED PYREXIA.  (Pyrexia is defined as an oral temperature >38°C sustained for one hour or any temperature of >=38.5°C).  Occasionally, septic neutropenic patients will not even be pyrexial (for example, sepsis may be masked by steroid therapy) and careful assessment of all symptoms and signs (eg unexplained cough or abdominal pain) must be made.  It is important to adhere to reverse barrier techniques (ie wearing of plastic aprons and hand-washing before and after coming into personal contact) when assessing these patients.  Patients should not be exposed to large numbers of visitors unnecessarily, they should be advised to avoid uncooked or inadequately cooked food and should not receive fresh flowers in hospital.  Because of the increased risk of infection and bleeding, invasive procedures such as arterial sampling, endoscopy, rectal examination and central line insertion should be considered with great care in these patients and should be discussed with the consultant haematologist beforehand.

MEDICAL MANAGEMENT OF A FEBRILE EPISODE:

It is most important to realise that neutropenic patients with a new pyrexial episode must be treated as a medical emergency as they may rapidly deteriorate.  You must respond immediately, quickly assess the patient, take the essential cultures (blood cultures from peripheral veins and central lines as a minimum) and start IV fluids and antibiotics – all within two hours.  The following is a more details guide – but remember that it is only a guide and you must use your clinical judgement!

1. ONCE CALLED TO A FEBRILE NEUTROPENIC PATIENT, YOU MUST RESPOND BY SEEING THE PATIENT YOURSELF IMMEDIATELY.  THIS IS A MEDICAL EMERGENCY.

2.   RELEVANT HISTORY: CONSIDER THE POSSIBLE CAUSES FOR PYREXIA: 

a)SEPSIS: ie cough, abdominal pain, pain around Hickman line, mouth ulceration, perianal pain, diarrhoea, dysphagia is often a sign of candida or Herpes oesophagitis.

 b) BLOOD PRODUCT TRANSFUSION: ie timing of pyrexia related to transfusion of blood product.  Transfusion associated itch/urticarial

c)  DRUG SENSITIVITY: Possible agents include antibiotics, Allopurinol or some cytotoxics eg Cytosine or Bleomycin.  Ask about itch or rash.

d)  VIRAL ILLNESS: History of nasal congestion, myalgia etc.  Remember that Herpes simplex in the mouth is a treatable common cause of pyrexia.

e)   PERSISTENT MALIGNANT DISEASE.

            a) PULSE/BP/URINARY OUTPUT: A slight fall in blood pressure may be the only              indications of incipient septic shock which usually indicates gram negative bacterial   infection.  If shock has already supervened, then see relevant section below.

b) RESPIRATORY SYSTEM.

c) CVS: new murmurs.

d) MOUTH & GI SYSTEM: Oral candidiasis or ulceration, abdominal tenderness, perianal inflammation or abscess, nature of diarrhoea (rectal examination is not recommended because if risks of introducing infection).

e) HICKMAN LINE AND PERIPHERAL LINES: Inspect for evidence of inflammation or tenderness.

f)  SKIN: Allergic rash, boils, septic emboli (often caused by Candida or Pseudomonas sp).

g) OTHER AS INDICATED.

4.  INVESTIGATIONS

a)  BLOOD CULTURES: This is MANDATORY (unless already sent within the previous 24 hours).  Sets of cultures must be taken from a peripheral vein and from each lumen of any central of Hickman lines.

b) FBC and U&E, CREATININE and CRP: (unless results available from previous 24 hours).

c) CHEST X-RAY: Urgent if new chest signs are present, otherwise CXR can wait till next working day.

d)  MSU, THROAT AND NASAL SWABS: (unless previously sent).

e)  FAECES FOR C&S, CANDIDA AND CLOSTRIDIA TOXIN: if diarrhoea is present.

5. MANAGEMENT OF PATIENT: GENERAL MEASURES

a) Reassure the patient.

b)  Establish high fluid intake 3-4 1/24 hours assuming normal urinary output.

c)  Treat shock if present.  Normally mild to moderate hypotension responds to infusion of crystalloids or synthetic colloid solutions.  If a systolic BP <90 mmHg persists, then proceed to Dopamine (low dose) and Dobutamine infusions as per BNF.

d) Symptoms related to pyrexia should be managed by tepid sponging and fanning.  Paracetamol is not desirable as it may mask response to antibiotics.

6. CHOICE OF ANTIBIOTICS

In many cases, there may be several explanations for unexplained pyrexia.  IF IN DOUBT, ASSUME SEPSIS IS THE CAUSE OF THE FEVER.  (Better safe than sorry).  The organisms most likely to cause septic shock are the gram negative bacteria and of these, Pseudomonas sp. are the most feared.  It has been demonstrated in many prospective clinical trials that the early empirical use of intravenous antibiotics with activity against gram negative bacteria and Pseudomonas in particular, will result in fewer episodes of septic shock and mortality.  The time delay between the onset of fever and the first injection of antibiotic should always be less than two hours.  Initial choice of antibiotics in this hospital for the average sized adult:

1st Line:            Ofloxacin 200 mg bd iv.

2nd Line:            Imipenem 500mg qid iv.

In addition to the above broad spectrum antibiotics, other antibiotics should be added for the following indications:

             Gentamicin IV (usually added if hypotension/shock supervenes)

             Teicoplanin (400mg  bd iv loading on first day; followed by 400mg od) or

            Vancomycin IV (usually 1g bd via a central line) if there is evidence if Hickman line or             skin/gram positive sepsis.

             Metronidazole IV (usually 500mg tid) if there is evidence of mouth or anal or antral sinus             sepsis.

             Acyclovir IV (usually 250mg tid) if there is evidence of Herpes simplex in the mouth,               oesophagus or genitalia.

             Fluconazole PO or IV (100-200mg od) if there is evidence of Candida in the mouth,              oesophagus or genitalia.

            Amphotericin IV (central line) if there is evidence for Aspergillus infection ie Aspergilloma on CXR or sinus X-ray.  Amphotericin should be added with caution as this drug is often poorly tolerated and is nephrotoxic (regular monitoring of serum electrolytes and creatinine mandatory).  (Amiloride 10mg od should be started at the same time as iv amphotericin to negate the potassium losing effect of the latter).  In a sick patient, one should aim to have administered 0.5 to 1.0 mg/kg of amphotericin IV by 24 hours from initiation.  The higher dose is required if Aspergillus infection is being seriously considered.  Usually a test dose of 5 mg amphotericin in 100 ml Dextrose 5% over 1 hour is given.  If well tolerated, 0.25mg/kg in 250ml Dextrose 5% is administered over 2 hours and the remaining dose (0.75 mg/kg in 500ml Dextrose 5%) is administered over four hours after a gap of about 8/9 hours.  Further infusions (1mg/kg in 500ml Dextrose 5%) are given once daily over 6 hours.  IV Pethidine and po Paracetamol may be necessary to control rigors caused by amphotericin.  The addition of flucytosine IV, or a change to liposomal amphotericin should be considered in patients not responding to proven fungal infections.

If the patients has already been established on broad spectrum antibiotics for more than 24 hours and remains pyrexial and unwell, with no focus for sepsis identified, then consideration of addition of antibiotics should be made.  Usually Teicoplanin or Vancomycin IV is added empirically after 24-48 hours and IV Amphotericin is added after 72 hours of unexplained non-responding pyrexia.  Always consult the Haematologist on-call for advice, unless an antibiotic ‘game plan’ has already been devised and written in the medical notes.  You are expected to call if there is any doubt.

Consultants:            Dr Paul Cervi & Dr Eric Watts 

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