Key facts:
Author: Suzanne Hall and Nick Jackson
Top Tip: If you suspect the diagnosis, give antibiotics immediately. Call their specialist ASAP
Key Differential Diagnosis
- Conventional sepsis, in patient having chemotherapy, e.g. non-neutropenic patient with community acquired pneumonia
Key Investigations
- FBC, CRP, U+E, LFT, Bone, Glucose
- ABG or VBG, esp for lactate: if unwell AND platelets known >50x109/L (for arterial)
- Blood culture (peripheral)
- Blood culture (central line); if trained to use the type of line in situ
-
CXR
Key Treatment
Follow local protocol, if available. A commonly used protocol:
- IV TAZOCIN 4.5 g QDS (unless penicillin allergic) + IV GENTAMICIN, 5 mg/kg STAT. Start these drugs immediately
- Do not wait for FBC
- ± IV TEICOPLANIN 600 mg BD if suspect line site infection, e.g. erythematous, tender exit site, rigors on flushing the line
- ± IV METRONIDAZOLE 500mg TDS if abdominal tenderness or marked diarrhoea
- IV FLUIDS; with fluid challenges if hypotensive (systolic BP <100mmHg)
Key Management Decisions
- ITU (fluid management, inotropic support)
- G-CSF
- Removal of tunnelled line
Background
The patient can seem quite well initially, complaining of non-specific symptoms
Introduction
- Significant infections are usually associated with a fever but the classic symptoms of fever and rigors are not always present. The patient can seem quite well initially, and may be asymptomatic
- (Updated November 2011) Patients at risk of neutropenic sepsis, e.g. those on chemotherapy, are asked to check their temperature regularly at home, even if they feel well; then seek medical advice rapidly if unwell, temperature or not. They may therefore present with no symptoms other than a fever. This should NOT reassure you that they are well; they may deteriorate quickly and require urgent intervention
- Whatever the clinical state of the patient, a possible diagnosis of neutropenic sepsis warrants immediate action. If you suspect the diagnosis, give antibiotics immediately after taking blood cultures - ie, if in doubt, treat. Do not wait for FBC
- Ie, if an 'at risk' patient presents with fever, it is better to give an unnecessary dose of antibiotics than allow shock to develop whilst awaiting tests. However, you MUST take blood cultures prior to giving antibiotics
- The most common time for the neutrophil nadir is 10 days following administration of chemotherapy and this is when patients are most at risk
- Treatment should be given within 60 mins of presentation
- Severely ill patients and those on high dose steroids may not mount a fever
- Most patients with prolonged neutropenia will develop mucositis (mouth or anywhere along the GI tract) and this is an important source of bacterial entry to the blood
- Involve the patient's specialist early. Good neutropenic sepsis management requires a combined approach from the ED, acute and specialist physicians
- If a patient is on immunosuppression (eg tacrolimus or ciclosporin, for a patient with a transplant) do NOT stop these drugs without discussion with their specialist
- Prognosis: neutropenic fever in cancer patients carries a mortality rate of 4-30%; 21% have serious medical complications
- The lower the neutrophil count, the steeper the fall or the longer the duration of neutropenia, the higher the risk of infection
- Only 40% of pts will have a positive blood culture
- Mortality correlates with duration and severity of neutropenia, and the time elapsed frompresentation until the first dose of antibiotics is administered
- Its important to record previous episodes of sepsis (especially the organisms cultured, and their antibiotic sensitivities) and treatment given; presence and recent use of indwelling lines; allergies and use of prophylactic G-CSF
NB: patients with dysfunctional neutrophils e.g. in myelodysplasia will also be at risk of 'neutropenic' sepsis, even if the count is normal
Definition
- The presence of symptoms or signs associated with infection in a patient with a neutrophil count of <1.0 x 109/L.
- By definition febrile patients with neutropenia will fulfill SIRS criteria (i.e. fever and low WBC)
Definition of neutropenia
- The normal range for neutrophils is 2.5 - 7.5 x 109/L
- Moderate neutropenia: neutrophil count 0.5 - 1 x 109/L
- Severe neutropenia is a count <0.5 x 109/L
NB: risk of infection increases progressively with declining neutrophil count and is especially marked below 0.1 x 109/L
Epidemiology
- Neutropenic sepsis occurs most commonly and seriously in patients with malignancy who have received chemotherapy. Neutropenia induced by other drugs, either idiosyncratically (e.g. carbimazole) or as an expected effect (e.g. mycophenolate, azathioprione) may also lead to severe sepsis
- Neutropenia induced by autoimmune disease (e.g. rheumatoid arthritis, SLE), viral infection (e.g. HIV) or haematinic deficiency may also predispose to infection. It can be very difficult to tell, in autoimmune disease such as SLE, whether neutropenia (or pancytopenia) is due to the disease or the treatment for the disease (ie immunosupprression), or both. Senior help is required
- Some racial groups have a lower reference range for neutrophils but rarely have neutrophils physiologically <1.0 x109/L
NB: most data has been collected from patients with neutropenia and cancer; this data is extrapolated to patients with neutropenia due to other causes
Site of infection
- Site of infection is not usually obvious; potential sites include chest, Hickman (or other central) line, mouth, perineal area, urine or skin
Common Organisms / Causes
Bacteria (NB: +ve BC in <40%)
- Gram +ve (60%)
- Coagulase negative staphylococci (eg from lines)
- Streptococci (viridans in mucositis, especially if previous exposure to quinolones)
Gram -ve (30%) - Escherichia coli
- Klebsiella
- Pseudomonas aeruginosa
Fungi
- Invasive fungal infections are associated with a high morbidity and mortality rate. They are more prevalent amongst those who have already received broad spectrum antibiotics (because competition by natural bacterial flora has been eradicated), and those undergoing allogeneic stem cell transplantation or treatment for acute leukaemia (these patients will normally be taking antifungal prophylaxis)
- Infections include systemic candidiasis and invasive aspergillosis
- Aspergillosis presents as pyrexia with pulmonary infiltrates and is difficult to treat
Viruses
- These are more usually associated with problems in defects of cellular immune function
- The commonest viruses that cause problems in neutropenic patients are herpes viruses
- Other viruses include respiratory syncytial virus
- It should never be assumed that ‘neutropenic sepsis’ is due to a viral infection until more rapidly fatal bacterial or fungal infections have been excluded
Symptoms
- Duration of fever
- Rigors
- Chest/urinary symptoms
- Rash or skin changes
- Diarrhoea and perianal pain
- Line site pain or discharge
Key questions
- “When did you start feeling unwell or pyrexial?"
- "Do you have a cancer or leukaemia?”
- “Are you on chemotherapy, when did the last course start/finish?; and what is the name of the chemotherapy you had?"
Signs
- Signs of shock
- Calculate your hospital’s ‘early warning score’ (eg MEWS)
- 4 hourly obs, but if BP low (systolic <100mmHg), then repeat every hour
- Possible sites of infection: central and peripheral line sites, intra oral mucositis, dentition), chest, abdomen, perianal region if symptomatic
NB: remember, without neutrophils the body cannot make pus and therefore signs may be atypical or even absent; also, PR is contraindicated (can cause bacteraemia)
Investigation
Take blood cultures BEFORE giving antibiotic treatment. However, antibiotics should only be delayed minimally to take these cultures. 40% do not grow an organism
Blood
- FBC, CRP
- U+E, LFTs, Calcium, Glucose
- Lactate
- Clotting screen (consider measuring fibrinogen if suspecting disseminated intravascular coagulation (DIC))
- Blood cultures BEFORE giving antibiotic treatment. However, antibiotics should only be delayed minimally to take these cultures. Cultures should be taken peripherally and from each lumen of any central/tunnelled lines: label them accordingly. Do not access tunnelled lines unless you have received specific training due to risk of introducing infection.
- The diagnosis of infection may depend on line cultures becoming positive prior to those from peripheral blood. It may be necessary to remove the line based on this information so it is important that sufficient samples are taken and labelled clearly
- ABG if platelets >50x109/L; otherwise venous gas will suffice
Other
- Urinalysis and culture (do not catheterise for sample unless requiring catheter for management of septic shock; risk of introducing infection to urinary tract and causing bacteraemia)
- ECG
- CXR (immediate if any respiratory symptoms or signs; next day if neither of these)
- Stool culture; if having diarrhoea (and request C Diff toxin)
- CT and LP, if meningism. NB CSF should undergo fungal staining for cryptococcus
- Other MB according to clinical picture:
- Line exit site swab if suspicious for infection
- Throat swabs if symptomatic
- Sputum culture if available
- Abdominal x-ray if abdominal pain and diarrhoea (?typhlitis ?C Diff with toxic megacolon), though if these diagnoses are strongly suspected, then CT is better
- Consider sending nasopharyngeal aspirates or dry nasal swabs (according to local protocol) for respiratory virus PCR, especially if T-cell depleted, e.g. treatment with fludarabine (purine analogue used in AML and CLL) or alemtuzumab (Campath, monoclonal antibody used in CLL), or allogeneic haemopoietic stem cell transplant
Key investigation
- BC
Specialist investigations
- Invasive cultures or biopsies (e.g. bronchoscopy, pleural tap)
- Fungal PCR, β-glucan, galactomannan
- Viral cultures or PCR
Differential diagnoses
- Conventional sepsis, in patient having chemotherapy
- Fever secondary to underlying malignancy (diagnosis of exclusion)
Treatment
If lactate >4 mmol/L or systolic BP <90 mmHg, contact ITU immediately. Reverse barrier nursing is required. Consider G-CSF
Treatment (first line)
Drugs
- Antibiotics (NB see local guidelines as policies vary), eg:
- IV TAZOCIN 4.5g QDS + IV GENTAMICIN 5 mg/kg STAT (max dose 400mg). The decision to continue gentamicin (5mg/kg OD) should be made by the patient’s own specialist team. A stat dose of 5mg/kg gentamicin can still be given in renal failure impairment, but levels should be monitored and dose adjusted accordingly if the decision is made to continue treatment. Consider omitting in the elderly (unless clinical signs of shock)
- If previous ESBL producer, use MEROPENEM 1g TDS instead of TAZOCIN (reduce frequency of Meropenem in renal failure). Note: don't forget TAZOCIN is a combination of a penicillin PIPERACILLIN and TAZOBACTAM so alternative antibiotics may be necessary if the patient has a significant penicillin allergy (see below)
- If signs and symptoms of line infection, add IV TEICOPLANIN 600mg 12 hourly for 3 doses followed by once daily dose. If weight >80kg use 800mg. If Staphylococcus aureus is cultured seek advice from local microbiology
- If perineal or abdominal symptoms and signs, add in IV METRONIDAZOLE 400mg TDS. If marked diarrhoea due to C Diff confirmed, treat as per local policy with oral metronidazole or oral vancomycin
- If anaphylactic or accelerated penicillin allergy (see below): IV GENTAMICIN 5 mg/kg OD + IV CIPROFLOXACIN 400 mg BD + IV TEICOPLANIN as above
- If non-severe penicillin allergy (i.e. not anaphylactic or accelerated): IV MEROPENEM and IV GENTAMICIN, doses as above
NB: monotherapy is rarely indicated as the patient may have more than one organism. If the patient has previously grown a resistant organism, this organism must be covered by the initial regimen; however, other organisms must also be covered; if a line with ≥1 lumen is in situ, give the antibiotics on a rotational basis through each lumen (drug administrators must be trained to use the lines)
Other
- Fluids: IV crystalloids should be given in all cases. If there are signs of septic shock (hypotension or serum lactate >4mmol/L), start aggressive fluid challenges aiming for 20ml/kg (e.g. repeated challenges of 500-1000ml) 0.9% SODIUM CHLORIDE. If still shocked, involve ITU and consider central line insertion, aiming for CVP of 8mmHg (remembering to give platelet support if platelets <50 x109/L)
- Aim for urine output >0.5ml/kg/hr or mean arterial pressure (MAP) >65mmHg. NB exercise caution when giving fluid challenges to the elderly and those with pre-existing heart disease
NB: do not take CVP readings from a Hickman line (unreliable); consider Hickman line as source of infection (but do not remove without discussion with specialist team) - OXYGEN, if SpO2 <92%, PaO2<8kPa, or routinely in the presence of septic shock. In patients with chronic obstructive pulmonary disease (COPD), consider early respiratory support if SpO2 <88% (discuss both with the patient’s own haematology/oncology team and with respiratory physicians)
- PLATELET transfusions: in most units, the policy in thrombocytopenic septic patients is to transfuse platelets to maintain platelet count >20 x 109/L (normal threshold, if not bleeding or septic, is 10 x 109/L); Usual dose is ‘one adult therapeutic dose’ (ATD), then recheck counts the next day. Platelet consumption is increased in sepsis, in addition to chemotherapy-induced thrombocytopenia
- RED BLOOD CELLS (RBC) should be transfused to keep haemoglobin (Hb) above 9.0g/dL to enable adequate oxygen delivery to the tissues. A higher target should be adopted in those with ischaemic heart disease. If a central line is present, transfuse if SvcO2 <70%
- FRESH FROZEN PLASMA (FFP), 15ml/kg, (if INR or aPTTR >1.8) and CRYOPRECIPITATE (2 bags = standard adult dose, if fibrinogen <1g/L) may be used to correct abnormal clotting in the presence of sepsis (i.e. disseminated intravascular coagulation (DIC)). This must be discussed with haematology
- Inotropes are indicated in those patients who remain hypotensive despite adequate fluid status (e.g. after fluid challenges) but these should only be given with input from the ITU team, and preferably in ITU
- IV steroids, e.g. HYDROCORTISONE, can be given in severe septic shock but again this should only be done in the ITU environment
- Recombinant human activated Protein C may be used in patients with severe sepsis and high risk of death but should only be given by those with experience, in the ITU environment
- Unless contraindicated (e.g. platelets <50 x 109/L, active bleeding), VTE prophylaxis, e.g. SC ENOXAPARIN 40mg OD, must be given
- Granulocyte colony stimulating factor (G-CSF, e.g. SC FILGRASTIM 300mcg OD) may be given, as per local policy
Procedures
- Reverse barrier nursing, in side room if available
- Urinary catheterisation only if septic shock; catheterisation in neutropenic patients may cause bacteraemia
- Central venous access should be established if inotropic support is required, both for monitoring (central venous pressures (aim 8-12mmHg) and central venous oxygen saturation (aim >70%) and for administration of inotropes
- Removal of Hickman line if septic shock and strong suspicion of line sepsis (e.g. rigors on flushing the line) BUT only on recommendation of specialist. If removed, send line tip immediately to microbiology for culture
Key management decision
- ITU (high or rising early warning scores, especially persistent hypotension despite fluid challenges, are indications to refer urgently to ITU/outreach team)
- G-CSF
- Removal of tunnelled line
- Antibiotic choice in penicillin allergy: (histamine mediated, occurring within 60mins of exposure; urticaria, wheeze, hypotension) or accelerated (1-72 hours post exposure; erythema, pruritis, angioedema, wheeze). These patients should NOT be given PENICILLIN (including tazocin), CEPHALOSPORINS or CARBAPENEMS (e.g. MEROPENEM, IMIPENEM)
NB: GI symptoms alone do not constitute allergy and penicillins/cephalosporins/carbapenems should not be withheld from patients on these grounds. It is generally safe to give, with care, a carbapenem to a patient with penicillin allergy which is not accelerated or anaphylactic
Stop
- Chemotherapy, immunosuppression (after DW specialist)
Treatment (second line)
Full daily examination
- Required to elicit signs as they emerge to help guide therapy and further investigation, especially if fever persists
Drugs (all should be on advice of specialist)
- Change antibiotics based on positive microbiology (if any)
- If fever persists after 48 hours with no positive microbiology, change to second line empirical antibiotics (e.g. to MEROPENEM and TEICOPLANIN as above)
- Antifungal treatment after 96 hours if still febrile despite appropriate antibiotics, and HRCT suggestive of Aspergillosis e.g. liposomal AMPHOTERICIN B 3mg/kg OD iv (a test dose e.g. 1mg over 10mins should be given first)
- (Updated March 2011) G-CSF is not usually indicated in treatment of neutropenic sepsis itself, but can be given if very unwell and a long delay expected before neutrophil recovery. Some physicians give G-CSF if there is fungal infection, or localized bacterial abscess.
Investigations (if fever persists >48 hours): - Repeat blood cultures (up to total 3 sets per episode), best taken at time of high fever
- High resolution CT (HRCT) chest to look for fungal infection (1mm slices at 1cm intervals)
- Consider bronchoscopy with bronchoalveolar lavage (BAL) for fungal infection
- Consider virus (e.g. CMV PCR (EDTA sample)), TB, or other opportunistic infection (e.g. Pneumocystis jirovecii pneumonia)
Prescribing issues
- IV antibiotics are not the only treatment; consider the other components of a severe sepsis pathway
- Arrange for subsequent gentamicin and vancomycin levels to be taken as appropriate
- Most patients are admitted and treated for 5-7 days or until neutrophil count improves, or the fever settles
- They may sometimes be converted to oral therapy once they are apyrexial for >48 hours and treatment continued at home
- Consider stopping antibiotic treatment in patients who have been afebrile for 48 hours, whose microbiology has remained negative, and in whom the suspicion of bacterial infection is low (specialist’s decision)
Prescribing issues
- IV antibiotics are not the only treatment; consider the other components of a severe sepsis pathway
- Arrange for subsequent gentamicin and vancomycin levels to be taken as appropriate
- Most patients are admitted and treated for 5-7 days or until neutrophil count improves, or the fever settles
- They may sometimes be converted to oral therapy once they are apyrexial for >48 hours and treatment continued at home
- Consider stopping antibiotic treatment in patients who have been afebrile for 48 hours, whose microbiology has remained negative, and in whom the suspicion of bacterial infection is low (specialist’s decision)
Admit?
- Always
Bed plan
- Ideally should be admitted directly from the ED to oncology or haematology (or other 'base' ward)
- ± ITU
Referrals
Medical
- Oncology or haematology (or other relevant specialist, e.g. renal, rheumatology)
- Microbiology
- ± ITU
Other
- Chemotherapy/haematology/oncology nurse specialist
The Rest
Any sign of severe sepsis should be considered a medical emergency. Call for senior help
Complications (and signs of severity)
- Acute Respiratory Distress Syndrome (ARDS) - commonly associated with viridans group streptococci (VGC)
- Disseminated intravascular coagulation (DIC)
- Multiple organ failure
- Of neutropenic sepsis protocol: antibiotics (eg C Diff)
- Failure to respond to antibiotics (see below)
- Platelet requirements increase during sepsis
Note: often also thrombocytopenic or pancytopenic
Prognosis
- Neutropenic fever in cancer patients carries a mortality rate of 4-30%; 21% have serious medical complications
- Poor prognosis is associated with
-haematological malignancy
-advanced age
-causative organism
Failure to respond to AB
- Wrong microbiological diagnosis (e.g. fungal or viral infection)
- Resistant organism, failure to cover previous organisms isolated
- Inadequate dosage (or drug not available within appropriate time frame etc)
- Foreign body (e.g. line)
- Infection at sites poorly penetrated by antibiotics, e.g. abdominal collection
- Fever due to haematological disease (diagnosis of exclusion)
- Drug fever
- Graft-versus-Host disease (allogeneic stem cell transplant patients)
- Relapse of underlying condition
Follow-up
- Oncology/haematology (or other specialist team) within 1 week
Risk stratification
2° Prevention + Health promotion
- Patients at risk of neutropenic sepsis are asked to check their temperature regularly at home, even if they feel well; then seek medical advice rapidly, if unwell (temperature or not)
- Wash perineum after defaecation
- Chlorhexidine mouth washes
- Consider secondary prophylaxis with G-CSF (specialist decision)
- Reinforce neutropenic advice:
- Use moisturiser to prevent breaks in the skin
- Wash hands regularly, especially before eating and after using the toilet
- Avoid crowded places, e.g. buses, cinemas
- Avoid contact with animal excrement
- Avoid undercooked food, or food that has been left on warmers e.g. buffet
- Avoid cream, ice cream, soft or blue cheese, live yoghurt, products containing raw egg, shellfish, raw fish, uncooked vegetables, unpeeled fruit and ground pepper (contains Aspergillus spores)
- Use soft toothbrush and avoid floss
Don't forget
- Give IV antibiotics immediately (after BC)
- Do not wait for FBC
- Involve patient's specialist ASAP
- Only 40% of pts will have a positive blood culture
- If fail to respond to antibiotics by 48 hrs, consider possible reasons (above)
- TAZOCIN is a combination of a penicillin PIPERACILLIN and TAZOBACTAM (think about penicillin allergy)
- Treat until fever resolved >48 hours AND neutrophils recovered
Red flags
- Signs of severe sepsis
- Previous infection with resistant organism
- Not better after 48h of IV antibiotics
