1. Clare Dikken Macmillan Senior Chemotherapy Nurse Sussex Cancer Network
Neutropenic Sepsis
Clare Dikken
Macmillan Senior Chemotherapy Nurse
Sussex Cancer Network

2. Aims and Objectives
To understand the terminology around neutropenic sepsis (NS)
To identify signs and symptoms associated with NS
To have a better understanding patho-physiology around NS
To articulate how a patient with NS should be managed initially

3. Treatment of cancer Escalating use of cytotoxic therapy
Used on a wide range of tumour sites
Greater use in palliative care
Increase in the number of lines of treatment
Drug developments: monoclonal antibodies, small molecules3
Over the last decade there has been an escalating use of chemotherapy in the treatment of cancer. It is now used in a wide range of tumours; in fact the tumours resistant to chemotherapy are fast disappearing due to the development of new and effective drugs. We have seen an increase in the use of palliative chemotherapy and this has resulted in patients receiving a greater number of lines of chemotherapy as their disease recurs and progresses. Recently there has been an increase in the use of monoclonal antibodies, such as herceptin, and small molecules such as glivec and a number of these are used in conjunction with chemotherapy. We are more successful at treating cancer. However chemotherapy has some negative effects

4. Side effects Chemotherapy affects actively dividing cells
It is not specific to cancer cells
Results in a wide range of side effects
Some can be life threatening
Neutropenic sepsis is a life threatening side effect of chemotherapy
Chemotherapy works by interfering with cell division; it has little effect on mature cells but targets new cells being produced which are undergoing cell division. It is not specific to cancer cells and therefore results in a wide range of adverse effects primarily effecting the hair follicles, any mucous membrane for example the G-I tract, the gonads and the bone marrow. Today we are going to look at neutropenic sepsis which is a life threatening side effect of chemotherapy. Before we look at neutropenic sepsis some clarification of terminology is required

5. The neutrophil and neutropenia
First line defence against bacterial infection
Neutropenia = abnormally low neutrophil count
Associated with an increased risk of potentially life threatening infection
In general this is considered as a neutrophil count of < 1.0
Measured by the absolute neutrophil count
The nadir = 7-14 days post chemo
Neutropenic sepsis
The neutrophil is a granulocyte, produced in the bone marrow and is the body’s first line defence against bacterial infection; neutropenia is an abnormally low neutrophil count and is associated with an increased risk of potentially life threatening infection. Neutropenia is measured by the absolute neutrophil count mild neutropenia is considered to be an absolute neutrophil count of , moderate neutropenia is considered between 0.6-1,0 and severe is below 0.5, although in some respects if a patient has an infection the actual level of neutropenia is not the most important factor anything below 1.0 would be considered significant and the important issue is to treat the infection urgently. The nadir (that is when the lowest point has been reached ) is usually 7-14 days post chemotherapy and the patient is at greatest risk of developing infection. Neutropenic sepsis refers to neutropenia with a related bacteremia/infection –bacterial infection is responsible for up to 60% of cases.

6. Sepsis Sepsis is the clinical syndrome from SIRS
Inflammatory reaction results from infection
Micro-organisms invade the blood and release toxins
Decrease tissue oxygenation is an important physiological factor
Septic shock
Sepsis describes the clinical syndromes resulting from systemic inflammatory response syndrome, it is based on an amplified inflammatory reaction which is initiated by infection and may be come dysregulated

7. SIRS Signs and Symptoms Hypothermia or fever Shaking or chills
Tachycardia
Hypotension
Tachypnoea
Systmeic inflammatory response syndrome is manifested by two or more of the following conditions:
A temperature of 38 degrees in the early phases the patient may actually be hypothermic with a temp of less than 36, patients may experiences spontaneous rigors or feel cold; a tachy >90 bpm, slight hypotension, increased RR >20 PER MIN.
Patients following chemotherapy may not amount a normal immune response and therefore the classic signs may be absent; often their only presenting symptom is feeling unwell

8. Sepsis Sepsis is the clinical syndrome from SIRS
Inflammatory reaction results from infection
Micro-organisms invade the blood and release toxins
Decrease tissue oxygenation is an important physiological factor
Septic shock
Internationally recognised definition for sepsis is the systemic inflammatory reaction induced by microorganisms invading the blood and their toxins being released. An important pathological factor involved in sepsis is decreased tissue oxygenation which contributes to the development of organ failure. Other pathophyiological changes during the development of sepsis include decreased vascular resistance, myeocardial depression, increased vscular permeability and venous pooling. Septic shock can develop if sepsis is not treated speedily or appropriately; septic shock carries a worse prognosis due to volume refractory hypotension and the development of multi-organ failure

9. Localised presence of infection Bacteraemia
Term
Definition
Infection
Localised presence of infection
Bacteraemia
Presence of viable bacteria in the blood
Systemic inflammatory response syndrome (SIRS)
At lease two of the previously mentioned conditions in response to clinical insult
Sepsis
Presence of two or more SIRS criteria with infection
Severe Sepsis
Sepsis with one or more signs of organ dysfunction
Septic Shock
Sepsis with hypotension unresponsive to fluids
Bone et al defined the spectrum of sepsis syndromes in order of severity: infection –presence of localised infection, bacteraemia- presence of baceria in the blood stream, systemic inflammatory response syndrome where at least two signs present e.g. temp and tachycardia – I think I would add here is that any one sign in a chemotherapy patient should be seen as significant as they cannot mount a normal immune response therefore do not wait for other signs to develop., there is then progress to sepsis, severe sepsis when organ failure begins to show and finally septic shock when the blood pressure drops and is unresponsive to fluid therapy, multiple organ failure follows septic shock.
Bone et al 1992

10. Risk factors Breakdown of skin/mucous membrane Age >65 or<1 yr
Neutropenia
Corticosteroids and immunosuppressive therapy
Antibiotic use
Increased risk of
septic shock
Invasive procedures
Malignancy
Hospitalisation
This slide indicates the risk factors for the development of septic shock, it can be seen that cancer patients undergoing chemotherapy have multiple risk factors. It is not difficult to imagine a cancer patients undergoing both chemotherapy and radiotherapy as an inpatient, who receives steroids as part of their treatment, may have a PICC line insitu and who has developed stomatitis as a result of their treatment; they will already have a significant risk of developing septic shock; the development of neutropenia will further add to their risk.
So let’s look at the pathophysiology of septic shock
Splenectomy
Malnutrition
Radiotherapy
Chemotherapy

11. End organ hypo-perfusion, ischemia and cell death
SOURCE OF INFECTION
IMMUNE RESPONSE
EFFECT ON BODY
Vasodilatation,
endothelial inflammation,
increased vascular permeability,
decreased arterial
and venous tone, hypotension, myocardial depression
Recruitment of plasma cells; neutrophils, macrophages, monocytes
Release of endo/exo toxins
Release of cytokines, proand anti-inflammatory response mediators:e.g. interleukins, nitric oxide, complement, platelet activating factors, protaglandins etc
END POINT
If the body if functioning normally a microbial intruder is recognised as foreign by the white cells - neutrophils, macrophages , lymphocytes and antibodies are recruited to the site of infection to prevent host colonisation. Phagocytosis occurs to neutralise the microbes and their toxins. If the invading microbe overcomes the host’s defence system then sepsis and septic shock can ensue.The pathophysiology of sepsis is complicated to say the least. What can be seen to the left of this diagram is the source of infection; the cell wall releases endotoxins or exotoxins this acts as a trigger for the development of cellular and haemodynamic changes such as fever, tachycardia, hypotension, decreased vascular resistance and myocardial depression. The body responds to the release of bacterial toxins by activating the immune system which results in the release of various cytokines and mediators initially there is a pro-inflammatory reaction to ensure short term survival, as infection persists there is an anti-inflammatory reaction, the immuno-suppressive features of an anti-inflammatory reaction can worsen the immuno-suppression already present in the oncology patient so that the patient is overwhelmed by the invading organism. In the early phases of sepsis there is a hyperinflammatory reaction which precipitates physiological changes such as increased vascular permeability, vasodilation, platelet and complement activation which results in defects in coagulation control. In patients following chemotherapy their immune system is not as effective as normal, the body tries to use other methods to regulate the inflammatory response e.g. release of corticosteroids which can result in further immuno suppression. Organ dysfunction is due to the direct effect of the inflammatory mediators and the microbial toxins.
End organ hypo-perfusion, ischemia and cell death

12. Signs and Symptoms
Clinical manifestations of neutropenic sepsis can be divided into early and late signs and symptoms. In the early phase the symptoms can be very vague, patient’s report feeling generally unwell sometimes with flu-like symptoms or nausea and diarrhoea they sometimes complain of feeling cold and shivery, they may have a temperature, although as previously mentioned this is not always the case 10-15% of cases may exhibit hypothermia the patient will often look well, they will feel warm and be well perfused and be alert and orientated, they may have a slight tachycardia and slight hypotension. As sepsis progresses their condition can deteriorate. Deterioration can be very rapid with change in conscious level ranging from apprehension confusion and withdrawal to coma changes to mental state occur because of hypoxia cerebral oedema and metabolic disorders. Hyperthermia usually occurs as well as , marked tachycardia and severe hypotension, skin can become quite mottled looking and they will feel cold and clammy, urine output will drop highlighting the beginning of organ failure. Multiple organ failure can be reversible although it is an important prognostic indicator for septic shock, prolonged failure of three or more organs correlates with a mortality rate of 70% or more..

13. Neutropenic sepsis
Incidence: depends on drug regime, patient and duration of neutropenia
Deaths are still occurring
Preventable deaths
Reason for deaths: delay in getting into acute hospital delay in diagnosis delay to first dose of antibiotic neutropenic policy not being followed
Many health professionals have never received any training or education on neutropenic sepsis
The incidence of neutropenic sepsis varies depending on the drug regime, onf, severity and duration of neutropenia. Sadly deaths are still occurring. Neutropenic sepsis audits in our network reveal some of the problems:
There are delays in getting the patients into hospital – sometimes the patient delays their own referral other times it is because the GP has not referred them urgently or has treated them with oral antibiotics at home, ambulances have sometimes been called but have not brought patients in urgently. Once in secondary care there are delays in diagnosis either with full blood counts not being taken quickly or the processing of results being slow, there are delays to the first dose of intravenous antibiotics and sometimes the wrong antibiotic is given i.e. the neutropenic sepsis policy is not followed. These problems are further compounded by the fact that many health care professionals have never received any education or training in how to recognise and treat neutropenic sepsis

14. What can you do? Recognise at risk patients
Recognise early and late presenting signs and symptoms
Rapid referral to Acute services
Use HEAT as a trigger
So what can you do as health professionals to reduce the risk of neutropenic sepsis deaths?
Fristly recognise patients at risk-

15. Patients at Risk Post chemotherapy 7-14 days Haematology patients
Heavily pre-treated
Prior history of neutropenic sepsis
Breaches to the skin/mucous membranes
Co-morbid conditions e.g.advanced cancer
Poor general health
Elderly
Chemotherapy patients greatest at risk are those who received treatment 7-24 days ago, because their neutrophil count will be at its lowest
Haematology patients have a greater risk because their disease is systemic and therefore the bone marrow is often not functioning normally because it is crowded out with abnormal cells
Patients who have had many lines of chemotherapy or those who have had a prior history of NS will be more at risk.
Intact skin represents an important barrier against invading organisms therefore presence of Indwelling lines such as PICC or STL increase the risk of infection, severe stomatitis has been linked to an increased risk of sepsis
Poor general health or other co-morbid conditions can also increase the risk; hence the elderly are considered more at risk

16. What can you do? Recognise at risk patients
Recognise early and late presenting signs and symptoms
Rapid referral to Acute services
Rapid diagnosis: FBC, blood cultures
Early intervention with appropriate treatment
Monitoring
Reporting
Recognise the early and late signs and symptoms, as already discussed and bare in mind that chemotherapy patients do not mount an normal immune response and therefore any one symptom should be considered significant. If the patient is within the community refer quickly to secondary care so that an urgent blood test can be processed. If time allows blood cultures should be taken and any potential sites for infection should be examined and samples taken. If neutropenic sepsis is diagnosed intravenous antibiotics must be delivered within 1 hour of admission according to the neutropenic sepsis policy, broad spectrum antibiotics are utilised against common gram-negative and gram-positive organisms. Patients must be carefully monitored – this includes temp pulse bp rr urine output and pulseoxymetry –any sign of deterioration should trigger an urgent review by the doctor so that supportive therapies can be introduced early e.g. oxygen therapy, IV fluids. Daily bloods should be taken to monitor neutrohil count.

17. The HEAT Trigger H- History E- Examine A- Action T- Treat
In the Sussex Cancer Network we have launched the HEAT campign. The heat trigger can be used as a reminder History does the patient have a diagnosis of cancer and if so have they received chemotherapy recently? When did they last receive chemotherapy: are they in the at risk period?
Examine – do they have any signs or symptoms e.g. feeling unwell, a temperature. Remember in the early phases the presentation is often vague but deterioration can occur rapidly
Action – an urgent full blood count is required to diagnose neutropenic sepsis. The blood results should be actively chased within 30 minutes to reduce any risk to delays in treatment
Treat with urgent intravenous antibiotics according to the local neutropenic sepsis policy. Continue to monitor the patient for any signs of deterioration, report any deterioration to the doctor

18. Patient on chemotherapy? ACT FAST TO PREVENT DEATH
Take home message
Patient on chemotherapy?
Be suspicious
ACT FAST TO PREVENT DEATH