Over the last decade, major improvements have been made in the treatment of cancer. The NHS Cancer Plan (Department of Health (DH), 2000) has assisted this by providing structure and funding to improve cancer services throughout England.
Chemotherapy, the use of cytotoxic medications, is one of the essential treatments available for cancer. There has been an exponential increase in the use of chemotherapies for a wide range of tumour sites—in fact, the list of chemotherapy resistant cancers is rapidly diminishing due to the development of new and effective drug therapies (Demetri et al, 2002; Goldman, 2003).
Over the years, chemotherapy treatments for advanced metastatic cancer have also improved which is resulting in patients receiving an increasing number of courses of treatment. Adjuvant chemotherapy has become more aggressive, with dose escalation and accelerated regimes being offered in trial settings.
Toxicities and complications from chemotherapy are known to occur and neutropenic sepsis is considered to be one of the biggest concerns as it is a potentially life-threatening side-effect of treatment.
Why does neutropenic sepsis occur?
Chemotherapy works by interfering with cell division—literally, the drugs are cytotoxic, ‘cell-toxic’. Chemotherapy is not specific to cancer cells alone and affects any rapidly reproducing cells; hence it has little effect on mature cells but targets new cells being produced which are undergoing cell division. This therefore results in a wide range of adverse side-effects—primarily affecting the hair follicles, all mucous membranes, the gonads and the bone marrow (Reigle and Denger, 2003).
The neutrophil is a white blood cell or immune system cell and is the body's first line of defence once bacteria have gained access to tissues or the bloodstream. Neutrophils have a very short life span, a few hours to a few days, and the stem cells that produce them in bone marrow must divide very rapidly to maintain circulating levels in the bloodstream (Kindt et al. 2007). Therefore, they are very sensitive to the effects of chemotherapy: it is precisely the type of cell that chemotherapy agents have an iatrogenic effect on.
Neutropenia is a profound loss of these white cells—the normal range for neutrophils is 2.5-7.5 x 109/ litre. Once the neutrophil count drops below 1.0 x 109/ litre, the patient becomes immunocompromized and at risk of serious infection which may be fatal. Moderate neutropenia is considered with counts of less than 1.0 109/ litre, and severe neutropenia occurs once the counts drops below 0.5 109/ litre.
These diagnostic findings clearly require laboratory tests that are not available in the prehospital setting. As we will see, suspicion of the complications of chemotherapy, coupled with a relevant history, are the cornerstones of ambulance personnel responding appropriately in a timely way.
Neutropenia is associated with an increased risk of potentially life-threatening infection because, in their absence, bacteria or other invading organisms can overwhelm the body's other defence mechanisms and cause a rapid and widespread infection. The ‘nadir’ neutrophil count is when it has reached its lowest point—this is when the patient is at greatest risk of developing an infection, most commonly this is approximately 7–14 days after chemotherapy, although there can be some variations.
The pathophysiology of neutropenic sepsis
The pathophysiology of any form of sepsis is complicated, to say the least. Sepsis is a complication of infection and is a leading cause of death and critical illness worldwide—and one that is increasing in its occurrence (Townsend et al, 2005). Typically, any microbial intruder—be it a bacteria, fungus or yeast, for example—is recognized as foreign by the white cells.
If it is a bacterium that is responsible for the infection, which is the case for a significant proportion of patients with neutropenic sepsis, the bacterial cell wall releases endotoxins or exotoxins. This acts as a trigger for the development of cellular and haemodynamic changes such as tachycardia, vasodilation, hypotension and fever (Barrett, 2010).
The immune system response is to produce and release inflammatory mediators (Penack et al, 2006) which recruit neutrophils, macrophages, lymphocytes and antibodies to act locally at the site of infection to prevent microbial colonisation. Phagocytosis, the devouring of the microbes and their toxins, is undertaken by the neutrophils and macrophages and supported by antibody identification of the microbes (Strelkauskas et al. 2010).
This initial pro-inflammatory reaction is to ensure short term survival and promote wound healing. If the infection persists, however, an anti-inflammatory reaction develops in response to the prolonged stresses of the infection. The anti-inflammatory reaction actually has immuno-suppressive features and these can magnify the compromized immune responses already present in the oncology patient due to their low white cell population or ‘neutropenia’, so the patient can become quickly overwhelmed by the invading organism.
In chemotherapy patients, because the functioning of the immune system is compromized, the body tries to use other methods to regulate the inflammatory response such as the release of corticosteroids which can, in turn, result in further immuno-suppression.
If the host's defences are not able to overcome the invading organism then sepsis and septic shock can ensue resulting in organ dysfunction.
Organ dysfunction occurs from the direct effect of the inflammatory mediators themselves and the microbial toxins as well as decreased tissue oxygenation (Barrett, 2010). If the microbe is able to enter the blood stream, it becomes active throughout the body rather than being locally contained, as the inflammatory response aims to achieve. This results in a systemic, rather than
localized, inflammatory reaction to the infection (Llewellyn and Cohen, 2007) which is sepsis. This will manifest as widespread vasodilation requiring a competent compensatory response.
It is important to remember that younger, fitter patients will have a better physiological reserve than older or frailer patients. They will therefore be able to maintain haemodynamic compensation for longer, thus masking the signs of deterioration.
Suspicion of the complications of chemotherapy, coupled with a relevant history, are the cornerstones of ambulance personnel responding appropriately in a timely way.
As sepsis progresses, the patient's condition will deteriorate. Deterioration can be very rapid indeed with change in conscious level ranging from apprehension, confusion and withdrawal to coma.
Changes to mental state occur because of hypoxia due to poor perfusion and also cerebral oedema due to the amplified inflammatory response.
In the late phase of neutropenic sepsis, hyperthermia usually occurs as well as marked tachycardia and severe hypotension, the skin can become quite mottled looking. By this stage, the patient 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 (Yarbo, Frogge and Goodman 2005).
As noted above, sepsis can manifest in varying degrees of severity leading, in the worst instances, to a state of shock and collapse of multiple organ systems. There are terms to define the progression of the illness that aim to define the scale of the damage that sepsis is causing to the patient—the terms used are sepsis, severe sepsis and septic shock which we should consider—they are terms which have remained unclear for some professionals and which have now had definitions agreed upon (Dellinger et al, 2008) (Table 1).
Important points about neutropenic patients
The importance of awareness and suspicion
It is recognized that an understanding of what sepsis is and why it is such a dangerous condition is poor in healthcare professionals generally (Poeze et al, 2004; Robson et al. 2006). This widespread lack of awareness about sepsis alone constitutes a barrier in recognizing when these patients are becoming very unwell and that they require an escalation of interventions to try and avoid the very serious, often fatal, consequences of the condition.
Certainly the recognition and appropriate treatment of neutropenic sepsis is recognized as a national problem and both the recent National Chemotherapy Advisory Group (NCAG) (2009) and the National Confidential Enquiry into Patient Outcome and Deaths (NCEPOD) (2008) reports have helped to highlight this.
It is easy to see how the development of neutropenic sepsis might well remain unsuspected
in a patient with one or two of the above rather general signs or symptoms which might be attributable to any number of causes, particularly if their history of chemotherapy is not brought to light. Also, although there are a variety of signs that the patient is developing sepsis, none of them alone are definitive of a septic patient.
They also do not allow for any sense of the ‘staging’ or progression of the condition, nor of prognosis (Levy et al, 2003); it is difficult to predict how poorly someone is becoming in early sepsis.
It is also important to recognize that the vague ‘fluey’ symptoms with or without a mild pyrexia can easily be interpreted as seasonal flu or pandemic flu (Crawford, 2009) and at certain times of the year this can be an obvious, though misleading, diagnosis.
What is needed is an enhanced ability to suspect sepsis in oncology patients earlier, catch its development and initiate support for the patient as quickly as possible. When a change in temperature or an unexplained tachycardia is noted, for example, in known oncology patients, it is imperative to consider them ‘time-critical’ and to transport them to specialist support in the hospital. The recognition of the relevance of a recent history of chemotherapy by emergency dispatch centre staff is also crucial in terms of the stratification of urgency of the call.
For neutropenic patients with sepsis, mortality rates within the first 48 hours of infectious symptoms have been documented approximately 50% (Reigle and Denger, 2003). Evidence from annual neutropenic sepsis audits reveal that there are still delays to the correct treatment being delivered. Recently, the NCEPOD (2008) report investigated 30 day mortality following chemotherapy. This report highlights that deaths are still occurring from neutropenic sepsis. These are largely preventable deaths. Education and training initiatives have been set up for NHS staff in order to raise awareness of neutropenic sepsis and improve responsiveness of health care professionals to this medical emergency.
The National Institute for Health and Clinical Excellence (NICE) has begun work on a clinical guideline for the prevention and management of neutropenic sepsis in patients with cancer (NICE, 2009); the consultation stages are expected to be finalized by 2012 (NICE, 2010).
The epidemiology of sepsis in general, which is the study of the spread of the condition throughout populations, is helpful to look at because its incidence is so pervasive and yet is underestimated by us as healthcare professionals (Surviving Sepsis Campaign, 2007). Worldwide, there are over 18 million cases of sepsis, in any of its forms, —each year. This is equivalent to the combined populations of Ireland, Norway, Denmark and Finland. Every day, approximately 1400 people die of sepsis (Townsend et al, 2005). In the UK, the estimated annual figure for deaths from sepsis is in the region of 37 000: a higher mortality than lung cancer and also higher than the combined figures for bowel and breast cancer (Daniels, 2007).
It is important to note that neutropenic sepsis can occur in patients that are not receiving chemotherapy, for example those with immune systems that are already compromized such as the elderly and those with concurrent chronic illness or substance dependencies are especially at risk. For those receiving chemotherapy, there are some who carry a greater risk: l Post chemotherapy 7–10 days. This is a classic time for neutropenia following chemotherapy, however delayed neutropenia can occur with some regimes
Current issues in managing neutropenic sepsis
Annual neutropenic sepsis audits are carried out in the national cancer networks. These have revealed some of the problems in managing neutropenic sepsis:
These problems are further compounded by the fact that many health care professionals, particularly working in non-oncology areas, have never received any education or training in how to recognize and treat neutropenic sepsis.
An educational survey conducted within the Sussex Cancer Network (Dikken, 2008) revealed that large numbers of frontline doctors and nurses in A&E and other acute ward areas had never received any training on neutropenic sepsis. These findings may very well be extrapolated to ambulance personnel, too, as there are no national guidelines on the management of neutropenic sepsis.
The HEAT campaign
HEAT is the culmination of an awareness raising campaign by the Sussex Cancer Network for non-specialist staff who come into contact with neutropenic sepsis—this, of course, encompasses ambulance personnel who may be called to patients at home once they are discharged from hospital following their chemotherapy treatment. HEAT is an acronym to summarise four important aspects in assessing and treating a patient with suspected neutropenic sepsis.
HEAT leaflets and posters indicating key signs and symptoms and a flow chart for clinical responses have been distributed to ambulance services as well as GP surgeries and acute NHS Trusts. A patient response card is given to at-risk patients, again detailing signs, symptoms and responses. An educational DVD on neutropenic sepsis funded by McMillan was made by the Sussex Cancer Network. For more information on this, please contact: amanda.lynch@scn.nhs.uk
Conclusion
Chemotherapy is an increasingly used and successful treatment for patients living with cancer. These powerful medications compromise the patient's immune cells and leave them vulnerable to opportunistic infection, especially in the one to two week period post therapy. Unable to mount a strong response to infection, patients often present with non-specific and vague symptoms easily discounted by uninformed clinicians.
The potential for the infective agent to overwhelm the patient and cause septic shock is very real and can happen over a very short period of time— certainly any degree of raised temperature is cause for enormous concern, for example. Sepsis, in any form, is a killer: these patients are least equipped to respond to it. A history of recent chemotherapy is indicative of the need to be highly protective of the patient and to consider them time-critical—alerting the hospital in transit saves the patient valuable time.