Oncology & Palliative Care
A 51 year old female patient, with known breast cancer, presents to ED unwell with pyrexia and rigors. She is currently receiving a course of chemotherapy. Her observations are: temp 38.9°C, HR 98 bpm, BP 110/70 mmHg, RR 16 breaths/min, sats 98% OA. Her blood results are:
- Hb 87 g/L
- Plts 65 x 10⁹/L
- WCC 1.2 x 10⁹/L
- Lymphocytes 0.2 x 10⁹/L
- Neutrophils 0.4 x 10⁹/L
- Monocytes 0.2 x 10⁹/L
Which of the following is the most appropriate antibiotic to start in this patient?
Answer:
Treat suspected neutropenic sepsis as an acute medical emergency and offer empiric antibiotic therapy immediately. Offer beta lactam monotherapy with piperacillin with tazobactam as initial empiric antibiotic therapy to patients with suspected neutropenic sepsis who need intravenous treatment unless there are patient-specific or local microbiological contraindications.Sepsis
Infectious Diseases / Resuscitation
Last Updated: 13th February 2024
Risk factors
Risk factors for sepsis include:
- Infants (under one year of age) and older people (over 75 years of age)
- People who are very frail
- People who are immunocompromised due to a comorbid condition (such as diabetes mellitus, HIV, cirrhosis, sickle cell disease, or asplenia)
- People who are immunosuppressed due to drug treatment (such as anticancer treatment, oral corticosteroids, or other immunosuppressive drugs)
- People who have had trauma, surgery, or other invasive procedures in the past six weeks
- People with any breach of skin integrity (for example cuts, burns, blisters, or skin infections)
- People who misuse intravenous drugs or alcohol
- People with indwelling lines or catheters
- Women who are pregnant, are post-partum, or have had a termination of pregnancy or miscarriage in the past six weeks
Original 'Surviving Sepsis Campaign' definitions
Sepsis is defined as presumed or confirmed infection with features of systemic inflammatory response syndrome (SIRS).
SIRS in an adult is the presence of two or more of the following features:
- Temperature of greater than 38°C or less than 36°C
- Heart rate greater than 90 beats per minute
- Respiratory rate greater than 20 breaths per minute
- New-onset confusion or drowsiness
- White blood cell count greater than 12 x 10⁹/L or less than 4.0 x 10⁹/L
- Blood glucose greater than 7.7 mmol/L (in a non-diabetic person)
Severe sepsis is the presence of presumed or confirmed infection, SIRS, and evidence of end-organ dysfunction.
Septic shock is the presence of presumed or confirmed infection, SIRS, and evidence of hypoperfusion (such as persistent hypotension despite fluid bolus, increased lactate, oliguria, and prolonged capillary refill)
New Sepsis-3 definitions
The original definitions of sepsis and related conditions (SIRS, severe sepsis and septic shock) are now more than 20 years old. A new definition of sepsis, known as Sepsis-3, was published in 2016. In Sepsis-3, ‘severe sepsis’ no longer exists as a concept, there is simply ‘sepsis’ and ‘septic shock’.
- Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection.
- Septic shock is a subset of sepsis, which describes circulatory, cellular, and metabolic abnormalities which are associated with a greater risk of mortality than sepsis alone. In a hospital setting, septic shock is defined as sepsis with persisting hypotension despite fluid correction and inotropes (requiring vasopressors to maintain a mean arterial pressure [MAP] of 65 mmHg or more), and hyperlactataemia with a serum lactate level of greater than 2 mmol/L, where MAP is the driving pressure of tissue perfusion.
Organ dysfunction can be identified using an acute change in the Sequential Organ Failure Assessment (SOFA) score ≥2 points as a result of the infection. The problem with the SOFA score is that it does rely on some laboratory data, which makes it difficult to use outside hospital or at the ‘front door’. A clinical model was thus developed, termed the qSOFA (quick SOFA), based only on respiratory rate, systolic blood pressure and altered mental state. One point is scored for (1) a RR ≥22 breaths per minute, (2) a systolic BP of ≤100 mm Hg and (3) altered mental state (GCS<15). A score of ≥2 in a patient with infection is associated with an increased risk of death.
Clinical features
Be aware that sepsis can be challenging to identify, as the clinical presentation is variable depending on the underlying cause and the person's age and comorbidities.
- Suspect sepsis in any person presenting with:
- Symptoms or signs indicating possible infection causing significant illness or deterioration. This includes people who are deteriorating unexpectedly, or failing to improve as expected.
- One or more risk factor(s) for sepsis, and who looks unwell.
- Concern from a relative or carer that there is a change in appearance or behaviour.
- Be aware that:
- People with sepsis may present with non-specific, non-localised clinical features, for example general malaise, agitation, or behavioural change.
- People with sepsis may not present with a high temperature, and may present with hypothermia.
- Sepsis may result from infection with almost any pathogen, therefore it may present with a wide range of clinical features depending on the site of infection and host response.
- Suspect a diagnosis of neutropenic sepsis in any person with known neutropenia or with risk factors for neutropenia (such as undergoing chemotherapy), and/or with risk factors for neutropenic sepsis who become unwell.
Differential diagnosis
Alternative conditions which may present similarly to sepsis include:
- Pulmonary embolism
- Acute myocardial infarction
- Heart failure
- Acute delirium
- Acute pancreatitis
- Diabetic ketoacidosis
- Adrenal insufficiency
- Acute blood loss and hypovolaemia
- Trauma and tissue injury, burns
- Drug reactions, including neuroleptic malignant syndrome
- Intoxication and poisoning, including carbon monoxide poisoning
Management principles
Specialist assessment and management in an acute hospital setting involves implementation of the UK Sepsis Trust 'Sepsis Six' bundle within the first hour following recognition of sepsis.
- Oxygen therapy (if required):
- Give oxygen to achieve a target saturation of 94−98% for adult patients or 88−92% for those at risk of hypercapnic respiratory failure.
- Oxygen should be given to children with suspected sepsis who have signs of shock or oxygen saturation (SpO2) of less than 92% when breathing air. Treatment with oxygen should also be considered for children with an SpO2 of greater than 92%, as clinically indicated.
- Venous blood tests (if required):
- Blood gas including glucose and lactate measurement — hypoglycaemia may result from depleted glycogen stores; hyperglycaemia may result from the stress response to sepsis; hyperlactataemia is a non-specific indicator of cellular or metabolic stress and is a marker of illness severity, with a higher level predictive of higher mortality rates.
- Blood culture — ideally done before antibiotic administration, to identify a primary bacteraemia.
- Full blood count — white cell count may be high or low; thrombocytopenia may indicate disseminated intravascular coagulation (DIC).
- C-reactive protein (CRP) — may indicate infection and/or inflammation.
- Creatinine, urea and electrolytes — may indicate dehydration and/or acute kidney injury.
- Liver function tests — increased bilirubin or alanine aminotransferase (ALT) levels may indicate cholestasis or other liver dysfunction.
- Clotting screen — if abnormal may indicate coagulopathy/DIC.
- Antibiotic treatment (if required):
- For patients in hospital who have suspected infections, take microbiological samples before prescribing an antimicrobial and review the prescription when the results are available. For people with suspected sepsis take blood cultures before antibiotics are given.
- If meningococcal disease is specifically suspected (fever and purpuric rash) give appropriate doses of parenteral benzylpenicillin in community settings and intravenous ceftriaxone in hospital settings.
- For people aged 18 years and over who need an empirical intravenous antimicrobial for a suspected infection but who have no confirmed diagnosis, use an intravenous antimicrobial from the agreed local formulary and in line with local (where available) or national guidelines.
- For people aged up to 17 years with suspected community acquired sepsis of any cause give ceftriaxone 80 mg/kg once a day with a maximum dose of 4 g daily at any age.
- For children younger than 3 months, give an additional antibiotic active against listeria (for example, ampicillin or amoxicillin).
- Intravenous fluids (if required):
- If patients over 16 years need intravenous fluid resuscitation, use crystalloids that contain sodium in the range 130–154 mmol/litre with a bolus of 500 ml over less than 15 minutes.
- If children and young people up to 16 years need intravenous fluid resuscitation, use glucose-free crystalloids that contain sodium in the range 130–154 mmol/litre, with a 10 ml/kg bolus.
- Reassess the patient after completion of the intravenous fluid bolus, and if no improvement give a second bolus. If there is no improvement after a second bolus alert a consultant to attend.
- Check serial lactate measurement.
- Check urine output, monitor fluid balance hourly and monitor the person's clinical condition. This may include using a track-and-trigger scoring system or early warning score to identify people at risk of deterioration.
Transfer to critical care may be needed to assess the need for central venous access and initiation of inotropes (increase cardiac output by increasing cardiac contractility) or vasopressors (increase blood pressure by increasing peripheral vascular resistance), to maintain perfusion pressure.
Finding source of infection:
- Carry out a thorough clinical examination to look for sources of infection, including sources that might need surgical drainage, as part of the initial assessment.
- Tailor investigations of the sources of infection to the person's clinical history and findings on examination. Consider urine analysis and chest X-ray to identify the source of infection in all people with suspected sepsis.
- Consider imaging of the abdomen and pelvis if no likely source of infection is identified after clinical examination and initial tests. Involve the adult or paediatric surgical and gynaecological teams early on if intra-abdominal or pelvic infection is suspected in case surgical treatment is needed.
- Consider lumbar puncture indications and contraindications.
- Source control to eliminate a focus of infection may be possible, such as abscess drainage, debridement of infected tissue, removal of infected devices or foreign bodies, or surgery.
Risk stratification
Use a sepsis risk stratification tool to assess the risk of clinical deterioration including severe illness or death from sepsis, depending on the person's age, risk factors, and clinical features of concern.
Risk stratification tool for children aged under 5 years with suspected sepsis
Risk stratification tool for children aged 5–11 years with suspected sepsis
For patients who have suspected sepsis and 1 or more high risk criteria:
- Arrange for immediate review by the senior clinical decision maker to assess the person and think about alternative diagnoses to sepsis.
- Carry out venous blood tests.
- Give a broad-spectrum antimicrobial at the maximum recommended dose without delay (within 1 hour of identifying that they meet any high risk criteria in an acute hospital setting).
- Discuss with a consultant.
- Intravenous fluid management:
- If lactate over 4 mmol/litre, or systolic blood pressure less than 90 mmHg: Give intravenous fluid bolus without delay (within 1 hour of identifying that they meet any high risk criteria in an acute hospital setting) AND in children < 12 years refer to critical care for review of central access and initiation of inotropes or vasopressors.
- If lactate between 2 and 4 mmol/litre: Give intravenous fluid bolus without delay (within 1 hour of identifying that they meet any high risk criteria in an acute hospital setting).
- If lactate below 2 mmol/litre: Consider giving intravenous fluid bolus.
- Monitor people with suspected sepsis who meet any high risk criteria continuously, or a minimum of once every 30 minutes depending on setting. Physiological track and trigger systems should be used to monitor all patients in acute hospital settings. Monitor the mental state of patients with suspected sepsis.
- Alert a consultant to attend in person if a person fails to respond within 1 hour of initial antibiotic and/or intravenous fluid resuscitation.
- Failure to respond in patients aged 12 years and older is indicated by any of:
- Systolic blood pressure persistently below 90 mmHg
- Reduced level of consciousness despite resuscitation
- Respiratory rate over 25 breaths per minute or a new need for mechanical ventilation
- Lactate not reduced by more than 20% of initial value within 1 hour
- Failure to respond in patients under 12 years is indicated by:
- Reduced level of consciousness despite resuscitation
- Heart rate or respiratory rate fulfil high risk criteria
- Lactate remains over 2 mmol/litre after 1 hour
- Failure to respond in patients aged 12 years and older is indicated by any of:
For patients with suspected sepsis and 2 or more moderate to high risk criteria:
- Carry out venous blood tests.
- Arrange for a clinician to review the person's condition and venous lactate results within 1 hour of meeting criteria in an acute hospital setting.
- If lactate over 2 mmol/litre or evidence of acute kidney injury: Treat as high risk and treat as above.
- If lactate less than 2 mmol/litre, no evidence of acute kidney injury and in whom a definitive condition cannot be identified: Repeat structured assessment at least hourly and ensure review by a senior clinical decision maker within 3 hours of meeting 2 or more moderate to high risk criteria in an acute hospital setting for consideration of antibiotics.
- If lactate less than 2 mmol/litre, no evidence of acute kidney injury and in whom a definitive condition or infection can be identified and treated: Manage the definitive condition and if appropriate, discharge with information depending on the setting.
For patients with suspected sepsis who meet only 1 moderate to high risk criterion:
- Arrange clinician review within 1 hour of meeting criterion for clinical assessment in an acute hospital setting and perform blood tests if indicated.
- If a definitive condition can be identified and treated: Manage the definitive condition and if appropriate, discharge with information depending on setting.
- If a definitive condition cannot be identified: Repeat structured assessment at least hourly and ensure review by a senior clinical decision maker within 3 hours of meeting moderate to high criterion in an acute hospital setting for consideration of antibiotics.
Arrange clinical assessment of patients who have suspected sepsis and no high risk or moderate to high risk criteria and manage according to clinical judgement.
Complications
Possible complications of sepsis include:
- Death
- Sepsis is the leading cause of avoidable death from infection, and 25–30% of people with sepsis die from the condition.
- Organ failure
- This may be multi-system and includes acute kidney injury (AKI), cholestasis, heart failure, acute respiratory distress syndrome (ARDS) or acute lung injury, and bone marrow suppression.
- Recurrent and secondary infection
- People who survive early sepsis may develop hospital-acquired infections with atypical organisms, and may have reactivation of latent viruses, due to an impaired ability to mount an appropriate immune response to superadded infections.
- People with neutropenic sepsis may develop opportunistic or hospital-acquired infections with atypical organisms such as Legionella sp and Mycoplasma sp, and may have reactivation of latent viruses, due to an impaired ability to mount an appropriate immune response. People receiving chemotherapy for acute myeloid leukaemia and undergoing haematopoietic stem cell transplantation are at risk of prolonged neutropenia and invasive fungal or atypical infections, such as systemic candidiasis and aspergillosis.
- Malnutrition
- This may be partly due to impaired intestinal barrier function.
- Coagulopathy
- This may cause thromboembolism or disseminated intravascular coagulation (DIC) characterised by microthrombosis and haemorrhage. Microvascular changes and DIC can result in loss of digits or limbs.
- Physical impairments
- A reduced quality of life may result from chronic pain and fatigue.
- Encephalopathy and delirium
- This may lead to reduced mobility and neuromuscular weakness, as well as longer lasting neurocognitive deficits such as memory problems and reduced concentration.
- Psychological sequelae
- These may include anxiety about recurrent infection and sepsis, post-traumatic stress disorder, loss of confidence and self-esteem.
- Neutropenic enterocolitis
- An acute life-threatening condition characterised by transmural inflammation of the caecum, often with involvement of the ascending colon and ileum, which is then vulnerable to bacterial intramural invasion. It typically presents with abdominal pain, diarrhoea, and fever.
Neutropenic sepsis
Definition
Neutropenic sepsis is a potentially life-threatening complication of anticancer and other immunosuppressive drug treatment. It is defined as a temperature of greater than 38°C or any symptoms and/or signs of sepsis, in a person with an absolute neutrophil count of 0.5 x 10⁹/L or lower, according to the NICE guidelines.
Neutropenic sepsis is commonly caused by bacterial infection with Gram-positive pathogens such as Staphylococcus aureus, Enterococcus sp, Streptococcus pneumoniae and S. pyogenes, and less commonly Gram-negative pathogens such as Escherichia coli, Klebsiella sp, Enterobacter sp, and Pseudomonas aeruginosa. Fungal infection with Candida sp or Aspergillus sp may be involved, especially if the person has had prolonged periods of neutropenia.
Diagnosis
People who are neutropenic and have an infection are at increased risk of sepsis compared with immunocompetent people, as their ability to respond to infection is compromised. Be aware that sepsis can be challenging to identify in people who are neutropenic, as there may be minimal or atypical symptoms and/or signs of infection or sepsis.
Suspect a diagnosis of neutropenic sepsis in any person with known neutropenia or with risk factors for neutropenia (such as undergoing chemotherapy), and/or with risk factors for neutropenic sepsis, who has any of the following features:
- Symptoms or signs indicating possible infection such as dysuria, diarrhoea, or productive cough (N.B. sepsis may result from infection with almost any pathogen, therefore it may present with a wide range of clinical features depending on the site of infection and host response).
- Who becomes unwell e.g. with chills, shivers, rigors, and/or a temperature greater than 38°C (N.B. people with neutropenic sepsis may not present with fever, and may present with hypothermia).
- Has clinical features of possible sepsis (N.B. people with sepsis may present with non-specific, non-localised clinical features, for example general malaise, agitation, or behavioural change).
- Concern from a relative or carer that there is a change in appearance or behaviour.
Management
- Emergency treatment and assessment
- Treat suspected neutropenic sepsis as an acute medical emergency and offer empiric antibiotic therapy immediately.
- Include in the initial clinical assessment of patients with suspected neutropenic sepsis:
- history and examination
- full blood count, kidney and liver function tests (including albumin), C-reactive protein, lactate and blood culture.
- Offer beta lactam monotherapy with piperacillin with tazobactam as initial empiric antibiotic therapy to patients with suspected neutropenic sepsis who need intravenous treatment unless there are patient-specific or local microbiological contraindications.
- Confirming a diagnosis
- Diagnose neutropenic sepsis in patients having anticancer treatment whose neutrophil count is 0.5 x 10⁹/L per litre or lower and who have either:
- a temperature higher than 38°C or
- other signs or symptoms consistent with clinically significant sepsis.
- Diagnose neutropenic sepsis in patients having anticancer treatment whose neutrophil count is 0.5 x 10⁹/L per litre or lower and who have either:
- Managing confirmed neutropenic sepsis
- A healthcare professional with competence in managing complications of anticancer treatment should assess the patient's risk of septic complications within 24 hours of presentation to secondary or tertiary care, basing the risk assessment on presentation features and using a validated risk scoring system.
- Patients at low risk of septic complications
- Consider outpatient antibiotic therapy for patients with confirmed neutropenic sepsis and a low risk of developing septic complications, taking into account the patient's social and clinical circumstances and discussing with them the need to return to hospital promptly if a problem develops.
- Patients at high risk of septic complications
- Offer discharge to patients having empiric antibiotic therapy for neutropenic sepsis only after:
- the patient's risk of developing septic complications has been reassessed as low by a healthcare professional with competence in managing complications of anticancer treatment using a validated risk scoring system and
- taking into account the patient's social and clinical circumstances and discussing with them the need to return to hospital promptly if a problem develops.
- Offer discharge to patients having empiric antibiotic therapy for neutropenic sepsis only after:
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
