Approach
Early recognition of sepsis is essential because early treatment - when sepsis is suspected but has not yet been confirmed - is associated with significant short- and long-term benefits in outcome.[6][50][57]
Detection can be challenging because the clinical presentation of sepsis can be subtle and non-specific. A low threshold for suspecting sepsis is therefore important. The aim is to identify those at risk of deterioration to possible sepsis before it develops. In general, sepsis should be considered in any child with a suspected infection with signs of a systemic response, which may be indicated by a change in observations or a change in a child’s normal behaviour.[24][50] Parental concern about a child’s behaviour or condition should always be taken into consideration as an important indicator.[50]
Even when a diagnosis of sepsis appears unlikely at the time of presentation, information provided to parents or carers should include:[50]
A specific instruction to seek further advice if warning symptoms develop or the patient's condition deteriorates
An indication of when and how to access further care ('safety netting')
Sepsis may present initially with non-specific, non-localised symptoms, such as feeling very unwell with normal temperature. If a child presents with signs or symptoms that indicate possible infection, regardless of temperature, sepsis should be considered.[50] Initial assessment includes identifying the likely source of infection, identifying risk factors for sepsis (e.g., very young [<1 year]; recent trauma, surgery or invasive procedure; impaired immunity due to illness or medication; maternal infection during perinatal period [e.g., maternal carriage of group B streptococci]; indwelling line or catheter; or any breach of skin integrity [e.g., cuts, burns, blisters, or skin infections]), and identifying indicators of clinical concern, such as abnormalities of behaviour, circulation, or respiration.
While laboratory tests (e.g., blood cultures, biomarkers) are helpful in supporting the diagnosis, the diagnosis is initially using clinical judgement. Diagnostic criteria from international consensus guidelines are primarily considered to be research criteria designed to facilitate meaningful research. Research criteria and clinical judgement do not always agree: up to one third of patients with clinical sepsis do not fulfil research diagnostic criteria.[58]
Therefore, given the time-critical nature of sepsis and septic shock, when sepsis is suspected on clinical grounds, it is usually best to initiate sepsis investigations and treatment and to continue until sepsis has been excluded.
Clinical features of sepsis
The typical presentation varies according to the age of the child. Whereas older children may present with a focus of infection, infants and neonates usually present with non-specific symptoms and signs.
Systemic inflammatory response syndrome (SIRS) is a generalised inflammatory response defined by the presence of 2 or more of the following criteria (abnormal temperature or white cell count must be one of the criteria):[3]
Abnormal core temperature (<36°C or >38.5°C [<97°F or >101°F])
Abnormal heart rate (>2 standard deviations above normal for age, or <10th percentile for age if child is <1 year of age)
Raised respiratory rate (>2 standard deviations above normal for age, or mechanical ventilation for acute lung disease)
Abnormal white blood cell count in circulating blood (above or below normal range for age, or >10% immature white cells)
Although not included in the SIRS definition, altered mental state (e.g., sleepiness, irritability, lethargy, floppiness, decreased conscious level) or reduced peripheral perfusion (e.g., prolonged capillary refill time) can also be signs of early sepsis.[59]
Though the above paediatric sepsis criteria is still clinically used, expert consensus has now recommended adopting the new Phoenix Sepsis Score in children in place of the above criteria for SIRS.[5] This change comes about mostly due to limitations of the criteria for SIRS including its poor predictive properties and use of the term severe sepsis, which is now deemed redundant. Survey data also found that most paediatric clinicians used the term sepsis to refer to infection with life-threatening organ dysfunction, which differs from the prior paediatric sepsis criteria that was used in the SIRS criteria.[5]
It is important to note that the Phoenix Sepsis Score is indicated for diagnosis of sepsis (i.e., infection with life-threatening organ dysfunction) and not as a screening tool for possible sepsis before organ dysfunction is overt.[5] It is highly recommended that local screening tools to recognise the early signs of sepsis should continue to be used. Phoenix criteria are not designed to replace existing screening tools.
For the diagnosis of sepsis, consensus criteria state that the core temperature must exceed 38.5°C (101°F).[3] However, a lower threshold is required in neutropenic patients, where sepsis should be considered if the core temperature is >38°C (>100°F).
In young infants, term and preterm neonates, the symptoms and signs of sepsis are often vague and non-specific so a low diagnostic threshold should be taken. Sepsis in this age group frequently manifests initially as a change in the normal trends of observations for that child. For example, a preterm infant in the neonatal intensive unit may demonstrate new onset bradycardic episodes, apnoeas, or feed intolerance as the first signs of sepsis. In older children, it is worth keeping a low threshold for diagnosis of sepsis if an acute illness has not been fully explained.
In all age groups, if sepsis has progressed, the patient may develop sepsis or septic shock. Septic shock may manifest in 2 main clinical pictures: vasoconstrictive ('cold') shock and vasodilatory ('warm') shock.
Vasoconstrictive shock:
This is the more common presentation of community-acquired sepsis in infants and young children.[12]
The clinical appearance is characterised by constricted peripheral systemic vasculature, resulting in cold peripheries, prolonged capillary refill time, increased core-toe temperature gap, and weak pulses.[3]
The blood pressure is usually preserved (or may even be high) unless the patient is moribund, but the patient is usually tachycardic.
The underlying problem is a low cardiac output, secondary to impaired myocardial contractility, resulting in low cardiac output and peripheral vasoconstriction.
Vasodilatory shock:
The clinical appearance of vasodilatory shock is characterised by vasoplegia, in which the systemic vascular resistance is low, so the capillary refill time is brisk ('flash' capillary refill) and pulses are usually felt to be full or bounding.
The pulse pressure is high (usually due to a low diastolic blood pressure) and the patient is usually tachycardic.
In terms of cardiac output, this is often a high cardiac output state, but the patient will be in shock due in part to enlargement of the circulation (through dilation of the systemic vasculature) beyond the scope of the cardiac output.
Vasodilatory shock is the more common presentation in older children (and adults) with sepsis, and may be more common in hospital-acquired sepsis.[12]
The use of clinical signs alone to distinguish between these states is no longer recommended, as observational studies have demonstrated poor correlation of clinical assessments with cardiac output and systemic vascular resistance as measured by advanced monitoring. However, the distinction may be helpful when advanced haemodynamic monitoring is available.[6]
In both shock states, the patient will demonstrate clinical signs of shock outside the cardiovascular system, the most important of which is impaired neurological function. This may manifest as irritability in infants and neonates, apnoeas in neonates and preterm infants, and drowsiness, obtundation, or delirium in older children.
Children and young people often maintain a normal blood pressure even in the late stages of shock; therefore, normal blood pressure should not exclude sepsis. Hypotension is often a terminal sign in septic shock. In children ages ≥12 years, systolic blood pressure <90 mmHg, or a reduction in systolic blood pressure >40 mmHg from baseline is a high risk criterion for sepsis.[50]
Purpura fulminans is a widespread non-blanching purpuric rash classically seen in meningococcaemia, but it may also be associated with sepsis from Streptococcus pneumoniae.
Decreased urine output is common in acutely ill children and often reflects a degree of dehydration (due to decreased intake, excessive fluid losses, or both). This is not a specific finding in sepsis, but is commonly present, especially if there has been a prodromal viral illness prior to the onset of sepsis.
In a move away from the SIRS and sequential organ failure assessment criteria recommended by international consensus guidelines, the National Institute for Health and Care Excellence (NICE) has recommended a risk stratification approach to identify early those patients (including children and neonates) at low risk, moderate to high risk, or high risk of severe illness and death from sepsis based on the following criteria:[50]
History (altered mental state; reduced functional ability; impaired immunity; or recent trauma, surgery, or invasive procedure)
Behaviour (altered behaviour; decreased activity; sleepy and unable to wake; non-responsiveness to social cues [neonates and infants]; weak high-pitched or continuous cry [neonates and infants])
Respiratory (apnoea; grunting; nasal flaring; raised respiratory rate; new need for oxygen to maintain saturation)
Circulation and hydration (reduced systolic blood pressure; reduced capillary refill time; raised heart rate; reduced urine output)
Skin (signs of infection; mottled or ashen appearance; cyanosis of skin, lips or tongue; non-blanching rash of skin)
Other (leg pain; cold hands or feet).
The NICE guidelines provide further recommendations for in-hospital clinical assessment and laboratory investigations (e.g., venous blood test for blood gas, including glucose and lactate measurement; blood culture; full blood count; C-reactive protein; urinalysis; urine culture; serum electrolytes; serum creatinine; and coagulation) based on the patient’s risk profile and symptoms.[50]
NICE has also developed a traffic light system based on clinical signs, which helps physicians assess the probability of serious illness in young children presenting with fever. NICE: traffic light system for identifying risk of serious illness Opens in new window
Blood cultures
No single laboratory test will confirm or refute the diagnosis of sepsis, but many can provide supporting or additional useful information.
As many infants and young children with sepsis have a primary bacteraemia, a blood culture is an important investigation.[9][60][61] This should be done as soon as possible when sepsis is suspected, and ideally before administration of antibiotics; however, empirical antibiotic therapy should not be withheld while awaiting results if sepsis is suspected.[6]
The sensitivity of blood culture is proportional to the volume of blood taken. When using a neonatal aerobic culture bottle in neonates, a minimum of 1 mL of blood from venipuncture or freshly inserted vascular catheter (arterial or venous) is likely to be adequate to diagnose bacteraemia.[9]
When standard aerobic culture bottles are used, a minimum of 4 mL of blood is required for a valid negative culture at 48 hours. Depending on the institutional preference, multiple cultures may be preferred, but it is important to avoid delay in antibiotic administration. Two sets of cultures are sometimes recommended to encourage clinicians to take the culture from an indwelling line (e.g., central line) and a peripheral site.
Blood culture results should be reviewed every 12 to 24 hours; most positive results will be detectable within 48 hours, and many will be positive within 24 hours.[62]
Other microbiological specimens
The clinical picture should direct the clinician to consider other microbiological specimens. For example, in term and preterm neonates with suspected meningitis, clinicians should consider a lumbar puncture (for cerebrospinal fluid protein and glucose concentrations, microscopy with Gram stain, and bacterial culture) when the child is stable and can safely undergo the procedure, as clinical signs of meningism in this age group are usually absent.[9][46] NICE sepsis guidelines recommend a lumbar puncture if sepsis is suspected in infants aged <1 month, and in all infants aged 1 to 3 months who appear unwell or have a white blood cell count <5×10⁹/L or >15×10⁹/L.[50] Lumbar puncture is usually contraindicated in children with sepsis until the patient is stabilised.
Urinalysis (urine sample for nitrites, microscopy, Gram stain, and culture) should be considered in all neonates with sepsis (although in the first week of life, a positive urine culture may simply reflect a severe bacteraemia). Urinalysis should be considered in older children with symptoms suggestive of a urinary tract infection.
Other clinical symptoms and signs will direct the clinician to specific microbiological samples. For example, bronchoalveolar lavage sample for microscopy and culture may be considered in a child in intensive care with a suspected ventilator-associated pneumonia; blood for meningococcal polymerase chain reaction (PCR) analysis may be considered to help confirm the diagnosis in equivocal clinical cases of meningococcal sepsis; serum serology or PCR for respiratory or opportunistic viruses (e.g., adenovirus, cytomegalovirus, herpes simplex virus) may be considered in immunocompromised children with sepsis (e.g., neutropenic child receiving chemotherapy for leukaemia). However, clinicians should consult local protocols regarding sample collection and testing. Consider ordering herpes simplex virus PCR (blood and cerebrospinal fluid) if neonatal herpes simplex infection is a possibility and seek expert consultation.[63]
Despite adequate microbiological sampling, it is important to remember that in many children with sepsis, the pathogen will not be identified. This is known as culture-negative sepsis.[64]
Molecular assays are coming into practice with the advantage of delivering rapid results.[65]
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]
The PhenoTest™ BC Kit can identify 14 species of bacteria and 2 species of yeast that commonly cause bloodstream infections, while also providing guidance on antibiotic sensitivity. The test compares the organism's DNA to a database, and then uses time-lapse images to analyse the organism’s response to antibiotics. It can identify a positive blood culture in 1.5 hours and guide antibiotic treatment in 6.5 hours. However, the test has been associated with false positive results.[66] Several other rapid detection methods for early pathogen detection and antimicrobial susceptibility testing are in clinical testing at present. Such assays could be of significant value in the personalised care of patients with presumed sepsis in the near future.
Biomarkers for organ dysfunction
Apart from the diagnosis and monitoring of sepsis, biomarkers are also useful for diagnosis and monitoring of the specific organ effects of sepsis. The following laboratory investigations should be requested in children with suspected sepsis:
Blood gases: although children rarely have arterial blood gases taken in the accident and emergency department, it is often possible to obtain clinically useful information from capillary or venous blood gases. Hypercapnia or hypoxaemia are supportive of a diagnosis of respiratory dysfunction. Pulse oximetry should be ordered as high fraction of inspired oxygen requirement is indicative of sepsis-related respiratory failure.
Serum lactate: elevated serum lactate is a marker of illness severity in sepsis. It is caused by beta-adrenoreceptor stimulation from endogenous catecholamines upregulating glycolysis leading to production of a high quantity of pyruvate. This production exceeds the utilisation capacity of the tricarboxylic acid cycle and excess pyruvate is converted to lactate. Lactate is often elevated in sepsis or septic shock. In certain situations lactataemia may represent decreased oxygen delivery.[67]
Serum electrolytes: frequently deranged.
Serum creatinine: elevated serum creatinine provides evidence of acute kidney injury.[3]
Liver function tests (LFTs): elevated bilirubin and/or elevated alanine aminotransferase/aspartate aminotransferase is suggestive of liver dysfunction.[3]
Coagulation studies: in the context of sepsis and thrombocytopenia, an INR >2, prolonged activated partial thromboplastin time (PTT), decreased fibrinogen level, and elevated D-dimer are indicative of disseminated intravascular coagulation.[3][68]
FBC: thrombocytopenia (and prolonged international normalised ratio [INR]) in the context of sepsis is suggestive of disseminated intravascular coagulation. Abnormal white blood cell count for age (high or low) is one of the diagnostic criteria for SIRS.
Serum glucose: hyperglycaemia is common as part of the stress response to sepsis. However, hypoglycaemia is not uncommon in young children, due to decreased fluid intake.
Inflammatory biomarkers
There is growing interest in the use of biomarkers for the diagnosis and monitoring of sepsis and septic shock. A key issue (particularly in intensive care) is the problem of distinguishing sepsis from SIRS (or organ dysfunction) without infection, where clinical signs may not be helpful. The 2 biomarkers most frequently used for this purpose are C-reactive protein (CRP) and serum procalcitonin. Serum procalcitonin shows the most potential in this area, showing greater accuracy for diagnosis of sepsis compared with CRP in neonates and older children.[69][70][71][72][73][74] There is also evidence that procalcitonin trends can be used to reduce the duration of antibiotic therapy and the hospital length of stay.[75]
Other biomarkers (e.g., CD64, interleukin [IL]-6, IL-8, IL-18, mass spectrometry, specific mRNA expression) are considered emerging and are not widely used or validated as yet, although offer significant promise in the future.[76][77][78][79][80]
Imaging
Specific imaging investigations will be indicated according to the clinical picture, but infants and small children with respiratory distress in the context of suspected sepsis should undergo chest x-ray to assess for pneumonic changes (e.g., lobar consolidation in bronchopneumonia); computed tomography (CT) may also play an important role in the evaluation of patients with suspected sepsis; however, the increased exposure to ionising radiation should be considered.[81] If symptoms are not suggestive of the origin of suspected sepsis then chest x-ray would also be an appropriate initial investigation with consideration of abdominal ultrasound or CT if appropriate.[81]
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