Sepsis in adults

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Key Recommendations

Sepsis is a spectrum of disease, where there is a systemic and dysregulated host response to an infection.[1] Presentation may range from nonspecific or nonlocalized symptoms (e.g., feeling ill with a normal temperature), to severe signs with evidence of multiorgan dysfunction and septic shock. Risk of progression to fulminant disease is determined by various factors, including:

Magnitude and nature of the infective focus;
Timeliness and quality of interventions; and
Genetic and acquired predisposition of the patient.

The importance of early recognition of suspected sepsis

Early recognition of sepsis is essential because early treatment - when sepsis is suspected but is yet to be confirmed - is associated with significant short- and long-term benefits in outcome.[10][65][66][67][68][69] However, detection can be challenging because the clinical presentation of sepsis can be subtle and nonspecific. A low threshold for suspecting sepsis is therefore important.

The key to early recognition is the systematic identification of any patient who fulfills both of the following criteria:

Has signs or symptoms suggestive of infection. The most common sources in patients who develop sepsis are respiratory, urinary tract, and lower gastrointestinal infections. Skin and soft-tissue infections also contribute.
Is at risk of deterioration due to organ dysfunction. Several approaches have been suggested for identifying patients at risk of deterioration. These include the use of an early warning score or risk stratification criteria. All of these approaches rely on systematic evaluation and recording of vital signs. It is important to check local guidance for information on which approach your institution recommends.

Initial presentation of infection

Sepsis may present initially with nonspecific, nonlocalized symptoms, such as feeling ill with normal temperature.[70] Sepsis should be considered if a patient presents with signs or symptoms that indicate possible infection, regardless of temperature.[10] This is partly because, although fever is frequently associated with sepsis, hypothermia is a common presenting sign and carries a worse prognosis.[71] Older patients are particularly prone to a blunted febrile response and may present with normothermia.[8][9]

The most common sources in patients who develop sepsis are respiratory, urinary tract, and lower gastrointestinal infections.[72] Symptoms of the underlying infection may or may not be evident at initial presentation.

The patient's history should seek out any risk factors for sepsis, including:

Age over 65 years
Impaired immunity
Diabetes
Recent surgery or other invasive procedure
Breach of skin integrity
Current or recent pregnancy
Indwelling intravenous or urinary catheters
Intravenous drug use
Current hemodialysis
Alcohol use disorder.

A higher index of suspicion for sepsis is warranted when a patient in one of these at-risk groups presents with signs of infection and acute illness.

Diagnosing sepsis and identifying patients at risk of deterioration due to organ dysfunction

Early identification of sepsis relies on the systematic evaluation of patients presenting with presumed infection to identify those at risk of deterioration due to organ dysfunction.

Several approaches have been proposed for everyday clinical practice. These include:

Early warning scores that aim to identify and risk stratify patients without the need to await laboratory investigations. Examples include the National Early Warning Score (NEWS), Modified Early Warning Score (MEWS), and Detect, Act, Reassess, Titrate (DART) tool.
Approaches that require blood test results, such as the Systemic Inflammatory Response Syndrome (SIRS) criteria.

Further research is required to determine the approach that offers an optimal balance of sensitivity and specificity for detecting sepsis as early as possible.

Any patient with suspected infection who is evaluated as being at risk of deterioration using any one of these approaches should be diagnosed with suspected sepsis and prioritized for immediate treatment.

All approaches rely on the systematic evaluation and recording of the patient’s vital signs.

Vital signs should always be interpreted in relation to the patient's known or likely baseline for that parameter; for example, a fall in systolic blood pressure (BP) of ≥40 mmHg from the patient's baseline is a cause for alarm, regardless of the systolic BP reading itself.[10]

Early warning scores

Early warning scores are in widespread use to facilitate risk stratification and detection of clinical deterioration or improvement over time.[73] Where infection is suspected, these scores can be used to identify those patients at highest risk of sepsis and resultant deterioration.[5][74][75][76] As with any scoring system, early warning scores are not 100% sensitive or 100% specific, so clinical judgment must play a key role.

Early warning scores are based on several physiologic parameters, where the greater the deviation from normal, the higher the score. Each parameter is evaluated individually and then the final score is aggregated. Examples include NEWS and MEWS.[77] Evidence suggests that early warning scores have better sensitivity and specificity than the Quick Sequential Organ Failure Assessment (qSOFA) score for predicting deterioration and mortality among patients presenting to the emergency department with suspected infection.[5][6]

NEWS

In an acutely ill patient with symptoms or signs of infection, NEWS can be an indicator of the likelihood of sepsis.[10] The aggregate NEWS score, in combination with clinical judgment (which should take into account the patient's history, physical exam, individual physiology, and comorbidities), triggers the level and urgency of response required.[10] The NEWS score is derived from assessing a patient's respiration rate, oxygen saturation, systolic BP, pulse rate, temperature, and level of consciousness.[77] A patient with a score ≥7 has a significant risk of mortality, and therefore this should prompt emergency evaluation by a critical care specialist and rapid initiation of treatment.[77][78] In the UK, NEWS2 (an updated version of NEWS) has been published by the Royal College of Physicians; this includes a separate scale for scoring oxygen saturation in patients with hypercapnic respiratory failure (e.g., due to COPD).[77]

One analysis of audit data from 20 UK emergency departments found that a single NEWS score calculated from the patient's initial signs was strongly predictive of adverse outcomes in sepsis; patients with a NEWS score of 5-6 had twice the mortality of those with a score of 0-4 (30-day mortality of 11.3% vs. 5.5%).[76] An observational study of 30,677 adults admitted via the emergency department with suspected infection found that the NEWS score performed better than either the MEWS or qSOFA scores in predicting the risk of death or need for an intensive care unit (ICU) transfer.[5]

MEWS

The MEWS score can be used for hospitalized patients to identify those at risk of clinical deterioration and those who may need higher levels of care. Evidence has shown that a MEWS score ≥5 is associated with increased risk of death, ICU admission, or high dependency care admission.[79] The MEWS score is based on assessment of the following clinical parameters:

Systolic BP
Heart rate
Respiratory rate
Temperature
AVPU (alert, voice, pain, unresponsive) score.

DART

DART is a tool used for risk stratification and is recommended by the American College of Emergency Physicians Expert Panel on Sepsis.[80]

Pregnancy

It is important to be aware that NEWS2 and MEWS have not been validated for use in pregnant women. Although there are early warning score variants that can be used in pregnancy (e.g., the Modified Early Obstetric Warning Score [MEOWS]), these have not been validated for use in patients with sepsis.

Sepsis diagnostic criteria that require laboratory investigations

The SIRS criteria for diagnosing sepsis require laboratory analysis of blood tests. This can lead to delays in recognizing patients at risk of deterioration and organ dysfunction due to sepsis.

The use of the SIRS criteria (together with suspicion of infection) to diagnose sepsis remains in widespread clinical practice. The Surviving Sepsis Campaign guideline favors use of one of SIRS, NEWS, or MEWS as a screening tool but nonetheless advises that clinicians should understand the limitations of the SIRS criteria.[3] Although they have a high sensitivity, their specificity is very low.[5] SIRS is defined by the presence of ≥2 of the following clinical signs and laboratory investigation findings:[7][70][81]

Temperature >100.4°F (>38°C) or <96.8°F (<36.0°C)
Tachycardia >90 bpm
Tachypnea >20 breaths/minute or PaCO₂ <32 mmHg
Leukocytosis (WBC count >12,000/microliter) or leukopenia (WBC count <4000/microliter) or normal WBC count with >10% immature forms.

Sequential Organ Failure Assessment (SOFA) criteria

In 2016, the Third International Consensus Group (Sepsis-3) recommended that organ dysfunction should be defined based on the full SOFA criteria.[1] The SOFA score is primarily used in research, and when used in clinical practice it is more commonly confined to an ICU setting. See Criteria.

qSOFA score

The qSOFA score is a modified version of the SOFA score for bedside use but the Surviving Sepsis Campaign recommends strongly against its use as a single screening tool for sepsis or septic shock because of its poor sensitivity compared with SIRS, NEWS, or MEWS.[3] A growing body of evidence suggests that qSOFA is a late indicator of deterioration.[5][6]

A point is scored for each of:[1]

Altered mental status (Glasgow Coma Scale [GCS] score <15)
Respiratory rate ≥22 breaths/minute
Systolic BP ≤100 mmHg.

A score ≥2 predicts a high risk of a poor outcome in a patient with infection.[1]

Initial evaluation

Initial evaluation includes identifying the likely source of infection, identifying risk factors for sepsis, determining the need for urgent source control (e.g., incision and drainage of an abscess), and identifying abnormalities of behavior, circulation, or respiration.

As is the case for all acutely sick patients, initial evaluation should follow the Airway, Breathing, Circulation, Disability, Exposure (ABCDE) format, to include assessment of the airway, respiratory and circulatory sufficiency, as well as conscious level (GCS or AVPU [Alert, responds to Voice, responds to Pain, Unresponsive]).

Attention should be paid to seeking other signs of organ dysfunction (e.g., jaundice, purpura fulminans, cyanosis), and signs of circulatory insufficiency including oliguria, mottling of the skin, and prolonged capillary refill times. Oxygen saturation, respiratory rate, heart rate, BP, temperature, and accurate hourly fluid balance (including urine output) should be monitored.

For the evaluation of new fever in patients in the ICU, central temperature monitoring methods (such as thermometers for pulmonary artery catheters, bladder catheters, or esophageal balloon thermometers) are preferred when these devices are in place. For patients without these devices in place, the Infectious Diseases Society of America (IDSA) recommends measuring oral or rectal temperatures.[82]

It is important to seek clinical evidence for the source of infection. This will aid diagnosis and provide vital information as to the patient's risk factors for sepsis.

Risk factors strongly associated with sepsis include: underlying malignancy, impaired immunity (e.g., due to illness or medications), recent surgery or other invasive procedures, breached skin integrity (e.g., wounds, skin infection), urinary and intravenous indwelling catheters, intravenous drug use, age >65 years or frailty, pregnancy or recent pregnancy, hemodialysis, history of alcoholism, immunocompromise, and diabetes mellitus. [Figure caption and citation for the preceding image starts]: Severe purpura fulminans, most commonly associated with pneumococcal septicemiaFrom the collection of Ron Daniels, MB, ChB, FRCA; used with permission [Citation ends].[Figure caption and citation for the preceding image starts]: Capillary refill time. Top image: normal skin tone; middle image: pressure applied for 5 seconds; bottom image: time to hyperemia measuredFrom the collection of Ron Daniels, MB, ChB, FRCA; used with permission [Citation ends].

Sepsis is typically diagnosed when there are alterations in conscious level, hypotension, and organ failure, manifesting for example as oliguria, hypoxemia, jaundice, or petechial rash. Delayed diagnosis and intervention are associated with increased morbidity, and a high index of suspicion in all patients with abnormal signs and a possibility of infection should be maintained. Sepsis should be suspected in patients with an unexplained altered mental status, tachypnea with a clear chest and normal oxygenation, or if the clinician's instinct indicates something unusual about a seemingly routine infection.[80]

Investigations

Initial investigations cover four purposes:

To identify causative organisms
To evaluate for organ dysfunction
To identify the source of infection
To aid prognosis and the selection of an appropriate level of care.

Priority should be given to those investigations that will help to answer important clinical questions, such as the source of infection and severity of illness. Cultures of blood and other fluids will take 48 to 72 hours to yield sensitivities of causative organisms (if identified), but are far less sensitive if delayed until after antimicrobial administration.

Investigations to identify causative organisms:

Blood cultures should be taken immediately, and preferably before antibiotics are started, provided their sampling will not delay administration of antibiotics.[10][70][82] Ideally, at least one set should be taken percutaneously, and one set from any vascular access device that has been in situ for more than 24 hours.[83][84] Other cultures (e.g., of sputum, cerebrospinal fluid [CSF], pleural fluid, joint fluid, stool, and urine) should be taken as clinically indicated.
If no localizing signs are present, systematic examination and culture of all potential sites of infection, including wounds, catheters, prosthetic implants, epidural sites, and pleural or peritoneal fluid, as indicated by the clinical presentation and history, is required.
If meningitis is suspected (e.g., headache, photophobia, neck stiffness, vomiting), a lumbar puncture (LP) for CSF microscopy and culture should be performed. A computed tomography (CT) scan prior to performing an LP to exclude elevated intracranial pressure is required if there is any clinical suspicion of this.
If an enclosed collection such as an abscess or empyema is suspected, it is recommended that this be drained and cultured early in the course of the illness (within 6-12 hours following identification).[3][85]
Intubated patients in whom there is a suspicion of pneumonia should have tracheal aspirates, bronchoalveolar lavage, or protected brush specimens taken.

Evaluation for organ dysfunction:

Baseline assessment should include liver function tests (notably bilirubin), a complete blood count (with differential), coagulation (international normalized ratio, activated partial thromboplastin time), serum creatinine, and blood urea nitrogen.
Serum electrolytes and glucose are frequently abnormal, and should be measured at baseline and regularly until the patient improves.
Elevated serum lactate highlights tissue hypoperfusion, and is assessed using a blood gas sample.[10] In practice, a venous blood gas sample is generally used, as it is generally easier and quicker to obtain compared with an arterial blood gas (ABG).
Markers of inflammation, including C-reactive protein (CRP) and procalcitonin, are of use in determining clinical progress and response to therapy. Serial measures of procalcitonin can be useful to guide the decision on when to discontinue antibiotics, alongside clinical evaluation.[3][86][87] Do not perform procalcitonin testing without an established, evidence-based protocol.[88]
Do not order erythrocyte sedimentation rate (ESR) to detect acute inflammation before a diagnosis has been established; CRP is a more sensitive and specific test for the acute phase of inflammation than ESR.[88]

Investigations to identify the source of the infection:

The source of infection may be immediately evident; for example, with classical signs and symptoms of pneumonia (purulent sputum, dyspnea, tachypnea, cyanosis) or an acute abdomen (abdominal pain, guarding, distension, tenderness, absent bowel sounds). However, in many patients the origin must be actively sought.
Diagnostic studies may identify a source of infection that requires removal of a foreign body or drainage to maximize the likelihood of a satisfactory response to therapy. Chest x-rays and ultrasound scans can be performed at the bedside.[89] Examinations such as CT scanning require transfer of potentially unstable patients and the benefit should be weighed against the risk.
An ECG should be arranged to help exclude other differential diagnoses, including myocardial infarction, pericarditis, and myocarditis. Sepsis also predisposes to myocardial dysfunction (particularly in septic shock) and arrhythmias (e.g., atrial fibrillation).[10][90]
In patients at risk of, or with symptoms compatible with, bacterial endocarditis, a transthoracic or transesophageal echocardiogram is useful. This is also helpful to differentiate between hypovolemic, cardiac, and septic shock, as well as alternative diagnoses, such as valvular abnormalities, pulmonary embolus, myocardial ischemia (with segmental or global dysfunction), hypovolemia, and pulmonary hypertension. If readily available, an echocardiogram may also be appropriate in patients with sepsis of unknown origin.

Certain investigations carry prognostic value and can help determine the need for critical care:

Lactate measurement is a useful assessment of perfusion once a diagnosis of sepsis has been established. Increasing levels of lactate are associated with increasing levels of anaerobic metabolism. Persistently elevated lactate levels may parallel the degree of hypoperfusion or organ failure. High lactate carries adverse prognostic value if elevated to >2 mmol/L (>18 mg/dL), and still worse outcomes are associated with levels >4 mmol/L (>36 mg/dL).[10][70] Lactate clearance (the rate at which lactate is cleared over a period of 6 hours) has been demonstrated to be as useful as more invasive tests, such as central venous oxygen saturation, in determining a patient's response to treatment.[91][92]
Studies with trauma patients have evaluated lactate levels against Acute Physiology and Chronic Health Evaluation (APACHE) scores and lactate clearance rates and found lactate levels to be inferior in informing the prognosis. However, an APACHE score takes 24 hours to calculate.[93]
An alternative measure is serum procalcitonin levels. In patients with acute respiratory infections (including those with sepsis), procalcitonin-guided antibiotic therapy has been shown to reduce the antibiotic course length, reduce antibiotic-related complications, and reduce the 30-day mortality rate.[94] However, evidence for the prognostic value of procalcitonin alone is unclear, and its use in the identification of sepsis is excluded from many guidelines.[3][95][96][97] Surviving Sepsis Campaign guidelines recommend the use of procalcitonin alongside clinical evaluation to guide decisions on the discontinuation of antibiotics in patients with sepsis, but not for the initiation of antibiotics.[3] One multicenter randomized trial of 2760 critically ill adults hospitalized with suspected sepsis found that a daily procalcitonin-guided protocol reduced antibiotic duration safely compared with standard care.[98] Changes in procalcitonin levels may occur later than those of lactate, although changes in both markers combined are highly predictive of outcome between 24 and 48 hours.[99]
Noninvasive impedance echocardiography has been shown to predict poor outcome if a cardiac index of <2 or reduced mitral annular plane systolic excursion is identified.[100][101]

Patients suffering from septic shock who have not responded to initial fluid resuscitation will require intensive monitoring and treatment in high dependency units.

Diagnostic lumbar puncture in adults: animated demonstration

How to perform a diagnostic lumbar puncture in adults. Includes a discussion of patient positioning, choice of needle, and measurement of opening and closing pressure.

Venepuncture and phlebotomy: animated demonstration

How to take a venous blood sample from the antecubital fossa using a vacuum needle.

How to perform an ECG: animated demonstration

How to record an ECG. Demonstrates placement of chest and limb electrodes.

Emerging tests

Molecular diagnostic assays are being developed that can test for common pathogens. Such assays allow more rapid organism identification and antimicrobial susceptibility testing than standard blood culture systems.[109][110][111]

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