Sepsis in adults

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

Key Recommendations

Early recognition and treatment of sepsis is key to improving outcomes. Treatment guidelines produced by the Surviving Sepsis Campaign (SSC) are the most widely accepted standards.[3] Current best practice is based on evidence for care bundles in sepsis.[3][124][125][126][127] The SSC recommends:

Obtaining blood cultures prior to administration of antibiotics.
Administering antimicrobials immediately, ideally within 1 hour of recognition (in adults with possible septic shock or a high likelihood for sepsis).
Administering empiric antimicrobials with methicillin-resistant Staphylococcus aureus (MRSA) coverage in patients with sepsis or septic shock at high risk of MRSA.
Administering 30 mL/kg crystalloid rapidly (within 3 hours) for hypotension or lactate ≥36 mg/dL (≥4 mmol/L), if no contraindications.
Obtaining serial measurement of blood lactate.
Aiming for a mean arterial pressure (MAP) of 65 mmHg in patients with septic shock.
Using dynamic measures to guide fluid resuscitation over physical exam or static measures alone. Dynamic parameters include response to a passive leg raise or a fluid bolus, using stroke volume (SV), stroke volume variation (SVV), pulse pressure variation (PPV), or echocardiography, where available.

For adults with possible (i.e., lower likelihood) sepsis without shock, if concern for infection persists, the SSC recommends that antibiotics should be given within 3 hours from the time when sepsis was first recognized.[3]

The Sepsis Six

One bundle dealing with basic therapies, the "Sepsis Six," has been shown to improve outcomes in septic patients. If the six factors are completed within the first hour following recognition of sepsis, the associated mortality has been reported to reduce by as much as 50%.[69] The six factors are as follows:

Administer oxygen, if indicated, to maintain target oxygen saturations greater than 94% (or 88% to 92% in people at risk of hypercapnic respiratory failure). One systematic review of acutely sick adult patients, including patients with sepsis, reported increased mortality among those who received liberal oxygen supplementation compared with those who received conservative oxygen supplementation. A target SpO₂ range of 94% to 96% was suggested for patients with critical illness.[128]
Take blood cultures and consider other sampling.
Give intravenous antibiotics.
Start intravenous fluid resuscitation.
Check serial lactate levels.
Monitor hourly urine output.

Patients who are refractory to initial treatments, in particular those with septic shock, may require invasive monitoring and consideration for organ support (e.g., central venous catheter and vasopressors), so management on a high dependency unit or an intensive care setting (ICU) may well be required.

One aspect of basic intervention, the delivery of appropriate rapid fluid challenges, is intended to restore the imbalance between oxygen supply and demand to the tissues. Patients who fail to respond to the rapid delivery of adequate volumes of intravenous fluids are in septic shock. The immediate priority in this group of patients is the restoration of the circulation and oxygen delivery.

Monitoring of vital signs and response to fluid therapy is essential. Assessment of oxygenation via pulse oximetry, serial lactate measurements, and monitoring of urinary output provide dynamic information to further assess your patient's condition. A failure of lactate to improve with therapy is indicative of a poor outcome. Lactate clearance has been shown to correlate positively with survival.[91] All patients receiving vasopressors should have an arterial catheter inserted as soon as it is practical to do so to aid more accurate monitoring of arterial blood pressure.[3]

Antibiotic therapy

Broad-spectrum intravenous antibiotics should be given before a pathogen is identified.[3][129][130] For every hour delay on antibiotic initiation for septic shock, there is a 7.5% to 10.0% increase in mortality.[130][131] Antibiotics should be commenced as soon as sepsis is suspected, preferably after cultures have been taken.[3][10] The timely delivery of appropriate antibiotics is of critical importance in maximizing chances of survival.[69][132][133][134][135][136][137][138] Once culture and sensitivity results are available, antibiotics can be tailored to the known pathogens.

Antibiotics should target the presumed site of infection. If there is no clinical evidence to suggest a specific site of infection and sepsis is still suspected, empiric broad-spectrum antibiotics should be given.

One systematic review found that prolonged infusion of antipseudomonal beta-lactam antibiotics over at least 3 hours (rather than a bolus or within 60 minutes) reduced mortality by up to 30% in patients with sepsis in the intensive care.[139] However, prolonged infusion times are off-label as most manufacturer administration recommendations advise infusion of beta-lactam antibiotics over 15-60 minutes.

Knowledge of locally prevalent pathogens and their antibiotic resistance patterns are important when deciding empiric therapy.[129][140] Empiric antibiotic recommendations will be necessarily individualized at the institutional level, based on regional resistance patterns.

Cultures should be repeated (e.g., at 6-hour to 8-hour intervals) if there are persistent or repeated fever spikes, or there is the identification of a new site of infection.

Empiric antibiotics should be narrowed as soon as a pathogen has been identified and sensitivities are available.[3][10][141]

Fluoroquinolone antibiotics should be avoided when effective and appropriate alternatives are available and can be given promptly. Systemic fluoroquinolone antibiotics may cause serious, disabling, and potentially long-lasting or irreversible adverse events. This includes, but is not limited to: tendinopathy/tendon rupture; peripheral neuropathy; arthropathy/arthralgia; aortic aneurysm and dissection; heart valve regurgitation; dysglycemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behavior.[142]

Prescribing restrictions apply to the use of fluoroquinolones, and these restrictions may vary between countries. In general, fluoroquinolones should be restricted for use in serious, life-threatening bacterial infections only.
Some regulatory agencies may also recommend that they must only be used in situations where other antibiotics that are commonly recommended for the infection are inappropriate (e.g., resistance, contraindications, treatment failure, unavailability). Consult your local guidelines and drug information source for more information on suitability, contraindications, and precautions.

Respiratory source

Respiratory infections account for approximately 30% to 50% of cases. Treatment regimens should cover common respiratory pathogens and atypical organisms such as Legionella pneumophila.

Antibiotics listed are suggested as guidance only.

American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines recommend that combination therapy for patients admitted to the hospital should include a beta-lactam, such as cefotaxime, ceftriaxone, ceftaroline, or ampicillin/sulbactam, with a macrolide, such as azithromycin.[143] Although ATS/IDSA guidelines recommend clarithromycin in these patients, it is only available as an oral formulation in the US so is unlikely to be useful in this setting. A beta-lactam and a fluoroquinolone (e.g., moxifloxacin, levofloxacin) combination may also be given to patients with severe community-acquired pneumonia. There is stronger evidence for the beta-lactam plus macrolide combination.

Risk factors for the presence of multiple-drug-resistant Pseudomonas aeruginosa and for MRSA will affect choice of antimicrobial agents and should be evaluated. These include hospitalization, prior isolation of these organisms (especially from the respiratory tract), or systemic antibiotic use within the previous 90 days.[143]

In patients at risk of MRSA who have severe pneumonia, or who have prior respiratory isolation of MRSA, vancomycin or linezolid should be added to the empiric beta-lactam combination regimen.[143] Patients with Pseudomonas infection who have severe pneumonia, or who have prior respiratory isolation of P aeruginosa, should be treated with piperacillin/tazobactam, cefepime, ceftazidime, imipenem/cilastatin, meropenem, or aztreonam in addition to the empiric beta-lactam combination regimen. Coverage for extended-spectrum beta-lactamase-producing Enterobacteriaceae should be considered only on the basis of patient or local microbiologic data.[143]

Urinary tract source

Urinary tract infections account for approximately 10% to 20% of cases. Ensuring patency of the urinary tract is vital. Cover should include gram-negative coliforms and Pseudomonas. Antibiotics listed are suggested as guidance only.

A suitable treatment regimen is to use a combination of either ampicillin or a cephalosporin (e.g., ceftriaxone, cefotaxime) plus gentamicin. Ciprofloxacin is a suitable alternative in patients with penicillin allergy if local sensitivity patterns are taken into account; it remains recommended for acute pyelonephritis or complicated urinary tract infection (consider safety issues).

Abdominal source

Infection arising from abdominal sources accounts for approximately 20% to 25% of cases. Gram-positive and gram-negative organisms including anaerobes should be covered. Peritonitis or intra-peritoneal abscesses require urgent surgical drainage or percutaneous drainage (where appropriate).[144]

Antibiotics listed are suggested as guidance only.

Treatment with ceftazidime or cefepime plus metronidazole is a suitable regimen, or alternatively, piperacillin/tazobactam.[145] A regimen ciprofloxacin or levofloxacin plus metronidazole is a suitable choice in patients with penicillin allergy.[145]

Patients with recurrent perforation of the large intestine are at increased risk of invasive fungemia. An azole, such as fluconazole, or an echinocandin, such as micafungin, should be added to the antibacterial cover. Non-albicans species of Candida are increasingly resistant to azoles.[47][48][146]

Soft-tissue and joint source

This heterogeneous group of infections includes septic arthritis, wound infections, cellulitis, and acute super-infections arising from chronic ulceration, and accounts for approximately 5% to 10% of cases.

A high index of suspicion should also be held for necrotizing fasciitis, which requires immediate surgical intervention (as does septic arthritis). Most infections are polymicrobial, and broad-spectrum cover against gram-positive and gram-negative organisms including anaerobes should be used.

Antibiotics listed are suggested as guidance only.

A suitable regimen is nafcillin (or tigecycline in penicillin-allergic patients) together with metronidazole. Alternatively, clindamycin may be used. If the patient has risk factors for MRSA, vancomycin (or alternatively linezolid) should be added.

If necrotizing fasciitis is suspected, a combination of vancomycin plus piperacillin/tazobactam plus clindamycin can be used. Nafcillin plus clindamycin is an alternative option. Vancomycin plus a carbapenem (e.g., meropenem or ertapenem) plus clindamycin may be used in penicillin-allergic patients.

Central nervous system (CNS) source

CNS infections are a relatively uncommon but potentially devastating cause of sepsis, accounting for under 5% of cases. Meningococcal septicemia can be extremely rapidly fatal, and if survived, can lead to greater morbidity than other forms. Immediate antibiotic therapy in suspected cases is essential. See Meningococcal disease.

Antibiotics listed are suggested as guidance only.

Suspected meningitis or meningococcal septicemia should be treated immediately using a third-generation cephalosporin (e.g., ceftriaxone, cefotaxime) in combination with vancomycin.[147][148] For patients with penicillin allergy, vancomycin with chloramphenicol is a suitable alternative. Some suggest the addition of rifampin to either regimen to aid penetration.

For patients aged over 50 years and those with a history of alcohol use disorder or other debilitating illness, with reduced cellular immunity or at increased risk of infection with Listeria (e.g., pregnant women, immunosuppression), cephalosporins alone provide inadequate cover. Ampicillin should be added to the regimen, provided the patient is not allergic to penicillin. For those allergic to penicillin, erythromycin or trimethoprim/sulfamethoxazole can be substituted.

Patients with a more insidious onset of CNS symptoms should be suspected as having viral encephalitis. Viruses cause sepsis extremely rarely, but early use of antiviral agents such as acyclovir may improve outcome.

Corticosteroids for bacterial meningitis can improve neurologic outcomes.[149]

Sepsis of unknown origin

Intensive efforts, including imaging, should be undertaken to attempt to evaluate the source of infection. Urgent broad-spectrum coverage to include all common pathogens should be administered.

Antibiotics listed are suggested as guidance only.

Carbapenems give appropriately broad cover, with imipenem/cilastatin or meropenem being suitable choices. Piperacillin/tazobactam with gentamicin is an alternative. If the patient has risk factors for MRSA, vancomycin should be added.

Fluid resuscitation

Early fluid resuscitation in sepsis-induced hypoperfusion (commenced within 1 hour of sepsis being suspected) is needed with at least 30 mL/kg body weight of crystalloid given within the first 3 hours.[127] However, optimal targets for fluid resuscitation should be individualized in certain patients, such as those with heart failure or chronic kidney disease, due to the risk of volume overload.[150][151][152]

Additional fluid may be required, but this should be guided by thorough clinical assessment of the patient's hemodynamic status.[3]

Repeated fluid boluses of crystalloid (typical volume 500 mL) given over 5 to 30 minutes may be effective in correcting hypotension secondary to hypovolemia. Boluses of a colloid solution (typical volume 250-300 mL) may be used as an alternative, but no evidence supports the use of colloids over other fluids such as crystalloids or albumin solution.[153][154][155][156][157] [ ]

Crystalloids and albumin should be given. Current evidence suggests that resuscitation using albumin-containing solutions is safe, but evidence of its efficacy is insufficient to recommend its use over crystalloids.[157][158][159][160] Balanced crystalloids may be preferable to normal saline in critically ill patients in intensive care.[161]

The Surviving Sepsis Campaign advises against the use of solutions containing hydroxyethyl starch (HES) for patients with sepsis and septic shock.[3] In July 2021, the US Food and Drug Administration (FDA) issued safety labeling changes for solutions containing HES stating that these products should not be used unless adequate alternative treatment is unavailable.[162] HES products are associated with adverse outcomes including kidney injury and death, particularly in critically ill patients and those with sepsis.[155][163] In view of the serious risks posed to these patient populations, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency in February 2022 recommended suspending HES solutions for infusion in Europe.[164]

Red cell or plasma transfusion may be considered to target specific deficiencies but should not be used for volume augmentation. Aggressive red cell transfusion has not been shown to improve outcomes.[165]

Patients should be monitored closely for signs of fluid overload (e.g., pulmonary or systemic edema).[166] The SSC recommends using dynamic measures to guide fluid resuscitation over physical exam or static measures alone. Dynamic parameters include response to a passive leg raise or a fluid bolus, using stroke volume (SV), stroke volume variation (SVV), pulse pressure variation (PPV), or echocardiography, where available.[3]

Glycemic control in the critically ill

There has been a shift of opinion and practice regarding glycemic control in critically ill patients from tight glycemic control to more conventional glycemic targets. Evidence suggests an increase in adverse events (e.g., severe hypoglycemia) in patients managed with tight glycemic control (target blood glucose 110 mg/dL).[167][168]

An international randomized controlled trial demonstrated an increase of 2.6 percentage points in the absolute risk of death at 90 days in the patient group managed with intensive glycemic control compared with the group managed with conventional glycemic control (blood glucose target of 180 mg/dL).[169]

The American Diabetes Association recommends a general glucose goal of 140 to180 mg/dL in critically ill diabetic patients, preferably with use of an insulin infusion protocol.[170] The SSC recommends the use of validated insulin infusion protocols targeting a blood glucose level of <180 mg/dL.[3]

Persistent hemodynamic instability

If hypotension persists, with a MAP of <65 mmHg, a vasopressor should be started.[3][70] Selection of appropriate vasoactive agents should only take place under critical care supervision and may vary according to clinician preference and local practice guidelines. Norepinephrine administered via a central venous catheter is the drug of choice as it increases MAP.[3][171][172]

Vasopressin can be added to norepinephrine to achieve the target MAP of 65 mmHg.[3][70]

All infusions of vasoactive medications to correct shock should be given via a secure catheter in a central vein with high flow, such as via a central venous catheter. Vasopressors may be started via a peripheral venous line if there is a delay in securing central venous access.[3][70]

Adjunctive therapies

In patients with low cardiac output despite adequate fluid resuscitation, inotropes (e.g., dobutamine) can be added. Low cardiac output suspected through clinical exam (prolonged capillary refill times, low urine output, poor peripheral perfusion) can be confirmed through the use of cardiac output monitoring or by sampling central venous or pulmonary arterial blood to measure oxygen saturations. Heart rate should be kept <100 bpm to minimize myocardial oxygen demand.[173]

Evidence for giving corticosteroids to patients with sepsis or septic shock is mixed and guideline recommendations vary.[3][70][174][175][176][177] [ ] [Evidence A]

One clinical practice guideline, informed by meta-analysis, reported that corticosteroids may reduce mortality (by approximately 2%) and increase the risk of neuromuscular weakness, but evidence is not definitive.[178][179] This effect was seen in sepsis, with and without shock, although the greatest benefit from corticosteroids was among those with septic shock. The clinical practice guideline concluded that both corticosteroid and non-corticosteroid management approaches are appropriate and suggested that the patient's values and preferences may guide the decision.[178] Patients who prioritize living over quality of life would likely choose to have corticosteroid treatment, whereas those who place more value on avoiding functional deterioration and maximizing quality of life than on avoiding death may be more likely to choose not to have corticosteroids.[178][179] The 2021 SSC guideline includes a weak recommendation to administer intravenous corticosteroids in adults with septic shock and an ongoing requirement for vasopressor therapy.[3]

BMJ Rapid Recommendations: corticosteroid therapy for sepsis - a clinical practice guideline Opens in new window

[Figure caption and citation for the preceding image starts]: BMJ Rapid Recommendations: intravenous corticosteroids plus usual care versus usual care onlyLamontagne F, et al. BMJ 2018;362:k3284 [Citation ends].

Bathing patients with chlorhexidine washes may reduce the risk of hospital-acquired infection.[180] Intravenous acetylcysteine as an adjuvant therapy in SIRS and sepsis has been found to be ineffective and its use is not recommended.[181]

Standard ICU supportive care

All patients with sepsis should be considered for admission to the high dependency unit or ICU.[65][166]

General intensive care measures include stress ulcer prophylaxis with H2 antagonists or proton-pump inhibitors (in patients at risk of gastrointestinal bleeding), deep venous thrombosis prophylaxis (with heparin and compression stockings), enteral or parenteral nutrition, and glycemic control.[3][182][183][184]

Transfusion of packed cells may be required; a restrictive transfusion strategy using a target hemoglobin concentration of 7 g/dL is recommended.[3][165][185][186] A higher hemoglobin level may be necessary in certain circumstances (myocardial ischemia, severe hypoxemia, or acute hemorrhage).[3][186] In the initial resuscitative phase a higher hematocrit of ≥30% may be appropriate.[65]

Patients requiring prolonged ventilatory support should receive lung-protective ventilation using minimal peak inspiratory pressures (<30 cmH₂O) and permissive hypercapnia to specifically limit pulmonary compromise.[187] FiO₂ should be titrated to lowest effective levels to prevent oxygen toxicity and maintain central venous oxygen tension. One systematic review of acutely sick adult patients, including patients with sepsis, reported increased mortality among those who received liberal oxygen supplementation compared with those who received conservative oxygen supplementation. A target SpO₂ range of 94% to 96% was suggested for all patients with critical sickness.[128]

Tracheal intubation: animated demonstration

How to insert a tracheal tube in an adult using a laryngoscope.

Bag-valve-mask ventilation: animated demonstration

How to use bag-valve-mask apparatus to deliver ventilatory support to adults. Video demonstrates the two-person technique.

Central venous catheter insertion: animated demonstration

Ultrasound-guided insertion of a non-tunnelled central venous catheter (CVC) into the right internal jugular vein using the Seldinger insertion technique.

Peripheral intravascular catheter: animated demonstration

How to insert a peripheral intravascular catheter into the dorsum of the hand.

Female urethral catheterization: animated demonstration

How to insert a urethral catheter in a female patient using sterile technique.

Male urethral catheterization: animated demonstration

How to insert a urethral catheter in a male patient using sterile technique.

For critically ill patients with fever, routine use of antipyretic medications should be avoided for the specific purpose of reducing the temperature.[82] However, where reduction of fever is required for the comfort of the patient, using antipyretics over nonpharmacologic methods to reduce body temperature is recommended.[82]

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