Suspected sepsis

Sepsis is life threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock is sepsis with persistent hypotension needing vasopressors to keep mean arterial pressure at 65 mmHg or more and with a lactate over 2 mmol/L despite adequate fluid. Early recognition, timely antimicrobials and source control reduce mortality, and each hour of delay in shock raises it.

Definitions in use.

• Organ dysfunction is an acute rise of 2 or more points in the Sequential Organ Failure Assessment score (PaO2/FiO2, platelets, bilirubin, mean pressure or vasopressor need, Glasgow Coma Scale, creatinine or urine output).
• The quick bedside score (qSOFA) of 2 or more of respiratory rate 22 breaths/min or over, altered mentation, systolic pressure 100 mmHg or under suggests higher risk but lacks sensitivity and is not a screening test on its own.
• Early warning scores (a total of 5 or more, or a single parameter score of 3) prompt urgent review.

Sources. Lung, urinary tract, abdomen and biliary tract, skin and soft tissue, central nervous system, bone and joint, bloodstream (including intravascular devices and endocarditis), obstetric and gynaecological, and unknown. Community acquired and hospital acquired sepsis carry different organisms and resistance.

Mechanisms. Pathogen products trigger innate immune activation, endothelial injury with capillary leak, vasodilatation, myocardial depression, microvascular thrombosis, mitochondrial dysfunction and immune paralysis.

Key distinctions. Fever may be absent in older adults, neonates, immunosuppression, alcohol misuse, uraemia and with corticosteroid or antipyretic use. Hypothermia indicates a worse prognosis. Many non-infectious conditions mimic sepsis, so reassess the diagnosis within the first hours.

History. Onset and tempo, fever and rigors, source symptoms (cough, dysuria, abdominal pain, wound, headache and neck stiffness, line site, joint pain, vaginal discharge, recent delivery or procedure). Recent hospitalisation or antibiotics, travel and exposures (malaria, typhoid, dengue, leptospirosis, melioidosis), HIV status, immunosuppression, diabetes, alcohol, splenectomy, intravenous drug use, indwelling devices, and pregnancy.

Examination.

• Temperature, heart rate, respiratory rate, blood pressure, capillary refill, mottling score, saturation, urine output, mental state.
• Source search: chest signs, abdomen (peritonism), skin and soft tissue (cellulitis, necrotising signs, abscess), joints, spine, line sites, mouth and teeth, ears, perineum, vagina and rectum, pressure areas and cardiac murmurs.
• Rash: petechial or purpuric (meningococcus), erythroderma (toxic shock), eschar (rickettsial disease).

Red flags.

• Systolic pressure under 90 mmHg, lactate over 2 mmol/L (over 4 mmol/L high risk), respiratory rate over 25 breaths/min, new confusion, urine output under 0.5 mL/kg/hour, mottled skin, non-blanching rash, bilirubin or creatinine rising, platelets under 100 x 10^9/L, or hypothermia.
• Neutropenia (neutrophils under 0.5 x 10^9/L), splenectomy, transplant or chemotherapy.
• Necrotising soft tissue infection (pain out of proportion, crepitus, rapid spread, bullae).
• Pregnancy or within 6 weeks of delivery, age under 1 year or over 75 years.

Special groups.

• Children: tachycardia, prolonged capillary refill and poor feeding come first, and hypotension is late.
• Pregnancy and postpartum: sepsis can progress rapidly. Take cultures, treat early and involve obstetrics.
• Older adults: confusion, falls or general decline can be the only sign.
• Immunosuppressed and HIV positive patients: consider opportunistic and atypical organisms, tuberculosis and fungal infection.
• Region specific: consider malaria, typhoid, leptospirosis, melioidosis, rickettsial infection and dengue in endemic or travel settings.

Common sources and syndromes.

• Pneumonia, urinary tract infection with pyelonephritis, urosepsis with obstruction, cholangitis, cholecystitis, intra-abdominal abscess, perforated viscus with peritonitis, diverticulitis, appendicitis.
• Cellulitis, necrotising fasciitis, toxic shock syndrome, septic arthritis, osteomyelitis, spinal epidural abscess, infective endocarditis, catheter related bloodstream infection.
• Bacterial meningitis, encephalitis, brain abscess, pelvic inflammatory disease, chorioamnionitis, endometritis, septic abortion, mastitis.
• Meningococcal disease, pneumococcal sepsis in asplenia, febrile neutropenia, Clostridioides difficile colitis.

Region and exposure specific infections. Malaria, typhoid fever, dengue, leptospirosis, melioidosis, scrub typhus and other rickettsial infections, brucellosis, tuberculosis (disseminated), invasive amoebiasis, viral haemorrhagic fevers, cholera, COVID-19 and influenza.

Non-infectious mimics. Acute pancreatitis, pulmonary embolism, myocardial infarction, diabetic ketoacidosis, adrenal crisis, thyrotoxic storm, anaphylaxis, drug fever, neuroleptic malignant syndrome, serotonin syndrome, alcohol withdrawal, transfusion reaction. Haemophagocytic lymphohistiocytosis, vasculitis, systemic lupus erythematosus flare, adult onset Still disease, tumour lysis syndrome, malignancy, heat stroke, burns, trauma and cardiogenic shock.

Immediate (within the first hour).

• Blood gas with lactate (over 2 mmol/L abnormal, over 4 mmol/L severe; repeat at 2 hours if raised), capillary glucose.
• Blood cultures (2 sets) before antimicrobials if this causes no more than 45 minutes delay, plus cultures from the suspected source: urine, sputum, wound, cerebrospinal fluid, joint aspirate, line tip, stool, vaginal swab, malaria film or rapid test, dengue test, and HIV test.
• Full blood count with differential, CRP, procalcitonin where available (supports but does not decide treatment), urea, creatinine, electrolytes, liver tests, bilirubin, coagulation with fibrinogen (disseminated intravascular coagulation), troponin, creatine kinase, group and save, urinalysis, pregnancy test and ECG.

Source identification.

• Chest radiograph, urine microscopy and culture, and abdominal ultrasound for obstruction or abscess.
• CT chest, abdomen and pelvis for unclear sources or suspected perforation, collection or ischaemia.
• Echocardiography for suspected endocarditis, lumbar puncture for suspected meningitis (after CT when indicated, never delaying antibiotics), MRI for spinal infection, and surgical exploration for necrotising infection (a clinical diagnosis, so do not wait for imaging).

Severity scoring. Calculate the Sequential Organ Failure Assessment score or an early warning score, monitor lactate, and repeat measurements after treatment.

Limitations. Cultures are negative in many patients with sepsis, and results take 24 to 48 hours. Procalcitonin rises in non-infectious inflammation (surgery, burns, trauma) and falls late in some infections. Lactate rises with adrenaline, seizures, liver failure, metformin and thiamine deficiency. Imaging should not delay antimicrobials or source control in shock.

Time targets. Start antimicrobials within 1 hour when shock is present or sepsis is probable, and within 3 hours when sepsis is possible and a rapid assessment is needed to decide, after taking cultures.

Resuscitation.

• Oxygen to saturation 94 to 98% (88 to 92% in those at risk of hypercapnic respiratory failure), two large bore cannulae or intraosseous access, continuous monitoring, and a urinary catheter.
• Fluids:
  • Balanced crystalloid 500 mL bolus over 15 minutes for hypotension or lactate 4 mmol/L or more, up to 30 mL/kg within the first 3 hours (evidence for this volume is limited), reassessing perfusion, lung signs and ultrasound after each bolus.
  • Stop fluids when there is no response or signs of overload.
  • Avoid starch and use albumin only for large volume needs (evidence is limited).
• Vasopressors for persistent hypotension (mean pressure under 65 mmHg after fluids, or during fluid resuscitation if life threatening):
  • Noradrenaline 0.05 to 0.5 micrograms/kg/min IV titrated to a mean arterial pressure of 65 mmHg or more, through a large peripheral vein if central access is delayed.
  • Continuous arterial pressure; monitor limb perfusion and extravasation; doses over 0.5 micrograms/kg/min need critical care direction.
  • Vasopressin 0.03 units/min IV fixed rate, added when noradrenaline reaches 0.25 to 0.5 micrograms/kg/min; maximum 0.04 units/min; monitor digital ischaemia and sodium.
  • Adrenaline 0.05 to 0.5 micrograms/kg/min as a further agent, and dobutamine 2.5 to 20 micrograms/kg/min for persistent hypoperfusion with low cardiac output (monitor arrhythmia).
• Hydrocortisone 50 mg IV every 6 hours (or 200 mg over 24 hours) when noradrenaline stays over 0.25 micrograms/kg/min for at least 4 hours; monitor glucose and sodium; stop when vasopressors are weaned.
• Targets: lactate falling, capillary refill under 3 seconds, urine output 0.5 mL/kg/hour or more, improved mentation.

Source control. Within 6 to 12 hours when feasible: drain abscesses and empyema, relieve urinary or biliary obstruction (nephrostomy, stent, ERCP), debride necrotising infection, remove infected lines and devices, and operate for perforation, ischaemia or peritonitis. Early surgical review for suspected necrotising infection.

Antimicrobials (choose by suspected source, local resistance, previous cultures, allergy, kidney and liver function, and risk of resistant organisms; narrow when cultures return).

• Community acquired sepsis, source unknown or respiratory, urinary or skin:
  • Ceftriaxone 2 g IV once daily (maximum 4 g daily); monitor creatinine, liver tests and diarrhoea.
  • Add azithromycin 500 mg IV once daily for 3 days for severe pneumonia with atypical cover (monitor QTc; no adjustment in mild kidney impairment).
• Hospital acquired, immunocompromised or intra-abdominal sepsis:
  • Piperacillin with tazobactam 4.5 g IV every 6 hours (maximum 18 g piperacillin daily).
  • Reduce to 4.5 g every 8 hours for CrCl 20 to 40 mL/min and every 12 hours for CrCl under 20 mL/min.
  • Monitor creatinine and full blood count.
• Resistant organism risk (previous extended spectrum beta lactamase, recent broad spectrum antibiotics, hospital stay):
  • Meropenem 1 g IV every 8 hours (1 g every 12 hours for CrCl 26 to 50 mL/min, 500 mg every 12 hours for CrCl 10 to 25 mL/min, and 500 mg every 24 hours under 10 mL/min).
  • Monitor seizures, creatinine and Clostridioides difficile infection.
• Methicillin resistant Staphylococcus aureus risk (previous isolation, intravenous drug use, line infection, severe skin infection):
  • Add vancomycin 25 mg/kg IV loading dose (maximum 3 g), then maintenance dosed by kidney function and levels (usually 15 to 20 mg/kg every 8 to 12 hours).
  • Maintain trough 15 to 20 mg/L or an area under the curve of 400 to 600 mg x hour/L.
  • Monitor creatinine and levels daily; slow infusion (maximum 10 mg/min) to avoid infusion reactions.
• Necrotising soft tissue infection and toxic shock:
  • Add clindamycin 600 to 900 mg IV every 8 hours (maximum 2.7 g daily) to stop toxin production.
  • Give with piperacillin with tazobactam 4.5 g IV every 6 hours or meropenem 1 g IV every 8 hours.
  • Doses adjusted for kidney function: piperacillin with tazobactam every 8 hours for CrCl 20 to 40 mL/min and every 12 hours under 20 mL/min.
  • Meropenem 1 g every 12 hours for CrCl 26 to 50 mL/min, 500 mg every 12 hours for CrCl 10 to 25 mL/min.
  • Consider intravenous immunoglobulin 1 to 2 g/kg as a single dose in streptococcal toxic shock (evidence is limited).
• Intra-abdominal source with ceftriaxone: add metronidazole 500 mg IV every 8 hours (maximum 1.5 g daily; monitor for neuropathy; reduce in severe liver impairment).
• Suspected meningitis or encephalitis:
  • Ceftriaxone 2 g IV every 12 hours (maximum 4 g daily) without waiting for lumbar puncture or CT.
  • Dexamethasone 10 mg IV every 6 hours for 4 days, started before or with the first antibiotic dose.
  • Add amoxicillin 2 g IV every 4 hours if aged over 60 or immunocompromised.
  • Add aciclovir 10 mg/kg IV every 8 hours when encephalitis is possible (every 12 hours for CrCl 25 to 50 mL/min, every 24 hours for CrCl 10 to 25 mL/min).
• Neutropenic sepsis:
  • Piperacillin with tazobactam 4.5 g IV every 6 hours (maximum 18 g piperacillin daily; every 8 hours for CrCl 20 to 40 mL/min and every 12 hours for CrCl under 20 mL/min), started within 1 hour.
  • Specialist direction on escalation to meropenem, vancomycin or antifungal cover for persistent shock.
• Severe malaria (travel or residence in an endemic area, or positive test):
  • Artesunate 2.4 mg/kg IV at 0, 12 and 24 hours, then once daily until oral therapy is tolerated (minimum 24 hours of IV treatment).
  • Children under 20 kg 3 mg/kg.
  • Monitor glucose every 1 to 2 hours, parasitaemia, haemoglobin and creatinine, and delayed haemolysis for up to 4 weeks.
• Region specific additions where relevant and local data supports it:
  • Doxycycline 100 mg IV or orally every 12 hours (maximum 200 mg daily; avoid in pregnancy and in children under 8 years except for rickettsial disease) for suspected scrub typhus or leptospirosis.
  • Early empiric treatment for typhoid and melioidosis under infectious diseases direction.
  • In advanced HIV infection, tuberculosis is a major cause of sepsis, and empiric antituberculous therapy is considered under specialist direction.
• Children: ceftriaxone 80 mg/kg IV once daily (maximum 4 g) within 1 hour, isotonic fluid boluses of 10 to 20 mL/kg with reassessment (10 mL/kg in settings without ventilatory support), and early vasoactive support.
• Pregnancy: ceftriaxone, piperacillin with tazobactam and meropenem can be used, and doxycycline is avoided.
• Review the regimen at 48 to 72 hours, narrow to the cultured organism, switch to oral treatment when improving, and continue for a total of 7 days for most infections (longer for undrained collections, endocarditis, bone and joint infection and bacteraemia with Staphylococcus aureus). Procalcitonin can support earlier stopping.

Supportive care.

• Transfuse red cells at haemoglobin under 70 g/L (target 70 to 90 g/L).
• Glucose 7.8 to 10 mmol/L with insulin infusion when over 10 mmol/L.
• Enoxaparin 40 mg subcutaneously once daily (20 mg if CrCl 15 to 30 mL/min; unfractionated heparin 5000 units subcutaneously every 8 to 12 hours if CrCl under 15 mL/min) for thromboprophylaxis.
• Omeprazole 20 to 40 mg daily for stress ulcer prophylaxis in patients with risk factors.
• Early enteral nutrition when tolerated.
• Sodium bicarbonate only for pH 7.20 or under with acute kidney injury (evidence is limited).
• Lung protective ventilation for respiratory failure (tidal volume 6 mL/kg ideal body weight, plateau pressure under 30 cm H2O), and renal replacement therapy for the usual indications.

Monitoring. Continuous ECG, saturation, arterial pressure, hourly urine output, lactate every 2 hours until falling, electrolytes, creatinine, glucose and blood gas every 4 to 6 hours, daily full blood count, CRP, liver tests and coagulation, and review of culture results every 12 hours.

Referral and escalation. Critical care for shock, lactate over 4 mmol/L, respiratory failure or organ support. Infectious diseases or microbiology for resistant organisms, immunosuppression, endocarditis or unclear source. Surgery, interventional radiology or urology for source control. Obstetrics for maternal sepsis, haematology for neutropenia, and palliative care when treatment goals are limited.

Admission criteria. Admit all patients with sepsis, to critical care when vasopressors, ventilation or organ support is needed. Patients with possible infection, normal observations, normal lactate and a clear source may be treated at home only after senior review, with safety netting and early follow up.

Discharge and safety netting. Discharge when afebrile for at least 24 to 48 hours, haemodynamically stable, eating and drinking, with a source controlled, oral antibiotics arranged and follow up booked. Patients and carers are told to return for fever or rigors, new confusion, breathlessness, mottled skin, reduced urine, severe pain or a spreading rash. Review for post-sepsis problems (weakness, fatigue, cognitive and psychological effects) at 4 to 6 weeks and arrange vaccination where indicated.