Sepsis and Septic Shock

Sepsis is life threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock is a subset in which underlying circulatory, cellular and metabolic abnormalities are profound enough to substantially increase mortality, identified clinically by the requirement for vasopressors to maintain a mean arterial pressure of 65 mmHg or above, together with a lactate above 2 mmol/L, in the absence of hypovolaemia.

The change in definition and why it matters

The older systemic inflammatory response syndrome criteria were abandoned as a defining feature because they are present in most hospitalised patients with any inflammatory insult and absent in around one in eight patients with sepsis who die. Organ dysfunction, not the inflammatory response, defines sepsis. Organ dysfunction is quantified by an acute rise of 2 or more points in the Sequential Organ Failure Assessment score, which covers respiration, coagulation, liver, cardiovascular, central nervous system and renal domains.

For bedside screening, a NEWS2 score of 5 or above, or clinical concern in a patient with suspected infection, is the practical trigger. Note that the older qSOFA screen has poor sensitivity and should not be used to rule out sepsis; a patient with suspected infection and a single deranged observation deserves assessment regardless.

Pathophysiology

• Pathogen associated molecular patterns activate pattern recognition receptors, releasing a cascade of cytokines including tumour necrosis factor alpha, interleukin 1 and interleukin 6.
• Endothelial injury with glycocalyx degradation produces capillary leak, interstitial oedema and intravascular volume loss despite total body fluid overload.
• Vasodilation from nitric oxide, prostacyclin and vasopressin deficiency, together with impaired vasopressor responsiveness, produces distributive shock.
• Microcirculatory failure with capillary shunting means that tissue hypoxia persists even when macrocirculatory parameters are corrected, which explains why a normal blood pressure does not mean adequate perfusion.
• Mitochondrial dysfunction impairs oxygen utilisation at the cellular level.
• Coagulopathy with activation of coagulation and inhibition of fibrinolysis produces microthrombosis and, in severe cases, disseminated intravascular coagulation.
• Sepsis induced myocardial depression with reduced ejection fraction and ventricular dilation, which is reversible over 7 to 10 days but which requires inotropic support in the acute phase.

Mortality and time dependence

Mortality is roughly 10 percent for sepsis and 30 to 40 percent or higher for septic shock. Each hour of delay in effective antimicrobial therapy in septic shock is associated with a measurable increase in mortality, which is the entire rationale for time bound bundles.

Suspicion

Any patient with a suspected or confirmed infection plus clinical concern or a NEWS2 score of 5 or above should be screened for sepsis.

Signs of organ dysfunction, which define sepsis

• Respiratory: tachypnoea, hypoxia, increased oxygen requirement.
• Cardiovascular: hypotension, tachycardia, prolonged capillary refill, mottled skin, cool peripheries, raised lactate.
• Renal: oliguria below 0.5 mL/kg/hour, rising creatinine.
• Neurological: new confusion, agitation, drowsiness, reduced Glasgow Coma Scale. In the elderly, new confusion is frequently the only feature and is routinely attributed to dementia.
• Haematological: thrombocytopenia, coagulopathy, bruising, purpura.
• Hepatic: jaundice, rising bilirubin.
• Metabolic: lactic acidosis, hyperglycaemia in a non diabetic, hypoglycaemia which is a marker of severity, particularly in children.

Signs of shock

• Mean arterial pressure below 65 mmHg.
• Tachypnoea.
• Cool clammy skin and cool peripheries.
• Hypotension and tachycardia.
• Urine output below 0.5 mL/kg/hour.
• Lactate above 2 mmol/L.

Presentations that are easily missed

• The elderly, who may be afebrile or hypothermic, with confusion or a fall as the only feature.
• The immunocompromised and neutropenic, in whom fever may be the only sign and in whom the threshold for treatment is far lower.
• Patients on beta blockers, who do not mount a tachycardia.
• Postpartum women, in whom sepsis progresses rapidly and in whom tachycardia and tachypnoea precede hypotension by a long interval.
• Children, in whom hypotension is a very late sign and in whom prolonged capillary refill, tachycardia, cool peripheries, reduced urine output and altered behaviour are the early indicators.
• Hypothermia, which is a marker of severe sepsis and carries a worse prognosis than fever.

Source identification

Examine the chest, abdomen, skin including the perineum, back and feet, all lines and catheters, surgical wounds, joints, the oral cavity and dentition, and perform a neurological examination for meningism. In endemic areas, malaria, typhoid, tuberculosis and HIV related infection must be considered. Necrotising soft tissue infection presents with pain out of proportion, skin changes that lag behind the deep destruction, crepitus and rapid progression, and it is a surgical emergency in which delay to debridement is the determinant of death.

Actions to be completed within 3 hours of identifying sepsis, and within 1 hour for septic shock

• Monitor and support airway, breathing and circulation.
• Full vital signs including blood pressure, pulse, respiratory rate, oxygen saturation, temperature and capillary blood glucose. Glucose is measured in every septic patient, since both hypoglycaemia and hyperglycaemia occur and hypoglycaemia is a marker of severity.
• Oxygen if saturation is below 94 percent, targeting 94 percent or above, and 88 to 92 percent in chronic carbon dioxide retention.
• Establish intravenous access, ideally two large bore cannulae.
• Send blood for full blood count, malaria testing where relevant, liver function, urea and electrolytes with creatinine, venous blood gas and serum lactate.
• Take two sets of blood cultures, 10 mL each, in both aerobic and anaerobic bottles, from two different sites, before antibiotics, provided this does not delay antibiotic administration by more than a few minutes. Blood culture yield falls sharply once antibiotics are given, and adequate volume is the main determinant of yield.
• Culture from the presumed source: urine, sputum, wound swab, cerebrospinal fluid, ascitic fluid, pleural fluid, joint aspirate.
• Give antibiotics.
• Give fluid.
• Measure urine output hourly, with a urinary catheter where accurate measurement is required.
• Repeat lactate within 2 to 4 hours if the initial value was above 2 mmol/L, since lactate clearance is a marker of resuscitation adequacy.

Further investigations

• Chest radiography.
• Urinalysis with microscopy and culture.
• Stool culture where diarrhoea is present.
• Lumbar puncture where meningitis is suspected, after imaging if there are focal signs, papilloedema or reduced consciousness, and never delaying antibiotics.
• Ultrasound and computed tomography to localise a collection, which should be obtained urgently since source control is time critical.
• Echocardiography where endocarditis is suspected or where cardiac dysfunction is contributing.
• Procalcitonin and C reactive protein, which are of limited value in the initial decision to treat but which are useful for guiding de escalation and duration.
• Coagulation screen and fibrinogen.
• HIV testing.

Antibiotics, which are the intervention with the greatest time dependent effect

• Give broad spectrum intravenous antibiotics immediately in septic shock, within 1 hour, and within 3 hours in sepsis without shock where the diagnosis is probable.
• Standard empirical choice for community acquired sepsis without a defined source: ceftriaxone 2 g intravenously as a stat dose, then daily.
• Add metronidazole 500 mg every 8 hours where an intra abdominal, pelvic, odontogenic or aspiration source is likely.
• Add gentamicin 5 to 7 mg/kg once daily for Gram negative cover in urinary and abdominal sepsis, with levels and renal function monitoring, and avoid in significant renal impairment.
• Suspected neutropenic sepsis, or infection acquired in hospital or in a patient admitted to hospital within the previous 3 months: imipenem 500 mg intravenously infused over 3 hours then four times daily for general sepsis, or meropenem 1 g intravenously infused over 3 hours then three times daily where central nervous system infection is possible, given better central nervous system penetration and a lower seizure risk than imipenem. Piperacillin with tazobactam 4.5 g every 6 hours is an alternative where carbapenems are being conserved.
• Extended infusion of beta lactams over 3 hours, or continuous infusion, increases the time above the minimum inhibitory concentration and is associated with improved outcomes in severe sepsis, which is why the infusion time is specified rather than a bolus.
• Add vancomycin with a loading dose of 25 to 30 mg/kg followed by maintenance targeting a trough of 15 to 20 mg/L, where methicillin resistant Staphylococcus aureus is suspected: line infection, injecting drug use, known colonisation, or severe skin and soft tissue infection.
• Add clindamycin 600 to 900 mg every 8 hours in suspected streptococcal or staphylococcal toxic shock and in necrotising infection, for its suppression of exotoxin production.
• Antimalarials without delay where malaria is possible: artesunate 2.4 mg/kg intravenously at 0, 12 and 24 hours then daily for severe malaria, which is superior to quinine.
• Antivirals and antifungals according to the clinical picture and host status.
• Give the first dose at full loading dose without renal adjustment, since underdosing the first dose is a common error; adjust subsequent doses for renal function.
• Narrow therapy as soon as cultures and sensitivities are available, and reassess daily. Duration is typically 7 days for most sources, extended for endocarditis, osteomyelitis, undrained collections and specific organisms.

Source control within 6 hours

Antibiotics do not sterilise an undrained abscess, an obstructed urinary tract, a perforated viscus, an infected line or necrotic tissue. Identify and control the source: drain collections percutaneously or surgically, remove infected lines and prostheses, relieve obstruction, and debride necrotic tissue. Necrotising fasciitis requires immediate radical debridement, repeated as necessary, and delay for imaging or for optimisation costs lives.

Fluid resuscitation

• Give at least 30 mL/kg of balanced crystalloid, preferably Ringer lactate, within the first 3 hours for hypotension or a lactate above 2 mmol/L. Balanced solutions are preferred to 0.9 percent sodium chloride, which causes hyperchloraemic acidosis and is associated with more renal dysfunction.
• Give this as repeated boluses of 250 to 500 mL with reassessment after each, rather than as an unmonitored infusion.
• After the initial 30 mL/kg, guide further fluid by dynamic measures rather than by static ones: passive leg raise with stroke volume or pulse pressure response, respiratory variation in inferior vena cava diameter on ultrasound, capillary refill time, and lactate clearance. Central venous pressure is a poor predictor of fluid responsiveness and should not be used to drive fluid administration.
• Restrict fluid and move earlier to vasopressors in patients with heart failure, end stage renal disease, severe malnutrition and severe anaemia, in whom 30 mL/kg causes pulmonary oedema. In severe malaria and in severely malnourished children, aggressive fluid bolus therapy increases mortality and fluids must be given far more cautiously.
• Albumin may be used in patients requiring large volumes of crystalloid. Starches must not be used, given renal injury and increased mortality.
• Monitor for fluid overload: rising oxygen requirement, crackles, raised jugular venous pressure and peripheral oedema.

Reassessment at 1 hour

Repeat blood pressure, mean arterial pressure, pulse, respiratory rate, oxygen saturation, temperature and serum lactate. Determine whether shock persists despite adequate fluid resuscitation, defined by any of:

• Mean arterial pressure below 65 mmHg.
• Signs of shock: tachypnoea, cool clammy skin, cool peripheries, hypotension, tachycardia.
• Urine output below 0.5 mL/kg/hour.
• Lactate above 2 mmol/L.

If none of these is present, consult a physician and consider admission for ongoing treatment. If any is present, the patient is in septic shock.

Septic shock: vasopressors

• Consult a physician and escalate to a high dependency or intensive care environment.
• Noradrenaline is the first line vasopressor, starting at 0.05 to 0.1 micrograms/kg/min and titrated up to 1.3 micrograms/kg/min or beyond, to achieve a mean arterial pressure of 65 mmHg or above.
• Adrenaline 0.05 to 0.3 micrograms/kg/min may be used in addition or as an alternative where noradrenaline is unavailable, accepting more tachyarrhythmia and a rise in lactate from beta 2 mediated glycolysis which can be misread as worsening perfusion.
• Start peripheral vasopressors through a large proximal cannula without waiting for central access in life threatening hypotension. Delaying vasopressors for central line insertion is harmful, and peripheral noradrenaline is safe for a limited period with vigilance for extravasation. Site the cannula in the antecubital fossa or larger, check it frequently, and have phentolamine available for extravasation.
• Insert central venous and arterial access as soon as feasible.
• Vasopressin 0.03 units/min may be added to reduce the noradrenaline requirement.
• Aim for a mean arterial pressure of 65 mmHg, targeting higher only in patients with chronic hypertension where a higher pressure demonstrably improves urine output and mental state.

Reassessment after vasopressors

If haemodynamic stability is achieved with adequate fluid and vasopressor therapy, admit to a high dependency or intensive care unit for continued management.

If shock persists:

• Give hydrocortisone 200 mg intravenously, either as a bolus followed by 200 mg per day by infusion or as 50 mg every 6 hours, for septic shock requiring ongoing vasopressor support. It shortens the duration of shock and time to vasopressor cessation. Taper when vasopressors are no longer required. Monitor for hyperglycaemia and hypernatraemia.
• Reassess for tissue hypoperfusion persisting despite adequate intravascular volume and an adequate mean arterial pressure, indicated by a lactate above 2 mmol/L or by decreased capillary refill and mottling.
• If hypoperfusion persists, give a dobutamine infusion up to 20 micrograms/kg/min, continuing the vasopressor, where there is myocardial dysfunction suggested by elevated cardiac filling pressures with low cardiac output, or where there are ongoing signs of hypoperfusion despite adequate volume and pressure. Echocardiography guides this decision. Watch for tachyarrhythmia and worsening hypotension from dobutamine mediated vasodilation.
• Admit to a high dependency or intensive care unit within 6 hours.

Adjunctive and supportive care

• Lung protective ventilation where mechanical ventilation is required: tidal volume 6 mL/kg predicted body weight, plateau pressure below 30 cmH2O, and appropriate positive end expiratory pressure. Prone positioning for severe acute respiratory distress syndrome.
• Glycaemic control targeting 7.8 to 10 mmol/L with insulin, avoiding both hyperglycaemia and tight control which causes hypoglycaemia.
• Venous thromboembolism prophylaxis with low molecular weight heparin unless contraindicated.
• Stress ulcer prophylaxis with a proton pump inhibitor in patients with risk factors.
• Early enteral nutrition within 48 hours.
• Transfusion threshold of 70 g/L in the absence of ischaemic heart disease, active haemorrhage or ongoing bleeding.
• Renal replacement therapy for refractory acidosis, hyperkalaemia, fluid overload and uraemia.
• Antipyretics for comfort, recognising that temperature control does not improve outcome.
• Daily review of antimicrobials for de escalation, and use of procalcitonin trends to support stopping.

Special populations

• Children: recognise that hypotension is a late and preterminal sign. Give fluid in 10 to 20 mL/kg boluses with reassessment after each, and start vasopressors early in fluid refractory shock. In settings with limited critical care, and in severe malaria and severe malnutrition, cautious fluid administration is essential since bolus therapy increases mortality in these groups.
• Pregnancy and the postpartum period: physiological tachycardia and low blood pressure mask deterioration, sepsis progresses rapidly, and group A streptococcal infection is fulminant. Involve obstetrics immediately, and consider delivery as source control in chorioamnionitis and endometritis.
• Neutropenic sepsis: treat as an emergency with antipseudomonal cover within an hour, before the neutrophil count is available.
• Asplenic patients: overwhelming post splenectomy infection with encapsulated organisms progresses within hours and requires immediate ceftriaxone.

Follow up and survivorship

Survivors carry substantial long term morbidity: physical deconditioning, cognitive impairment, post traumatic stress and increased mortality for years afterwards. Arrange structured follow up, rehabilitation, medication review, and vaccination against pneumococcus, influenza and meningococcus where relevant. Identify and address the reason the patient became septic, including immunosuppression, diabetes, HIV, alcohol use and functional decline.