Sepsis: Recognition and Management

Introduction

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.¹ The definition matters because it moves the focus away from the infection itself and onto the host's response to it: two patients with the same organism and the same focus can have entirely different outcomes, because sepsis is what happens when the immune and coagulation systems that are meant to contain an infection instead cause collateral damage throughout the body.

Septic shock is the subset of sepsis in which circulatory, cellular and metabolic abnormalities are profound enough to substantially increase mortality. Clinically it is identified by persisting hypotension requiring vasopressors to maintain a mean arterial pressure of 65 mmHg or above, together with a serum lactate greater than 2 mmol/L, despite adequate fluid resuscitation.¹

Sepsis is common and dangerous: it affects an estimated 245,000 people a year in the UK and contributes to around 48,000 deaths, a toll comparable to the combined total from bowel, breast and prostate cancer.² It is also entirely time-critical - every hour that appropriate antibiotics are delayed after the onset of septic shock is associated with a measurable rise in mortality - which is why it dominates acute care teaching and is a near-certain OSCE and written exam topic.

Pathophysiology

Pathogen molecules are recognised by pattern-recognition receptors on innate immune cells, triggering release of pro-inflammatory cytokines including TNF-alpha, IL-1 and IL-6. In a contained, local infection this response is proportionate and helpful. In sepsis it becomes systemic and dysregulated.

• Vasodilatation - widespread nitric oxide release drops systemic vascular resistance, producing warm, flushed peripheries early on ("warm shock")
• Capillary leak - endothelial injury lets fluid escape into the interstitium, causing relative hypovolaemia despite a normal or expanded total body fluid volume
• Coagulation activation - tissue factor exposure triggers widespread microvascular thrombosis, consuming clotting factors and platelets and predisposing to disseminated intravascular coagulation
• Myocardial depression - circulating cytokines directly impair contractility, even before hypoperfusion itself contributes
• Mitochondrial dysfunction - cells become unable to use oxygen effectively even when it is delivered, so tissue hypoxia can persist despite a normal or high cardiac output

The net effect is a fall in effective circulating volume and systemic vascular resistance that outstrips any compensatory rise in cardiac output, producing tissue hypoperfusion and, if uncorrected, progressive organ dysfunction: acute kidney injury, hepatic dysfunction, respiratory failure, encephalopathy and myocardial depression. Untreated, warm shock progresses to cold, vasoconstricted shock as compensatory mechanisms fail.

Causes and risk factors

Any infection can cause sepsis. The commonest sources are the respiratory tract, urinary tract, abdomen and skin/soft tissue, and in a hospitalised patient, vascular access devices. Gram-positive and Gram-negative bacteria are the commonest causes; fungal sepsis occurs mainly in the immunocompromised or those with prolonged broad-spectrum antibiotic exposure or central lines.

• Age under 1 year or over 75 years, or frailty
• Immunosuppression - chemotherapy, long-term steroids, biologics, asplenia, HIV
• Diabetes mellitus
• Recent surgery, invasive procedures or trauma in the past 6 weeks
• Any breach of skin integrity - wounds, burns, pressure sores, IV drug use
• Indwelling lines, catheters or other prosthetic material
• Pregnancy, within 6 weeks postpartum, or after miscarriage or termination
• Impaired mobility or a debilitating illness

Clinical features

Sepsis has no single defining sign - it is recognised by the combination of a suspected or confirmed infection with evidence of physiological compromise. Symptoms may point to a source (cough and pleuritic pain, dysuria and loin pain, abdominal pain, a hot swollen joint, a discharging wound) but a source is not always obvious, particularly in the very young, the very old, or anyone who is immunosuppressed.

• Fever or hypothermia - a temperature below 36°C is a marker of severity, not reassurance
• Tachycardia and tachypnoea
• Altered mental status, confusion or reduced consciousness - often the presenting feature in older adults
• Reduced urine output
• Non-blanching rash, mottled or ashen skin, or peripheral cyanosis
• Prolonged capillary refill time and cool peripheries as shock progresses
• Non-specific deterioration: 'just not right', poor feeding in an infant, new inability to stand

Recognition and risk stratification

NEWS2 (the National Early Warning Score) is used on every adult ward and in ambulance and ED triage to flag physiological deterioration from any cause, sepsis included, and to trigger an escalation response.³ It is not sepsis-specific, but a high or rapidly rising NEWS2 score in a patient with a possible infection should immediately prompt a formal sepsis risk assessment.

NICE NG51 sets out the risk stratification used once infection is suspected.⁴ Patients with any high-risk criterion need the Sepsis Six within 1 hour; those with moderate-to-high risk features need same-priority senior review and, generally, treatment within 3 hours.

Equivalent age-specific criteria exist for children under the NICE pathway; a systematically unwell, floppy or unrousable child, one with a capillary refill ≥3 seconds, or one with grunting, apnoea or a non-blanching rash all meet high-risk thresholds and need the same urgency.

Differential diagnosis

Several conditions mimic sepsis by causing a systemic inflammatory response or shock without an infective driver, and some directly complicate it:

• Non-infective SIRS: acute pancreatitis, major trauma, burns, or a post-surgical inflammatory response
• Other causes of shock: cardiogenic (look for a cardiac history and signs of failure), hypovolaemic (bleeding), anaphylactic (exposure, urticaria, angioedema, wheeze)
• Adrenal crisis: hypotension with hyponatraemia and hyperkalaemia, often in a patient on long-term steroids
• Thyroid storm: fever, tachycardia and agitation in known or unrecognised hyperthyroidism
• Drug reactions: neuroleptic malignant syndrome, serotonin syndrome or malignant hyperthermia, each with a relevant drug history and additional features such as rigidity or clonus
• Transfusion reaction in a patient who has recently received blood products

None of these should delay treating suspected sepsis: where there is diagnostic uncertainty and the patient is deteriorating, the safer default is to treat for sepsis while pursuing the alternative diagnosis in parallel.

Investigations

Investigation runs alongside treatment, not before it - taking blood cultures should never delay the first dose of antibiotics by more than a few minutes.

• Blood cultures - at least one set, ideally two from different sites, taken before antibiotics wherever this does not cause delay
• Venous or arterial blood gas with lactate - the single most useful severity marker, and repeated to track response to treatment
• FBC, U&Es, LFTs, CRP and clotting screen - baseline organ function and a first look for DIC
• Glucose - hyperglycaemia is common even without known diabetes
• Urinalysis and culture, sputum culture, wound or line-tip culture, stool culture - directed by the likely source
• Imaging - chest X-ray, abdominal or pelvic imaging, or CT depending on the suspected focus
• Source-specific sampling - joint aspiration, CSF, or drainage fluid where indicated, ideally before or without delaying the first antibiotic dose

A source should always be actively sought. In roughly a third of cases of sepsis no organism is ever isolated, which does not change the need for treatment but does mean antibiotic choice and duration rest partly on clinical judgement and local epidemiology.

Management

Management starts with an ABCDE assessment and runs in parallel with, not after, investigation. The core of initial treatment is the Sepsis Six: three tests and three treatments, all delivered within 1 hour of recognising high-risk sepsis.⁵

Antibiotics

Empirical antibiotic choice follows local trust guidelines, which weigh the likely source, local resistance patterns and any allergy or recent antibiotic exposure. Broad-spectrum cover is started immediately and de-escalated once culture and sensitivity results return - the priority in the first hour is speed, not precision. Every hour of delay to appropriate antibiotics after the onset of septic shock is associated with increased mortality.

Fluid resuscitation

An initial crystalloid bolus (for example 500 mL over under 15 minutes, or 250-500 mL boluses in patients at risk of fluid overload such as those with heart failure or end-stage renal disease) is given and the response reassessed - heart rate, blood pressure, urine output, lactate trend and signs of fluid overload. Further boluses are given up to a total of around 30 mL/kg while monitoring for the point at which the patient stops responding, at which point ongoing fluid without response risks harm rather than benefit.

Escalation and septic shock

If hypotension or a raised lactate persists despite adequate fluid resuscitation, this is septic shock, and the patient needs urgent critical care review for vasopressor support - first-line noradrenaline, delivered via a central line, titrated to a mean arterial pressure of at least 65 mmHg. Refractory shock may need the addition of vasopressin or hydrocortisone, and some patients need invasive ventilation and renal replacement therapy as part of multi-organ support.

Source control

Antibiotics cannot sterilise an undrained abscess, an infected prosthesis or dead tissue. Source control - draining a collection, removing an infected line or catheter, or surgical debridement - is as essential as antibiotics and fluids, and delaying it while pursuing purely medical management is a common and dangerous error.

Complications

Sepsis can affect every organ system, and the pattern of dysfunction determines the acute picture and the long-term outlook:

• Acute kidney injury - from hypoperfusion and direct inflammatory injury; may need renal replacement therapy
• Acute respiratory distress syndrome - from systemic inflammation acting on the pulmonary capillary bed
• Disseminated intravascular coagulation - simultaneous widespread clotting and bleeding as clotting factors and platelets are consumed
• Myocardial depression - reduced ejection fraction that is usually reversible over days to weeks
• Multi-organ dysfunction syndrome - the cumulative failure of two or more systems, and the principal cause of death
• Post-sepsis syndrome - persistent fatigue, cognitive impairment, muscle weakness and psychological effects that can last months after apparent recovery, disproportionately affecting ICU survivors

Red flags

Prognosis

Outcome depends heavily on how quickly sepsis is recognised and treated, on the severity of organ dysfunction at presentation, and on the patient's baseline health. Mortality in sepsis without shock is in the region of 10%, rising sharply once septic shock develops, where reported mortality is commonly 30-40% depending on the population studied.

Survivors, particularly those who needed critical care, are at risk of post-sepsis syndrome and of a persistently increased risk of further infection, cardiovascular events and death for months to years afterwards, which is why safety-netting and follow-up matter well beyond hospital discharge.