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Heather Baid

, Fiona Creed

, and Jessica Hargreaves

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date: 02 July 2022


Despite an extensive amount of research aimed at understanding the pathogenesis of SIRS and sepsis and translating this into improved clinical management, mortality remains high, with up to 50% of patients still dying from severe sepsis and septic shock.1 In the UK, sepsis accounts for 37 000 deaths each year, and also carries an annual financial cost of £2 billion.2

Although the prevailing view of the pathophysiology of SIRS is of an overwhelming and inappropriately exaggerated immune response to a trigger, more recent research has shown that there may be a variety of immunological responses.3 These range from anti-inflammatory to hyper-inflammatory responses. When immunosuppression occurs as an anti-inflammatory response, there may be increased susceptibility to further infection. Stimulation of the inflammatory response will cause release and activation of a complex range of inflammatory mediators from white cells, concomitant activation of inflammatory pathways, and endothelial damage. These result in major alterations to fluid and blood flow redistribution, vasodilatation, microvascular obstruction, altered mitochondrial function, and increased or otherwise altered metabolic demand. The consequence of this may be organ dysfunction, which ranges from ‘mild’ to severe, and affects one or more organs. Box 11.1 lists the common triggers of SIRS.

Systemic inflammatory response syndrome (SIRS)

This is a non-specific generalized inflammatory response of the body to an extrinsic insult. It typically presents with two or more of the following:

  • temperature >38°C or < 36°C

  • heart rate > 90 beats/min

  • respiratory rate > 20 breaths/min or hyperventilation with PaCO2 < 4.3 kPa (32 mmHg)

  • WBC count > 12 000 cells/mm3 or < 4 000 cells/mm3, or > 10% immature forms.


This is defined as SIRS when the trigger for the massive systemic inflammation is a suspected or identified infection.

Severe sepsis

This is sepsis complicated by organ dysfunction or tissue hypoperfusion.

Septic shock

This is a type of distributive shock in which severe sepsis resulting in hypotension is unresponsive to fluid resuscitation (see Sepsis p. [link]).

Sepsis-induced hypotension

This is low blood pressure resulting from sepsis in the absence of other causes as evidenced by any of the following:

  • systolic blood pressure (SBP) < 90 mmHg

  • mean arterial pressure (MAP) < 70 mmHg

  • drop in SBP by 40 mmHg compared with patient’s baseline value.

Sepsis-induced tissue hypoperfusion

This is poor tissue perfusion as evidenced by any of the following:

  • sepsis-induced hypotension

  • hyperlactataemia

  • oliguria.


1 Levy MM. Introduction. In: R Daniels and T Nutbeam (eds) ABC of Sepsis. Wiley-Blackwell: Chichester, 2010. pp. 1–4.Find this resource:

2 The UK Sepsis Trust. Sepsis. Sepsis

3 Mitchell E and Whitehouse T. The pathophysiology of sepsis. In: R Daniels and T Nutbeam (eds) ABC of Sepsis. Wiley-Blackwell: Chichester, 2010. pp. 20–24.Find this resource:

Further reading

Daniels R et al. Sepsis: a guide for patients and relatives. UK Sepsis Trust: Sutton Coldfield, 2012. Sepsis this resource:

Global Sepsis Alliance (GSA). Sepsis

Kleinpell R et al. Implications of the new international sepsis guidelines for nursing care. American Journal of Critical Care 2013; 22: 212–22.Find this resource:

UK Sepsis Group.

UK Sepsis Trust. Sepsis

US Sepsis Alliance.

World Sepsis Day.

Sepsis presentation

The Surviving Sepsis Campaign4 defines sepsis as a documented or suspected infection with some of the clinical variables outlined in the diagnostic criteria listed in Table 11.1. Because of this extensive list of associated clinical signs and symptoms, and the numerous types of microorganisms that can potentially cause an infection, sepsis is considered to be a syndrome rather than a specific disease.

Table 11.1 Clinical presentation of sepsis (adapted from the Surviving Sepsis Campaign guidelines4)

Type of variable

Clinical findings


  • ↑ or ↓ Temperature

  • ↑ Heart rate > 90 beats/min

  • ↑ Respiratory rate

  • ↓ Blood pressure

  • Altered mental status

  • Oedema and positive fluid balance

  • Hyperglycaemia in the absence of diabetes


  • ↑ or ↑ WBC count

  • ↑ CRP

  • ↑ Procalcitonin

Organ dysfunction

  • ↓ PaO2 and ↓ SpO2

  • ↓ Urine output despite fluid resuscitation

  • ↑ Creatinine

  • Coagulation abnormalities

  • Ileus (absent bowel sounds)

  • Thrombocytopenia

  • Hyperbilirubinaemia

Tissue perfusion

  • ↑ Lactate

  • ↓ Capillary refill or mottling

Assessment findings

In addition to the clinical signs and symptoms listed in Table 11.1, other findings in a patient with sepsis may include:

  • ↓ systemic vascular resistance (SVR)

  • ↓ stroke volume

  • ↓ central venous pressure (CVP)

  • relative hypovolaemia despite oedema (third spacing)

  • impaired tissue oxygen utilization (↑ lactate and i SVO2)

  • ↓ SVO2 if tissues are extracting high levels of oxygen

  • acidosis.

Further physical assessment and haemodynamic monitoring findings depend on the progression of sepsis as the patient moves from the hyperdynamic state of early sepsis to a hypodynamic presentation (see Table 11.2). Early sepsis is typical of a distributive type of shock in which the initial clinical problem is a reduced afterload from the systemic vasodilation. Preload is relatively low as a result, and the cardiac output may be high or normal if the patient’s cardiac function is capable of increasing inotropy as a compensation response.

Table 11.2 Comparison of early and late sepsis

Early sepsis: hyperdynamic

Late sepsis: hypodynamic





Bounding pulse

Thready pulse

↑ Respiratory rate


↑ Cardiac output (or normal)

↓ Cardiac output

If the infective cause of the sepsis is not resolved, the body’s compensation mechanisms begin to fail. Myocardial depression may also result from the inflammatory processes of the SIRS response. As the sepsis progresses, the patient becomes cooler, with a reduced cardiac output.


4 Dellinger RP et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Critical Care Medicine 2013; 41: 580–637.Find this resource:

Severe sepsis presentation

Sepsis is considered to be a critical and serious problem when the severity increases to the point of organ dysfunction or tissue hypo-perfusion.

The diagnostic criteria for severe sepsis in the guidelines of the Surviving Sepsis Campaign5 include:

  • sepsis-induced hypotension

  • lactate levels above upper limit of laboratory normal reference range

  • urine output < 0.5 mL/kg/h for > 2 h despite fluid resuscitation

  • acute lung injury: PaO2/FiO2 < 250 in the absence of pneumonia

  • acute lung injury: PaO2/FiO2 < 200 in the presence of pneumonia

  • creatinine > 2.0 mg/dL (176.8 µmol/L)

  • bilirubin > 2 mg/dL (34.2 µmol/L)

  • platelets < 100 000/µL

  • coagulopathy (INR > 1.5).


5 Dellinger RP et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Critical Care Medicine 2013; 41: 580–637.Find this resource:

Neutropenic sepsis


A neutrophil is a type of white blood cell that plays an important role in the inflammatory response to fighting off microorganisms. Patients with a low neutrophil count (< 1.0 × 109/L) are therefore significantly at risk of developing infections because of their immunocompromised state. If the infection of a patient with neutropenia results in sepsis, neutropenic sepsis occurs. The typical causes of neutropenia are listed in Box 11.2.

Patients who are receiving chemotherapy have an even higher risk of neutropenic sepsis if any of the following circumstances are also present:6

  • time period of 7–10 days after chemotherapy administration

  • previous or multiple chemotherapy treatments

  • haematological conditions

  • invasive intravenous device

  • elderly age group

  • comorbidities

  • advanced cancer

  • general poor health

  • patients on clinical drug trials.

Patients with neutropenic sepsis can initially present with quite vague symptoms and appear to be ‘well’ with only mild tachycardia or hypotension. However, once the compensation mechanisms begin to fail, severe sepsis and septic shock can develop extremely quickly because of the lack of neutrophils to manage the infection.


6 Barrett K and Dikken C. Neutropenic sepsis: preventing an avoidable tragedy. Journal of Paramedic Practice 2011; 3: 116–22.Find this resource:

Further reading

National Institute for Health and Care Excellence (NICE). Neutropenic Sepsis: prevention and management of neutropenic sepsis in cancer patients. CG151. NICE: London, 2012. this resource:

Sepsis 6

The Sepsis 6 is a list of key interventions for improving patient outcome. They should be completed in a timely manner, ideally within the first hour after sepsis is diagnosed. Based on the Surviving Sepsis Campaign guidelines, the Sepsis 6 offers a simplified pathway relevant to the ward setting, and serves as a reminder to critical care clinicians of the fundamental actions necessary to prevent the development of severe sepsis and septic shock.7

Sepsis 6 interventions

  • High-flow oxygen.

  • Blood cultures.

  • Antibiotics.

  • Lactate and FBC.

  • IV fluid administration.

  • Check urine output hourly.


7 Daniels R et al. The sepsis six and the severe sepsis resuscitation bundle: a prospective observational cohort study. Emergency Medicine Journal 2011; 28: 507–12.Find this resource:

Early goal-directed therapy

The concept of early goal-directed therapy was introduced in 2001 by Rivers and colleagues,8 and involved actively attempting to correct preload, afterload, and contractility in patients with severe sepsis or septic shock. This was achieved by aiming for normal values of the specific resuscitation end points of ScVO2, lactate, base deficit, and pH in an attempt to balance oxygen delivery with oxygen demand. The study by Rivers and colleagues8 demonstrated that patients with sepsis who had early goal-directed therapy initiated on arrival at hospital had a reduced mortality (P = 0.0009) and less severe organ dysfunction (P < 0.001) compared with patients who received standard therapy. However, there has been criticism of their study because it was a single-centre trial and did not clearly show whether the results were due to the therapy as a whole or to individualized components.9 Recently, three large multi-centred studies regarding the effectiveness of early goal directed therapy have shown different results to the Rivers study including: Protocolized management in sepsis (PROMISE)10, Australasian resuscitation in sepsis evaluation (ARISE)11 and Protocol-based care for early septic shock (ProCESS)12. In all three of these trials, aggressive early goal directed therapy care with specific protocols for sepsis did not improve patient outcomes compared with ‘usual care’. What constitutes ‘usual care’ has changed greatly since the original Rivers study in 2001 because of the wide awareness of the Surviving Sepsis Campaign principles which may account for this lack of difference in outcomes.13 Nevertheless, the findings from PROMISE, ARISE and ProCESS have prompted debate and re-evaluation of the role of early goal directed therapy for septic patients.


8 Rivers E et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. New England Journal of Medicine 2001; 345: 1368-1377.Find this resource:

9 Marik PE. Surviving sepsis: going beyond the guidelines. Annals of Intensive Care 2011; 1: 17.Find this resource:

10 Mouncey PR, Osborn TM, Power GS et al. Trial of early, goal-directed resuscitation for septic shock. The New England Journal of Medicine 2015; 372: 1301–11.Find this resource:

11 The ARISE Investigators and the ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock The New England Journal of Medicine 2014; 371: 1496–506.Find this resource:

12 The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. The New England Journal of Medicine 2014; 370: 1683–93.Find this resource:

Sepsis care bundles

The Surviving Sepsis Campaign13 has provided two different care bundles for patients with sepsis to standardize practice and ensure that priority actions are completed as early as possible. Time zero is considered to be the point at which the clinical findings of sepsis initially present.

Complete within the first 3 hours

  • Lactate measurement.

  • Blood cultures prior to antibiotics.

  • Broad-spectrum antibiotics.

  • Crystalloid 30 mL/kg for hypotension or lactate ≥ 4 mmol/L.

Complete within the first 6 hours

  • Vasopressor for hypotension that is unresponsive to initial fluid resuscitation to maintain MAP at ≥ 65 mmHg.

  • If hypotension persists despite volume resuscitation (septic shock) or initial lactate > 4 mmol/L, reassess volume status and tissue perfusion.

  • Remeasure lactate if levels were previously high.


13 Dellinger RP et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Critical Care Medicine 2013; 41: 580–637.Find this resource:

Management of severe sepsis

The Surviving Sepsis Campaign guidelines for the management of severe sepsis and septic shock14 provide a comprehensive overview of various aspects of care, which will now be summarized, highlighting the most relevant aspects for critical care nursing practice.

Initial resuscitation and infection issues

Initial resuscitation

During the first 6 h of resuscitation of a patient with sepsis-induced hypotension, a protocolized approach may be used to guide care, which is aimed at achieving the following goals:

  • CVP 8–12 mmHg

  • MAP ≥ 65 mmHg

  • urine output 0.5 mL/kg/h

  • ScVO2 ≥ 70% or SVO2 ≥ 65%.

Resuscitation should also be tailored to achieving a normal lactate level if hypoperfusion has caused an elevated lactate level.

Screening and performance improvement

Early recognition of sepsis is more likely if sepsis screening tools are used to identify patients who have a potential or actual infection. If sepsis is detected early on using this type of screening, the sepsis care bundles can then be initiated as soon as possible.

Performance improvement efforts in relation to multidisciplinary actions to improve outcomes for patients with sepsis can include activities such as sepsis-related education programmes, protocols, and auditing. Feedback for all members of the critical care team about local data related to septic patients and areas for further improvement of sepsis care is also important.


Before the initiation of antibiotic therapy, cultures should be taken from potential sources of infection, such as:

  • blood (two separate cultures for both aerobic and anaerobic bottles)

  • urine

  • sputum

  • other potential areas of infection (e.g. wounds, cerebrospinal fluid).

Further investigations to identify an infection may also be required (e.g. X-ray, CT scan, ultrasound, or MRI).

Antimicrobial therapy

The specific antimicrobial agent that is needed for a particular patient with sepsis will depend on the type of pathogen that is causing the infection (e.g. bacteria, virus, or fungus). Antimicrobial therapy should begin within the first hour after identifying severe sepsis or septic shock, and should initially adopt an empirical anti-infective approach, until the laboratory results have confirmed the type and source of infection. Daily review of antimicrobial therapy is necessary to ensure discontinuation when clinically appropriate.

Source control

Once the location of the infection that is causing sepsis has been identified, interventions should be implemented that limit the impact and spread of the infection from this source (e.g. drainage of an abscess, debridement of necrotic tissue, or removal of invasive devices). Intravenous access devices in particular should be removed and re-sited if they are still required.

Infection control

Infection control precautions should be maintained at all times to reduce the spread of the infection to other patients, and to prevent the introduction of new microorganisms to the septic patient. See Sepsis p. [link] for a review of infection control priorities in intensive care, including the role of selective oral decontamination and selective digestive decontamination.

Haemodynamic support

Fluid therapy

Initially, liberal amounts of intravenous fluids are typically required for sepsis-induced tissue hypoperfusion, due to the extensive vasodilation and leaky capillaries that occur as a result of the systemic inflammatory response. A 30 mL/kg crystalloid fluid challenge should be given, with further rapid administration of intravenous fluids provided as needed to achieve predefined goals (e.g. goals for pulse pressure, stroke volume variation, mean arterial pressure, heart rate, lactate concentration, and urine output). Hydroxyethyl starches should not be used, although albumin may have a role in patients who require large amounts of crystalloid fluid resuscitation (see Sepsis p. [link]). If multi-organ dysfunction syndrome (MODS) develops as the sepsis progresses, over-resuscitation can cause pulmonary oedema, acute kidney injury, and intra-abdominal hypertension. Cautious administration of intravenous fluids or fluid removal may be required for later stages of sepsis15 (see Figure 11.1).

Figure 11.1 Fluid management in patients with severe sepsis. MAP, mean arterial pressure (adapted from the three-hit model and global increased permeability syndrome)15.

Figure 11.1 Fluid management in patients with severe sepsis. MAP, mean arterial pressure (adapted from the three-hit model and global increased permeability syndrome)15.


  • The target mean arterial pressure (MAP) should initially be 65 mmHg, and then be evaluated to establish which MAP is needed to achieve resuscitation end points (e.g. lactate, signs of skin perfusion, mental status, urine output).

  • Noradrenaline infusion is the vasopressor of choice for sepsis-induced hypotension.

  • Adrenaline infusion can be considered if noradrenaline is insufficient to maintain an adequate MAP.

  • Vasopressin infusion at 0.03 units/min can also supplement noradrenaline, either to help to reach the target MAP or to decrease the amount of noradrenaline needed.

Inotropic therapy

  • Dobutamine infusion up to 20 mcg/kg/min should be administered if there is evidence of:

    • myocardial dysfunction (e.g. low cardiac output, increased cardiac filling pressures)

    • continual hypoperfusion even when the target MAP has been reached by using fluid resuscitation and vasopressor therapy.

  • Inotropes should not be administered to elevate cardiac output to supranormal levels.


  • Intravenous hydrocortisone should only be given if fluid resuscitation and vasopressor therapy do not improve the MAP, and it should not be given in the absence of shock.

    • Administer 200 mg/day as a continuous intravenous infusion.

    • Avoid suddenly stopping hydrocortisone (taper down once vasopressors are no longer required).

Other supportive therapy

  • Blood products:

    • red blood cells only if Hb is < 7.0 g/dL

    • fresh frozen plasma should not be given in the absence of bleeding or scheduled invasive procedures

    • platelets should be given if the platelet count is < 10 × 109/L in the absence of bleeding, < 20 × 109/L if there is a risk of bleeding, or < 50 × 109/L in the presence of active bleeding, surgery, or invasive procedures.

  • Erythropoietin, antithrombin, immunoglobulins, selenium, and recombinant activated protein C should not be used as specific treatments for severe sepsis and septic shock.

  • Mechanical ventilation of sepsis-induced ARDS:

    • protective lung strategies (see Sepsis p. [link])

    • recruitment manoeuvres for severe refractory hypoxaemia

    • prone positioning for PaO2/FiO2 ≤ 100 mmHg (see Sepsis p. [link])

    • head of bed elevated to 30–45° if the patient is being mechanically ventilated

    • non-invasive ventilation as appropriate (see Sepsis p. [link])

    • weaning protocol that includes regular spontaneous breathing trials and extubation as soon as clinically feasible (see Sepsis p. [link])

    • pulmonary artery catheter should not be routinely used for sepsis-induced ARDS

    • conservative approach to fluid therapy in the absence of tissue hypoperfusion

    • β‎-2 agonists should not be used to treat sepsis-induced ARDS unless there is evidence of bronchospasm.

  • Sedation, analgesia, and neuromuscular blockade:

    • sedation should be minimized and goal directed (see Sepsis p. [link])

    • neuromuscular blocking agents (NMBAs) should be avoided if possible in the absence of ARDS, but are indicated for early sepsis-induced ARDS and PaO2/FiO2 < 150 mmHg (see Sepsis p. [link])

    • train-of-four monitoring for patients who are receiving NMBAs (see Sepsis p. [link]).

  • Insulin infusion to maintain blood glucose concentration at ≤ 10 mmol/L.

  • Renal replacement therapy as required using continuous therapy for haemodynamically unstable septic patients (see Sepsis p. [link]).

  • Bicarbonate therapy should not be used to improve haemodynamic status or for lactic acidosis with pH ≥ 7.15.

  • DVT prophylaxis using low-molecular-weight heparin and compression devices or thromboembolic-deterrent (TED) stockings.

  • Stress ulcer prophylaxis for patients with risk factors for gastrointestinal bleeding.

  • Nutrition:

    • administer enteral or oral feeding as soon as possible, starting with low-dose feeding (up to 500 calories/day) and increasing caloric intake only as tolerated (see Sepsis p. [link])

    • instead of total parenteral nutrition (TPN) alone, use glucose and enteral nutrition or supplemental parenteral nutrition (TPN and enteral) in the first week after severe sepsis or septic shock has been identified (see Sepsis p. [link]).

  • Do not use nutrition with specific immunomodulating supplements.

  • Set goals of care and discuss the prognosis with the patient and their family as early as possible, or at least within 72 h after ICU admission.


14 Dellinger RP et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Critical Care Medicine 2013; 41: 580–637.Find this resource:

15 Cordemans C et al. Fluid management in critically ill patients: the role of extravascular lung water, abdominal hypertension, capillary leak, and fluid balance. Annals of Intensive Care 2012; 2 (Suppl. 1): S1. Sepsis