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'Could this be sepsis?'.

SEPSIS IS a leading cause of preventable death, the incidence of which has increased markedly over the past 40 years. While mortality rates are improving, one-fifth of patients with severe sepsis die. Early identification and intervention are key to survival--delayed care for inpatients who develop sepsis is the main reason why this group has a higher mortality rate than people admitted with sepsis. Internationally, the Surviving Sepsis Campaign promotes screening of "every patient, every shift, every day" for sepsis, while new United Kingdom guidelines recommend health practitioners ask, "Could this be sepsis?" for any patient with signs of a possible infection.

Nurses are best placed to identify sepsis early and ensure timely treatment. A thorough understanding of the events underlying development of sepsis, and its risks, will help nurses in this life-saving role. The goal is that all nurses, in all settings, consider, as a first priority, the possibility of sepsis in any infant, child or adult presenting with an infection.


The incidence of sepsis is increasing worldwide, due to ageing populations, increased disease survival, and greater recognition of the condition. The true incidence is unknown, but may range between 0.4 to 2.4 cases per 1000 people, (1,2) making it a leading cause of critical illness worldwide. (3) Sepsis mortality rates have been very high--up to 80 per cent for septic shock?--but recent data suggest the overall mortality rate is falling. Mortality rates for severe sepsis in Australia and New Zealand fell from 35 percent in 2000 to 18 per cent in 2012. (4)

Survivors of sepsis are often left with long-term cognitive, physical and psychological disabilities, along with significant social and financial costs. As incidence and survival rates increase, post-sepsis syndrome will have an increasing impact on the health system. (7) Monetary and social costs can be significantly reduced by timely identification and management of sepsis, and early, intensive rehabilitation.

The majority (70 per cent) of sepsis cases develop in the community and in long-term care facilities. Risk is increased in the very young and old, and those with compromised immune systems. One to two per cent of people admitted to hospital acutely will develop sepsis symptoms within the first two days. (8) For every hour's delay in starting antibiotics, the risk of death for patients in septic shock increases 7.6 per cent. (8) Nurses must ensure they can rapidly identify and escalate care for people in both hospital and community settings.


The definition of sepsis is changing. Before 2016, it was stratified into three main categories, plus a category of systemic inflammatory response syndrome (SIRS). Since the start of 2016, a new definition has been implemented internationally that differentiates between sepsis and uncomplicated infection, and describes only two separate clinical identities: sepsis and septic shock. (3)


Before 2016, sepsis definition were: (1,3)

Sepsis: Signs of systemic inflammation (SIRS), with proven or presumed infection.

Severe sepsis: Sepsis, accompanied by life-threatening organ dysfunction.

Septic shock: Sepsis-induced hypotension, despite adequate fluid resuscitation.

The new Sepsis-3 definitions are:

Sepsis: Life-threatening organ dysfunction caused by dysregulated responses to infection.

Septic shock: A subset of sepsis with profound abnormalities of circulation and cellular/metabolic function.

Sepsis is now the equivalent of severe sepsis in the old definition because sepsis is more than the presence of infection (see Figure 1, p21). It is better described as a severe infection with some degree of organ dysfunction (low blood pressure, reduced urine output, etc). (3,9)

Both definitions include the presence of infection, but many patients who are clinically identified as being in septic shock have no identified causative infection. This may be due to microbiological diagnostic techniques--not all microorganisms can be identified using standard laboratory practices--but can also occur where there is a non-infectious trigger of shock, such as pancreatitis or tissue ischaemia. Differentiating between septic and other forms of shock is important for clinical management, but in practice may be very difficult during the essential first hour of treatment. (1)


SIRS has been used in the past to predict and diagnose sepsis, but has been eliminated from the new definition of sepsis. SIRS is defined as two or more of: (1)

* Hypo- or hyperthermia (<36[degrees]C or >38[degrees]C)

* Tachycardia (>90 beats/minute)

* Tachypnoea (>20 breaths per minute) or an arterial carbon dioxide concentration of <32 mmHg

* White blood cell count >12 x [10.sup.9]/L or <4 x [10.sup.9]/L.

However, SIRS is common in hospitalised patients, even in the absence of infection, and may also be absent in some patients with sepsis, so it lacks specificity. (10) The new definitions of sepsis use a more specific assessment tool--SOFA (sequential organ failure assessment). The quick version of this tool (qSOFA) can be used at the bedside in the ward or emergency department. With qSOFA, two out of the three following variables must be met: (10)

* Hypotension (systolic BP [less than or equal to] 100mgHg).

* Altered mental status (Glasgow Coma Score <15).

* Tachypnoea ([greater than or equal to] 22 breaths/minute).

The full SOFA assessment includes renal function, oxygenation and coagulation status, and liver function. (9) This is used in many critical care settings, although the Acute Physiology, Age and Chronic Health Evaluation (APACHE II) is more common in Australia and New Zealand. SOFA has been well validated in clinical use, but qSOFA requires further validation. (9)


Sepsis arises when the complex pro-inflammatory and anti-inflammatory responses to infectious microorganisms become dysregulated. Infections trigger a complex and rapidly changing cascade of cytokines and other signalling molecules in the body that depends, at least in part, on the nature of the microorganism triggering the response. (1)

In a contained infection, the presence of a microorganism, or its toxins, will trigger self-limiting innate and adaptive immune responses that eventually destroy the invader. During this process, the release of signalling molecules, destruction of the microorganisms, and sacrifice of immune cells all cause symptoms of infection, ranging from localised inflammation to systemic effects--fever, chills, tachycardia, aching joints, etc.

Because fighting infection rapidly is essential to survival, there are many pathways for immune signalling, and treatments that focus on single pathways have been unsuccessful.

A combination of over-activation of pro-inflammatory pathways and disruption of anti-inflammatory pathways is the most likely scenario in the development of sepsis.

Pro-inflammatory signals

Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), released from invading pathogens or damaged host cells, activate receptors on local immune and epithelial cells. This triggers the release of pro-inflammatory and antimicrobial factors such as interferons, tumour necrosis factor and interleukins. In turn, these factors activate further immune responses, increasing the numbers and activity of immune cells in the area and triggering platelet activation. Activated platelets induce localised coagulation, to trap microorganisms in microemboli, to prevent them from spreading via the blood. Pro-inflammatory cytokines also induce nitric oxide and production of acute phase proteins, such as C-reactive protein, from the liver. (11) Nitric oxide is a potent vasodilator that contributes to endothelial dysfunction and the hypotension associated with sepsis. (12)


If control of these inflammatory signals is lost--either through faulty signalling or overwhelming infection--systemic damage begins. Reactive oxygen species (ROS) designed to damage microorganisms begin damaging host cells. Acute phase proteins released from the liver increase ROS production and increase permeability of blood vessel walls, allowing fluid to escape into the tissues (extravasation). Widespread activation of the coagulation system causes coagulopathy--which can progress to disseminated intravascular coagulation. It also damages small blood vessels, impairing blood flow to tissues and organs, and causing extravasation, and increased inflammation. (1)

Anti-inflammatory signals

Even as pro-inflammatory factors are released, the signalling molecules to limit their activity are activated. Interleukins and receptor-blocking molecules prevent over-activation of inflammatory pathways, while specialised vesicles package up DAMPs and PAMPs for removal. ROS are neutralised and excess immune cells are ingested by macrophages. These pathways are complex and our understanding of how these fail in the development of sepsis is minimal. (1) The damage caused by this dysregulation of inflammation leads to body-wide organ dysfunction and the signs and symptoms associated with sepsis.


ROS damage cell structures, especially mitochondrial proteins. Mitochondria are responsible for generating ATP in cells, the energy source reguired for all cellular activity. As mitochondria become dysfunctional, ATP levels within the cells decrease and cells reduce or stop their specialised functions in order to survive. This effect persists even when oxygen levels are normal (the reason oxygen therapy in sepsis is not as effective as could be expected). (13) Specialised organ functions become impaired, leading or contributing to multi-organ dysfunction syndrome (MODS), which involves:

* Acute kidney injury.

* Impaired liver function.

* Myocardial depression.

* Encephalopathy.

* Loss of immune cells and impaired immune function.

* Acute lung injury with pulmonary oedema.

* Loss of epithelial barrier in the gastrointestinal tract.

Loss of the epithelial barrier in the gut allows resident gut bacteria, gut contents and pancreatic enzymes to cross into the circulation. This causes more damage to the gut and worsens systemic inflammation, aggravating MODS. In the lungs, damaged endothelial and epithelial barriers allow protein-rich fluid out of the lung capillaries and into the alveoli (pulmonary oedema), reducing lung compliance and causing ventilation-perfusion mismatch and arterial hypoxaemia, ie acute respiratory distress syndrome (ARDS). (1)

Immune function itself is affected by MODS. Severe sepsis is associated with loss of many essential T-lymphocytes. This makes patients very vulnerable to secondary infections, including reactivation of viruses (eg Cytomegalovirus and herpes) and bacterial or fungal infections, with associated increased mortality. (1)

In the meantime, inflammatory cytokines are also directly damaging cells, causing both organ and endothelial dysfunction. Fluid leaking from damaged capillary walls causes oedema, which impairs nutrient, waste and oxygen exchange between cells and their capillaries. Micro-emboli, triggered by activation of the coagulation system, reduce blood flow through the arterioles, capillaries and venules, preventing delivery of oxygen and nutrients to cells, and removal of waste.

Blood pressure

Septic shock is a form of distributive shock - the total volume of fluid in the body does not fall, but it is diverted away from essential organs to the skin, skeletal muscle and fat, and into the tissues. This causes initial flushing and warmth at the onset of sepsis in adults (called warm shock). The key factors causing this redistribution of blood are nitric oxide and lactic acid. Both these trigger arterial and venous vasodilation.

Initially the body can compensate by increasing heart rate and, in the absence of cardiac disease, cardiac contractility. As sepsis progresses, the myocardium becomes depressed, contractility is reduced and the compensatory mechanisms that would normally divert blood flow to essential organs remain dysregulated, due to nitric oxide and lactate. Hypotension worsens into shock, although this is a very late (premorbid) sign in infants and children. With any type of shock, global lack of oxygen delivery to the tissues usually causes death within one hour of onset. (13)

In septic shock, hypotension--lack of oxygen delivery to the tissues--combines with the inability of cells to use available oxygen due to their mitochondrial damage. (12)

Lactic acid

In sepsis, there is increased lactate production and reduced clearance, causing hyperlactatemia due to: (13)

* Inadeguate whole body oxygen delivery, due to hypotension.

* Impaired regional oxygen delivery, due to microemboli and endothelial inflammation.

* Impaired oxygen extraction, due to impaired mitochondrial function.

* Increased stress-induced glycolysis, triggered by adrenaline and noradrenaline.

* Impaired liver clearance, especially with pre-existing liver dysfunction.

As lactate accumulates, the pH of the blood reduces and acidosis occurs. The body relies on adeguate lung and renal function to correct this, both of which may be impaired due to MODS, which in turn is increased by the acidosis.

Blood lactate concentration is an essential early tool in diagnosis of sepsis. In patients with elevated temperature and abnormal white blood-cell count, but who are otherwise haemodynamically stable, an elevated lactate level is associated with development of septic shock within 48 hours. (13) Blood lactate of greater than 4mmol/L is one of the assessment criteria for life-threatening sepsis.

Catabolic state

Patients with sepsis, especially those with MODS, experience rapid and severe Loss of skeletal muscle mass. This is due to the increased need for amino acids to make glucose to fuel the massive proliferation of immune cells. Patients become hyperglycaemic and insulin resistant, proportional to the severity of their sepsis. Strict glycaemic control in sepsis (4.8-6.6mol/L) has been associated with increased mortality. It is now recommended that plasma glucose concentrations be kept at less than lO.Smmol/L. (1)


Sepsis is a leading cause of preventable death. Mortality rates range from 20 to 80 per cent of patients, although this is improving, especially with the recent emphasis on early and aggressive fluid resuscitation and antibiotic therapy. Risk of death increases with the presence of underlying risk factors, organ dysfunction, and progression of sepsis to shock.

Much of the morbidity associated with sepsis is an outcome of the medical and nursing interventions reguired to support life. MODS and its management can prolong critical illness by various mechanisms, leading to a state of chronic critical illness.

Chronic critical illness

ARDS frequently necessitates invasive mechanical ventilation (risking secondary infection), use of sedation, and potential for further injury to the lungs. Sedation required for ventilation may worsen encephalopathy and delirium, decrease mobility, potentiate catabolism and lead to prolonged neuromuscular impairment during recovery.

Loss of the epithelial barrier in the gut, aside from causing bacteria to enter the body, also impairs nutrition at a time where excess metabolic demand and ongoing catabolism require increased nutrient intake.

Antibiotic therapy is usually broad-spectrum, at least until pathogens are identified. This allows opportunistic pathogens and resistant bacteria to generate superinfection. In addition, indwelling catheters, endotracheal tubes (and suctioning), and vascular access devices are all portals for nosocomial infection in the presence of severely impaired immune function. (7)

Long term morbidity--surviving sepsis

The risk of death remains elevated following sepsis for up to five years, and is especially high in the first two years. More than one in five survivors of sepsis will die within 32 days to two years after their illness. (14) Sepsis survivors experience post-sepsis syndrome: residual organ dysfunction that can severely affect their quality of life and functional health--even survivors who did not have an ICU admission.

Persistent fatigue, dyspnoea, insomnia, chronic pain, mental impairment and depression have been reported. (15) At three months following discharge, 40 per cent of survivors had global cognition scores equivalent to moderate brain injury, and 26 per cent to mild Alzheimer's disease. (16) Risk increases with age, as well as the presence and duration of delirium, and degrees of hypoxia, hypotension, glucose dysregulation, and kidney injury experienced during the acute illness.

Many people, especially those with pre-existing depression, suffer from post-traumatic stress disorder, ranging from 10 per cent at three months to 16 per cent at six months. Depression occurs in 28 per cent of survivors, and anxiety in 24 per cent. (16) Partners of survivors are also known to experience increased rates of depression, anxiety and PTSD.

Physical limitations may occur in up to 60 per cent of sepsis survivors, persisting after five years. In addition, inflammation persists following sepsis, increasing the risk of cardiovascular disease, including myocardial infarction, heart failure and hypertension. Atrial fibrillation is also increased, boosting risk of heart failure and stroke. (16)

Immunosuppression persists following the resolution of acute sepsis, accounting for high readmission rates for new or recurrent infections in sepsis survivors. Thirty per cent of sepsis survivors are readmitted to hospital within 90 days of discharge; this figure increases to 63 per cent within one year. Latent viral reactivation contributes to high mortality rates at 90 days. (16)

The increasing incidence of sepsis, combined with increasing survival rates, suggests the burden of sepsis on the health-care system will only increase in future and may generate a "hidden health disaster". (17) Best possible rehabilitation for survivors could help to reduce this.


Early identification of sepsis is essential to rapid treatment. Administration of antibiotics within one hour of diagnosis increases survival, but the most recent United Kingdom National Institute for Health and Care Excellence (NICE) guideline notes only 32 per cent of patients receive antibiotics in the first hour of arriving at an emergency department. (5) The ability to identify sepsis in the community (where up to 70 per cent of cases originate), in ED or in the general hospital setting is vital for patient survival. Knowing which patients are most at risk helps early identification: (5)

* The very young (less than one year), older adults (over 75), and the very frail.

* People with impaired immunity, including those undergoing chemotherapy, long-term steroid therapy or other immuno-suppressant drugs; people with diabetes, sickle cell disease, or who have had their spleens removed.

* Anyone who has had surgery or other invasive procedures in the previous six weeks.

* Those with impaired skin integrity (eg cuts, blisters, burns) or cellulitis.

* Intravenous drug users.

* People with indwelling catheters or vascular access devices.

* Women who are pregnant or up to six weeks post-pregnancy (including miscarriage and termination), especially those exposed to other risk factors.

* Neonates with high infection risks.

Anyone presenting with signs or symptoms of a possible infection should be considered for risk of sepsis. Not all infections are sepsis, but at the same time, not all sepsis cases present as classical infections (fever etc). Nonspecific symptoms may include a general feeling of being very unwell, changes from usual behaviour, and changes in cardiovascular and respiratory status. The presence of fever is not a reliable predictor of sepsis. Some people may be hypothermic, especially as shock progresses. Older adults, the very young or frail, people having chemotherapy or immunosuppressant drugs, and the severely ill may present with little or no elevation in temperature. Remember also that peripheral temperature measurement (and also pulse oximetry) may not be accurate in severe shock states.

Risk assessment

Early warning scores (both adult and paediatric) used in many hospital units are not specific to sepsis but can provide timely evidence in patients with infection. NICE5 suggests that while these scoring systems are not well validated, they may also be useful in community care settings, and possibly emergency care. The qSOFA score included as part of the Sepsis-3 update allows rapid risk assessment for adults. (10)

For children, sepsis-specific scores must use age-specific data to assess core temperature (abnormally high or low), heart rate (tachycardia or bradycardia), altered mental state, reduced urine output and poor peripheral perfusion. (18) Hypotension is a late and dangerous sign in children.

Assessment factors for risk of severe illness or death in adults and children over the age of 12 can be seen in Table 1 (p23). (5)


Management of sepsis is driven by the need to: (12)

* Provide appropriate antibiotic therapy as early as possible.

* Correct hypotension, hypoxia and hypoperfusion (cardiovascular and respiratory support).

* Identify and treat the source of infection.

* Support organ function to prevent progression to MODS.

Initial management of sepsis includes blood tests, fluid resuscitation and antibiotics. Lactate levels should be assessed urgently for anyone who meets the criteria for moderate or high risk of illness.

Blood cultures should be obtained but administration of antibiotics should not await these results. Only 30 per cent of patients with septic shock have positive blood cultures, and 25 per cent of patients will have no positive culture results from any source. (12) Other blood tests assess immune function (looking for elevated or decreased white blood cell count), indications of inflammation (C-reactive protein), and organ/system dysfunction (creatinine, coagulation abnormalities, thrombocytopenia, hyperbilirubinaemia, arterial blood gases, and pH).

Guidelines published by the international Surviving Sepsis Campaign provide a bundle of care, referred to as early goal-directed therapy (EGDT).ig But clinical trials, including the Australasian Resuscitation In Sepsis Evaluation (ARISE) study, found no difference in outcomes between EGDT and local protocols for prompt, aggressive and individualised care. (12)

Local protocols for antibiotic and fluid regimes generally reflect patient age and comorbidities, as well as regional differences in antibiotic resistance patterns. Fluid resuscitation is usually achieved using crystalloids (eg plasmalyte, normal saline), but brings risks such as fluid overload and worsening oedema, so should be carefully monitored. (20) If the patient's blood pressure does not respond, vasopressor drugs may be required. Vasopressors (eg norepinephrine/noradrenaline) stimulate vasoconstriction, reversing the effects of nitric oxide and other triggers of dysregulated blood distribution, thus increasing blood pressure and blood flow to vital organs. Other therapies are used as necessary to protect and support organ function (mechanical ventilation, renal dialysis, etc).

Uncertainties remain about the best fluid type and volume for resuscitation, the timing and choice of vasopressors, the threshold for blood transfusion, optimal sedation regimes, renal dialysis dosing, and timing and intensity of nutritional support. (1) Current major research projects are hoping to address these.

All current therapies used to manage sepsis and septic shock are supportive, or aimed at eliminating the infection source. Therapies that can interrupt the inflammatory cascade underlying sepsis do not yet exist. High doses of corticosteroids, which suppress inflammation, have been found harmful, but lower doses for patients with adrenal insufficiency can prove helpful (due to improved haemodynamic outcomes, not suppression of inflammation). (12)

Therapies targeting bacterial endotoxins (for patients with Gramnegative bacterial sepsis), specific inflammatory cytokines, and other molecules in the inflammatory pathway have not been successful in clinical trials. (21) All of these therapies showed some success in preclinical trials, but fail to translate to large patient populations. This is due partly to the huge differences in patients with sepsis--different ages, comorbidities, and sources of infection. It is also a result of the multiple pathways for inflammation that exist, and the limitations of animal models of sepsis. (10

Future therapies may include boosting immune function in the later stages of sepsis, limiting MODS by enhancing epithelial and endothelial barrier function, and exploring the signalling pathways for resolution of inflammation in more depth. (1)


Early identification, and escalation of sepsis care is important. In hospitals, nurses are frequently the first to recognise deterioration in a patient. The Surviving Sepsis Campaign promotes the assessment of every patient, every shift, every day for sepsis. (22)

Early warning score (EWS) protocols can aid assessment but are not specific for sepsis. Education for nurses that promotes critical thinking about EWS scores and what they can and cannot tell about the patient's condition, is essential. As part of this education, the skills to communicate suspicions and trigger action in the medical team need to be enhanced, minimising delay on wards before sepsis protocols are implemented. (23)

Minimising long-term complications in survivors is an important part of the nursing care. Practices to mitigate the mental health impact of ICU are increasingly common, along with innovations in reducing delirium and preserving physical function. But these are not commonly carried through to ward-based care for sepsis patients. An essential role for nurses is the promotion of infection control protocols to protect sepsis patients from secondary and nosocomial infections. (24)

Early and sustained physical and cognitive rehabilitation, including pulmonary rehabilitation, have been shown to improve outcomes, but the optimum delivery of these remains unknown. (16)


Sepsis and septic shock are life-threatening illnesses where early intervention has a significant impact on survival. Nurses are ideally situated in the community, in long-term care facilities and in general hospital wards to monitor for sepsis and ensure escalation of care. Survivors of sepsis are increasing in number as therapeutic interventions improve. This group of patients requires intensive and specialised support on discharge--nurses must ensure they do not fall through the gaps in the health-care system.

* References for this article can be found at


After reading this article and completing the online learning activities, you should be able to:

* Outline the molecular events that underlie sepsis and septic shock.

* Discuss the causes and outcomes of organ dysfunction in sepsis.

* Describe risk factors for, and signs and symptoms of sepsis.

* Outline current and future therapies for sepsis.


Earn two hours of CPD

By reading this article and doing the associated online learning activities, you can receive a certificate for two hours of continuing professional development (CPD).

Go to to complete the learning activities for this article. The online service costs $19.95 per article.

These articles are supplied by CPD4nurses, an independent education company. CPD4nurses is not an NZNO service.

Georgina Casey, RN, BSc, PGDipSci, MPhil (nursing), is the director of She has an extensive background in nursing education and clinical experience in a wide variety of practice settings.
Table 1: Assessing risk of severe illness or death from
sepsis in adults and children aged 12 or over (NICE 2016)

               Moderate to high risk--      High risk--any one
               any one of the following     of the following

Mental state   New onset of changed         Objective evidence of new
               behaviour or mental state    onset changes in mental
               as reported by patient,      status
               relative or friend.

Respiratory    RR 21-14 breaths per         Respirations [greater than
function       minute                       or equal to] 25 per minute
                                            Or the need for 40% oxygen
                                            to maintain saturations at
                                            more than 92% (88% with
                                            known chronic respiratory

Heart rate     91-130 beats per minute or   [greater than or equal to]
               new onset dysrhythmia        130 beats per minute

Systolic       91-100mmHg                   [less than or equal to] 90
blood                                       mHg Or > 40mmHg below
pressure                                    patient's normal pressure

               No urine passed in the       No urine passed in the
               previous 12-18 hours.        previous 18 hours, or in
               Or in the presence of a      the presence of a
               catheter, output             catheter, output < 0.5 ml/
               0.5-1.0ml/kg/hr.             kg/hour.

Tympanic       Less than 36degC

Appearance     Signs of potential           Mottled, ashen.
               infection at surgical        Cyanosis of skin,
               sites or wounds.             lips or tongue.
                                            Non-blanching rash.
History        Impaired immune system
               Trauma, surgery or
               invasive procedure in
               previous 6 weeks.
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Title Annotation:CPD+nurses; progression of sepsis
Author:Casey, Georgina
Publication:Kai Tiaki: Nursing New Zealand
Article Type:Disease/Disorder overview
Date:Aug 1, 2016
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