Sepsis: an update on identification and management

Sepsis is characterised by life threatening organ dysfunction caused by dysregulated host response to infection. It is a major health concern, with its incidence estimated to be 300 cases per 100,000 people in the United States, of which around half of cases occur outside the intensive care unit (ICU)^[1]
.

In the UK, the National Confidential Enquiry into Patient Outcome and Death (NCEPOD), an independent charity and company separate from government bodies and professional associations, highlighted sepsis as being a leading cause of avoidable death that kills more people than breast, bowel and prostate cancer combined^[2]
. The 2014 NCEPOD report estimated that the international prevalence of sepsis is around 300 per 100,000, suggesting that there are around 200,000 cases a year in the UK alone, with a mortality rate of 29% (2). The European Sepsis Occurrence in Acutely ill Patients (SOAP) study suggests that each case of sepsis costs a healthcare system in a developed country €25,000, which equates to around £2bn annually in the UK^[3]
. In addition, a recent analysis of data obtained from the Intensive Care National Audit and Research Centre, an independent UK charity, demonstrates that unadjusted mortality for severe sepsis on ICUs and general hospital admission in 2012 was 23% and 32%, respectively^[4]
.

Despite sepsis being a severe condition, its definition, identification and treatment is not straightforward, owing to its various manifestations. Although patients with sepsis are often treated in the ICU, signs and symptoms may arise outside the ICU. Therefore, it is crucial for all healthcare professionals, including pharmacists, to be aware of the clinical features and management of sepsis. This article summarises the recent changes in the definitions of sepsis in adults, as well as its management.

Definitions

Recently, the definition of sepsis has changed significantly from the initial consensus definition of sepsis and descriptors of systemic inflammatory response (SIRS) to infection, which was published in 1992^[5]
. In this original definition, SIRS was described as a systemic inflammatory response independent of cause^[5]
, sepsis represented SIRS plus infection and sepsis plus organ dysfunction described severe sepsis^[5]
. Organ dysfunction included hypoxaemia, hypotension, oliguria, metabolic acidosis, thrombocytopaenia or reduced consciousness. Septic shock described severe sepsis with hypotension despite adequate fluid resuscitation^[5]
. These definitions were widely used in practice and served as the foundation of inclusion criteria for research.

The international consensus review of 2001 decided that these definitions should remain^[6]
. However, the group recognised that the definitions did not allow for precise staging of the host’s response to infections. Furthermore, while SIRS remained a useful concept, the diagnostic criteria were overly sensitive and non-specific for infection or sepsis. Despite this criticism, the group expanded the list of signs and symptoms taking the view that these needed to reflect the observed clinical response to infections and, therefore, facilitating bedside diagnosis, which should take priority over research criteria^[6]
.

Since then, several large studies have been conducted in patients with sepsis, however the control groups produced radically different results from those expected and between each of the studies. A series of large single centre studies led to changes in how sepsis was managed, however when they were repeated in multi-centre settings, the results were not reproducible. These studies included: Protocolised Care for Early Septic Shock (PROCESS)^[7]
, Australasian Resuscitation in Sepsis Evaluation (ARISE)^[8]
, Protocolised Management of Sepsis (ProMIse)^[9]
, and Drotrecogin Alfa (Activated) in adults with septic shock (PROWESS – SHOCK) trial^[10]
.

After these studies were concluded and reported in 2014, clinicians and researchers started to rethink what sepsis really encapsulated. The problem with previous definitions of sepsis was that they could include trivial syndrome when strictly applying the definitions or indeed non-infectious inflammation, while in practice most clinicians think of ‘sepsis’ representing an infection with a poor outcome. A new definition was required to help clinicians to improve recognition, outcomes and surveillance in practice and for researchers to reliably test future innovations.

In 2016, a third international consensus definition for sepsis and septic shock was published in view of the advances in the pathobiology, management and epidemiology of sepsis^[11]
. This defined sepsis as a life threatening organ dysfunction caused by dysregulated host response to infection. Put simply, sepsis is a life threatening condition that arises when the body’s response to an infection injures its own tissues and organs (see ‘Figure 1: Definition of sepsis’).

The degree of organ dysfunction can be assessed using the Sepsis-related Organ Failure Assessment, also known as Sequential Organ Failure Assessment (SOFA) score (see Table 1).

Abbreviations: FiO₂, fraction of inspired oxygen; MAP, mean arterial pressure; PaO₂, partial pressure of oxygen; Catecholamine doses given as µg/kg/min for at least 1 hour; Glasgow coma score range from 3-15; higher score indicate better neurological function.

An acute change in the baseline SOFA score by ≥2 points resulting from infection reflects an overall mortality risk of around 10% in a general hospital population. In ‘out of hospital’, emergency departments or general hospital ward settings, the quick SOFA (qSOFA) score (i.e. alteration in mental state, systolic pressure ≤100mmHg or respiratory rate ≥22/min), can be used to identify patients who are likely to have a prolonged ICU stay or die in hospital^[11]
. qSOFA has not yet been validated in the UK, however, it conveniently uses three of the seven National Early Warning Score (NEWS) criteria used to identify a whole range of acute deterioration of patients^[11]
. This consensus group emphasised that the SOFA score is not intended to be used as a tool for patient management, but as a means to clinically characterise septic patients, since a high SOFA score is associated with an increased probability of mortality.

The SIRS criteria, such as pyrexia, neutrophilia and increased heart rate, indicate inflammation and infection but are unhelpful in identifying sepsis because the SIRS criteria are present in many hospitalised patients, including those who never develop infection and never incur adverse outcomes^[5]
. Septic shock affects a subset of patients with sepsis and can be defined as sepsis with persisting hypotension requiring vasopressors, such as noradrenaline or vasopressin, to maintain a mean arterial pressure (MAP) ≥65mmHg and having a serum lactate level >2mmol/l, despite adequate fluid resuscitation (‘Figure 2: Definition of septic shock’).

Septic shock accounts for hospital mortality in excess of 40%^[11]
. The term ‘severe sepsis’ is now redundant and, in general, patients with sepsis generally warrant greater levels of monitoring and intervention, including possible admission to critical care or high dependency units^[11]
.

The National Institute for Health and Care Excellence (NICE), England’s health technology assessment body, recently published guidance on sepsis recognition, diagnosis and early management^[12]
. This guidance describes the stratification of risk of severe illness or death from sepsis based on mental state, respiratory support, cardiovascular, circulation, hydration, temperature and skin appearance^[12]
. This stratification is similar to the SOFA score but with two significant differences. When considering circulation and hydration, NICE describes urine output for moderate risk as 0.5–1ml/kg/hour for catheterised patients. However, many practitioners will consider this range to be normal and not necessarily indicative of severe illness or death^[12]
. Additionally, the NICE guidance has highlighted temperature and skin appearance in the risk stratification, which does not correspond to the definitions of sepsis^[12]
. Temperature and skin appearance give indication of infection do not necessarily indicate sepsis. It also highlights the diagnostic implication of a lactate level >4mmol//l but the Sepsis-3 group have provided evidence that lactate did not meet the threshold for inclusion in qSOFA^[13]
.

Pathophysiology

Sepsis is extremely complex and a detailed account is outside the scope of this article. Previously, it was believed that sepsis represented an exaggerated hyper-inflammatory response with patients dying from inflammatory-induced organ failure. More recent data suggest that sepsis involves both pro- and anti-inflammatory responses together with changes in non-immunological pathways, such as cardiovascular, neuronal, autonomic, hormonal, bioenergetics, metabolic and coagulation, all of which have prognostic significance. Organ dysfunction, even when severe, is not associated with substantial cell death. In addition, biological and clinical heterogenicity exists in affected individuals with age, underlying comorbidities, concurrent injuries, medications and source of infection adding further complexity^[14]
. Research continues in order to define the principal alterations in sepsis. Areas under investigation include dysregulated coagulation, inflammatory responses, cellular dysfunction and metabolic alterations, with a view to determine immunopathologic processes that account for morbidity and mortality in sepsis.

Management

Similar to the identification of sepsis, attempts to normalise or enhance various aspects of the physiology of patients with sepsis (e.g. gas exchange, glucose control or oxygen delivery) have been either ineffective or harmful to patients. More information on the early management of sepsis can be found in box 1.

Prior to 2001, there was no standard for the early management of sepsis or septic shock. The Surviving Sepsis Campaign (SSC) of 2002 aimed to promote best practice in the management of sepsis^[15]
using Early Goal-Directed Therapy (EGDT). EGDT comprised of early identification of high risk patients, source control and appropriate and timely administration of antibiotics. This was followed by early haemodynamic optimisation of oxygen delivery with central venous pressure (CVP)-guided fluid resuscitation and/or MAP-guided vasopressor administration. In addition, arterial oxygen content supplementation was advised via packed red blood cells or oxygen supplementation. Maintenance of contractility was recommended using inotropic agents,  while a reduction in oxygen requirements could be achieved by using mechanical ventilation and sedation guided by central venous oxygen saturation (ScvO₂)^[16]
. EGDT essentially was haemodynamic treatment and, therefore, uptake was limited owing to concerns regarding the external validity of results obtained from a single-centre trial that had an unusually high control group mortality of 46.5%, the complexity of protocol delivery and the potential risks of the components and resource required for implementation. This in turn generated significant scientific interest to “disassemble or unbundle” early sepsis resuscitation and question the value of its individual components^[16]
.

Recently, a trio of trials including ProCESS^[7]
, ARISE^[8]
and ProMISe^[9]
investigated this issue with two main objectives. First, to estimate the effect of EGDT compared with usual resuscitation on mortality at 90 days following randomisation and second, to assess incremental cost-effectiveness at one year. These studies concluded that there was no significant difference in all-cause mortality at 90 days^[7],[8],[9]
. Furthermore, on average, costs were higher in the EGDT group than usual resuscitation and cost-effectiveness was <30%^{[7],
[8],
[9]}
. This difference between EGDT and the trio of trials may have arisen because of an overall improvement in the standard care provided to the control groups over time since EGDT was published.

In terms of managing patients with sepsis, it is clear from the literature that patients identified with confirmed or suspected sepsis require urgent escalation and a set of investigations and interventions performed without delay. This requires considerable organisation within the hospital. This issue has been recognised by NHS England such that for 2016–2017, a Commissioning for Quality and Innovation (CQIN) has been issued for the systematic screening for sepsis of appropriate patients, and where sepsis is identified, that timely, appropriate treatment is available and continually reviewed. Often the screening and initiation of prompt treatment occurs outside the ICU, in which pharmacists can play an important role. The rest of this article focuses on the drug-related aspects of the management of sepsis and septic shock.

Broad spectrum antibiotics have been recommended by NICE, CQIN and SSC for use within an hour of suspected or confirmed sepsis; the so-called ‘golden hour’ where mortality increases by 12% for each hour that antibiotic administration is delayed^[17]
. Sterling et al. recently conducted a meta-analysis that did not show increased mortality in patients receiving antibiotics more than one hour after sepsis recognition or three hours after presenting to emergency departments^[18]
. However, this analysis was criticised for excluding other relevant trials that could have contributed to a biased outcome.

Antibiotic selection and administration should also be coupled with investigations to identify the source of infection and sampling of infected tissues/fluids before antibiotics are administered. The results of these investigations would further guide the focus of the antibiotic therapy, in line with the Start Smart, Then Focus campaign. This focus on appropriate and timely antibiotics needs to be weighed against another CQIN issued for 2016–2017, which aims to encourage NHS organisations to reduce antibiotic consumption to 2013–2014 levels and draw focus on antimicrobial stewardship and 72-hour reviews of all antibiotic prescriptions. Therefore, pharmacists have a crucial role to play in balancing delivery of both these CQINs by continuing to be antimicrobial stewards (including ensuring timely access to initial antibiotics for sepsis) and also optimising antimicrobial prescribing based on pharmacokinetic and pharmacodynamic data. For example, studies using Monte Carlo simulation suggest that the time with concentration above minimum inhibitory concentration (MIC) for meropenem 500mg infused over three hours every eight hours was similar to that of meropenem 1g infused over 30 minutes every eight hours for Pseudomonas aeruginosa isolates^[19]
.

These studies have influenced some centres to start using intermittent or continuous infusions for certain antibiotics that can help maximise antibacterial exposure, improve clinical outcomes, and reduce usage and costs. It is worth noting that this practice is off-label.

The Beta-Lactam Infusion in Severe Sepsis (BLISS) trial showed that there was no difference in survival outcomes at 14 and 30 days in patients receiving continuous infusion versus intermittent bolus^[20]
. Despite this, some centres in the UK use continuous or extended infusions to optimise the pharmacokinetic characteristics of beta-lactam antibiotics and/or to reduce antibiotic usage. In the future, we may see antibiotic therapy individually titrated based on therapeutic drug monitoring and the MIC of the causative organism.

Fluid resuscitation represents the first-line therapy for the management of sepsis. NICE guidance (outside the ICU) recommends intravenous fluid resuscitation should be glucose-free crystalloids that contain sodium in the range 130–154mmol/l (i.e. Hartmann’s or sodium chloride 0.9%, with a bolus of 500ml over less than 15 minutes)^[21]
. Uncertainty still exists regarding the optimal type of fluid, optimal volume and the best way to monitor the response to resuscitation therapy after the initial 500ml. The SSC suggested the use of either colloids or crystalloids; colloids are generally considered to be more potent plasma expanders than crystalloids and are comprised of hydroxyethyl starch (HES), gelatin or albumin.

Recent evidence suggests that patients with sepsis receiving HES had a higher risk of death at 90 days and were also more likely to require renal replacement therapy, compared with patients receiving Hartmann’s solution^[22]
. HES products are no longer licensed for use in sepsis. The Albumin Italian Outcome Sepsis (ALBIOS) study concluded that the use of albumin replacement in addition to crystalloids in patients with sepsis did not provide survival benefit at 28 days or 90 days despite improvements in haemodynamic variables^[23]
. There is a lack of evidence for benefit/harm when gelatins are used in sepsis management. Crystalloids (Hartmann’s, sodium chloride 0.9% or glucose) redistribute out of the blood compartment quicker than colloids, therefore large volumes are required in resuscitation, which can cause oedema. Many centres avoid use of sodium chloride because of an increased incidence of hyperchloraemic acidosis, although at this low volume this is usually not problematic. Generally balanced crystalloids (e.g. Hartmann’s) or low volume sodium chloride 0.9% are suitable for resuscitation in ward areas and in some ICUs; other ICUs use a gelatin, ideally formulated in a balanced (Hartmann’s-like) fluid.

Vasopressors cause a rise in blood pressure and are used to reverse circulatory failure in critically ill patients. However, despite the immediate haemodynamic effects, their effects on patient relevant outcomes remain controversial. EGDT recommended noradrenaline or dopamine for initial use as they both exert their effect via stimulation of the α-adrenoceptors. However, a Cochrane review examined the use of vasopressor in septic shock and concluded that there was no difference in total mortality^[24]
. However, more arrhythmias were observed in the patient who received dopamine^[24]
. While noradrenaline is primarily used as a vasopressor, it also has inotropic properties.

Vasopressin, also known as anti-diuretic hormone (ADH), has two primary functions: it increases water retention via tubular reabsorption while causing smooth muscle contraction, particularly in the capillary bed, hence diminishing leaky capillaries in patients with sepsis.

The Vasopressin and Septic Shock Trial (VASST) reported that there were benefits in mortality only when low-dose vasopressin at 0.01–0.03units/min was added to noradrenaline in less severe septic shock^[25]
. The rationale for vasopressin therapy in septic shock was to reduce high, potentially toxic noradrenaline dosages. However, this study has been criticised because the mean noradrenaline dose for the study group was 0.27µg/kg/min, which is below the generally recognised toxic limit of 0.6µg/kg/min, therefore the risk of noradrenaline toxicity was low.

In practice, vasopressin (argipressin) is reserved as salvage therapy in severely sick patients who are expected to die in 12 hours, or for patients with high-risk cardiac disease who are sensitive to catecholamines as they are expected to benefit from vasopressin-mediated decreases in catecholamine dosages. There is experience with using terlipressin by infusion (1.3µg/kg/hr) as an alternative to vasopressin for this indication^[26]
. Recently, the vasopressor versus noradrenaline as initial therapy in septic shock (VANISH) trial showed that the early use of vasopressin did not improve the number of kidney failure-free days, therefore there is no evidence to use vasopressin in place of noradrenaline^[27]
.

Inotropes, such as adrenaline or dobutamine, are used to treat myocardial failure in sepsis. These agents preferentially stimulate the β₁ adrenoceptors which leads to increased myocardial contractility. However, they can also contribute to myocardial ischaemia, therefore the minimum dose possible should be used for the shortest possible time. Adrenaline has vasoconstrictor properties as well being an inotropic.

Drotrecogin alfa is a recombinant human activated protein C (rhAPC). The PROWESS trial reported that rhAPC was associated with a 6.1% improvement in absolute survival in severe sepsis with multi organ failure^[10]
. However, conflicting reports on the efficacy of rhAPC led to the PROWESS-SHOCK trial, which concluded that rhAPC did not significantly reduce mortality at 28 days or 90 days^[10]
, leading to the withdrawal of the drug from the market.

Levosimendan is a positive inotrope with a dual mechanism of action. It sensitises Troponin C to calcium, thereby increasing calcium dependant myocardial contractility without increasing oxygen consumption. In addition, it also acts on ATP-dependant potassium channels in myocytes and vascular smooth muscle resulting in vasodilation, which reduces afterload and increases coronary blood flow^[28]
.

There has been some interest in the use of levosimendan for the prevention of acute organ dysfunction in sepsis. A meta-analysis by Zangrillo et al. of seven randomised controlled trials comparing levosimendan versus standard inotropic drugs in patients with sepsis found a significant reduction in mortality in the levosemendan group^[29]
. Additionally, serum lactate levels were also reduced. By contrast, the recently published levosimendan for Prevention of Acute Organ Dysfunction in Sepsis (LeoPARDS) trial concluded that in adult patients with sepsis, the addition of levosimendan to standard care was not associated with less severe organ dysfunction or lower mortality^[30]
. Furthermore, patients receiving levosimendan required more noradrenaline, were less likely to be successfully weaned from mechanical ventilation, had more tachycardia and had higher rates of supraventricular arrhythmias compared with those receiving placebo^[30]
.

Glucocorticoid therapy was among one of the first treatments studied for severe sepsis and septic shock since excessive inflammation had been recognised and associated with sepsis. However, the use of glucocorticoid therapy remains controversial. In 2002, Annane et al. demonstrated a significant increase in 28-day survival in a multicentre study that recruited 300 critically ill patients with vasopressor-refractory septic shock and multi-organ dysfunction. Patients received 200mg per day of intravenous hydrocortisone plus fludrocortisone 50µg per day. Both were administered for seven days^[31]
. This finding led to the SSC recommending the use of intravenous hydrocortisone in treatment of septic shock^[15]
.

In 2008, the multicentre corticosteroid therapy in septic shock (CORTICUS) study found no reduction in 28-day mortality in patients receiving intravenous hydrocortisone 50mg every 6 hours. In the hydrocortisone group, shock was reversed more quickly than placebo but more episodes of super-infection were observed^[32]
. The CORTICUS patients were less severely sick than the patients in the study by Annane et al
^[31]
.

Recently, the effect of hydrocortisone on the development of shock among patients with severe sepsis was investigated in the HYPRESS trial. The authors concluded that among adults with severe sepsis not in shock, the use of hydrocortisone compared with placebo did not reduce the risk of developing septic shock at 14 days. The hydrocortisone group reported an increased incidence of secondary infections, muscle weakness and hyperglycaemia and no difference in weaning failure^[33]
.

In 2012, the SSC recommended not using intravenous hydrocortisone to treat septic shock if patients have received adequate fluid resuscitation and vasopressor therapy is able to restore haemodynamic stability. Where this has not been possible, the guideline suggests intravenous hydrocortisone 200mg per day. We await the results of the upcoming adjunctive corticosteroid treatment in critically ill patients with septic shock (ADRENAL) study.

Other therapies

A range of other therapies that are not specific to sepsis but are applicable to all critically ill patients can be used, these include: thromboprophylaxis, stress ulcer prophylaxis, sedation, analgesia, delirium management and blood glucose control to achieve normal targets (since tight control has been shown to increase mortality)^[34]
(34).

• On 13 January 2017, ‘Table 1: Sepsis-related organ failure assessment’ was corrected from ‘Dopamine 5.1–15 or epinephrine ≤0.1 or noradrenaline ≤0’ to ‘Dopamine 5.1–15 or adrenaline ≤0.1 or noradrenaline ≤0.1’.