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Be alert to sepsis and help save lives

A patient with sepsis is five times more likely to die than a patient who has suffered a heart attack, yet the condition remains relatively unrecognised, says Jenna Bowen

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Every year millions of people contract infections of bacterial, viral or fungal origin. Most of these will either be self-limiting or be efficiently treated by empirical antimicrobial therapies.

In recent years, however, multi-drug resistant infections, particularly nosocomial ones, have increased significantly. In 2004, the Infectious Diseases Society of America published a report that highlighted the disparity between the dwindling number of new antimicrobial therapies and the increasing occurrence of bacteria resistant to multiple antibiotic classes.1 Little has changed since and the situation seems unlikely to improve; the Chief Medical Officer for England recently ranked antimicrobial resistance as as great a threat to the nation as terrorism.2

Key points

  • Sepsis is a life-threatening condition that arises when the body’s response to an infection injures its own tissues and organs. Mortality rates are up to 50 per cent.
  • Early diagnosis and rapid initiation of effective antimicrobial therapy is vital to ensure best patient outcomes.
  • Be alert to fever, rapid breathing, clammy pale skin and confusion, and ask if the person has a wound, or respiratory or urinary tract infection.

Despite multi-drug resistant Gram-positive bacterial infections such as meticillin-resistant Staphylococcus aureus being highlighted as a public health crisis, little attention has been paid to Gram-negative organisms, including Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, that are rapidly developing resistance.

As a consequence, for a growing number of Gram-negative infections there are no effective antimicrobial interventions currently available or in the advanced stages of development.3 With the emergence of multi-drug resistant pathogens, in a population that is ageing and has an increased number of immunocompromised patients, it is not surprising that infective diseases such as sepsis are ever more prevalent.

Sepsis is defined as “a life-threatening condition that arises when the body’s response to an infection injures its own tissues and organs”.4 An estimated 20–30 million people worldwide are affected each year and, with mortality rates of 35–50 per cent, the disease carries a significant economic and emotional burden. In the UK alone, sepsis costs the NHS more than £2.3bn and kills between 36,000 and 64,000 people every year.5 Despite these startling statistics, public and professional awareness is poor. In order for patient outcomes to improve, sepsis needs to be recognised as a medical emergency.

Pathophysiology

Sepsis is a complex, rapidly evolving condition and although the underlying immunological factors have been extensively studied, much remains poorly understood. Organ failure — the leading cause of death in sepsis — is undeniably a consequence of an excessive and disproportionate inflammatory response to infection.

However, there is growing evidence that, in addition to an “immunological over-reaction”, patients with severe sepsis suffer profound immune paralysis that is associated with failure to clear secondary infections. Furthermore, although the symptoms of sepsis are similar in most patients, the underlying cause and immunological responses differ and this means patient response to treatment varies widely despite uniform levels of care.

Bacteraemia is a critical feature of sepsis and is defined as the presence of bacteria in the systemic circulation. Bacterial toxins, such as lipopolysaccharide (LPS) located in the outer membrane of Gram-negative bacteria, are ubiquitously implicated in disease presentation and progression.

Low doses of microbial toxins are believed to be beneficial to the host in helping to maintain a basal level of immune attentiveness,6 but prolonged activation of the innate immune system by LPS and other bacterial products leads to a systemic immune response disproportionate to the initial antigenic insult. Recognition of microbial components by the host leads to an immunological cascade resulting in the production of cytokines and other inflammatory mediators.

Actions of both the activated immune cells and inflammatory mediators lead to the development of the clinical picture associated with sepsis (ie, fever, endothelial damage, peripheral vascular dilation, coagulation disorders and myocardial depression), which can eventually result in multi-organ failure, shock and death.

The most susceptible organs are the brain, heart, kidneys, liver and lungs, giving rise to altered levels of mental alertness, myocardial depression, acute renal and hepatic failure and respiratory distress syndrome, respectively.7 If the patient survives this initial “cytokine storm” and the resultant systemic inflammatory response syndrome (SIRS), a compensatory anti-inflammatory response syndrome (CARS) follows (see Figure 1: Inflammatory profile of a patient with sepsis. Adapted from 8).

CARS is the body’s attempt to restore homeostasis following the initial hyper-inflammatory state but it renders the patient susceptible to secondary infections. The relative time spent in each inflammatory state differs between individuals and is influenced by variables including type of infection, presence of comorbidities, patient age and genetic factors.8

Although some patients are able to recover from CARS, others will continue to deteriorate. The time of onset of sepsis is almost impossible to define. There is a growing school of thought that believes patients, when admitted to an intensive care unit with clinical symptoms of sepsis, are often already well advanced beyond the original hyper-immune state.

Diagnosis

For every hour of delay in diagnosis (and hence initiation of antimicrobial therapy), the risk of death from sepsis increases by 6–10 per cent, with survival rates of just 30 per cent at six hours.9

As a consequence of the inherent complexity of the condition and the activation of numerous signalling cascades, more than 170 host biomarkers have been implicated in sepsis.10

A number have been investigated for their potential as diagnostic or prognostic indicators yet, to date, no clinically useful diagnostic assay exists. As a consequence, early-stage diagnosis relies largely on the intuition and experience of the clinician. In a situation where a timely diagnosis is critical in determining patient outcome, the need for an objective indicator of early stage sepsis is significant.

Diagnostic criteria defining the progress of SIRS through sepsis, severe sepsis and, finally, septic shock are outlined in the Panel on this page. The difficulty in diagnosis in the early stages is evident when reviewing these criteria; many of the early indicators could be indicative of a number of other physiological conditions.

The most important diagnostic criterion is the presence of infection and so blood, sputum or urine cultures should be ordered at the earliest opportunity so as to inform the most appropriate antimicrobial therapy.

Of all the biomarkers investigated, C-reactive protein, procalcitonin and lactate levels are the most widely used indicators of patient condition. However these markers are not sepsis-specific; rather they are indicative of an systemic inflammatory process and are little use in predicting patient response to therapy and hence final outcome.10

Treatments

In February 2013, the Surviving Sepsis Campaign Guidelines Committee published international guidelines for management of severe sepsis and septic shock.11 The main stay of treatment is the administration of effective antimicrobial therapy, informed by the results of blood or infection site cultures where possible, within the first hour.

This should be supplemented with appropriate fluids in an attempt to counteract hypoperfusion and hypotension. If fluid resuscitation proves inadequate, vasopressors such as noradrenaline should be added to increase the tone of peripheral blood vessels, helping to maintain blood pressure.

Diagnostic criteria for sepsis5

A definitive diagnosis of sepsis can be made in patients presenting with two or more SIRS criteria and a confirmed or suspected clinical infection. These criteria are:

  • Heart rate >90bpm (60–90bpm)
  • Respiratory rate >20 breaths/minute (12–20 breaths/minute)
  • Temperature <36.0 or >38.3C (36.1–37.2C)
  • Blood glucose >7.7mmol/L in absence of diabetes (4.4—6.1mmol/L)
  • White blood cell count <4 or >12x109/L (4.3–10.8x109/L)
  • Acutely altered mental state, confusion, slurring of speech

The most likely sources of sepsis are pneumonia, urinary tract infection, peritonitis, appendicitis, cellulitis (see CPD article, pp193–6) and wound infection.

Severe sepsis is defined as sepsis with the dysfunction of one or more organ systems.

Septic shock is the final stage where hypotension persists despite adequate fluid resuscitation.

A number of other pharmacological interventions have been investigated as potential sepsis treatments but with limited success. Because patients cycle between pro-inflammatory and immunosuppressed states, it is unsurprising that empirical use of anti-inflammatory agents has failed to demonstrate clinical benefit. The difficulties encountered in treating sepsis are exemplified by the PROWESS-SHOCK trial of activated protein C (Xigris), an anti-inflammatory, antithrombotic therapy.

In a series of large-scale clinical trials, activated protein C failed to demonstrate significant clinical benefit and this, coupled with a moderate increase in risk of adverse events, led to the withdrawal in 2011 of this therapy that was originally hailed as “game-changing”.12 There is currently no sepsis-specific therapy available. Although antibiotics are an important weapon, the ever-increasing incidence of resistance coupled with the alarming paucity in pipeline Gram negative therapies means the need for effective therapies to treat sepsis is greater than ever.

The ability to time interventions to target specific phases in the pro- or anti-inflammatory cycle is key to the advancement of new therapies, but diagnostic tools capable of differentiating patients on such a basis are currently unavailable.

In addition to the challenge of timing appropriate therapies there is consensus that although sepsis appears to be a uniform clinical entity there can be much variation in the underlying pathophysiology; attempts to treat all patients with a single therapeutic strategy are, therefore, unlikely to succeed. Patient genetic and proteomic variability means that therapies, even when appropriately timed, will manifest in a wide variation in patient outcomes.

It is not currently possible to stratify patient cohorts into subgroups reflective of treatment susceptibility at point-of-care. Although no single biomarker has demonstrated efficacy in predicting outcome it is reasonable to expect that such stratification could be achieved given a better understanding of the interrelationships within an array of biomarker targets, which may, in turn, identify novel therapeutic strategies.

Role for pharmacists

Pharmacists are ideally placed to facilitate early diagnosis of sepsis and, therefore, ensure rapid treatment. In community settings, pharmacists are often the first healthcare professional a patient presents to when feeling unwell. Access to medication records, a knowledge of co-existing medical conditions and recognition of the presenting symptoms may allow for the early referral of those patients at risk of developing sepsis.

Pharmacists working in secondary care can work with intensive care clinicians to ensure that patients receive antimicrobial therapy early following diagnosis. Currently, only 25 per cent of patients receive antimicrobial therapy within the hour following diagnosis.

Recently, a hospital in South Wales set up a “sepsis bag” initiative where bags containing the necessary medicines and fluids are stocked on hospital wards to minimise the time between diagnosis and initiation of treatment.14 Pharmacists could help establish similar initiatives within their hospitals, to ensure a greater percentage of patients receive broad-spectrum antimicrobial therapy and fluids within the “golden hour”.

Most importantly, perhaps, all pharmacists can play an educating role with regard to the problem of antimicrobial resistance and, in the process, help to achieve better awareness of sepsis and contribute to the goals of the World Sepsis Declaration, which can be found at www.world-sepsis-day.org.

About the author

Jenna Bowen, MPharm, PhD, is a post-doctoral researcher at the School of Pharmacy and Pharmaceutical Sciences, Cardiff University, and a community locum pharmacist

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2013.11124593

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