Sepsis: What we need to know now

The man doing a spot of gardening cleaning out his fishpond in Europe, the woman who becomes unwell after giving birth in rural India, the child with pneumonia in Rwanda, and the senior citizen who develops diverticulitis in Singapore – the triggers are different but they all die from the same disease process: sepsis.

Sepsis is a condition of impaired homeostasis involving the immune and neuroendocrine systems. Colloquially it may be referred to as “blood poisoning” or “septicaemia”. The immune response to sepsis is a complex balance between pro- and anti-inflammatory components triggered by the infection or insult to the body (e.g. an episode of diverticulitis). This results in immune suppression, altered cellular bioenergetics, failure of endothelial and epithelial cell barriers, organ dysfunction, and coagulation abnormalities. The balance between these responses is, in some cases, affected by genetic differences between individuals and explains why the same trigger may produce minimal impact in some people and produce life-threatening organ system failures in others.

Death is always a tragedy, but survival can be profoundly debilitating with chronic ill health, or loss of limbs and function. Those who have needed admission to critical care will have often suffered failure of several organ systems including blood circulation, the lungs, and the kidneys and will have needed these to be artificially supported during the worst of their illness. As a result, survivors from severe sepsis have often required prolonged treatment in the hospital, followed by long term physical, cognitive, and psychological complications impacting both the sufferer and their family.

Worldwide, there are 19 million cases of severe sepsis annually with a mortality of 26-40%. In the UK alone, there are 150,000 cases annually and 44,000 deaths – more than breast and bowel cancers combined. The incalculable human cost also carries a financial burden, estimated at £170 million to the NHS in the UK, and $20 billion in hospital costs worldwide. It is the most common and pervasive form of critical illness, and is the worldwide cause of many thousands of admissions to intensive care units each year.

Sepsis should be attracting finance for large multicentre research projects aimed at heightening public awareness, improving treatment pathways, and targeting drug treatments but its multifactorial origins work against it. Most major research grants are structured to provide finance for issues affecting a single patient group or underlying disease state. However, because it occurs in a wide range of situations and lacks a single validated diagnostic test, research into sepsis suffers. For the same reasons, it is unfortunately not always easy to diagnose and treat. This is particularly important because outcome is improved by early treatment.

Attention recently has focussed on clarifying terminology, with the production of international ‘Sepsis 3’ definitions based on clinical signs and symptoms. Sepsis is now defined as a “life-threatening organ dysfunction due to a dysregulated host response to infection” with evidence of two points or more of hypotension, an altered mental status, and tachypnoea. These parameters have been identified by multivariable logistic regression analysis as the three variables most likely to be found in patients with sepsis.

A severe subset of sepsis, septic shock, is defined as evidence of persistent hypotension despite volume resuscitation requiring vasopressors to maintain a mean arterial blood pressure > 65 mmHg and a blood lactate level > 2mmol/l.

Both definitions, whilst useful in a hospital or developed world setting, don’t reflect the clinical needs and facilities of low and middle income countries where sepsis is often unrecognised. Additional considerations have been raised about these definitions in high-income healthcare environments, but overall, the simplification is to be welcomed in helping to make it easier to ensure timely treatment and attract funding and recruitment to the necessary research studies.

So what’s needed now?

Source control and early administration of appropriate antibiotics is vital for improving outcome. Bacteria are multiplying in the blood, but may not always be diagnosed with confidence, because blood cultures only reveal micro-organisms in 60% of cases. Antibiotics are often selected on a ‘best guess’ basis pending further information or test results. Recognition and timely empirical treatment has the potential to improve worldwide outcomes considerably, and failure to act quickly may have disastrous consequences for patients.

Future research into sepsis is needed in four broad categories.

1. Techniques that speed and add reliability to early recognition are a priority.
2. Research is also needed into how best to support patients who are being resuscitated from or are recovering from septic shock. Sepsis damage affects all the body’s systems and organs. Often survivors are so weak that they cannot even breathe for themselves as they start to recover, and having survived the initial infection they may go on to die because they lack the physiological and body reserves to fend off new problems. In an attempt to offset this, complex bundles of treatments to reduce this ongoing risk to patients have been introduced. Often these packages of care are aimed at reducing the adverse effects of the very treatments that are keeping the person alive.
3. More fundamentally, targeted treatments that impact the complex generic processes that are triggered by sepsis are vital. Unfortunately, so called ‘magic bullet’-type treatments have so far failed to reduce deaths from sepsis. The two most prominent attempts to clinically reduce the impact of septic shock have been “Centoxin”, a monoclonal antibody product aimed at reducing endotoxin produced by gram negative bacteria and activated protein C (Drotrecogin Alfa, “Xigris”), which was designed to reduce the abnormal clotting caused by sepsis in capillaries and so reduce organ damage. Both have now been removed from use. Sepsis is a complex process that expresses itself differently in individuals and is caused by many different infections. Expecting a single treatment to halt it universally is almost certainly naïve, just as it would be to expect a single drug to treat all cancers or to cure all aspects of HIV.
4. Future research needs to be a systematic exploration of sepsis from the laboratory to the bedside. It will be expensive and difficult, with many avenues and differences in human response to explore. It may well rely on early confirmation of the type of infection, the varied and complex modes of human response to sepsis, and will involve a range of possible therapies.

Finally, a better understanding of the interaction between different infectious agents including viral, bacterial, and fungal infections and continued research into new antimicrobial agents will be key for the successful treatment of sepsis and septic shock.

Featured image credit: Amoxicillin capsules by Brett_Hondow. CC0 Public Domain via .