Speeding up sepsis diagnosis

Diagnosing sepsis in intensive care units can be a difficult, but critical task – Edward W. Burnham discusses ways to speed up diagnosis

Sepsis is the systemic inflammatory response to infection and represents a major cause of morbidity and mortality in patients admitted to intensive care units (ICU). The condition is relatively common and as a result has a major impact on healthcare expenditure and resources.¹ Within Europe, cases of sepsis have been estimated at 90.4 per 100,000 population. To put this in context the incidence of breast cancer is 58 per 100,000.² Therefore in a lifetime an individual is around 60% more likely to develop severe sepsis than to be diagnosed with breast cancer. In 2009, the worldwide documented incidences of sepsis was 1.8 million cases annually, however this figure reflected low rates of recognition and diagnosis and the causative pathology (e.g. pneumonia) rather than sepsis. Later estimates suggest around 2 million cases are admitted to intensive care units alone^3,4.

Critical Care Units (incorporating Intensive Care and High Dependency Care in most UK hospitals) are among the most expensive areas for patient care. This arises from the high nurse-to-patient ratio needed to provide the required level of care. Within the UK, most units estimate that a typical bed day costs around £1,500. The cost for patients with severe sepsis is likely to be higher due to their greater dependency. In European studies, it has been estimated that a typical episode of severe sepsis costs a healthcare organisation approximately €25,000⁵. Assuming that there are 100,000 cases of severe sepsis per annum, this equates to a direct cost to the NHS of over £2.3 billion. The annual cost to Europe as a whole has been estimated to be approximately €7.6 billion².

Similar to an acute myocardial ischemic attack or an acute brain attack, the speed and appropriateness of therapy administered in the initial hours after sepsis develops can significantly influence the outcome for the patient. However diagnosis of sepsis is highly challenging. For many disease processes, specific symptoms are available to aid in a clear and conclusive diagnosis, yet for sepsis the process of diagnosis is much more ambiguous. Physicians must rely on the presence of a series of signs and symptoms, none of which are specific for sepsis but, when present in combination, strongly support a septic diagnosis. In addition, since the infection can progress quickly if not treated in a timely fashion, antibiotics are often administered to patients as a precaution prior to the time-consuming laboratory confirmation of the condition. However, recent research has shown that certain antibiotics may worsen sepsis because they increase the breakdown of and the release of toxins into the blood stream.

One of the most widely and currently used markers for the detection of sepsis is procalcitonin (PCT). PCT is a naturally occurring precursor of the hormone calcitonin and is produced in very low levels in the thyroid. In healthy people, PCT is almost undetectable. However, bacterial infections such as sepsis cause PCT levels in the blood to increase rapidly. This increase is detectable about three hours following bacterial infection and reaches maximum values after six to 12 hours. PCT kinetics play a vital role in assessing sepsis as PCT levels in the blood reflect the severity of the bacterial infection, with very high values noted in cases of severe sepsis and septic shock. Viral infections do not cause this increase in PCT blood levels, thereby enabling bacterial infections to be identified specifically by the marker. Once the infection is under control, PCT levels decrease quickly.

A PCT biomarker assay can detect the production of the PCT pro-hormone and allow physicians to assess the severity of infection. PCT was shown to be the only marker that gave definitive results as to the severity of sepsis in a 2001 study of inflammatory markers, in which the accuracy of sepsis determination was based on clinical models with and without PCT⁶. In the study, PCT yielded the highest discriminative value to differentiate patients with Systemic Inflammatory Response Syndrome (SIRS) from those with sepsis-related conditions. The study concluded that the addition of PCT to a model based solely on standard indicators made a significant improvement on detecting sepsis.

The PCT assay is already established in Europe, particularly Germany, France and Switzerland, where it has been used for risk assessment of sepsis in patients for more than ten years. One of the main benefits of PCT is that it is specific to severe bacterial infections, and does not rise in cases of viral infection. Therefore, application of PCT in Europe and the rest of the world has also been shown to accurately predict the absence of the condition early in the diagnosis stage, reducing costs and unnecessary antibiotic use.

Recent technological advances have led to the development of innovative PCT immunochemical biomarker assays, to be used to assess septic complications and overall prognosis in patients at risk of progression to severe sepsis or septic shock. The advanced PCT immunoassays enable ICU physicians to make a more fully informed risk assessment if other conditions can be excluded and others can be more readily identified leading to more rapid treatment. Particularly in SIRS and sepsis patients, fast diagnosis and accurate treatment are vital in improving mortality rates.

If physicians using the novel PCT immunoassays find that PCT levels are not rising, but other sepsis symptoms such as fever, rapid pulse and respiratory disorders are present, viral, fungal or other sources of infection may be present. Because the PCT immunoassay is specific to bacterial infection, the assays can be used to help physicians rule out other disorders and more quickly identify and treat bacterial sepsis.

Early and accurate diagnosis of sepsis is essential to provide effective therapy. Research has confirmed that failure to diagnoseand provide antimicrobial intervention is the most common avoidableerror in sepsis-related mortality. Studies analysing theeffect of delayed diagnosis use different definitions for "adequacyof treatment", although all emphasise that efficacy of the antimicrobialagainst the identified pathogen and timeliness of administrationare critical.

Recent developments into the research of PCT markers have resulted in the development of PCT immunoassays for the detection of sepsis. These immunoassays offer the capacity to rapidly and effectively measure the levels of the PCT biomarker in patients. As a result, the accuracy of information provided to a physician when making a critical decision regarding the nature and severity of an infection, is greatly improved. Evidence demonstrates that the PCT biomarker can play a vital role in ensuring the accurate identification of critically ill patients, ensuring timely and effective treatment of patients suffering from sepsis and reducing the overall mortality rate.

References

1. http://www.library.nhs.uk/emergency/ViewResource.aspx?resID=269230&tabID=290&catID=1870, Incidence, mortality and economic burden of sepsis, Dr Ron Daniels, September 2007. Accessed on 01/04/11

2. Davies A, Green C, Hutton J. 581 Severe sepsis: a European estimate of the burden of disease in ICU [oral presentation abstract from 14th Annual Congress of the European Society of Intensive Care Medicine, Geneva, Switzerland, 30 September-3 October 2001]. Intensive Care Medicine 2001; 27(Suppl 2):S284.

3. Karlsson S, Varpula M, Ruokonen E et al. Incidence, treatment and outcome of severe sepsis in ICU-treated adults in Finland- the Finnsepsis Study. Intensive Care Medicine 2007; 33(3): 435-443.

4. Blanco J, Muriel-Bombin A, Sagredo V et al. Incidence, organ dysfunction and mortality in severe sepsis: a Spanish multi-centre study. Critical Care 2008; 12(6) :R158

5. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, et al. Sepsis in European intensive care units: results of the SOAP study. Critical Care Medicine 2006; 34(2):344-53.

6. Harbarth S., et al. Am J Respir Crit Care Med 2001, 164: 396-402