The Global Sepsis Alliance reflects on the progress made in tackling sepsis and the hurdles that remain in relation to healthcare-associated infections.
The term sepsis stems from the ancient Greek word sepein, indicating putrefaction or cell decay as a result of invasive infection. Sepsis continues to represent one of the leading causes of global morbidity and mortality annually, with over 50 million children and adults affected and over 10 million deaths caused by sepsis, as evidenced by the 2020 Global Burden of Disease Study.1
While the human species has been exposed to the threat of infectious agents for thousands of years, modern medicine providing clean sanitation, vaccinations, and access to antimicrobials has enabled major improvements in infection-related mortality, compared to the pre-antibiotic era. However, the vulnerability of humankind to infectious diseases persists, as exemplified by the current COVID-19 pandemic, which to date has affected over a quarter billion and caused the deaths of over five million people, many of which were due to sepsis.2 Yet, unlike the concerted response to the pandemic from government, technology, research, and healthcare sectors, the huge, ongoing burden imposed by sepsis is not met with proportionate and coordinated efforts at national or global levels. Efforts to address this burden of sepsis include the successful collaboration between the Global Sepsis Alliance (GSA) and the World Health Assembly, which issued the Sepsis Resolution in 2017, recognising sepsis as a major contributor to global morbidity and mortality, and demanding urgent actions by its Member States to improve the prevention, recognition, treatment, and long-term management of sepsis around the world.3 Now, almost five years later, it is important to reflect on achievements to date, as well as the ongoing hurdles in the effort to reduce the burden of sepsis.
A number of countries have already undertaken initiatives or implemented action plans integrating sepsis management in their national health systems. For example, the European Sepsis Alliance (ESA) recently published a report illustrating the initiatives of the ten European countries where government or local health authorities have taken encouraging steps in this direction.1 The ESA has also called upon the European Centre for Disease Prevention and Control (ECDC) and the European Commission to support the rest of the European Union (EU) Member States in integrating sepsis in their strategies and work programmes, through guidelines, awareness campaigns, improved data collection and incentives to promote research on sepsis.
The origins of the Global Sepsis Alliance
The Global Sepsis Alliance (GSA) is a non-profit organisation, headquartered in Berlin, Germany, and founded at the Merinoff Symposium in 2010, aiming to raise awareness for sepsis worldwide. With the vision of a world free of sepsis, the GSA has been providing global leadership to reduce the burden of sepsis. The GSA is further supported by the World Federation of Societies of Intensive and Critical Care Medicine, the World Federation of Pediatric Intensive and Critical Care Societies, the International Sepsis Forum, the World Federation of Critical Care Nurses, and the Sepsis Alliance. The GSA currently hosts five regional sepsis alliances, including the European Sepsis Alliance (ESA), the African Sepsis Alliance (ASA), the Asia Pacific Sepsis Alliance (APSA), the Eastern Mediterranean Sepsis Alliance (EMSA), and the Latin American Sepsis Institute (LASI). Over one hundred societies and organisations have become members of the GSA. The GSA hosts the World Sepsis Conferences and the World Sepsis Spotlight meetings, and promotes activities on World Sepsis Day on September 13 each year4,5. In addition, the GSA coordinates exchange of ideas and sharing of resources between quality improvement initiatives to facilitate synergisms.6
Sepsis occurs both in the community setting, and as a result of healthcare-associated infections (HAI). The peak in incidence affects early life, in particular among neonates and young children, with lowest rates seen during young adulthood, before incidence rises in senescence.1 Globally, the majority of sepsis cases (up to 90%) relate to community-acquired pathogens1.5, which are primarily bacterial, although viral, fungal, and parasitic infections can all lead to sepsis. Early detection in the community, with timely referral to hospital services enabling rapid initiation of treatment, has been shown to save lives.7 Meanwhile, sepsis resulting from healthcare-associated infections represents an increasing, yet potentially preventable problem.
Healthcare-associated infections originate from pathogens acquired during hospitalisation, which can often colonise patients for days to weeks before leading to apparent infections. Healthcare-associated infections can include pathogens transmitted from patients, or healthcare workers, as well as pathogens selected during the course of prolonged hospital stay as a result of broad-spectrum antimicrobial therapy. Among the most common sites for healthcare-associated infections are blood stream infections, in particular those associated with central venous catheters, lower respiratory tract infections (such as ventilator-associated pneumonia), urinary tract infections, and surgical site infections. In a recent neonatal and pediatric study, the prevalence of healthcare-associated infections was found to be 4.2% (95% CI 3.7-4.8) in Europe and was highest in ICU patients.8 In adult patients, HAIs remain very common, and account for substantial attributable mortality, especially in ICU settings.9 Risk factors for healthcare-associated infections include prematurity, major chronic conditions, and severe disease requiring ICU support, and are aggravated by malnutrition and immunosuppression.
Strategies to minimise the risk of patients and staff contracting or spreading healthcare-associated infections
First, a vast amount of evidence supports hand hygiene as a key pillar for the effective prevention of HAIs.10 Systematic training of medical, nursing, and allied healthcare staff can dramatically increase compliance with hand hygiene, and lead to substantial reductions in the transmission of HAIs. Second, particularly in ICU patients, HAIs are often associated with iatrogenic factors, including interventions such as central venous catheters (CVCs) or invasive ventilation, which may be life saving initially, but can turn into a potential threat to the patient over time. Accordingly, the Choosing Wisely Campaign recommends systematic daily screening to foster removing CVCs, weaning from ventilators, and enabling early mobilisation and rehabilitation.11 Third, certain populations are at particularly high risk for HAIs, such as very preterm babies, or cancer patients. Of note, healthcare-associated infections may not only cause mortality and immediate morbidity, but have also been shown to be associated with poor long-term outcomes.12, 13 Finally, HAIs due to multidrug-resistant (MDR) pathogens represent an increasing problem around the world, and pose a major threat to antibiotics as a mainstay of sepsis treatment. Therefore, it is imperative to support campaigns for antimicrobial stewardship as a key strategy to reduce the emergence of MDR strains.
Quality improvement initiatives to improve recognition and treatment of sepsis due to HAIs
Sepsis is differentiated from infection by the presence of organ dysfunction. The Surviving Sepsis Campaign recommends that healthcare institutions implement systematic methods to screen patients for sepsis, enabling earlier detection of infection-related organ dysfunction.14,15 Specifically, such programmes should educate healthcare workers to recognise signs of sepsis, such as altered mentation, shock, and respiratory distress through systematic recognition tools, which may either be embedded in the electronic health record (EHR), or be paper-based. These programmes often stem from the experiences acquired in Emergency Departments as well as from in-patient programmes, developed to recognise sepsis and deteriorating patients in general. One of the most widely analysed programmes was based on the New York State sepsis mandate, which has been implemented for almost a decade, and which has been shown to save thousands of lives.7,16,17 Once sepsis is recognised, sepsis quality improvement initiatives teach, train, and empower healthcare workers to proceed with timely escalation and to initiate prompt delivery of a sepsis bundle, consisting of blood culture and lactate sampling, antibiotic treatment, and an initial fluid bolus, followed by reassessment and consideration of further management options. Adherence to these recommendations has been shown to result in substantially reduced mortality across age groups.
Key challenges and opportunities pertinent to the management of sepsis due to HAIs
Contrary to the average population presenting at Emergency Departments, in-patients suffer from much higher rates of comorbidities and complex conditions, and may accumulate multiple vulnerabilities rendering them more susceptible to sepsis. These susceptibilities include indwelling devices and surgical wounds, malnutrition, iatrogenic immunosuppression, and breakdown of barriers to infection, for example in neutropenic mucositis. At the same time, many in-patients manifest abnormal vital signs, even in the absence of sepsis, or have a degree of organ dysfunction at baseline. Traditional signs such as fever and tachycardia may not be sensitive nor specific enough to detect sepsis, given many causes other than sepsis resulting in fever.
Accordingly, accurately differentiating between HAI with or without progression to organ dysfunction and abnormal physiology as a result of a non infectious triggers can be challenging. This challenge imposes further urgency on appropriate training and research to improve high performant recognition tools. With the availability of artificial intelligence-algorithms embedded in routine monitoring, the opportunities to identify those patients who are on a trajectory towards deterioration early becomes more feasible.18 At the same time, initial experience with EHR driven algorithms have revealed that optimising trigger thresholds is a key necessity in avoiding alarm fatigue.19 Furthermore, in-patients with healthcare-associated infections are at significantly higher risk of harbouring MDR organisms, posing additional relevance on antimicrobial stewardship, appropriate drug selection, and effective drug dosing.
In the future, novel diagnostic modalities such as rapid molecular tests, or bedside gene expression markers may considerably improve the diagnostic accuracy in decision making around antimicrobial treatment choices. In addition, novel approaches to optimise individual drug dosing carry great potential to reduce toxicity from antimicrobials, while enhancing drug effectiveness.20
Sepsis remains a major threat to global health across all ages and all continents, whether in the community or in the healthcare setting in the form of HAIs. Quality improvement initiatives to reduce the propagation of HAIs have been shown to decrease rates of infection acquired during treatment in the in-patient setting. Importantly, customisation of tools to facilitate early recognition of sepsis caused by HAIs is necessary to improve timely recognition and treatment of this highly time sensitive condition. Reducing the tremendous burden of HAIs, as well as of community-acquired sepsis, should be the duty of relevant regional, national and local authorities and policymakers, through ensuring a capillary implementation of policies and tools that would facilitate the timely recognition and treatment of sepsis.
Conflict of interest disclosure
All authors work on the Global Sepsis Alliance Executive Board. No other conflicts of interests were disclosed.
Luregn J Schlapbach, MD, PhD, FCICM
Department of Intensive Care and Neonatology, and Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland Child Health Research Centre, The University of Queensland, Brisbane, Australia
Imrana A. Malik, MD
Department of Critical Care Medicine, University of Texas MD, Anderson Cancer Center, Houston, Texas, USA
Children’s and Women’s Global Health, University of British Columbia and British Columbia Children’s Hospital, Vancouver, Canada
On behalf of the Global Sepsis Alliance (GSA) Executive Board: Niranjan Kissoon (President), Konrad Reinhart (Past President), Abdulelah Alhawsawi, Maha H. Aljuaid, Ron Daniels, Luis A. Gorordo-Delsol, Flavia Machado, Imrana Malik, Emmanuel Fru Nsutebu, Luregn J. Schlapbach, Simon Finfer, Dennis Kredler
- Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet 2020;395(10219):200-211. (In eng). DOI: 10.1016/S0140-6736(19)32989-7.
- Fay K et al. Assessment of health care exposures and outcomes in adult patients with sepsis and septic shock. JAMA Netw Open 2020 Jul 7; 3:e206004. (doi.org/10.1001/jamanetworkopen.2020.6004.)
- Levy MM, Finfer SS, Machado F, et al. Reducing the global burden of sepsis: a positive legacy for the COVID-19 pandemic? Intensive Care Medicine 2021. DOI: 10.1007/s00134-021-06409-y.
- Reinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S. Recognizing Sepsis as a Global Health Priority – A WHO Resolution. N Engl J Med 2017;377(5):414-417. DOI: 10.1056/NEJMp1707170.
- Schlapbach LJ, Reinhart K, Kissoon N. A Pediatric Perspective on World Sepsis Day in 2021 – Leveraging Lessons from The Pandemic to Reduce the Global Pediatric Sepsis Burden? Am J Physiol Lung Cell Mol Physiol 2021 (In eng). DOI: 10.1152/ajplung.00331.2021.
- Schlapbach LJ, Kissoon N, Alhawsawi A, et al. World Sepsis Day: a global agenda to target a leading cause of morbidity and mortality. Am J Physiol Lung Cell Mol Physiol 2020;319(3):L518-l522. (In eng). DOI: 10.1152/ajplung.00369.2020.
- Machado FR, Nsutebu E, AbDulaziz S, et al. Sepsis 3 from the perspective of clinicians and quality improvement initiatives. Journal of critical care 2017;40:315-317. (In eng). DOI: 10.1016/j.jcrc.2017.04.037.
- Seymour CW, Gesten F, Prescott HC, et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N Engl J Med 2017;376(23):2235-2244. DOI: 10.1056/NEJMoa1703058.
- Zingg W, Hopkins S, Gayet-Ageron A, et al. Health-care-associated infections in neonates, children, and adolescents: an analysis of paediatric data from the European Centre for Disease Prevention and Control point-prevalence survey. Lancet Infect Dis 2017;17(4):381-389. DOI: 10.1016/S1473-3099(16)30517-5.
- Vincent J-L, Sakr Y, Singer M, et al. Prevalence and Outcomes of Infection Among Patients in Intensive Care Units in 2017. JAMA 2020;323(15):1478-1487. DOI: 10.1001/jama.2020.2717.
- Allegranzi B, Tartari E, Pittet D. An Important Announcement from the World Health Organization: “Seconds Save Lives-Clean your Hands”: The May 5, 2021, World Health Organization SAVE LIVES: Clean Your Hands campaign. Infect Control Hosp Epidemiol 2021;42(5):649-651. (In eng). DOI: 10.1017/ice.2021.93.
- Zimmerman JJ, Harmon LA, Smithburger PL, et al. Choosing Wisely For Critical Care: The Next Five. Crit Care Med 2021;49(3):472-481. DOI: 10.1097/CCM.0000000000004876.
- Prescott HC, Iwashyna TJ, Blackwood B, et al. Understanding and Enhancing Sepsis Survivorship. Priorities for Research and Practice. Am J Respir Crit Care Med 2019;200(8):972-981. DOI: 10.1164/rccm.201812-2383CP.
- Schlapbach LJ, Aebischer M, Adams M, et al. Impact of sepsis on neurodevelopmental outcome in a Swiss National Cohort of extremely premature infants. Pediatrics 2011;128(2):e348-57. (In eng). DOI: 10.1542/peds.2010-3338.
- Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Critical Care Medicine 2021. DOI: 10.1097/ccm.0000000000005337.
- Weiss SL, Peters MJ, Alhazzani W, et al. Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Intensive Care Med 2020;46(Suppl 1):10-67. (In eng). DOI: 10.1007/s00134-019-05878-6.
- Evans IVR, Phillips GS, Alpern ER, et al. Association Between the New York Sepsis Care Mandate and In-Hospital Mortality for Pediatric Sepsis. JAMA 2018;320(4):358-367. (In eng). DOI: 10.1001/jama.2018.9071.
- Levy MM, Gesten FC, Phillips GS, et al. Mortality Changes Associated with Mandated Public Reporting for Sepsis. The Results of the New York State Initiative. Am J Respir Crit Care Med 2018;198(11):1406-1412. (In eng). DOI: 10.1164/rccm.201712-2545OC.
- Komorowski M, Celi LA, Badawi O, Gordon AC, Faisal AA. The Artificial Intelligence Clinician learns optimal treatment strategies for sepsis in intensive care. Nat Med 2018;24(11):1716-1720. DOI: 10.1038/s41591-018-0213-5.
- Scott HF, Balamuth F, Paul RM. Sepsis Bundles and Mortality Among Pediatric Patients. JAMA 2018;320(21):2271. (In eng). DOI: 10.1001/jama.2018.16748.
- Tu Q, Cotta M, Raman S, Graham N, Schlapbach L, Roberts JA. Individualized precision dosing approaches to optimize antimicrobial therapy in pediatric populations. Expert Review of Clinical Pharmacology 2021:1-17. DOI: 10.1080/17512433.2021.1961578.
Global Sepsis Alliance
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